Medicines
Find Medicines
Search 21,000+ medicines by brand, generic, indication, or drug class
Ptrim
Sulphamethoxazole + Trimethoprim
Ptrim
Sulphamethoxazole + Trimethoprim
Indications
Urinary tract infection
Indication detailsView
Cotrimoxazole is bactericidal in vitro to a wide range of Gram-positive and Gram-negative organisms, including Streptococcus, Staphylococcus, Pneumococcus, Neisseria, B. catarrhalis, Escherichia coli, Klebsiella, Proteus spp., Haemophilus, Salmonella, Shigella, Vibrio cholerae, Brucella, Pneumocystis carinii, Nocardia and Bordetella. A particularly high degree of activity is exhibited against Haemophilus influenzae, E. coli and Proteus spp., making Cotrimoxazole particularly suitable for the treatment of chronic bronchitis and urinary tract infections. Cotrimoxazole exerts its bactericidal action by the sequential blockade of two bacterial enzyme systems in the biosynthesis of Folinic acid in the micro-organisms. The synergy thus produced accounts for the high degree of bactericidal activity.
Indications are :
Indications are :
- Respiratory tract infections, including acute and chronic bronchitis (treatment and prophylaxis), bronchiectasis, lung abscess, lobar and broncho-pneumonia, Pneumocystis carinii pneumonitis, sinusitis and otitis media.
- Genito-urinary tract infections, including urethritis, acute and chronic cystitis, pyelonephritis, prostatitis and gonorrhoea.
- Gastro-intestinal tract infections, caused by Salmonella typhi and Salmonella paratyphi, including the chronic carrier state.
- Other infections, caused by a wide range of organisms confirmed to be susceptible to Cotrimoxazole and where the therapeutic benefits are considered to outweigh the possible occurrence of adverse events.
- Such infections include acute and chronic osteomyelitis, acute brucellosis, skin infections including pyoderma, abscesses and wound infections, septicaemia, bacillary dysentery and cholera (as an adjuvant to fluid and electrolyte replacement), nocardiosis and mycetoma.
Therapeutic classView
Anti-diarrhoeal Antimicrobial drugs, Sulphonamides & Trimethoprim
PharmacologyView
Cotrimoxazole having broad spectrum bactericidal activity against a wide range of gram-positive & gram-negative bacteria and some protozoa. Co-trimoxazole containing Trimethoprim and Sulphamethoxazole in a 1:5 combination exerts its bactericidal action by the sequential blockade of two bacterial enzyme systems in the biosynthesis of folinic acid in the microorganism.
DosageView
Cotrimoxazole double strength tablet: Over 12 years
- For mild to moderate infections: 1 tablet twice daily.
- For severe infections: 1.5 tablets twice daily.
- Long term therapy (>14 days): 0.5 tablet twice daily.
- Gonorrhoea: 2 tablets every 12 hours for two days or 2.5 tablets followed by a further dose of 2.5 tablets after 8 hours.
- For mild to moderate infections: 2 tablets twice daily.
- For severe infections: 2 tablets thrice daily.
- Long term therapy: (>14 days): 1 tablet twice daily.
- 6-12 years: 2 teaspoonful twice daily.
- 6 month-5 years: 1 teaspoonful twice daily.
- 6 weeks-6 months: 0.5 teaspoonful twice daily.
Side effectsView
The side effects like crystalluria, allergic reactions, haemolysis, thrombocytopenia, neutropenia, agranulocytosis etc. have been reported rarely with Sulphamethoxazole-Trimethoprim combination. Other side effects are less serious in nature such as malaise, headache, nausea and vomiting. These are normally transient and do not require withdrawal of treatment.
ContraindicationsView
- Hypersensitivity to trimethoprim or sulphonamides.
- Patients with documented megaloblastic anaemia due to folate deficiency.
- Patients showing marked liver parenchymal damage, blood dyscrasia, severe renal insufficiency, glucose 6-phosphate dehydrogenase deficiency.
PrecautionsView
Prolonged full dose treatment with sulfamethoxazole-trimethoprim combination is associated with the risk of macrocytic anaemia due to the drug’s interference in the conversion of Folic acid into Folinic acid. If this occurs, it can be reversed by giving Folinic acid. Care should be taken when giving this combination to diabetic patients receiving sulphonylurea drug for possible potentiation of action of sulphonylurea.
Pregnancy & lactationView
Pregnancy and during the nursing period, because sulphonamides pass the placenta and are excreted in the breast milk and may cause kernicterus.
StorageView
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
Pukenil
Ondansetron
Pukenil
Ondansetron
Indications
Post-operative nausea and vomiting
Indication detailsView
Ondansetron is a serotonin subtype 3 (5-HT3) receptor antagonist indicated:
- Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy.
- Prevention and treatment of post-operative nausea and vomiting.
- Prevention of radiotherapy-induced nausea and vomiting.
Therapeutic classView
Anti-emetic drugs
PharmacologyView
Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.
DosageView
Chemotherapy-Induced Nausea and Vomiting-
Adults, Pediatric patients (6 months to 18 years):
Adults:
Adults:
Pediatrics (40 kg): Injection: 0.1 mg/kg
Chemotherapy-induced Nausea and Vomiting-
Adults/Geriatric/Child of 12 years or over:
Radiotherapy induced Nausea and Vomiting (Adults/Geriatric/Child of 12 years or over):
Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy:
Adults, Pediatric patients (6 months to 18 years):
- 8 mg tablet/orodispersible tablet: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose.
- 4 mg orodispersible tablet: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose.
- Injection: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose, infused intravenously over 15 minutes.
Adults:
- 8 mg tablet/orodispersible tablet: Initial Dose: 8 mg orally 1 to 2 hours before radiotherapy. Post Radiotherapy: 8 mg orally every 8 hours for up to 5 days after a course of treatment.
- 4 mg orodispersible tablet: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose.
- Injection: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose, infused intravenously over 15 minutes.
Adults:
- 8 mg tablet/orodispersible tablet: 16 mg given as two 8 mg tablets
- 4 mg orodispersible tablet: 16 mg
- Injection: 4 mg
Pediatrics (40 kg): Injection: 0.1 mg/kg
Chemotherapy-induced Nausea and Vomiting-
Adults/Geriatric/Child of 12 years or over:
- Highly emetogenic cancer chemotherapy: 30 ml (24 mg) Ondansetron Oral Solution administered 30 minutes before start of emetogenic chemotherapy.
- Moderate emetogenic cancer chemotherapy: 10 ml (8 mg) Ondansetron Oral Solution administered 30 minutes before start of emetogenic chemotherapy. A further 10 ml dose should be administered after 8 hours of the first dose. One 10 ml dose should be administered twice a day (every 12 hours) for 1-2 days after completion of chemotherapy.
Oral solution:
Radiotherapy induced Nausea and Vomiting (Adults/Geriatric/Child of 12 years or over):- The recommended oral dosage: 10 ml (8 mg) Ondansetron Oral Solution 3 times daily.
- For total body irradiation: 10 ml (8-mg) Ondansetron Oral Solution should be administered 1 to 2 hours before each fraction of radiotherapy administered each day.
- For single high-dose fraction radiotherapy to the abdomen: one 10 ml Ondansetron Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.
- For daily fractionated radiotherapy to the abdomen: 10 ml (8-mg) Ondansetron Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.
- 20 ml (16 mg) Ondansetron Oral Solution 1 hour before induction of anesthesia
Oral Soluble Film:
Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy:- Adult oral dose: 24 mg given successively as three 8 mg films 30 minutes before the start of chemotherapy.
- Adults and pediatric patients 12 years of age and older: One 8 mg film 30 minutes before chemotherapy followed by an 8 mg dose 8 hours later. Administer one 8 mg film twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.
- Pediatric patients 4 through 11 years of age: One 4 mg film three times a day. Administer the first dose 30 minutes before chemotherapy, with subsequent doses 4 and 8 hours later. Administer one 4 mg film three times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy.
- Prevention of nausea and vomiting associated with radiotherapy: The adult dosage is one 8 mg film three times a day.
- Postoperative nausea and vomiting: The adult dose is 16 mg given successively as two 8 mg films 1 hour before anesthesia.
AdministrationView
Administration of Oral Soluble Film:
- Step 1: Tear the pouch carefully along with the edge tear mark.
- Step 2: Put the Ondansetron film on top of your tongue. It will dissolve within 20 seconds
- Step 3: Do not chew or swallow the film whole.
- Step 4: Swallow after the Onsaf oral soluble film dissolves. You may swallow the dissolved film with or without liquid.
- Step 5: Wash your hands after taking Onsaf oral soluble film
Side effectsView
Frequently reported adverse events were headache, constipation and diarrhea, but the majority have been mild or moderate in nature. In chemotherapy-induced nausea and vomiting, rash has occurred in approximately 1% of patients receiving Ondansetron. There also have been reports to a sensation of flushing or warmth, hiccups and liver enzyme abnormalities. Rare cases of anaphylaxis, brochospasm, tachycardia, angina (chest pain), hypokalemia, shortness of breath have also been reported, except for bronchospasm and anaphylaxis, the relationship to Ondansetron is unclear. There have been no evidence to extrapyramidal reactions, in rare case oculogyric crisis appearing alone, as well as with other dystonic reactions without definitive clinical evidence. In case of PONV, with the exception of headache, rates of these events were not significantly different in the Ondansetron and placebo groups.
ContraindicationsView
Contraindicated in patients known to have hypersensitivity to the drug or any of its components. Concomitant use of apomorphine.
PrecautionsView
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of Ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension.
InteractionsView
Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because Ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and hence, the half-life of Ondansetron. On the basis of available data, no dosage adjustment of Ondasetron is recommended for patients on these drugs.
Pregnancy & lactationView
Carcinogenic effects were not seen in 2-year studies in rats and mice with oral Ondansetron doses up to 10 and 30 mg/kg per day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of Ondansetron up to 15 mg/kg per day did not affect fertility or general reproduction performance of male and female rats.
Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg per day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to Ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Ondansetron is excreted in the breast milk of rats. So caution should be exercised when Ondansetron is administered to a nursing women.
Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg per day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to Ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Ondansetron is excreted in the breast milk of rats. So caution should be exercised when Ondansetron is administered to a nursing women.
Pediatric usageView
Dosage Adjustment for Patients With Impaired Renal Function: The dosage recommendation is the same as for the general population.
Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe hepatic impairment, a single maximal daily dose of 8 mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended.
4 years of age or younger: Little information is available about dosage in pediatric patients 4 years of age or younger.
Over the age of 65: Dosage adjustment is not needed in patients over the age of 65.
Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe hepatic impairment, a single maximal daily dose of 8 mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended.
4 years of age or younger: Little information is available about dosage in pediatric patients 4 years of age or younger.
Over the age of 65: Dosage adjustment is not needed in patients over the age of 65.
StorageView
Store at temperature not exceeding 30ºC in a dry place. Protect from light and moisture.
Pukenil
Ondansetron
Pukenil
Ondansetron
Indications
Post-operative nausea and vomiting
Indication detailsView
Ondansetron is a serotonin subtype 3 (5-HT3) receptor antagonist indicated:
- Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy.
- Prevention and treatment of post-operative nausea and vomiting.
- Prevention of radiotherapy-induced nausea and vomiting.
Therapeutic classView
Anti-emetic drugs
PharmacologyView
Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.
DosageView
Chemotherapy-Induced Nausea and Vomiting-
Adults, Pediatric patients (6 months to 18 years):
Adults:
Adults:
Pediatrics (40 kg): Injection: 0.1 mg/kg
Chemotherapy-induced Nausea and Vomiting-
Adults/Geriatric/Child of 12 years or over:
Radiotherapy induced Nausea and Vomiting (Adults/Geriatric/Child of 12 years or over):
Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy:
Adults, Pediatric patients (6 months to 18 years):
- 8 mg tablet/orodispersible tablet: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose.
- 4 mg orodispersible tablet: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose.
- Injection: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose, infused intravenously over 15 minutes.
Adults:
- 8 mg tablet/orodispersible tablet: Initial Dose: 8 mg orally 1 to 2 hours before radiotherapy. Post Radiotherapy: 8 mg orally every 8 hours for up to 5 days after a course of treatment.
- 4 mg orodispersible tablet: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose.
- Injection: Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose, infused intravenously over 15 minutes.
Adults:
- 8 mg tablet/orodispersible tablet: 16 mg given as two 8 mg tablets
- 4 mg orodispersible tablet: 16 mg
- Injection: 4 mg
Pediatrics (40 kg): Injection: 0.1 mg/kg
Chemotherapy-induced Nausea and Vomiting-
Adults/Geriatric/Child of 12 years or over:
- Highly emetogenic cancer chemotherapy: 30 ml (24 mg) Ondansetron Oral Solution administered 30 minutes before start of emetogenic chemotherapy.
- Moderate emetogenic cancer chemotherapy: 10 ml (8 mg) Ondansetron Oral Solution administered 30 minutes before start of emetogenic chemotherapy. A further 10 ml dose should be administered after 8 hours of the first dose. One 10 ml dose should be administered twice a day (every 12 hours) for 1-2 days after completion of chemotherapy.
Oral solution:
Radiotherapy induced Nausea and Vomiting (Adults/Geriatric/Child of 12 years or over):- The recommended oral dosage: 10 ml (8 mg) Ondansetron Oral Solution 3 times daily.
- For total body irradiation: 10 ml (8-mg) Ondansetron Oral Solution should be administered 1 to 2 hours before each fraction of radiotherapy administered each day.
- For single high-dose fraction radiotherapy to the abdomen: one 10 ml Ondansetron Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.
- For daily fractionated radiotherapy to the abdomen: 10 ml (8-mg) Ondansetron Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.
- 20 ml (16 mg) Ondansetron Oral Solution 1 hour before induction of anesthesia
Oral Soluble Film:
Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy:- Adult oral dose: 24 mg given successively as three 8 mg films 30 minutes before the start of chemotherapy.
- Adults and pediatric patients 12 years of age and older: One 8 mg film 30 minutes before chemotherapy followed by an 8 mg dose 8 hours later. Administer one 8 mg film twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.
- Pediatric patients 4 through 11 years of age: One 4 mg film three times a day. Administer the first dose 30 minutes before chemotherapy, with subsequent doses 4 and 8 hours later. Administer one 4 mg film three times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy.
- Prevention of nausea and vomiting associated with radiotherapy: The adult dosage is one 8 mg film three times a day.
- Postoperative nausea and vomiting: The adult dose is 16 mg given successively as two 8 mg films 1 hour before anesthesia.
AdministrationView
Administration of Oral Soluble Film:
- Step 1: Tear the pouch carefully along with the edge tear mark.
- Step 2: Put the Ondansetron film on top of your tongue. It will dissolve within 20 seconds
- Step 3: Do not chew or swallow the film whole.
- Step 4: Swallow after the Onsaf oral soluble film dissolves. You may swallow the dissolved film with or without liquid.
- Step 5: Wash your hands after taking Onsaf oral soluble film
Side effectsView
Frequently reported adverse events were headache, constipation and diarrhea, but the majority have been mild or moderate in nature. In chemotherapy-induced nausea and vomiting, rash has occurred in approximately 1% of patients receiving Ondansetron. There also have been reports to a sensation of flushing or warmth, hiccups and liver enzyme abnormalities. Rare cases of anaphylaxis, brochospasm, tachycardia, angina (chest pain), hypokalemia, shortness of breath have also been reported, except for bronchospasm and anaphylaxis, the relationship to Ondansetron is unclear. There have been no evidence to extrapyramidal reactions, in rare case oculogyric crisis appearing alone, as well as with other dystonic reactions without definitive clinical evidence. In case of PONV, with the exception of headache, rates of these events were not significantly different in the Ondansetron and placebo groups.
ContraindicationsView
Contraindicated in patients known to have hypersensitivity to the drug or any of its components. Concomitant use of apomorphine.
PrecautionsView
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of Ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension.
InteractionsView
Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because Ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and hence, the half-life of Ondansetron. On the basis of available data, no dosage adjustment of Ondasetron is recommended for patients on these drugs.
Pregnancy & lactationView
Carcinogenic effects were not seen in 2-year studies in rats and mice with oral Ondansetron doses up to 10 and 30 mg/kg per day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of Ondansetron up to 15 mg/kg per day did not affect fertility or general reproduction performance of male and female rats.
Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg per day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to Ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Ondansetron is excreted in the breast milk of rats. So caution should be exercised when Ondansetron is administered to a nursing women.
Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg per day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to Ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Ondansetron is excreted in the breast milk of rats. So caution should be exercised when Ondansetron is administered to a nursing women.
Pediatric usageView
Dosage Adjustment for Patients With Impaired Renal Function: The dosage recommendation is the same as for the general population.
Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe hepatic impairment, a single maximal daily dose of 8 mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended.
4 years of age or younger: Little information is available about dosage in pediatric patients 4 years of age or younger.
Over the age of 65: Dosage adjustment is not needed in patients over the age of 65.
Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe hepatic impairment, a single maximal daily dose of 8 mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended.
4 years of age or younger: Little information is available about dosage in pediatric patients 4 years of age or younger.
Over the age of 65: Dosage adjustment is not needed in patients over the age of 65.
StorageView
Store at temperature not exceeding 30ºC in a dry place. Protect from light and moisture.
Pulbo
Pirfenidone
Pulbo
Pirfenidone
Indications
Idiopathic Pulmonary Fibrosis
Indication detailsView
Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).
Therapeutic classView
Immunosuppressant
PharmacologyView
Pirfenidone is an orally active, small molecule that shows a wide range of biologic activity. In vitro evidence has shown that pirfenidone inhibits collagen synthesis, down-regulates profibrotic cytokines and decreases fibroblast proliferation. Pirfenidone leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, pirfenidone reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis.
DosageView
Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine 267 mg tablets or one 801 mg tablet per day over a 14-days period for adult as follows:
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
- Days 1 to 7: One 267 mg tablet administered three times a day (801 mg/day)
- Days 8 to 14: One 534 mg tablets administered three times a day (1602 mg/day)
- Day 15 onward: Three 267 mg tablets or one 801 mg tablet administered three times a day (2403 mg/day)
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
Side effectsView
The safety of Pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients. The most commonly reported (10%) adverse reactions during clinical study experience with Pirfenidone at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.8% versus 13.3%), rash (28.7% versus 8.6%), fatigue (22.3% versus 13.3%), diarrhoea (21.7% versus 13.5%), dyspepsia (16.8% versus 5.5%), and photosensitivity reaction (12.2% versus 1.7%). Serious adverse reactions were recorded at similar frequencies among patients treated with 2403 mg/day of Pirfenidone and placebo in clinical studies. The adverse reactions reported at a frequency of 2% in 345 patients receiving Pirfenidone at the recommended dose of 2403 mg/day in two pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping the adverse reactions are presented in order of decreasing seriousness.
ContraindicationsView
Hypersensitivity to the active substance or to any of the excipients, concomitant use of fluvoxamine, severe hepatic impairment or end stage liver disease, severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Pregnancy & lactationView
Pregnancy: There are no data from the use of Pirfenidone in pregnant women. In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in fetal viability. As a precautionary measure, it is preferable to avoid the use of Pirfenidone during pregnancy.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Overdose effectsView
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a dose of 4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
StorageView
Store in a cool and dry place, protected from light.
Pulbo
Pirfenidone
Pulbo
Pirfenidone
Indications
Idiopathic Pulmonary Fibrosis
Indication detailsView
Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).
Therapeutic classView
Immunosuppressant
PharmacologyView
Pirfenidone is an orally active, small molecule that shows a wide range of biologic activity. In vitro evidence has shown that pirfenidone inhibits collagen synthesis, down-regulates profibrotic cytokines and decreases fibroblast proliferation. Pirfenidone leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, pirfenidone reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis.
DosageView
Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine 267 mg tablets or one 801 mg tablet per day over a 14-days period for adult as follows:
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
- Days 1 to 7: One 267 mg tablet administered three times a day (801 mg/day)
- Days 8 to 14: One 534 mg tablets administered three times a day (1602 mg/day)
- Day 15 onward: Three 267 mg tablets or one 801 mg tablet administered three times a day (2403 mg/day)
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
Side effectsView
The safety of Pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients. The most commonly reported (10%) adverse reactions during clinical study experience with Pirfenidone at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.8% versus 13.3%), rash (28.7% versus 8.6%), fatigue (22.3% versus 13.3%), diarrhoea (21.7% versus 13.5%), dyspepsia (16.8% versus 5.5%), and photosensitivity reaction (12.2% versus 1.7%). Serious adverse reactions were recorded at similar frequencies among patients treated with 2403 mg/day of Pirfenidone and placebo in clinical studies. The adverse reactions reported at a frequency of 2% in 345 patients receiving Pirfenidone at the recommended dose of 2403 mg/day in two pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping the adverse reactions are presented in order of decreasing seriousness.
ContraindicationsView
Hypersensitivity to the active substance or to any of the excipients, concomitant use of fluvoxamine, severe hepatic impairment or end stage liver disease, severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Pregnancy & lactationView
Pregnancy: There are no data from the use of Pirfenidone in pregnant women. In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in fetal viability. As a precautionary measure, it is preferable to avoid the use of Pirfenidone during pregnancy.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Overdose effectsView
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a dose of 4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
StorageView
Store in a cool and dry place, protected from light.
Pulbo
Pirfenidone
Pulbo
Pirfenidone
Indications
Idiopathic Pulmonary Fibrosis
Indication detailsView
Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).
Therapeutic classView
Immunosuppressant
PharmacologyView
Pirfenidone is an orally active, small molecule that shows a wide range of biologic activity. In vitro evidence has shown that pirfenidone inhibits collagen synthesis, down-regulates profibrotic cytokines and decreases fibroblast proliferation. Pirfenidone leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, pirfenidone reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis.
DosageView
Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine 267 mg tablets or one 801 mg tablet per day over a 14-days period for adult as follows:
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
- Days 1 to 7: One 267 mg tablet administered three times a day (801 mg/day)
- Days 8 to 14: One 534 mg tablets administered three times a day (1602 mg/day)
- Day 15 onward: Three 267 mg tablets or one 801 mg tablet administered three times a day (2403 mg/day)
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
Side effectsView
The safety of Pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients. The most commonly reported (10%) adverse reactions during clinical study experience with Pirfenidone at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.8% versus 13.3%), rash (28.7% versus 8.6%), fatigue (22.3% versus 13.3%), diarrhoea (21.7% versus 13.5%), dyspepsia (16.8% versus 5.5%), and photosensitivity reaction (12.2% versus 1.7%). Serious adverse reactions were recorded at similar frequencies among patients treated with 2403 mg/day of Pirfenidone and placebo in clinical studies. The adverse reactions reported at a frequency of 2% in 345 patients receiving Pirfenidone at the recommended dose of 2403 mg/day in two pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping the adverse reactions are presented in order of decreasing seriousness.
ContraindicationsView
Hypersensitivity to the active substance or to any of the excipients, concomitant use of fluvoxamine, severe hepatic impairment or end stage liver disease, severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Pregnancy & lactationView
Pregnancy: There are no data from the use of Pirfenidone in pregnant women. In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in fetal viability. As a precautionary measure, it is preferable to avoid the use of Pirfenidone during pregnancy.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Overdose effectsView
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a dose of 4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
StorageView
Store in a cool and dry place, protected from light.
Pulfibro
Pirfenidone
Pulfibro
Pirfenidone
Indications
Idiopathic Pulmonary Fibrosis
Indication detailsView
Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).
Therapeutic classView
Immunosuppressant
PharmacologyView
Pirfenidone is an orally active, small molecule that shows a wide range of biologic activity. In vitro evidence has shown that pirfenidone inhibits collagen synthesis, down-regulates profibrotic cytokines and decreases fibroblast proliferation. Pirfenidone leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, pirfenidone reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis.
DosageView
Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine 267 mg tablets or one 801 mg tablet per day over a 14-days period for adult as follows:
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
- Days 1 to 7: One 267 mg tablet administered three times a day (801 mg/day)
- Days 8 to 14: One 534 mg tablets administered three times a day (1602 mg/day)
- Day 15 onward: Three 267 mg tablets or one 801 mg tablet administered three times a day (2403 mg/day)
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
Side effectsView
The safety of Pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients. The most commonly reported (10%) adverse reactions during clinical study experience with Pirfenidone at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.8% versus 13.3%), rash (28.7% versus 8.6%), fatigue (22.3% versus 13.3%), diarrhoea (21.7% versus 13.5%), dyspepsia (16.8% versus 5.5%), and photosensitivity reaction (12.2% versus 1.7%). Serious adverse reactions were recorded at similar frequencies among patients treated with 2403 mg/day of Pirfenidone and placebo in clinical studies. The adverse reactions reported at a frequency of 2% in 345 patients receiving Pirfenidone at the recommended dose of 2403 mg/day in two pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping the adverse reactions are presented in order of decreasing seriousness.
ContraindicationsView
Hypersensitivity to the active substance or to any of the excipients, concomitant use of fluvoxamine, severe hepatic impairment or end stage liver disease, severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Pregnancy & lactationView
Pregnancy: There are no data from the use of Pirfenidone in pregnant women. In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in fetal viability. As a precautionary measure, it is preferable to avoid the use of Pirfenidone during pregnancy.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Overdose effectsView
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a dose of 4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
StorageView
Store in a cool and dry place, protected from light.
Pulfibro
Pirfenidone
Pulfibro
Pirfenidone
Indications
Idiopathic Pulmonary Fibrosis
Indication detailsView
Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).
Therapeutic classView
Immunosuppressant
PharmacologyView
Pirfenidone is an orally active, small molecule that shows a wide range of biologic activity. In vitro evidence has shown that pirfenidone inhibits collagen synthesis, down-regulates profibrotic cytokines and decreases fibroblast proliferation. Pirfenidone leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, pirfenidone reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis.
DosageView
Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine 267 mg tablets or one 801 mg tablet per day over a 14-days period for adult as follows:
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
- Days 1 to 7: One 267 mg tablet administered three times a day (801 mg/day)
- Days 8 to 14: One 534 mg tablets administered three times a day (1602 mg/day)
- Day 15 onward: Three 267 mg tablets or one 801 mg tablet administered three times a day (2403 mg/day)
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
Side effectsView
The safety of Pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients. The most commonly reported (10%) adverse reactions during clinical study experience with Pirfenidone at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.8% versus 13.3%), rash (28.7% versus 8.6%), fatigue (22.3% versus 13.3%), diarrhoea (21.7% versus 13.5%), dyspepsia (16.8% versus 5.5%), and photosensitivity reaction (12.2% versus 1.7%). Serious adverse reactions were recorded at similar frequencies among patients treated with 2403 mg/day of Pirfenidone and placebo in clinical studies. The adverse reactions reported at a frequency of 2% in 345 patients receiving Pirfenidone at the recommended dose of 2403 mg/day in two pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping the adverse reactions are presented in order of decreasing seriousness.
ContraindicationsView
Hypersensitivity to the active substance or to any of the excipients, concomitant use of fluvoxamine, severe hepatic impairment or end stage liver disease, severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Pregnancy & lactationView
Pregnancy: There are no data from the use of Pirfenidone in pregnant women. In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in fetal viability. As a precautionary measure, it is preferable to avoid the use of Pirfenidone during pregnancy.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Overdose effectsView
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a dose of 4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
StorageView
Store in a cool and dry place, protected from light.
Pulfibro
Pirfenidone
Pulfibro
Pirfenidone
Indications
Idiopathic Pulmonary Fibrosis
Indication detailsView
Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).
Therapeutic classView
Immunosuppressant
PharmacologyView
Pirfenidone is an orally active, small molecule that shows a wide range of biologic activity. In vitro evidence has shown that pirfenidone inhibits collagen synthesis, down-regulates profibrotic cytokines and decreases fibroblast proliferation. Pirfenidone leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, pirfenidone reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis.
DosageView
Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine 267 mg tablets or one 801 mg tablet per day over a 14-days period for adult as follows:
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
- Days 1 to 7: One 267 mg tablet administered three times a day (801 mg/day)
- Days 8 to 14: One 534 mg tablets administered three times a day (1602 mg/day)
- Day 15 onward: Three 267 mg tablets or one 801 mg tablet administered three times a day (2403 mg/day)
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
Side effectsView
The safety of Pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients. The most commonly reported (10%) adverse reactions during clinical study experience with Pirfenidone at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.8% versus 13.3%), rash (28.7% versus 8.6%), fatigue (22.3% versus 13.3%), diarrhoea (21.7% versus 13.5%), dyspepsia (16.8% versus 5.5%), and photosensitivity reaction (12.2% versus 1.7%). Serious adverse reactions were recorded at similar frequencies among patients treated with 2403 mg/day of Pirfenidone and placebo in clinical studies. The adverse reactions reported at a frequency of 2% in 345 patients receiving Pirfenidone at the recommended dose of 2403 mg/day in two pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping the adverse reactions are presented in order of decreasing seriousness.
ContraindicationsView
Hypersensitivity to the active substance or to any of the excipients, concomitant use of fluvoxamine, severe hepatic impairment or end stage liver disease, severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Pregnancy & lactationView
Pregnancy: There are no data from the use of Pirfenidone in pregnant women. In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in fetal viability. As a precautionary measure, it is preferable to avoid the use of Pirfenidone during pregnancy.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Overdose effectsView
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a dose of 4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
StorageView
Store in a cool and dry place, protected from light.
Pulmicort
Budesonide (Nasal Spray)
Pulmicort
Budesonide (Nasal Spray)
Indications
Vasomotor rhinitis
Indication detailsView
- Prophylaxis and treatment of seasonal and perennial allergic rhinitis.
- Prophylaxis and treatment of vasomotor rhinitis.
- Symptomatic relief of nasal polyposis.
- Prevention against nasal polyps after polypectomy.
Therapeutic classView
Nasal Decongestants & Other Nasal Preparations, Respiratory corticosteroids
PharmacologyView
Budesonide is a synthetic corticosteroid having potent glucocorticoid activity and weak mineralocorticoid activity. It has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (e.g. mast cell, eosinophil, neutrophil, macrophage, and lymphocyte) and mediators (e.g. histamine, eicosanoids, leukotriene, and cytokine) involved in allergic mediated inflammation.
DosageView
Adults and children 6 years of age and older: 100 mcg per day administered as one spray per nostril once daily.
Adults (12 years of age and older): The maximum recommended dose is 400 mcg per day administered as four sprays per nostril once daily.
Pediatric Use: Safety and effectiveness in pediatric patients below 6 years of age have not been established.
Adults (12 years of age and older): The maximum recommended dose is 400 mcg per day administered as four sprays per nostril once daily.
Pediatric Use: Safety and effectiveness in pediatric patients below 6 years of age have not been established.
AdministrationView
How to use the Nasal Spray-
- Shake the bottle gently and remove the dust cover.
- Hold the spray with your forefinger and middle finger on either side of the nozzle and your thumb underneath the bottle. Press down until a fine spray appears. If using for the first time or if you have not used it for a week or more, press the nasal applicator several times until a fine moist comes out from the container.
- Gently blow the nose to clear the nostrils.
- Close one nostril and carefully insert the nasal applicator into the open nostril. Tilt your head forward slightly and keep the spray upright. Breathe in through your nose and while breathing in, press the white-collar of nasal applicator firmly down once to release a spray.
- Breathe out through your mouth.
- Repeat the above steps in the same/ other nostril for consecutive doses.
- Remove the dust cover.
- Gently pull off the nasal applicator.
- Wash the applicator and dust cover in warm water.
- Shake off the excess water and leave to dry in a normal place. Avoid to apply additional heat.
- Gently push the applicator back on the top of the bottle and re-fix the dust cover.
Side effectsView
Adverse local reactions following budesonide use are mild and usually transient. Systemic side effects have not been reported during clinical studies of budesonide nasal preparations. Sneezing, headache, sore throat, dry mouth, nausea etc. have been reported as the common side effects.
PrecautionsView
Budesonide nasal spray should be used with caution in patients with active or quiescent tuberculous infection, untreated fungal, bacterial, or systemic viral infections, or ocular herpes simplex infection. Patients with recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid.
InteractionsView
No significant drug interaction has been reported.
Pregnancy & lactationView
Pregnancy: Inhaled budesonide has been assigned to pregnancy category B by the FDA. Budesonide has not been shown to be teratogenic in animals when given in high doses by inhalation. Despite the animal findings, it would appear that the possibility of fetal harm is remote if the inhaled drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, inhaled budesonide should be used during pregnancy only if clearly needed.
Lactation: The amounts of inhaled budesonide excreted into breastmilk are minute and infant exposure is negligible. Reviewers and an expert panel consider inhaled corticosteroids acceptable to use during breastfeeding. When taken by mouth, budesonide is only about 9% bioavailable; bioavailability in the infant is likely to be similarly low for any budesonide that enters the breastmilk.
Lactation: The amounts of inhaled budesonide excreted into breastmilk are minute and infant exposure is negligible. Reviewers and an expert panel consider inhaled corticosteroids acceptable to use during breastfeeding. When taken by mouth, budesonide is only about 9% bioavailable; bioavailability in the infant is likely to be similarly low for any budesonide that enters the breastmilk.
Overdose effectsView
Like any other nasally administered corticosteroids, acute overdosing is unlikely in view of the total amount of active ingredient present. Clinically significant systemic adverse events would most likely not occurs if the entire contents of the bottle were administered all at once, via either oral or nasal application. Chronic overdosage may result in signs/symptoms of hypercorticism.
StorageView
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
Pulmicort-F
Budesonide + Formoterol Fumarate
Pulmicort-F
Budesonide + Formoterol Fumarate
Indication detailsView
This is indicated in the regular treatment of asthma. They are also indicated in the symptomatic treatment of severe chronic obstructive pulmonary disease (COPD), with a history of repeated exacerbations despite regular therapy with long-acting bronchodilators.
PharmacologyView
Budesonide: It is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
Formoterol Fumarate Dihydrate: It is a long-acting, selective β2 - adrenergic agonist with a rapid onset of action. Inhaled Formoterol Fumarate Dihydrate BP acts locally in the lungs as a bronchodilator. The pharmacological effects of β2-adrenoceptor agonist drugs are attributable to the stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic AMP. Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibit the release of mediators of immediate hypersensitivity from the cells, especially from mast cells.
Formoterol Fumarate Dihydrate: It is a long-acting, selective β2 - adrenergic agonist with a rapid onset of action. Inhaled Formoterol Fumarate Dihydrate BP acts locally in the lungs as a bronchodilator. The pharmacological effects of β2-adrenoceptor agonist drugs are attributable to the stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic AMP. Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibit the release of mediators of immediate hypersensitivity from the cells, especially from mast cells.
DosageView
Inhaler (For Asthma)-
Adults and adolescents (12 years and older):
- Adults and adolescents (12 years and older): The recommended maintenance dose is 1 puff twice daily or 2 puffs once daily. For some patients a maintenance dose of 2 puffs twice daily may be appropriate (for 160/4.5 mcg/inhalation only). Patients should take 1 additional puff as needed in response to symptoms. If symptoms persist after a few minutes, the additional puff should be taken. Not more than 6 puffs should be taken on any single occasion.
- Children: The usual maintenance dose is 1 -2 puffs once or twice daily. Patients should take 1 additional puff as needed in response to symptoms. If symptoms persist after a few minutes, the additional puff should be taken. Not more than 4 puffs should be taken on any single occasion.
Adults and adolescents (12 years and older):
- Maintenance dose: Budesonide and Formoterol 100 & 200 Inhalation Capsule twice daily
- Reliever dose: 1 additional Inhalation Capsule as needed in response to symptoms. If symptoms persist after a few minutes, an additional Inhalation Capsule should be taken. Not more than 6 Inhalation Capsule should be taken on any single occasion. A total daily dose of more than 8 Inhalation Capsule is not normally needed, however, a total daily dose of up to 12 Inhalation Capsule can be used temporarily.
- Maintenance dose: Budesonide and Formoterol 100 Inhalation Capsule once daily.
- Reliever dose: 1 additional Inhalation Capsule as needed in response to symptoms. If symptoms persist after a few minutes, an additional Inhalation Capsule should be taken. Not more than 4 Inhalation Capsule should be taken on any single occasion. A total daily dose of more than 4 Inhalation Capsule is not normally needed, however, a total daily dose of up to 8 Inhalation Capsule could be used temporarily.
- 200 Inhalation Capsule: 2 Inhalation Capsule twice daily. Maximum daily maintenance dose: 4 Inhalation Capsule
- 400 Inhalation Capsule: 1 Inhalation Capsule twice daily. Maximum daily maintenance dose: 2 Inhalation Capsule.
AdministrationView
Using an Inhaler seems simple, but most patients do not know how to use it in the right way. If the Inhaler is used in the wrong way, less medicine can reach the lungs. Correct and regular use of the Inhaler will prevent or lessen the severity of asthma attacks.
Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):
Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):
- Take off the cap.
- Shake the inhaler (at least six times) vigorously before each use.
- If the inhaler is new or if it has not been used for a week or more, shake it well and release one puff into the air to make sure that it works.
- Breathe out as full as comfortably possible & hold the inhaler upright.
- Place the actuator into mouth between the teeth and close lips around the mouthpiece.
- While breathing deeply and slowly through the mouth, press down firmly add fully on the canister to release medicine.
- Remove the inhaler from mouth. Continue holding breath for at least for 10 seconds or as long as it is comfortable.
- If doctor has prescribed more than one inhalation per treatment, wait 1 minute between puffs (inhalations). Shake the inhaler well and repeat steps 4 to 7.
- After use, replace the cap on the mouthpiece. After each treatment, rinse mouth with water.
- Check your technique in front of a mirror from time to time, if you see a white mist during the inhalation, you may not have closed your lips properly around mouthpiece, or you may not be breathing in as you press the can. This indicates failure of technique. If this happens, repeat the procedure from step 4 carefully.
Side effectsView
Budesonide: Hoarseness, and candidiasis (thrush) of the mouth and throat can occur in some patients. Cutaneous hypersensitivity reactions have been reported.
Formoterol Fumarate Dihydrate: Tremor, palpitations, and headache have been reported. Cardiac arrhythmias, muscle cramps, and hypersensitivity reactions, including rash, oedema, and angio-oedema, may occur in some patients.
Formoterol Fumarate Dihydrate: Tremor, palpitations, and headache have been reported. Cardiac arrhythmias, muscle cramps, and hypersensitivity reactions, including rash, oedema, and angio-oedema, may occur in some patients.
ContraindicationsView
Hypersensitivity to Budesonide, Formoterol or to Lactose.
PrecautionsView
Treatment with Budesonide and Formoterol combination should not be initiated to treat a severe exacerbation or if patients have significantly worsening or acutely deteriorating asthma.
InteractionsView
Concomitant treatment with Ritonavir, Itraconazole, Ketoconazole or other potent CYP3A4 inhibitors should be avoided.
Pregnancy & lactationView
Administration of Budesonide & Formoterol Fumarate in pregnant women and lactating mother should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus
Pediatric usageView
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re evaluated with the aim of reducing the dose of inhaled corticosteroid. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition consideration should be given to referring the patient to a paediatric respiratory specialist.
StorageView
Protect from light, store in cool & dry place. Do not store above 30° C. Keep out of the reach of children. Protect from freezing.
Pulmidone
Pirfenidone
Pulmidone
Pirfenidone
Indications
Idiopathic Pulmonary Fibrosis
Indication detailsView
Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).
Therapeutic classView
Immunosuppressant
PharmacologyView
Pirfenidone is an orally active, small molecule that shows a wide range of biologic activity. In vitro evidence has shown that pirfenidone inhibits collagen synthesis, down-regulates profibrotic cytokines and decreases fibroblast proliferation. Pirfenidone leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, pirfenidone reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis.
DosageView
Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine 267 mg tablets or one 801 mg tablet per day over a 14-days period for adult as follows:
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
- Days 1 to 7: One 267 mg tablet administered three times a day (801 mg/day)
- Days 8 to 14: One 534 mg tablets administered three times a day (1602 mg/day)
- Day 15 onward: Three 267 mg tablets or one 801 mg tablet administered three times a day (2403 mg/day)
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
Side effectsView
The safety of Pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients. The most commonly reported (10%) adverse reactions during clinical study experience with Pirfenidone at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.8% versus 13.3%), rash (28.7% versus 8.6%), fatigue (22.3% versus 13.3%), diarrhoea (21.7% versus 13.5%), dyspepsia (16.8% versus 5.5%), and photosensitivity reaction (12.2% versus 1.7%). Serious adverse reactions were recorded at similar frequencies among patients treated with 2403 mg/day of Pirfenidone and placebo in clinical studies. The adverse reactions reported at a frequency of 2% in 345 patients receiving Pirfenidone at the recommended dose of 2403 mg/day in two pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping the adverse reactions are presented in order of decreasing seriousness.
ContraindicationsView
Hypersensitivity to the active substance or to any of the excipients, concomitant use of fluvoxamine, severe hepatic impairment or end stage liver disease, severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Pregnancy & lactationView
Pregnancy: There are no data from the use of Pirfenidone in pregnant women. In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in fetal viability. As a precautionary measure, it is preferable to avoid the use of Pirfenidone during pregnancy.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Overdose effectsView
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a dose of 4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
StorageView
Store in a cool and dry place, protected from light.
Pulmidone
Pirfenidone
Pulmidone
Pirfenidone
Indications
Idiopathic Pulmonary Fibrosis
Indication detailsView
Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).
Therapeutic classView
Immunosuppressant
PharmacologyView
Pirfenidone is an orally active, small molecule that shows a wide range of biologic activity. In vitro evidence has shown that pirfenidone inhibits collagen synthesis, down-regulates profibrotic cytokines and decreases fibroblast proliferation. Pirfenidone leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, pirfenidone reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis.
DosageView
Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine 267 mg tablets or one 801 mg tablet per day over a 14-days period for adult as follows:
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
- Days 1 to 7: One 267 mg tablet administered three times a day (801 mg/day)
- Days 8 to 14: One 534 mg tablets administered three times a day (1602 mg/day)
- Day 15 onward: Three 267 mg tablets or one 801 mg tablet administered three times a day (2403 mg/day)
Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 capsules (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to 3 capsules/day (1 capsule three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.
Side effectsView
The safety of Pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients. The most commonly reported (10%) adverse reactions during clinical study experience with Pirfenidone at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.8% versus 13.3%), rash (28.7% versus 8.6%), fatigue (22.3% versus 13.3%), diarrhoea (21.7% versus 13.5%), dyspepsia (16.8% versus 5.5%), and photosensitivity reaction (12.2% versus 1.7%). Serious adverse reactions were recorded at similar frequencies among patients treated with 2403 mg/day of Pirfenidone and placebo in clinical studies. The adverse reactions reported at a frequency of 2% in 345 patients receiving Pirfenidone at the recommended dose of 2403 mg/day in two pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping the adverse reactions are presented in order of decreasing seriousness.
ContraindicationsView
Hypersensitivity to the active substance or to any of the excipients, concomitant use of fluvoxamine, severe hepatic impairment or end stage liver disease, severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Hepatic function: Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations: If a patient exhibits an aminotransferase elevation to >3 to ≤5 X ULN after starting Pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of Pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone may be re-escalated to the recommended daily dose if tolerated. If a patient exhibits an aminotransferase elevation to >5 X ULN accompanied by symptoms or hyperbilirubinaemia, Pirfenidone should be discontinued and the patient should not be rechallenged. If a patient exhibits an aminotransferase elevation to >5 X ULN, Pirfenidone should be discontinued and the patient should not be rechallenged.
Hepatic impairment: In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor. Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash: Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash.
Dizziness: Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination. In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.
Fatigue: Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination.
Weight loss: Weight loss has been reported in patients treated with Pirfenidone. Physicians should monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance. Interactions with other medicinal products and other forms of interaction. Approximately 70-80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.
Fluvoxamine and inhibitors of CYP1A2: In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers. Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine. Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment. In vitro in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of Pirfenidone should be reduced to 801 mg daily (one capsule, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary.
Co-administration of Pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily cannot be avoided, the dose of Pirfenidone should be reduced to 1602 mg daily (two capsules, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250 mg or 500 mg once or twice daily. Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone). Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).
Cigarette smoking and inducers of CYP1A2: A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of Pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone. In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels. Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.
Pregnancy & lactationView
Pregnancy: There are no data from the use of Pirfenidone in pregnant women. In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in fetal viability. As a precautionary measure, it is preferable to avoid the use of Pirfenidone during pregnancy.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Lactation: It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.
Fertility: No adverse effects on fertility were observed in preclinical studies. Effects on ability to drive and use machines: No studies on the effects of the ability to drive and use machines have been performed. Pirfenidone may cause dizziness and fatigue, which could influence the ability to drive or use machines.
Overdose effectsView
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a dose of 4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.
StorageView
Store in a cool and dry place, protected from light.
Pulmino
Doxophylline
Pulmino
Doxophylline
Indications
Severe bronchospasm
Indication detailsView
Doxophylline is used to treat in following indications:
- Bronchial asthma
- Bronchospasm
- Chronic obstructive pulmonary disease (COPD)
- Pulmonary disease with spastic bronchial component.
Therapeutic classView
Bronchodilator, Methyl xanthine derivatives
PharmacologyView
Doxophylline is a novel bronchodilator. It structurally differs from Theophylline due to the presence of a dioxolane group in position 7. Doxophylline selectively inhibits phosphodiesterase 4 thereby relaxes bronchial smooth muscle. However, differently from Theophylline, Doxophylline appears to have decreased affinities toward adenosine A1 and A2 receptors, which may account for the better safety profile of the drug. Doxophylline is reported to inhibit platelet activating factor (PAF) and generation of leukotriene production.
DosageView
Elderly: 200 mg tablet two or three times daily.
Adults: 400 mg tablet two or three times daily or as prescribed by the physician.
Children:
Adults: 400 mg tablet two or three times daily or as prescribed by the physician.
Children:
- >12 years of age: 10 ml syrup or 200 mg tablet two or three times daily.
- 6-12 years of age: 6-9 mg/kg body weight two times daily, i.e. if body weight is 10 kg, 3 ml (60 mg) two times daily or as prescribed by the physician.
Side effectsView
Doxophylline rarely causes serious side effects, however possible side effects are similar for taking excess amount of caffeine. These include: nausea, vomiting, headache, upset stomach and heartburn.
ContraindicationsView
Doxophylline is contraindicated in acute myocardial infarction. It is also contraindicated in patients with hypotension, in lactating women & patients who have shown hypersensitivity to its components.
PrecautionsView
The half-life of xanthine derivatives is influenced by a number of known variables. It may be prolonged in patients with liver disease, in patients with congestive heart failure and in those patients taking certain other drugs like erythromycin, troleandomycin, lincomycin, allopurinol, cimetidine, propanolol and anti-flu vaccine. In these cases, a lower dose of Doxophylline may be needed. Phenytoin, other anticonvulsants and smoking may cause an increase in clearance with a shorter mean half-life. In these cases higher doses of Doxophylline may be needed.
InteractionsView
Doxophylline should not be administered together with other xanthine derivatives. Toxic synergism with ephedrine has been documented for xanthines. Like other xanthines, concomitant therapy with troleandomycin, lincomycin, clindamycin, allopurinol, cimetidine, ranitidine, propranolol and anti-flu vaccine may decrease the hepatic clearance of xanthines causing an increase in blood levels. No evidence of a relationship between Doxophylline serum concentrations and toxic events have been reported.
Pregnancy & lactationView
Animal reproduction studies indicate that, Doxophylline does not cause fetal harm when administered to pregnant animals or can not affect reproduction capacity. However, since there is limited experience in human during pregnancy, xanthines should be given to pregnant women only if clearly needed. Doxophylline is contraindicated in nursing mothers.
Overdose effectsView
In case of overdose severe cardiac arrhythmias and tonic-clonic seizure may occur. These effects may represent the first signs of intoxication. The appearance of side effects may require discontinuation of the treatment which, if necessary, at the physician’s discretion, may be resumed at lower doses after all signs and symptoms of toxicity have subsided.
As there is no specific antidote, in case of overdose a symptomatic treatment of cardiovascular collapse should be instituted.
As there is no specific antidote, in case of overdose a symptomatic treatment of cardiovascular collapse should be instituted.
StorageView
Keep in a dry place away from light and heat. Keep out of the reach of children. Doxophylline should be used only on prescription of specialist physician.
Pulmino
Doxophylline
Pulmino
Doxophylline
Indications
Severe bronchospasm
Indication detailsView
Doxophylline is used to treat in following indications:
- Bronchial asthma
- Bronchospasm
- Chronic obstructive pulmonary disease (COPD)
- Pulmonary disease with spastic bronchial component.
Therapeutic classView
Bronchodilator, Methyl xanthine derivatives
PharmacologyView
Doxophylline is a novel bronchodilator. It structurally differs from Theophylline due to the presence of a dioxolane group in position 7. Doxophylline selectively inhibits phosphodiesterase 4 thereby relaxes bronchial smooth muscle. However, differently from Theophylline, Doxophylline appears to have decreased affinities toward adenosine A1 and A2 receptors, which may account for the better safety profile of the drug. Doxophylline is reported to inhibit platelet activating factor (PAF) and generation of leukotriene production.
DosageView
Elderly: 200 mg tablet two or three times daily.
Adults: 400 mg tablet two or three times daily or as prescribed by the physician.
Children:
Adults: 400 mg tablet two or three times daily or as prescribed by the physician.
Children:
- >12 years of age: 10 ml syrup or 200 mg tablet two or three times daily.
- 6-12 years of age: 6-9 mg/kg body weight two times daily, i.e. if body weight is 10 kg, 3 ml (60 mg) two times daily or as prescribed by the physician.
Side effectsView
Doxophylline rarely causes serious side effects, however possible side effects are similar for taking excess amount of caffeine. These include: nausea, vomiting, headache, upset stomach and heartburn.
ContraindicationsView
Doxophylline is contraindicated in acute myocardial infarction. It is also contraindicated in patients with hypotension, in lactating women & patients who have shown hypersensitivity to its components.
PrecautionsView
The half-life of xanthine derivatives is influenced by a number of known variables. It may be prolonged in patients with liver disease, in patients with congestive heart failure and in those patients taking certain other drugs like erythromycin, troleandomycin, lincomycin, allopurinol, cimetidine, propanolol and anti-flu vaccine. In these cases, a lower dose of Doxophylline may be needed. Phenytoin, other anticonvulsants and smoking may cause an increase in clearance with a shorter mean half-life. In these cases higher doses of Doxophylline may be needed.
InteractionsView
Doxophylline should not be administered together with other xanthine derivatives. Toxic synergism with ephedrine has been documented for xanthines. Like other xanthines, concomitant therapy with troleandomycin, lincomycin, clindamycin, allopurinol, cimetidine, ranitidine, propranolol and anti-flu vaccine may decrease the hepatic clearance of xanthines causing an increase in blood levels. No evidence of a relationship between Doxophylline serum concentrations and toxic events have been reported.
Pregnancy & lactationView
Animal reproduction studies indicate that, Doxophylline does not cause fetal harm when administered to pregnant animals or can not affect reproduction capacity. However, since there is limited experience in human during pregnancy, xanthines should be given to pregnant women only if clearly needed. Doxophylline is contraindicated in nursing mothers.
Overdose effectsView
In case of overdose severe cardiac arrhythmias and tonic-clonic seizure may occur. These effects may represent the first signs of intoxication. The appearance of side effects may require discontinuation of the treatment which, if necessary, at the physician’s discretion, may be resumed at lower doses after all signs and symptoms of toxicity have subsided.
As there is no specific antidote, in case of overdose a symptomatic treatment of cardiovascular collapse should be instituted.
As there is no specific antidote, in case of overdose a symptomatic treatment of cardiovascular collapse should be instituted.
StorageView
Keep in a dry place away from light and heat. Keep out of the reach of children. Doxophylline should be used only on prescription of specialist physician.
PulmoCare
Salbutamol (Inhaler)
PulmoCare
Salbutamol (Inhaler)
Indications
Emphysema
Indication detailsView
Bronchospasm: Salbutamol Inhaler is indicated for the treatment or prevention of bronchospasm in bronchial asthma and for the treatment of reversible airway obstruction associated with bronchitis and emphysema.
Exercise-Induced Bronchospasm: Salbutamol Inhaler may be used to relieve attacks of acute dyspnoea and may also be taken prophylactically before exertion or to prevent exercise-induced asthma
Exercise-Induced Bronchospasm: Salbutamol Inhaler may be used to relieve attacks of acute dyspnoea and may also be taken prophylactically before exertion or to prevent exercise-induced asthma
Therapeutic classView
Short-acting selective & β2-adrenoceptor stimulants
PharmacologyView
Salbutamol is a selective β2-adrenoceptor agonist. At therapeutic doses, it acts on the β2-adrenoceptors of bronchial smooth muscle, with little or no action on the β1-adrenoceptors of cardiac muscle. Salbutamol provides short-acting (4-6 hours) bronchodilatation with a fast onset (within 5 minutes) in reversible airway obstruction. It also has an anti-inflammatory effect on mast cells causing inhibition of release of bronchoconstrictor mediators including histamine, neutrophil chemotactive factor (NCF) and prostaglandin D2.
DosageView
Administer Salbutamol Inhaler by oral inhalation only. Shake Salbutamol Inhaler well before each spray.
For relief of acute episodes of bronchospasm:
For relief of acute episodes of bronchospasm:
- Adults: 1 or 2 puffs as necessary. The maximum dose is up to 8 puffs in 24 hours.
- Children: Half the adult dose.
- Adults: 2 puffs 15 minutes prior to exercise or exposure to the allergen. The maximum dose is 2 puffs, up to 4 times a day.
- Children: Half the adult dose.
- Adults: Up to 200 mcg (2 puffs) four times daily.
- Children: Up to 200 mcg (2 puffs) four times daily.
AdministrationView
Using an Inhaler seems simple, but most patients do not know how to use it in the right way. If the Inhaler is used in the wrong way, less medicine can reach the lungs. Correct and regular use of the Inhaler will prevent or lessen the severity of asthma attacks.
Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):
Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):
- Take off the cap.
- Shake the inhaler (at least six times) vigorously before each use.
- If the inhaler is new or if it has not been used for a week or more, shake it well and release one puff into the air to make sure that it works.
- Breathe out as full as comfortably possible & hold the inhaler upright.
- Place the actuator into mouth between the teeth and close lips around the mouthpiece.
- While breathing deeply and slowly through the mouth, press down firmly add fully on the canister to release medicine.
- Remove the inhaler from mouth. Continue holding breath for at least for 10 seconds or as long as it is comfortable.
- If doctor has prescribed more than one inhalation per treatment, wait 1 minute between puffs (inhalations). Shake the inhaler well and repeat steps 4 to 7.
- After use, replace the cap on the mouthpiece. After each treatment, rinse mouth with water.
- Check your technique in front of a mirror from time to time, if you see a white mist during the inhalation, you may not have closed your lips properly around mouthpiece, or you may not be breathing in as you press the can. This indicates failure of technique. If this happens, repeat the procedure from step 4 carefully.
Side effectsView
Salbutamol is generally well tolerated. Few side effects have been observed during inhalation. There are tremors, anxiety, muscle cramps, headache, palpitation, a compensatory small increase in heart rate, cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles), tachycardia may occur in some patients. Mouth and throat irritation may occur with inhaled salbutamol
ContraindicationsView
Salbutamol inhaler is contraindicated in patients with a history of hypersensitivity to salbutamol or any other components of Salbutamol inhaler.
PrecautionsView
Paradoxical Bronchospasm: Inhaled salbutamol sulfate can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, the Salbutamol inhaler should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm when associated with inhaled formulations; frequently occurs with the first use of a new canister.
Cardiovascular Effects: Salbutamol inhaler, like all other β2-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients such as changes in pulse rate or blood pressure. If such effects occur, Salbutamol inhaler may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiograms (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST-segment depression. The clinical relevance of these findings is unknown. Therefore, Salbutamol inhaler, like all other sympathomimetic amines, should be used with caution in patients with underlying cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of salbutamol sulfate inhalation aerosol, as demonstrated by cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. Discontinue Salbutamol inhaler if immediate hypersensitivity reactions occur.
Coexisting Conditions: Salbutamol inhaler, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous salbutamol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
Cardiovascular Effects: Salbutamol inhaler, like all other β2-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients such as changes in pulse rate or blood pressure. If such effects occur, Salbutamol inhaler may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiograms (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST-segment depression. The clinical relevance of these findings is unknown. Therefore, Salbutamol inhaler, like all other sympathomimetic amines, should be used with caution in patients with underlying cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of salbutamol sulfate inhalation aerosol, as demonstrated by cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. Discontinue Salbutamol inhaler if immediate hypersensitivity reactions occur.
Coexisting Conditions: Salbutamol inhaler, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous salbutamol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
InteractionsView
Salbutamol and non-selective beta-blocking drugs such as propranolol should generally not be prescribed together. Potentially serious hypokalaemia may result from β2-agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids, diuretics, and by hypoxia. It is recommended that serum potassium levels are monitored in such situations.
Pregnancy & lactationView
Pregnancy Category C. There are no adequate and well-controlled studies of Salbutamol inhaler or salbutamol sulfate in pregnant women. This inhaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether the components of Salbutamol inhaler are excreted in human milk. Caution should be exercised when this inhaler is administered to a nursing woman.
Pediatric usageView
Use in children: The safety and effectiveness of Salbutamol inhaler in children 4 years of age and older have been established.
StorageView
Pressurized canister. Do not puncture, break or burn even when apparently empty. Keep away from sunlight and heat. Store below 30°C. Do not freeze. Keep away from eyes. Keep away from children. To be dispensed only on or by the prescription of a registered physician.
PulmoCare
Salbutamol
PulmoCare
Salbutamol
Indications
Emphysema
Indication detailsView
Salbutamol is indicated as a bronchodilator for use in-
- Asthma
- Chronic Bronchitis
- Emphysema and
- Other conditions associated with airways obstruction.
Therapeutic classView
Short-acting selective & β2-adrenoceptor stimulants
PharmacologyView
Salbutamol is a synthetic sympathomimetic agent with predominant beta-2 adrenergic activity. Salbutamol produces bronchodilatation through stimulation of beta-2-adrenergic receptors in bronchial smooth muscles, thereby causing relaxation of bronchial muscle fibers. This action is manifested by an improvement in pulmonary function as demonstrated by spirometric measurements.
DosageView
Salbutamol tablet or syrup-
Children:
Salbutamol Respirator Solution: To be used with a suitable nebulizer device under the direction of a physician. The solution must not be injected or ingested.
Method-1 (Intermittent Administration):
Salbutamol nebulizer solution: To be used with a suitable nebulizer device under the direction of a physician. The solution must not be injected or ingested.
Adults:
Salbutamol Inhalation Capsule:
Children:
- 2-6 years: 2.5 ml syrup, 3-4 times daily
- 6-12 years: 5 ml syrup, 3-4 times daily
- Over 12 years: 5-10 ml syrup, 3-4 times daily (2-4 mg tablet, 3-4 times daily)
Salbutamol Respirator Solution: To be used with a suitable nebulizer device under the direction of a physician. The solution must not be injected or ingested.
Method-1 (Intermittent Administration):
- Adults (and the elderly): 0.5 ml-1.0 ml salbutamol up to four times a day. Up to 40mg per day can be given under strict medical direction in the hospital. 0.5-1 ml solution should be diluted to final volume of 2-4 ml with sterile normal saline solution. It will take time about 10 minutes.
- Salbutamol respiratory solution may be used undiluted for intermittent administration. For this 2.0 ml of the solution is placed in the nebulizer and the patient allowed to inhale until bronchodilation is achieved. This usually takes 3-5 minutes.
- Children under 12 years of age: 0.5 ml of the solution diluted to 2.0-4.0 ml with normal saline. Some children may however require higher doses of up to 1.0 ml of the solution. Intermittent treatment may be repeated four times a day.
Salbutamol nebulizer solution: To be used with a suitable nebulizer device under the direction of a physician. The solution must not be injected or ingested.
- Adults & Elderly: 2.5 mg to 5 mg Salbutamol up to 4 times a day. Up to 40 mg/day may be given under strict medical direction in the hospital.
- Children under 12 years: 2.5 mg up to 4 times a day. A higher dose up to 5 mg four times a day may be used if required.
Adults:
- Salbutamol I.V. infusion solution is used to prepare a solution for continuous intravenous infusion. It should not be injected undiluted. A suitable solution for infusion may be prepared by diluting 5 mL of Salbutamol I.V. infusion solution (1000 mcg/mL) in 500 mL of a chosen i.v. solution to provide a salbutamol concentration of 10 mcg/mL.
- The only recommended diluents are Sodium Chloride Injection, or Sodium Chloride and Dextrose Injection.
- Infusion rates providing 3 to 20 micrograms salbutamol/minute (0.3 to 2ml/minute of the above infusion solution) are usually adequate. Infusion rates can be started at 5 mcg of salbutamol/min., and can be increased to 10 mcg/min., and 20 mcg/min. at 15 - 30 minute intervals, if necessary.
- As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration.
- All unused admixtures of Salbutamol infusion solution with infusion fluids should be discarded 24 hours after preparation.
Salbutamol Inhalation Capsule:
- Adults: For the relief of bronchospasm and for managing intermittent episodes of asthma, one or two inhalation capsule may be administered as a single dose. The usual recommended dosage of Salbutamol inhalation capsule for inhalation for adults for maintenance or prophylactic therapy is the contents of one 200 microgram capsule every 4 to 6 hours using a device. In some patients, the contents of two 200 microgram capsules inhaled every 4 to 6 hours may be required. Large doses or more frequent administration is not recommended. The use of salbutamol powder for inhalation can be continued as medically indicated to control recurring/intermittent episodes of bronchospasm.
- Children: One Salbutamol inhalation capsule is the recommended dose for relief of acute bronchospasm in the maintenance of episodic asthma or before exercise of children 4 years of age and older. One inhalation should be administered for three or four times a day for routine maintenance or prophylactic therapy. This dosage may be increased to inhalation of two inhalation capsule, if necessary. The bronchodilator effect of each administration of inhaled Salbutamol inhalation capsule lasts for at least four hours. Such patients should be warned not to increase the dose of inhaler, but should seek medical advice immediately.
- Adults: 400 microgram
- Child: 200 microgram, 15-30 minutes prior to any physical exertion.
Side effectsView
Salbutamol may cause fine tremor of skeletal muscles (particularly the hands), palpitations and muscle cramps. Tachycardia, tenseness, headaches and peripheral vasodilatation have been reported after large doses.
PrecautionsView
Salbutamol should be used with caution in patients with hyperthyroidism, cardiovascular disease, occlusive vascular disorders, hypertension and aneurysms. Hypokalaemia associated with high doses of Salbutamol may result in increased susceptibility to digitalis-induced cardiac arrhythmia. Tachyphylaxis with resistance may occur with prolonged use of high dosage. Care is necessary when treating patients with diabetes mellitus or closed angle glaucoma, and in those receiving antihypertensive therapy.
Pregnancy & lactationView
The drug should be used during pregnancy only if the potential benefit justifies the potential risk of the fetus. It is not known whether this drug is excreted in human milk. Because of the potential of tumorigenecity shown for Salbutamol in some animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Overdose effectsView
The symptoms with overdosage are angina, headache, nausea, vomiting, tremor etc. The preferred antidote for overdosage with Salbutamol is a cardio-selective beta-blocking agent but beta-blocking drugs should be used with caution in patients with a history of bronchospasm.
StorageView
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
PulmoCare (with device)
Salbutamol
PulmoCare (with device)
Salbutamol
Indications
Emphysema
Indication detailsView
Salbutamol is indicated as a bronchodilator for use in-
- Asthma
- Chronic Bronchitis
- Emphysema and
- Other conditions associated with airways obstruction.
Therapeutic classView
Short-acting selective & β2-adrenoceptor stimulants
PharmacologyView
Salbutamol is a synthetic sympathomimetic agent with predominant beta-2 adrenergic activity. Salbutamol produces bronchodilatation through stimulation of beta-2-adrenergic receptors in bronchial smooth muscles, thereby causing relaxation of bronchial muscle fibers. This action is manifested by an improvement in pulmonary function as demonstrated by spirometric measurements.
DosageView
Salbutamol tablet or syrup-
Children:
Salbutamol Respirator Solution: To be used with a suitable nebulizer device under the direction of a physician. The solution must not be injected or ingested.
Method-1 (Intermittent Administration):
Salbutamol nebulizer solution: To be used with a suitable nebulizer device under the direction of a physician. The solution must not be injected or ingested.
Adults:
Salbutamol Inhalation Capsule:
Children:
- 2-6 years: 2.5 ml syrup, 3-4 times daily
- 6-12 years: 5 ml syrup, 3-4 times daily
- Over 12 years: 5-10 ml syrup, 3-4 times daily (2-4 mg tablet, 3-4 times daily)
Salbutamol Respirator Solution: To be used with a suitable nebulizer device under the direction of a physician. The solution must not be injected or ingested.
Method-1 (Intermittent Administration):
- Adults (and the elderly): 0.5 ml-1.0 ml salbutamol up to four times a day. Up to 40mg per day can be given under strict medical direction in the hospital. 0.5-1 ml solution should be diluted to final volume of 2-4 ml with sterile normal saline solution. It will take time about 10 minutes.
- Salbutamol respiratory solution may be used undiluted for intermittent administration. For this 2.0 ml of the solution is placed in the nebulizer and the patient allowed to inhale until bronchodilation is achieved. This usually takes 3-5 minutes.
- Children under 12 years of age: 0.5 ml of the solution diluted to 2.0-4.0 ml with normal saline. Some children may however require higher doses of up to 1.0 ml of the solution. Intermittent treatment may be repeated four times a day.
Salbutamol nebulizer solution: To be used with a suitable nebulizer device under the direction of a physician. The solution must not be injected or ingested.
- Adults & Elderly: 2.5 mg to 5 mg Salbutamol up to 4 times a day. Up to 40 mg/day may be given under strict medical direction in the hospital.
- Children under 12 years: 2.5 mg up to 4 times a day. A higher dose up to 5 mg four times a day may be used if required.
Adults:
- Salbutamol I.V. infusion solution is used to prepare a solution for continuous intravenous infusion. It should not be injected undiluted. A suitable solution for infusion may be prepared by diluting 5 mL of Salbutamol I.V. infusion solution (1000 mcg/mL) in 500 mL of a chosen i.v. solution to provide a salbutamol concentration of 10 mcg/mL.
- The only recommended diluents are Sodium Chloride Injection, or Sodium Chloride and Dextrose Injection.
- Infusion rates providing 3 to 20 micrograms salbutamol/minute (0.3 to 2ml/minute of the above infusion solution) are usually adequate. Infusion rates can be started at 5 mcg of salbutamol/min., and can be increased to 10 mcg/min., and 20 mcg/min. at 15 - 30 minute intervals, if necessary.
- As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration.
- All unused admixtures of Salbutamol infusion solution with infusion fluids should be discarded 24 hours after preparation.
Salbutamol Inhalation Capsule:
- Adults: For the relief of bronchospasm and for managing intermittent episodes of asthma, one or two inhalation capsule may be administered as a single dose. The usual recommended dosage of Salbutamol inhalation capsule for inhalation for adults for maintenance or prophylactic therapy is the contents of one 200 microgram capsule every 4 to 6 hours using a device. In some patients, the contents of two 200 microgram capsules inhaled every 4 to 6 hours may be required. Large doses or more frequent administration is not recommended. The use of salbutamol powder for inhalation can be continued as medically indicated to control recurring/intermittent episodes of bronchospasm.
- Children: One Salbutamol inhalation capsule is the recommended dose for relief of acute bronchospasm in the maintenance of episodic asthma or before exercise of children 4 years of age and older. One inhalation should be administered for three or four times a day for routine maintenance or prophylactic therapy. This dosage may be increased to inhalation of two inhalation capsule, if necessary. The bronchodilator effect of each administration of inhaled Salbutamol inhalation capsule lasts for at least four hours. Such patients should be warned not to increase the dose of inhaler, but should seek medical advice immediately.
- Adults: 400 microgram
- Child: 200 microgram, 15-30 minutes prior to any physical exertion.
Side effectsView
Salbutamol may cause fine tremor of skeletal muscles (particularly the hands), palpitations and muscle cramps. Tachycardia, tenseness, headaches and peripheral vasodilatation have been reported after large doses.
PrecautionsView
Salbutamol should be used with caution in patients with hyperthyroidism, cardiovascular disease, occlusive vascular disorders, hypertension and aneurysms. Hypokalaemia associated with high doses of Salbutamol may result in increased susceptibility to digitalis-induced cardiac arrhythmia. Tachyphylaxis with resistance may occur with prolonged use of high dosage. Care is necessary when treating patients with diabetes mellitus or closed angle glaucoma, and in those receiving antihypertensive therapy.
Pregnancy & lactationView
The drug should be used during pregnancy only if the potential benefit justifies the potential risk of the fetus. It is not known whether this drug is excreted in human milk. Because of the potential of tumorigenecity shown for Salbutamol in some animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Overdose effectsView
The symptoms with overdosage are angina, headache, nausea, vomiting, tremor etc. The preferred antidote for overdosage with Salbutamol is a cardio-selective beta-blocking agent but beta-blocking drugs should be used with caution in patients with a history of bronchospasm.
StorageView
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
PulmoCare-L
Levosalbutamol
PulmoCare-L
Levosalbutamol
Indications
Severe bronchospasm
Indication detailsView
Levosalbutamol Nebuliser Solution or Inhaler is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children with reversible obstructive airway disease.
Therapeutic classView
Short-acting selective & β2-adrenoceptor stimulants
PharmacologyView
Levosalbutamol Nebuliser Solution is a sterile, clear, colorless, preservative-free solution of the hydrochloride salt of Levosalbutamol, the (R)-enantiomer of the drug substance racemic salbutamol. Levosalbutamol Hydrochloride is a relatively selective β2 adrenergic receptor agonist.
Activation of β2 adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic AMP. This increase in cAMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Levosalbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Levosalbutamol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor.
Activation of β2 adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic AMP. This increase in cAMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Levosalbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Levosalbutamol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor.
DosageView
Nebuliser Solution: This Nebuliser Solutions supplied in unit-dose ampoules and requires no dilution before administration by nebulization.
- Children (6 months-11 years): The recommended dosage is 0.31 mg administered three times a day, by nebulization. Routine dosing should not exceed 0.63 mg three times a day.
- Adults and Adolescents above 12 years old: The recommended starting dosage is 0.63 mg administered three to four times a day, every 6 to 8 hours, by nebulization.
- Patients 12 years of age and older: With more severe asthma or patients who do not respond adequately: 0.63 mg of Levosalbutamol Nebuliser Solution may benefit from a dosage of 1.25 mg three times a day.
AdministrationView
Using an Inhaler seems simple, but most patients do not know how to use it in the right way. If the Inhaler is used in the wrong way, less medicine can reach the lungs. Correct and regular use of the Inhaler will prevent or lessen the severity of asthma attacks.
Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):
Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):
- Take off the cap.
- Shake the inhaler (at least six times) vigorously before each use.
- If the inhaler is new or if it has not been used for a week or more, shake it well and release one puff into the air to make sure that it works.
- Breathe out as full as comfortably possible & hold the inhaler upright.
- Place the actuator into mouth between the teeth and close lips around the mouthpiece.
- While breathing deeply and slowly through the mouth, press down firmly add fully on the canister to release medicine.
- Remove the inhaler from mouth. Continue holding breath for at least for 10 seconds or as long as it is comfortable.
- If doctor has prescribed more than one inhalation per treatment, wait 1 minute between puffs (inhalations). Shake the inhaler well and repeat steps 4 to 7.
- After use, replace the cap on the mouthpiece. After each treatment, rinse mouth with water.
- Check your technique in front of a mirror from time to time, if you see a white mist during the inhalation, you may not have closed your lips properly around mouthpiece, or you may not be breathing in as you press the can. This indicates failure of technique. If this happens, repeat the procedure from step 4 carefully.
Side effectsView
Potentially serious hypokalaemia may result from beta 2 - agonist therapy. This effect may be potentiated by hypoxia. Other side effects such as palpitation, fine tremors of the skeletal muscle (particularly the hand) and muscle cramps may occur. In few cases nervousness, headache, dizziness, fatigue and sleeplessness have also been reported.
PrecautionsView
Levosalbutamol Hydrochloride, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Levosalbutamol Nebuliser Solution or Inhaler must not be injected.
InteractionsView
Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should be used with caution with Levosalbutamol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.
Beta-blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists such as Levosalbutamol Nebuliser Solution or Inhaler, but may also produce severe bronchospasm in asthmatic patients. However, under certain circumstances, e.g. prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardio selective beta-blockers could be considered with caution.
Diuretics: The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics can be acutely worsened by beta-agonists when the recommended dose of the beta-agonist is exceeded.
Digoxin: It is necessary to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and Levosalbutamol Nebuliser Solution or Inhaler.
Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: Levosalbutamol Nebuliser Solution or Inhaler should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents.
Beta-blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists such as Levosalbutamol Nebuliser Solution or Inhaler, but may also produce severe bronchospasm in asthmatic patients. However, under certain circumstances, e.g. prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardio selective beta-blockers could be considered with caution.
Diuretics: The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics can be acutely worsened by beta-agonists when the recommended dose of the beta-agonist is exceeded.
Digoxin: It is necessary to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and Levosalbutamol Nebuliser Solution or Inhaler.
Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: Levosalbutamol Nebuliser Solution or Inhaler should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents.
Pregnancy & lactationView
Pregnancy: There are no adequate and well-controlled studies of Levosalbutamol Nebuliser Solution in pregnant women. Levosalbutamol Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known whether Levosalbutamol is excreted in human milk. Caution should be exercised when Levosalbutamol Nebuliser Solution is administered to a nursing woman.
Lactation: It is not known whether Levosalbutamol is excreted in human milk. Caution should be exercised when Levosalbutamol Nebuliser Solution is administered to a nursing woman.
Overdose effectsView
The expected symptoms with over dosage are those of excessive beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of the symptoms listed under side effects. Treatment consists of discontinuation of Levosalbutamol Nebuliser Solution or Inhaler together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered.
StorageView
Store below 25°C. Protect from light. Do not refrigerate.
Pulmodox
Doxophylline
Pulmodox
Doxophylline
Indications
Severe bronchospasm
Indication detailsView
Doxophylline is used to treat in following indications:
- Bronchial asthma
- Bronchospasm
- Chronic obstructive pulmonary disease (COPD)
- Pulmonary disease with spastic bronchial component.
Therapeutic classView
Bronchodilator, Methyl xanthine derivatives
PharmacologyView
Doxophylline is a novel bronchodilator. It structurally differs from Theophylline due to the presence of a dioxolane group in position 7. Doxophylline selectively inhibits phosphodiesterase 4 thereby relaxes bronchial smooth muscle. However, differently from Theophylline, Doxophylline appears to have decreased affinities toward adenosine A1 and A2 receptors, which may account for the better safety profile of the drug. Doxophylline is reported to inhibit platelet activating factor (PAF) and generation of leukotriene production.
DosageView
Elderly: 200 mg tablet two or three times daily.
Adults: 400 mg tablet two or three times daily or as prescribed by the physician.
Children:
Adults: 400 mg tablet two or three times daily or as prescribed by the physician.
Children:
- >12 years of age: 10 ml syrup or 200 mg tablet two or three times daily.
- 6-12 years of age: 6-9 mg/kg body weight two times daily, i.e. if body weight is 10 kg, 3 ml (60 mg) two times daily or as prescribed by the physician.
Side effectsView
Doxophylline rarely causes serious side effects, however possible side effects are similar for taking excess amount of caffeine. These include: nausea, vomiting, headache, upset stomach and heartburn.
ContraindicationsView
Doxophylline is contraindicated in acute myocardial infarction. It is also contraindicated in patients with hypotension, in lactating women & patients who have shown hypersensitivity to its components.
PrecautionsView
The half-life of xanthine derivatives is influenced by a number of known variables. It may be prolonged in patients with liver disease, in patients with congestive heart failure and in those patients taking certain other drugs like erythromycin, troleandomycin, lincomycin, allopurinol, cimetidine, propanolol and anti-flu vaccine. In these cases, a lower dose of Doxophylline may be needed. Phenytoin, other anticonvulsants and smoking may cause an increase in clearance with a shorter mean half-life. In these cases higher doses of Doxophylline may be needed.
InteractionsView
Doxophylline should not be administered together with other xanthine derivatives. Toxic synergism with ephedrine has been documented for xanthines. Like other xanthines, concomitant therapy with troleandomycin, lincomycin, clindamycin, allopurinol, cimetidine, ranitidine, propranolol and anti-flu vaccine may decrease the hepatic clearance of xanthines causing an increase in blood levels. No evidence of a relationship between Doxophylline serum concentrations and toxic events have been reported.
Pregnancy & lactationView
Animal reproduction studies indicate that, Doxophylline does not cause fetal harm when administered to pregnant animals or can not affect reproduction capacity. However, since there is limited experience in human during pregnancy, xanthines should be given to pregnant women only if clearly needed. Doxophylline is contraindicated in nursing mothers.
Overdose effectsView
In case of overdose severe cardiac arrhythmias and tonic-clonic seizure may occur. These effects may represent the first signs of intoxication. The appearance of side effects may require discontinuation of the treatment which, if necessary, at the physician’s discretion, may be resumed at lower doses after all signs and symptoms of toxicity have subsided.
As there is no specific antidote, in case of overdose a symptomatic treatment of cardiovascular collapse should be instituted.
As there is no specific antidote, in case of overdose a symptomatic treatment of cardiovascular collapse should be instituted.
StorageView
Keep in a dry place away from light and heat. Keep out of the reach of children. Doxophylline should be used only on prescription of specialist physician.