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Doxophylline is used to treat in following indications:

• Bronchial asthma
• Bronchospasm
• Chronic obstructive pulmonary disease (COPD)
• Pulmonary disease with spastic bronchial component.

Bronchodilator, Methyl xanthine derivatives

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.

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:

• >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.

If required daily dose of Doxophylline is 400 mg then Doxophylline SR tablet to be taken once daily or as prescribed by the physician

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.

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.

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.

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.

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.

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.

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.

Doxophylline is used to treat in following indications:

• Bronchial asthma
• Bronchospasm
• Chronic obstructive pulmonary disease (COPD)
• Pulmonary disease with spastic bronchial component.

Bronchodilator, Methyl xanthine derivatives

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.

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:

• >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.

If required daily dose of Doxophylline is 400 mg then Doxophylline SR tablet to be taken once daily or as prescribed by the physician

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.

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.

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.

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.

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.

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.

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.

Montelukast Sodium is indicated for:

• Prophylaxis and chronic treatment of asthma
• Acute prevention of Exercise-Induced Bronchoconstriction (EIB)
• Relief of symptoms of Allergic Rhinitis (AR): Seasonal & Perennial Allergic Rhinitis

Leukotriene receptor antagonists

Montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene receptor (CysLT₁). The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. Cysteinyl leukotrienes and leukotriene receptor occupation have been correlated with the pathophysiology of asthma & allergic rhinitis, including airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma.

Adults & adolescents (15 years & older)-

• Asthma & Allergic Rhinitis: 10 mg/day 
• Exercise-Induced Bronchoconstriction: 10 mg/day

Pediatric patients (6 to 14 years)-

• Asthma & Allergic Rhinitis: 5 mg/day 
• Exercise-Induced Bronchoconstriction: 5 mg/day

Pediatric patients (6 months to 5 years)-

• Asthma & Allergic Rhinitis: 4 mg/day 
• Exercise-Induced Bronchoconstriction: Not recommended

Patients with both asthma and allergic rhinitis should take only one dose daily in the evening. For prevention of Acute prevention of Exercise-Induced Bronchoconstriction, a single dose should be taken at least 2 hours before exercise.

Route of administration: Oral. Montelukast may be taken with or without food or as directed by the physician.

Common: Diarrhoea, fever, gastrointestinal discomfort, headache, nausea, vomiting, skin reactions, upper respiratory tract infection.

Uncommon: Akathisia, anxiety, arthralgia, asthenia, abnormal behavior, depression, dizziness, drowsiness, dry mouth, haemorrhage, irritability, malaise, muscle complaints, oedema, seizure, abnormal sensation, sleep disorders.

Rare: Angioedema, concentration impaired, disorientation, eosinophilic granulomatosis with polyangiitis, erythema nodosum, hallucination, hepatic disorders, memory loss, palpitations, pulmonary eosinophilia, suicidal tendencies, tremor.

Montelukast is contraindicated in patients who are hypersensitive to any component of this product.

Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmatic. Neuropsychiatric events including agitation, hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide) and tremor.

With medicine: No dose adjustment is needed when montelukast is co-administered with theophylline, prednisone, prednisolone, terfenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative-hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, oral contraceptives, and Cytochrome P450 (CYP) enzyme inducers.

With food and others: Bioavailability and other conditions were not significantly observed with food & other conditions.

There are no adequate and well-controlled studies in pregnant women. Montelukast should be used during pregnancy only if clearly needed. Montelukast is excreted in breast milk. So caution should be exercised when Montelukast is given to a nursing mother.

There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of Montelukast and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.

Store in cool & dry place below 30°C, protect from light & moisture. Keep out of reach of children.

Montelukast Sodium is indicated for:

• Prophylaxis and chronic treatment of asthma
• Acute prevention of Exercise-Induced Bronchoconstriction (EIB)
• Relief of symptoms of Allergic Rhinitis (AR): Seasonal & Perennial Allergic Rhinitis

Leukotriene receptor antagonists

Montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene receptor (CysLT₁). The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. Cysteinyl leukotrienes and leukotriene receptor occupation have been correlated with the pathophysiology of asthma & allergic rhinitis, including airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma.

Adults & adolescents (15 years & older)-

• Asthma & Allergic Rhinitis: 10 mg/day 
• Exercise-Induced Bronchoconstriction: 10 mg/day

Pediatric patients (6 to 14 years)-

• Asthma & Allergic Rhinitis: 5 mg/day 
• Exercise-Induced Bronchoconstriction: 5 mg/day

Pediatric patients (6 months to 5 years)-

• Asthma & Allergic Rhinitis: 4 mg/day 
• Exercise-Induced Bronchoconstriction: Not recommended

Patients with both asthma and allergic rhinitis should take only one dose daily in the evening. For prevention of Acute prevention of Exercise-Induced Bronchoconstriction, a single dose should be taken at least 2 hours before exercise.

Route of administration: Oral. Montelukast may be taken with or without food or as directed by the physician.

Common: Diarrhoea, fever, gastrointestinal discomfort, headache, nausea, vomiting, skin reactions, upper respiratory tract infection.

Uncommon: Akathisia, anxiety, arthralgia, asthenia, abnormal behavior, depression, dizziness, drowsiness, dry mouth, haemorrhage, irritability, malaise, muscle complaints, oedema, seizure, abnormal sensation, sleep disorders.

Rare: Angioedema, concentration impaired, disorientation, eosinophilic granulomatosis with polyangiitis, erythema nodosum, hallucination, hepatic disorders, memory loss, palpitations, pulmonary eosinophilia, suicidal tendencies, tremor.

Montelukast is contraindicated in patients who are hypersensitive to any component of this product.

Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmatic. Neuropsychiatric events including agitation, hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide) and tremor.

With medicine: No dose adjustment is needed when montelukast is co-administered with theophylline, prednisone, prednisolone, terfenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative-hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, oral contraceptives, and Cytochrome P450 (CYP) enzyme inducers.

With food and others: Bioavailability and other conditions were not significantly observed with food & other conditions.

There are no adequate and well-controlled studies in pregnant women. Montelukast should be used during pregnancy only if clearly needed. Montelukast is excreted in breast milk. So caution should be exercised when Montelukast is given to a nursing mother.

There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of Montelukast and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.

Store in cool & dry place below 30°C, protect from light & moisture. Keep out of reach of children.

Salbutamol is indicated as a bronchodilator for use in-

• Asthma
• Chronic Bronchitis
• Emphysema and
• Other conditions associated with airways obstruction.

Short-acting selective & β2-adrenoceptor stimulants

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.

Salbutamol tablet or syrup-
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)

Adults: 2-4 mg tablet, 3-4 times daily. Maximum single dose is 8 mg tablet.

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.

Method-2 (Continuous administration): 1-2 ml solution is diluted to make up to 100 ml with normal saline solution. The diluted solution is administered by a suitable nebulizer devise. When there is risk of anoxia through hypoventilation, oxygen should be added to the inspired air.

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.

Salbutamol injection:
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.

Children and Adolescents (<18 years of age): The dosage of Salbutamol infusion solution in the pediatric age group has not been established. At present, there are insufficient data to recommend a dosage regimen for children.

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.

Excercise-induced Asthma:

• Adults: 400 microgram
• Child: 200 microgram, 15-30 minutes prior to any physical exertion.

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.

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.

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.

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.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Salbutamol is indicated as a bronchodilator for use in-

• Asthma
• Chronic Bronchitis
• Emphysema and
• Other conditions associated with airways obstruction.

Short-acting selective & β2-adrenoceptor stimulants

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.

Salbutamol tablet or syrup-
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)

Adults: 2-4 mg tablet, 3-4 times daily. Maximum single dose is 8 mg tablet.

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.

Method-2 (Continuous administration): 1-2 ml solution is diluted to make up to 100 ml with normal saline solution. The diluted solution is administered by a suitable nebulizer devise. When there is risk of anoxia through hypoventilation, oxygen should be added to the inspired air.

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.

Salbutamol injection:
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.

Children and Adolescents (<18 years of age): The dosage of Salbutamol infusion solution in the pediatric age group has not been established. At present, there are insufficient data to recommend a dosage regimen for children.

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.

Excercise-induced Asthma:

• Adults: 400 microgram
• Child: 200 microgram, 15-30 minutes prior to any physical exertion.

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.

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.

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.

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.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Montelukast Sodium is indicated for:

• Prophylaxis and chronic treatment of asthma
• Acute prevention of Exercise-Induced Bronchoconstriction (EIB)
• Relief of symptoms of Allergic Rhinitis (AR): Seasonal & Perennial Allergic Rhinitis

Leukotriene receptor antagonists

Montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene receptor (CysLT₁). The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. Cysteinyl leukotrienes and leukotriene receptor occupation have been correlated with the pathophysiology of asthma & allergic rhinitis, including airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma.

Adults & adolescents (15 years & older)-

• Asthma & Allergic Rhinitis: 10 mg/day 
• Exercise-Induced Bronchoconstriction: 10 mg/day

Pediatric patients (6 to 14 years)-

• Asthma & Allergic Rhinitis: 5 mg/day 
• Exercise-Induced Bronchoconstriction: 5 mg/day

Pediatric patients (6 months to 5 years)-

• Asthma & Allergic Rhinitis: 4 mg/day 
• Exercise-Induced Bronchoconstriction: Not recommended

Patients with both asthma and allergic rhinitis should take only one dose daily in the evening. For prevention of Acute prevention of Exercise-Induced Bronchoconstriction, a single dose should be taken at least 2 hours before exercise.

Route of administration: Oral. Montelukast may be taken with or without food or as directed by the physician.

Common: Diarrhoea, fever, gastrointestinal discomfort, headache, nausea, vomiting, skin reactions, upper respiratory tract infection.

Uncommon: Akathisia, anxiety, arthralgia, asthenia, abnormal behavior, depression, dizziness, drowsiness, dry mouth, haemorrhage, irritability, malaise, muscle complaints, oedema, seizure, abnormal sensation, sleep disorders.

Rare: Angioedema, concentration impaired, disorientation, eosinophilic granulomatosis with polyangiitis, erythema nodosum, hallucination, hepatic disorders, memory loss, palpitations, pulmonary eosinophilia, suicidal tendencies, tremor.

Montelukast is contraindicated in patients who are hypersensitive to any component of this product.

Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmatic. Neuropsychiatric events including agitation, hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide) and tremor.

With medicine: No dose adjustment is needed when montelukast is co-administered with theophylline, prednisone, prednisolone, terfenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative-hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, oral contraceptives, and Cytochrome P450 (CYP) enzyme inducers.

With food and others: Bioavailability and other conditions were not significantly observed with food & other conditions.

There are no adequate and well-controlled studies in pregnant women. Montelukast should be used during pregnancy only if clearly needed. Montelukast is excreted in breast milk. So caution should be exercised when Montelukast is given to a nursing mother.

There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of Montelukast and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.

Store in cool & dry place below 30°C, protect from light & moisture. Keep out of reach of children.

Montelukast Sodium is indicated for:

• Prophylaxis and chronic treatment of asthma
• Acute prevention of Exercise-Induced Bronchoconstriction (EIB)
• Relief of symptoms of Allergic Rhinitis (AR): Seasonal & Perennial Allergic Rhinitis

Leukotriene receptor antagonists

Montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene receptor (CysLT₁). The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. Cysteinyl leukotrienes and leukotriene receptor occupation have been correlated with the pathophysiology of asthma & allergic rhinitis, including airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma.

Adults & adolescents (15 years & older)-

• Asthma & Allergic Rhinitis: 10 mg/day 
• Exercise-Induced Bronchoconstriction: 10 mg/day

Pediatric patients (6 to 14 years)-

• Asthma & Allergic Rhinitis: 5 mg/day 
• Exercise-Induced Bronchoconstriction: 5 mg/day

Pediatric patients (6 months to 5 years)-

• Asthma & Allergic Rhinitis: 4 mg/day 
• Exercise-Induced Bronchoconstriction: Not recommended

Patients with both asthma and allergic rhinitis should take only one dose daily in the evening. For prevention of Acute prevention of Exercise-Induced Bronchoconstriction, a single dose should be taken at least 2 hours before exercise.

Route of administration: Oral. Montelukast may be taken with or without food or as directed by the physician.

Common: Diarrhoea, fever, gastrointestinal discomfort, headache, nausea, vomiting, skin reactions, upper respiratory tract infection.

Uncommon: Akathisia, anxiety, arthralgia, asthenia, abnormal behavior, depression, dizziness, drowsiness, dry mouth, haemorrhage, irritability, malaise, muscle complaints, oedema, seizure, abnormal sensation, sleep disorders.

Rare: Angioedema, concentration impaired, disorientation, eosinophilic granulomatosis with polyangiitis, erythema nodosum, hallucination, hepatic disorders, memory loss, palpitations, pulmonary eosinophilia, suicidal tendencies, tremor.

Montelukast is contraindicated in patients who are hypersensitive to any component of this product.

Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmatic. Neuropsychiatric events including agitation, hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide) and tremor.

With medicine: No dose adjustment is needed when montelukast is co-administered with theophylline, prednisone, prednisolone, terfenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative-hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, oral contraceptives, and Cytochrome P450 (CYP) enzyme inducers.

With food and others: Bioavailability and other conditions were not significantly observed with food & other conditions.

There are no adequate and well-controlled studies in pregnant women. Montelukast should be used during pregnancy only if clearly needed. Montelukast is excreted in breast milk. So caution should be exercised when Montelukast is given to a nursing mother.

There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of Montelukast and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.

Store in cool & dry place below 30°C, protect from light & moisture. Keep out of reach of children.

Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).

Immunosuppressant

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.

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:

• 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)

The recommended daily dose of Pirfenidone for patients with IPF is three 267 mg tablets or one 801 mg three times a day with food for a total of 2403 mg/day. Doses above 2403 mg/day are not recommended for any patient. Patients who miss 14 consecutive days or more of Pirfenidone treatment should re-initiate therapy by undergoing the initial 2-week titration regimen up to the recommended daily dose. For treatment interruption of less than 14 consecutive days, the dose can be resumed at the previous recommended daily dose without titration.

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.

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.

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.

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.

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.

Store in a cool and dry place, protected from light.

Pirfenidone is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF).

Immunosuppressant

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.

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:

• 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)

The recommended daily dose of Pirfenidone for patients with IPF is three 267 mg tablets or one 801 mg three times a day with food for a total of 2403 mg/day. Doses above 2403 mg/day are not recommended for any patient. Patients who miss 14 consecutive days or more of Pirfenidone treatment should re-initiate therapy by undergoing the initial 2-week titration regimen up to the recommended daily dose. For treatment interruption of less than 14 consecutive days, the dose can be resumed at the previous recommended daily dose without titration.

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.

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.

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.

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.

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.

Store in a cool and dry place, protected from light.

Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class Ill. Efficacy has been shown in: Some improvements have also been shown in patients with PAH WHO functional class ll.

Anti-hypertensive, Endothelin receptor antagonist

Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both endothelin A and B (ETA and ETB) receptors. Bosentan decreases both pulmonary and systemic vascular resistance resulting in increased cardiac output without increasing heart rate.

The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can also promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling, and is pro-inflammatory. These effects are mediated by endothelin binding to ETA and ETB receptors located in the endothelium and vascular smooth muscle cells. ET-1 concentrations in tissues and plasma are increased in several cardiovascular disorders and connective tissue diseases, including pulmonary arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic hypertension and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases. In pulmonary arterial hypertension and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and prognosis of these diseases

Tablets are to be taken orally morning and evening, with or without food.

Pulmonary arterial hypertension: ln adult patients, Bosentan treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily.

For paediatric patients aged 2 years or older, the optimal maintenance dose has not been defined in well-controlled studies. However, paediatric pharmacokinetic data have shown that Bosentan plasma concentrations in children were on average lower than in adult patients and were not increased by increasing the dose of Bosentan above 2 mg/kg body weight twice daily.

Discontinuation of treatment: lf the decision to withdraw Bosentan is taken, it should be done gradually while an alternative therapy is introduced.

Treatment with bosentan has been associated with dose dependent elevations in liver aminotransferases and decreases in haemoglobin concentration. Other side effects include Anaemia, haemoglobin decrease, Thrombocytopenia, Neutropenia, leucopenia, Hypersensitivity reactions, Headache, Syncope, Palpitations, Flushing, Hypotension, Gastroesophageal reflux disease, Aminotransferase elevations associated with hepatitis and/or jaundice, Liver cirrhosis, liver failure (rarely), Erythema, Diarrhoea, Oedema, fluid retention.

• Hypersensitivity to the active substance or to any of the excipients
• Moderate to severe hepatic impairment, i.e., Child-Pugh class B or C.
• Baseline values of liver aminotransferases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT), greater than 3 times the upper limit of normal
• Concomitant use of cyclosporine A.
• Pregnancy

Special warnings and precautions for use Liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals for the duration of treatment with Bosentan. ln addition, liver aminotransferase levels must be measured 2 weeks after any dose increase.

Consider discontinuation of therapy if pulmonary oedema occurs. Avoid abrupt withdrawal and consider dose reduction (e.g. half the dose for 3-7 days) to minimise risk of clinical deterioration. Lactation.

Increased bosentan levels with CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, diltiazem), CYP2C9 inhibitors (e.g. amiodarone, fluconazole), tacrolimus. Rifampicin initially increases but subsequently decreases bosentan concentration. May decrease plasma levels of warfarin, statins (e.g. simvastatin, lovastatin), hormonal contraceptives, sildenafil, tadalafil.

Pregnancy: Bosentan is contraindicated in pregnancy.

Use during lactation: lt is not known whether bosentan is excreted into human breast milk. Breast-feeding is not recommended during treatment with Bosentan.

Effects on ability to drive and use machines: Bosentan may cause dizziness, which could affect the ability to drive or use machines.

Dosage in hepatic impairment: No dose adjustment is needed in patients with mild hepatic impairment. Bosentan is contraindicated in patients with moderate to severe liver dysfunction.

Dosage in renal impairment: No dose adjustment is required in patients with renal impairment. No dose adjustment is required in patients undergoing dialysis.

Dosage in elderly patients: No dose adjustment is required in patients over the age of 65 years.

Symptoms: Nausea, vomiting, hypotension, dizziness, sweating and blurred vision.

Management: Symptomatic and supportive treatment.

Store below 30°C. Store in a cool and dry place, protected from light. Keep out of children’s reach.

Follitropin beta injection is indicated for the development of multiple follicles in ovulatory patients participating in an Assisted Reproductive Technology (ART) program. Follitropin beta is also indicated for the induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure.

Drugs for Infertility

Follitropin beta is a human FSH preparation of recombinant DNA origin. It stimulates ovarian follicular growth in women who do not have primary ovarian failure.

Ovulation induction: IM or SC admin: Initiate with 75 IU daily for up to 14 days, may increase by 37.5 IU at wkly intervals. Once follicular growth or serum estradiol levels indicates an adequate response, administer a single dose of hCG (5,000-10,000 IU) after the last dose to induce ovulation. Withhold hCG if the ovaries are abnormally enlarged or if abdominal pain occurs. Max: 300 IU/day.

Assisted reproductive technologies: IM or SC admin: 150-225 IU /day for at least 1st 4 days of treatment. Adjust dose based on individual ovarian response. Usual maintenance dose: 75-300 IU for 6-12 days; 375-600 IU for poor responders. Max (clinical studies): 600 IU/day. Upon adequate follicular development, a single dose of hCG (5,000-10,000 IU) is administered for final oocyte maturation. Oocyte retrieval can be done 34-36 hr later. Withhold hCG if ovaries are abnormally enlarged on the last day of follicular treatment.

Ovarian cysts, mild to severe inj site reactions, headache, mild to moderate OHSS, abdominal pain, GI disturbances. Rarely, severe OHSS, ovarian torsion, thromboembolism, mild systemic allergic reactions.

Abnormal genital bleeding of undetermined origin, hormone sensitive malignancies; ovary, breast, uterus, hypothalamus, testes or pituitary gland tumor; ovarian cysts or enlargement not due to the polycystic ovary syndrome; high levels of FSH indicating primary gonadal failure (ovarian or testicular); uncontrolled thyroid or adrenal dysfunction; presence of any cause of infertility other than anovulation; hypersensitivity; pregnancy, lactation.

May result in multiple births. Ovarian hyperstimulation syndrome (OHSS), serious pulmonary conditions and thromboembolic events may occur. Evaluate patients for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia, pituitary and hypothalamic tumors before starting therapy.

No drug-drug interaction studies have been performed.

Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

May lead to OHSS and multiple gestations.

Store at 2-8°C.

Follitropin beta injection is indicated for the development of multiple follicles in ovulatory patients participating in an Assisted Reproductive Technology (ART) program. Follitropin beta is also indicated for the induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure.

Drugs for Infertility

Follitropin beta is a human FSH preparation of recombinant DNA origin. It stimulates ovarian follicular growth in women who do not have primary ovarian failure.

Ovulation induction: IM or SC admin: Initiate with 75 IU daily for up to 14 days, may increase by 37.5 IU at wkly intervals. Once follicular growth or serum estradiol levels indicates an adequate response, administer a single dose of hCG (5,000-10,000 IU) after the last dose to induce ovulation. Withhold hCG if the ovaries are abnormally enlarged or if abdominal pain occurs. Max: 300 IU/day.

Assisted reproductive technologies: IM or SC admin: 150-225 IU /day for at least 1st 4 days of treatment. Adjust dose based on individual ovarian response. Usual maintenance dose: 75-300 IU for 6-12 days; 375-600 IU for poor responders. Max (clinical studies): 600 IU/day. Upon adequate follicular development, a single dose of hCG (5,000-10,000 IU) is administered for final oocyte maturation. Oocyte retrieval can be done 34-36 hr later. Withhold hCG if ovaries are abnormally enlarged on the last day of follicular treatment.

Ovarian cysts, mild to severe inj site reactions, headache, mild to moderate OHSS, abdominal pain, GI disturbances. Rarely, severe OHSS, ovarian torsion, thromboembolism, mild systemic allergic reactions.

Abnormal genital bleeding of undetermined origin, hormone sensitive malignancies; ovary, breast, uterus, hypothalamus, testes or pituitary gland tumor; ovarian cysts or enlargement not due to the polycystic ovary syndrome; high levels of FSH indicating primary gonadal failure (ovarian or testicular); uncontrolled thyroid or adrenal dysfunction; presence of any cause of infertility other than anovulation; hypersensitivity; pregnancy, lactation.

May result in multiple births. Ovarian hyperstimulation syndrome (OHSS), serious pulmonary conditions and thromboembolic events may occur. Evaluate patients for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia, pituitary and hypothalamic tumors before starting therapy.

No drug-drug interaction studies have been performed.

Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

May lead to OHSS and multiple gestations.

Store at 2-8°C.

Cytotoxic Chemotherapy

Mercaptopurine is a purine antagonist which is converted intracellularly into its active nucleotides, including thioinosinic acid. The nucleotides inhibit several reactions which ultimately interferes with nucleic acid synthesis and prevents the formation of RNA and DNA.

Crohn's disease:

• Adult: Initially 1-1.5 mg/kg daily, may increase to 125 mg daily.
• Child: Initially 1-1.5 mg/kg daily increased to a max of 75 mg daily

Acute lymphocytic leukemia:

• Adult: Usual maintenance dose: Initially, 1.5-2.5 mg/kg daily as a single dose, usually used in combination with methotrexate. Dose may vary individually based on response and tolerance. Monitor blood counts at least once wkly. Withdraw treatment immedietely if there is a sharp drop in the white cell count or severe bone-marrow depression. May resume treatment slowly and carefully if white cell count remains constant for 2-3 days or rises. Reduce dose when used with allopurinol.
• Child: Usual maintenance dose: Initially, 1.5-2.5 mg/kg daily as a single dose, usually used in combination with methotrexate. Dose may vary individually based on response and tolerance. Monitor blood counts at least once wkly. Withdraw treatment immedietely if there is a sharp drop in the white cell count or severe bone-marrow depression. May resume treatment slowly and carefully if white cell count remains constant for 2-3 days or rises. Reduce dose when used with allopurinol.

Should be taken on an empty stomach. Best taken on an empty stomach 1 hr before or 2 hr after meals. Ensure adequate fluid intake.

Hyperuricaemia, bone marrow toxicity, hypoplasia, anorexia, diarrhoea, leukopenia, thrombocytopenia, intestinal ulceration, crystalluria with haematuria, immunosuppression, interstitial pneumonitis. Cutaneous hyperpigmentation, alopecia.

Pregnancy and lactation. Prior resistance to mercaptopurine or thioguanine; severe liver disease; severe bone marrow suppression.

Hepatic or renal dysfunction; monitor hepatic function periodically. Mercaptopurine is potentially carcinogenic. Thiopurine S-methyl transferase (TPMT) deficiency; porphyria.

Anticoagulant action of warfarin may be inhibited by mercaptopurine. Enhanced toxicity with myelosuppressive drugs.

Pregnancy category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Renal Impairment: Dosage may need to be reduced.

Hepatic Impairment:

• Crohn's disease: Dosage may need to be reduced.
• Acute lymphocytic leukemia: Dosage may need to be reduced

Dosage adjustment in patients with thiopurine-S-methyl transferase (TPMT) deficiency to prevent life-threatening myelotoxicity.

For patients with homozygous TPMT deficiency: Substantial reduction is required.

For patients with heterozygous TPMT deficiency: Some may require reduction but most will tolerate the usual dosages.

Store at 20-25° C

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Dexibuprofen (S (+)-ibuprofen) is considered as the pharmacologically active enantiomer of racemic ibuprofen. Like racemic ibuprofen, Dexibuprofen is a non-steroidal anti-inflammatory drug with analgesic action. Like ibuprofen, Dexibuprofen acts by inhibiting prostaglandin synthesis.

Pharmacokinetics: Dexibuprofen is absorbed primarily from the small intestine. After metabolic transformation in the liver (hydroxylation, carboxylation) the pharmacologically inactive metabolites are completely excreted, mainly by the kidneys (90%), but also in the bile. The elimination half-life is 1.8-3.5 hours; the plasma protein binding is about 99%. Maximum plasma levels are reached about 2 hours after oral administration. The administration of dexibuprofen with a meal delays the time to reach maximum concentrations (from 2.1 hours after fasting conditions to 2.8 hours after non-fasting conditions) and decreases the maximum plasma concentrations (from 20.6 to 18.1 mcg/ml, which is of no clinical relevance), but has no effect on the extent of absorption.

The dosage must be adjusted to the seriousness of the syndrome and the complaints of the patient. During chronic pain, the dosage must be adapted to the lowest effective dose.

The recommended dosage: 600-900 mg Dexibuprofen per day, at 2-3 divided doses. The dosage can be raised temporarily up to 1200 mg Dexibuprofen per day in patients with acute disorders or exacerbations. The maximum daily dose is 1200 mg.

At dysmenorrhea: A dosage of 600 up to 900 mg Dexibuprofen per day, at a divided dose.

Clinical experience has shown that adverse effects of Dexibuprofen are similar to those of racemic ibuprofen. Common side-effects are dyspepsia, diarrhea, fatigue, and headache, nausea, vomiting, abdominal pain, hypersensitivity reactions - bleeding, ulcer.

Dexibuprofen is contraindicated in patients with previous history of hypersensitivity to Dexibuprofen, or another NSAID, or any other component of the product. Patients, who experience attack of asthma, arouse bronchospasm, acute rhinitis, urticaria or edema after use of similar drugs (e.g. aspirin or other NSAID's). It is also contraindicated in patients with active or suspected hemorrhage, Crohn's disease or ulcerative colitis, patients with serious heart diseases, kidney function impairment (GFR <30ml/min), and liver function impairment.

Dexibuprofen should be used with particular caution in patients with bronchial asthma or other chronic diseases of the pulmonary tract as well as in persons prone to allergy. The drug should be used in patients with hepatic, renal or cardiac insufficiency and with hypertension not responding to any treatment. Consultation with a doctor is recommended for patients with systemic lupus or with other autoimmunological disease before beginning therapy using the drug. Dexibuprofen should be used with extreme cautions in active and suspected hemorrhagic conditions such as gastro-duodenal ulcers, ulcerative colitis, Crohn's disease, alcoholism. Allergic reactions to the drug may appear even for the first-time user and in such case, it should immediately be stopped.

The reported drug interactions of Dexibuprofen are similar to that of racemic mixture of ibuprofen. Drug interactions is noticed with simultaneous use of anticoagulant, hydantoine and sulfonamide, ticlopidine, lithium, other NSAID's, ACE inhibitors, beta blockers, cyclosporine, tacrolimus, corticosteroids, digoxin, methotrexate, pentoxyfiline, phenytoine, probenecid, sulfinpyrazon, sulfonylurea, thiazide and thiazide type diuretics, and zidovudine.

Pregnancy: Although no teratogennic impact has been observed in the animal-experimental research with dexibuprofen or ibuprofen, the use should be avoided during the pregnancy. However, animal reproduction studies are not always predictive of human response. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

Lactation: Studies at people have shown that racimic ibuprofen proceed in small to negligible degree in mother milk. So, Dexibuprofen should be used with cautions in nursing mothers.

Hepatic impairment: Patients with mild to moderate liver function impairments must start with low amounts, and must closely be monitored. Dexibuprofen should not be used in patients with serious liver function impairments.

Renal impairment: The start amount must be reduced at patients with mild to moderate kidney function impairments. Dexibuprofen cannot be used patients with serious kidney function impairments.

Children Dose: Although Dexibuprofen is not licensed for use in children under 18 years of age in the UK, some countries permit such use. For example, in Switzerland, Dexibuprofen has been given to children aged 6 years and over at a dose of 10 to 15 mg/kg daily in 2-4 divided doses.

For elderly people: Lowest effective dose is recommended. The dosage can be raised to adult dosage if well tolerated.

Dexibuprofen has low acute toxicities. Symptoms of toxicity occur at doses between 80 and 100 mg/kg body weight. Mild symptoms are abdominal pain, nausea, vomiting, lethargy, headache, tinnitus and ataxia. Moderate to serious symptoms, such as flatulence, hypotension, hypothermia, metabolic acidosis, reduced kidney function, coma, and apnoea. The treatment must be symptomatic: there is no specific antidote. In case of large quantities of Dexibuprofen, activated charcoal should be administered. Vomiting can be induced only when life-threatening quantities of the substance ingested and the procedure can be carried out within 60 minutes after ingestion. Dialysis and hemodialysis are of little value as Dexibuprofen binds strongly to plasma protein.

Do not store above 30°C. Keep away from light and out of the reach of children

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Dexibuprofen (S (+)-ibuprofen) is considered as the pharmacologically active enantiomer of racemic ibuprofen. Like racemic ibuprofen, Dexibuprofen is a non-steroidal anti-inflammatory drug with analgesic action. Like ibuprofen, Dexibuprofen acts by inhibiting prostaglandin synthesis.

Pharmacokinetics: Dexibuprofen is absorbed primarily from the small intestine. After metabolic transformation in the liver (hydroxylation, carboxylation) the pharmacologically inactive metabolites are completely excreted, mainly by the kidneys (90%), but also in the bile. The elimination half-life is 1.8-3.5 hours; the plasma protein binding is about 99%. Maximum plasma levels are reached about 2 hours after oral administration. The administration of dexibuprofen with a meal delays the time to reach maximum concentrations (from 2.1 hours after fasting conditions to 2.8 hours after non-fasting conditions) and decreases the maximum plasma concentrations (from 20.6 to 18.1 mcg/ml, which is of no clinical relevance), but has no effect on the extent of absorption.

The dosage must be adjusted to the seriousness of the syndrome and the complaints of the patient. During chronic pain, the dosage must be adapted to the lowest effective dose.

The recommended dosage: 600-900 mg Dexibuprofen per day, at 2-3 divided doses. The dosage can be raised temporarily up to 1200 mg Dexibuprofen per day in patients with acute disorders or exacerbations. The maximum daily dose is 1200 mg.

At dysmenorrhea: A dosage of 600 up to 900 mg Dexibuprofen per day, at a divided dose.

Clinical experience has shown that adverse effects of Dexibuprofen are similar to those of racemic ibuprofen. Common side-effects are dyspepsia, diarrhea, fatigue, and headache, nausea, vomiting, abdominal pain, hypersensitivity reactions - bleeding, ulcer.

Dexibuprofen is contraindicated in patients with previous history of hypersensitivity to Dexibuprofen, or another NSAID, or any other component of the product. Patients, who experience attack of asthma, arouse bronchospasm, acute rhinitis, urticaria or edema after use of similar drugs (e.g. aspirin or other NSAID's). It is also contraindicated in patients with active or suspected hemorrhage, Crohn's disease or ulcerative colitis, patients with serious heart diseases, kidney function impairment (GFR <30ml/min), and liver function impairment.

Dexibuprofen should be used with particular caution in patients with bronchial asthma or other chronic diseases of the pulmonary tract as well as in persons prone to allergy. The drug should be used in patients with hepatic, renal or cardiac insufficiency and with hypertension not responding to any treatment. Consultation with a doctor is recommended for patients with systemic lupus or with other autoimmunological disease before beginning therapy using the drug. Dexibuprofen should be used with extreme cautions in active and suspected hemorrhagic conditions such as gastro-duodenal ulcers, ulcerative colitis, Crohn's disease, alcoholism. Allergic reactions to the drug may appear even for the first-time user and in such case, it should immediately be stopped.

The reported drug interactions of Dexibuprofen are similar to that of racemic mixture of ibuprofen. Drug interactions is noticed with simultaneous use of anticoagulant, hydantoine and sulfonamide, ticlopidine, lithium, other NSAID's, ACE inhibitors, beta blockers, cyclosporine, tacrolimus, corticosteroids, digoxin, methotrexate, pentoxyfiline, phenytoine, probenecid, sulfinpyrazon, sulfonylurea, thiazide and thiazide type diuretics, and zidovudine.

Pregnancy: Although no teratogennic impact has been observed in the animal-experimental research with dexibuprofen or ibuprofen, the use should be avoided during the pregnancy. However, animal reproduction studies are not always predictive of human response. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

Lactation: Studies at people have shown that racimic ibuprofen proceed in small to negligible degree in mother milk. So, Dexibuprofen should be used with cautions in nursing mothers.

Hepatic impairment: Patients with mild to moderate liver function impairments must start with low amounts, and must closely be monitored. Dexibuprofen should not be used in patients with serious liver function impairments.

Renal impairment: The start amount must be reduced at patients with mild to moderate kidney function impairments. Dexibuprofen cannot be used patients with serious kidney function impairments.

Children Dose: Although Dexibuprofen is not licensed for use in children under 18 years of age in the UK, some countries permit such use. For example, in Switzerland, Dexibuprofen has been given to children aged 6 years and over at a dose of 10 to 15 mg/kg daily in 2-4 divided doses.

For elderly people: Lowest effective dose is recommended. The dosage can be raised to adult dosage if well tolerated.

Dexibuprofen has low acute toxicities. Symptoms of toxicity occur at doses between 80 and 100 mg/kg body weight. Mild symptoms are abdominal pain, nausea, vomiting, lethargy, headache, tinnitus and ataxia. Moderate to serious symptoms, such as flatulence, hypotension, hypothermia, metabolic acidosis, reduced kidney function, coma, and apnoea. The treatment must be symptomatic: there is no specific antidote. In case of large quantities of Dexibuprofen, activated charcoal should be administered. Vomiting can be induced only when life-threatening quantities of the substance ingested and the procedure can be carried out within 60 minutes after ingestion. Dialysis and hemodialysis are of little value as Dexibuprofen binds strongly to plasma protein.

Do not store above 30°C. Keep away from light and out of the reach of children

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Dexibuprofen (S (+)-ibuprofen) is considered as the pharmacologically active enantiomer of racemic ibuprofen. Like racemic ibuprofen, Dexibuprofen is a non-steroidal anti-inflammatory drug with analgesic action. Like ibuprofen, Dexibuprofen acts by inhibiting prostaglandin synthesis.

Pharmacokinetics: Dexibuprofen is absorbed primarily from the small intestine. After metabolic transformation in the liver (hydroxylation, carboxylation) the pharmacologically inactive metabolites are completely excreted, mainly by the kidneys (90%), but also in the bile. The elimination half-life is 1.8-3.5 hours; the plasma protein binding is about 99%. Maximum plasma levels are reached about 2 hours after oral administration. The administration of dexibuprofen with a meal delays the time to reach maximum concentrations (from 2.1 hours after fasting conditions to 2.8 hours after non-fasting conditions) and decreases the maximum plasma concentrations (from 20.6 to 18.1 mcg/ml, which is of no clinical relevance), but has no effect on the extent of absorption.

The dosage must be adjusted to the seriousness of the syndrome and the complaints of the patient. During chronic pain, the dosage must be adapted to the lowest effective dose.

The recommended dosage: 600-900 mg Dexibuprofen per day, at 2-3 divided doses. The dosage can be raised temporarily up to 1200 mg Dexibuprofen per day in patients with acute disorders or exacerbations. The maximum daily dose is 1200 mg.

At dysmenorrhea: A dosage of 600 up to 900 mg Dexibuprofen per day, at a divided dose.

Clinical experience has shown that adverse effects of Dexibuprofen are similar to those of racemic ibuprofen. Common side-effects are dyspepsia, diarrhea, fatigue, and headache, nausea, vomiting, abdominal pain, hypersensitivity reactions - bleeding, ulcer.

Dexibuprofen is contraindicated in patients with previous history of hypersensitivity to Dexibuprofen, or another NSAID, or any other component of the product. Patients, who experience attack of asthma, arouse bronchospasm, acute rhinitis, urticaria or edema after use of similar drugs (e.g. aspirin or other NSAID's). It is also contraindicated in patients with active or suspected hemorrhage, Crohn's disease or ulcerative colitis, patients with serious heart diseases, kidney function impairment (GFR <30ml/min), and liver function impairment.

Dexibuprofen should be used with particular caution in patients with bronchial asthma or other chronic diseases of the pulmonary tract as well as in persons prone to allergy. The drug should be used in patients with hepatic, renal or cardiac insufficiency and with hypertension not responding to any treatment. Consultation with a doctor is recommended for patients with systemic lupus or with other autoimmunological disease before beginning therapy using the drug. Dexibuprofen should be used with extreme cautions in active and suspected hemorrhagic conditions such as gastro-duodenal ulcers, ulcerative colitis, Crohn's disease, alcoholism. Allergic reactions to the drug may appear even for the first-time user and in such case, it should immediately be stopped.

The reported drug interactions of Dexibuprofen are similar to that of racemic mixture of ibuprofen. Drug interactions is noticed with simultaneous use of anticoagulant, hydantoine and sulfonamide, ticlopidine, lithium, other NSAID's, ACE inhibitors, beta blockers, cyclosporine, tacrolimus, corticosteroids, digoxin, methotrexate, pentoxyfiline, phenytoine, probenecid, sulfinpyrazon, sulfonylurea, thiazide and thiazide type diuretics, and zidovudine.

Pregnancy: Although no teratogennic impact has been observed in the animal-experimental research with dexibuprofen or ibuprofen, the use should be avoided during the pregnancy. However, animal reproduction studies are not always predictive of human response. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

Lactation: Studies at people have shown that racimic ibuprofen proceed in small to negligible degree in mother milk. So, Dexibuprofen should be used with cautions in nursing mothers.

Hepatic impairment: Patients with mild to moderate liver function impairments must start with low amounts, and must closely be monitored. Dexibuprofen should not be used in patients with serious liver function impairments.

Renal impairment: The start amount must be reduced at patients with mild to moderate kidney function impairments. Dexibuprofen cannot be used patients with serious kidney function impairments.

Children Dose: Although Dexibuprofen is not licensed for use in children under 18 years of age in the UK, some countries permit such use. For example, in Switzerland, Dexibuprofen has been given to children aged 6 years and over at a dose of 10 to 15 mg/kg daily in 2-4 divided doses.

For elderly people: Lowest effective dose is recommended. The dosage can be raised to adult dosage if well tolerated.

Dexibuprofen has low acute toxicities. Symptoms of toxicity occur at doses between 80 and 100 mg/kg body weight. Mild symptoms are abdominal pain, nausea, vomiting, lethargy, headache, tinnitus and ataxia. Moderate to serious symptoms, such as flatulence, hypotension, hypothermia, metabolic acidosis, reduced kidney function, coma, and apnoea. The treatment must be symptomatic: there is no specific antidote. In case of large quantities of Dexibuprofen, activated charcoal should be administered. Vomiting can be induced only when life-threatening quantities of the substance ingested and the procedure can be carried out within 60 minutes after ingestion. Dialysis and hemodialysis are of little value as Dexibuprofen binds strongly to plasma protein.

Do not store above 30°C. Keep away from light and out of the reach of children

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Dexibuprofen (S (+)-ibuprofen) is considered as the pharmacologically active enantiomer of racemic ibuprofen. Like racemic ibuprofen, Dexibuprofen is a non-steroidal anti-inflammatory drug with analgesic action. Like ibuprofen, Dexibuprofen acts by inhibiting prostaglandin synthesis.

Pharmacokinetics: Dexibuprofen is absorbed primarily from the small intestine. After metabolic transformation in the liver (hydroxylation, carboxylation) the pharmacologically inactive metabolites are completely excreted, mainly by the kidneys (90%), but also in the bile. The elimination half-life is 1.8-3.5 hours; the plasma protein binding is about 99%. Maximum plasma levels are reached about 2 hours after oral administration. The administration of dexibuprofen with a meal delays the time to reach maximum concentrations (from 2.1 hours after fasting conditions to 2.8 hours after non-fasting conditions) and decreases the maximum plasma concentrations (from 20.6 to 18.1 mcg/ml, which is of no clinical relevance), but has no effect on the extent of absorption.

The dosage must be adjusted to the seriousness of the syndrome and the complaints of the patient. During chronic pain, the dosage must be adapted to the lowest effective dose.

The recommended dosage: 600-900 mg Dexibuprofen per day, at 2-3 divided doses. The dosage can be raised temporarily up to 1200 mg Dexibuprofen per day in patients with acute disorders or exacerbations. The maximum daily dose is 1200 mg.

At dysmenorrhea: A dosage of 600 up to 900 mg Dexibuprofen per day, at a divided dose.

Clinical experience has shown that adverse effects of Dexibuprofen are similar to those of racemic ibuprofen. Common side-effects are dyspepsia, diarrhea, fatigue, and headache, nausea, vomiting, abdominal pain, hypersensitivity reactions - bleeding, ulcer.

Dexibuprofen is contraindicated in patients with previous history of hypersensitivity to Dexibuprofen, or another NSAID, or any other component of the product. Patients, who experience attack of asthma, arouse bronchospasm, acute rhinitis, urticaria or edema after use of similar drugs (e.g. aspirin or other NSAID's). It is also contraindicated in patients with active or suspected hemorrhage, Crohn's disease or ulcerative colitis, patients with serious heart diseases, kidney function impairment (GFR <30ml/min), and liver function impairment.

Dexibuprofen should be used with particular caution in patients with bronchial asthma or other chronic diseases of the pulmonary tract as well as in persons prone to allergy. The drug should be used in patients with hepatic, renal or cardiac insufficiency and with hypertension not responding to any treatment. Consultation with a doctor is recommended for patients with systemic lupus or with other autoimmunological disease before beginning therapy using the drug. Dexibuprofen should be used with extreme cautions in active and suspected hemorrhagic conditions such as gastro-duodenal ulcers, ulcerative colitis, Crohn's disease, alcoholism. Allergic reactions to the drug may appear even for the first-time user and in such case, it should immediately be stopped.

The reported drug interactions of Dexibuprofen are similar to that of racemic mixture of ibuprofen. Drug interactions is noticed with simultaneous use of anticoagulant, hydantoine and sulfonamide, ticlopidine, lithium, other NSAID's, ACE inhibitors, beta blockers, cyclosporine, tacrolimus, corticosteroids, digoxin, methotrexate, pentoxyfiline, phenytoine, probenecid, sulfinpyrazon, sulfonylurea, thiazide and thiazide type diuretics, and zidovudine.

Pregnancy: Although no teratogennic impact has been observed in the animal-experimental research with dexibuprofen or ibuprofen, the use should be avoided during the pregnancy. However, animal reproduction studies are not always predictive of human response. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

Lactation: Studies at people have shown that racimic ibuprofen proceed in small to negligible degree in mother milk. So, Dexibuprofen should be used with cautions in nursing mothers.

Hepatic impairment: Patients with mild to moderate liver function impairments must start with low amounts, and must closely be monitored. Dexibuprofen should not be used in patients with serious liver function impairments.

Renal impairment: The start amount must be reduced at patients with mild to moderate kidney function impairments. Dexibuprofen cannot be used patients with serious kidney function impairments.

Children Dose: Although Dexibuprofen is not licensed for use in children under 18 years of age in the UK, some countries permit such use. For example, in Switzerland, Dexibuprofen has been given to children aged 6 years and over at a dose of 10 to 15 mg/kg daily in 2-4 divided doses.

For elderly people: Lowest effective dose is recommended. The dosage can be raised to adult dosage if well tolerated.

Dexibuprofen has low acute toxicities. Symptoms of toxicity occur at doses between 80 and 100 mg/kg body weight. Mild symptoms are abdominal pain, nausea, vomiting, lethargy, headache, tinnitus and ataxia. Moderate to serious symptoms, such as flatulence, hypotension, hypothermia, metabolic acidosis, reduced kidney function, coma, and apnoea. The treatment must be symptomatic: there is no specific antidote. In case of large quantities of Dexibuprofen, activated charcoal should be administered. Vomiting can be induced only when life-threatening quantities of the substance ingested and the procedure can be carried out within 60 minutes after ingestion. Dialysis and hemodialysis are of little value as Dexibuprofen binds strongly to plasma protein.

Do not store above 30°C. Keep away from light and out of the reach of children

Levosalbutamol is indicated for the treatment or prevention of bronchospasm in adults, adolescents and children 6 years of age and older with reversible obstructive airway disease.

Short-acting selective & β2-adrenoceptor stimulants

Levosalbutamol is a single isomer beta 2-agonist that differs from racemic salbutamol by elimination of (S)-salbutamol. Levosalbutamol is an effective bronchodilator whose primary mechanism of action is unimpeded by (S)-salbutamol. Thus, when compared with racemic salbutamol, clinically comparable bronchodilation can be achieved with doses that substantially lessen beta-mediated side effects.

Tablet-

• Adults and adolescents above 12 years: 1-2 mg three times daily.
• Children (6 -11 years): 1 mg three times daily.

Syrup-

• Adults : 5-10 ml three times daily.
• Childrn (6-11 years): 5 ml three times daily.

Hypocalcaemia, palpitation, fine tremors of the skeletal muscle and muscle cramps may occur. The other likely side effects are nausea, vomiting, burning substernal or epigastric pain and diarrhoea.

Levosalbutamol is contraindicated in patients with a history of hypersensitivity to levosalbutamol or any of its components.

Particular caution is advised in acute severe asthma as this effect may be potentiated by hypoxia and by concomitant treatment with xanthine derivatives, steroids and diuretics. Serum potassium levels should be monitored in such situations.

Other short acting sympathomimetic bronchodilators or epinephrine should be used with caution with Levosalbutamol. If additional adrenergic drugs are to be administered by any route, they will be used with caution to avoid deleterious cardiovascular effects.

The drug should be used during pregnancy only if the potential benefit justifies the potential risk of the fetus. It is not known whether Levosalbutamol is excreted in human milk. Caution should be exercised when oral Levosalbutamol is administered to a nursing woman.

The expected symptoms with over dosage are those of excessive beta-adrenergic stimulation and the symptoms listed under side effects. In the event of serious poisoning, the stomach should be emptied and, if necessary, a beta-blocker administered with caution in patients with a history of bronchospasm.

Keep all medicines out of reach of children. Store in a cool and dry place, protected from light.

Levosalbutamol is indicated for the treatment or prevention of bronchospasm in adults, adolescents and children 6 years of age and older with reversible obstructive airway disease.

Short-acting selective & β2-adrenoceptor stimulants

Levosalbutamol is a single isomer beta 2-agonist that differs from racemic salbutamol by elimination of (S)-salbutamol. Levosalbutamol is an effective bronchodilator whose primary mechanism of action is unimpeded by (S)-salbutamol. Thus, when compared with racemic salbutamol, clinically comparable bronchodilation can be achieved with doses that substantially lessen beta-mediated side effects.

Tablet-

• Adults and adolescents above 12 years: 1-2 mg three times daily.
• Children (6 -11 years): 1 mg three times daily.

Syrup-

• Adults : 5-10 ml three times daily.
• Childrn (6-11 years): 5 ml three times daily.

Hypocalcaemia, palpitation, fine tremors of the skeletal muscle and muscle cramps may occur. The other likely side effects are nausea, vomiting, burning substernal or epigastric pain and diarrhoea.

Levosalbutamol is contraindicated in patients with a history of hypersensitivity to levosalbutamol or any of its components.

Particular caution is advised in acute severe asthma as this effect may be potentiated by hypoxia and by concomitant treatment with xanthine derivatives, steroids and diuretics. Serum potassium levels should be monitored in such situations.

Other short acting sympathomimetic bronchodilators or epinephrine should be used with caution with Levosalbutamol. If additional adrenergic drugs are to be administered by any route, they will be used with caution to avoid deleterious cardiovascular effects.

The drug should be used during pregnancy only if the potential benefit justifies the potential risk of the fetus. It is not known whether Levosalbutamol is excreted in human milk. Caution should be exercised when oral Levosalbutamol is administered to a nursing woman.

The expected symptoms with over dosage are those of excessive beta-adrenergic stimulation and the symptoms listed under side effects. In the event of serious poisoning, the stomach should be emptied and, if necessary, a beta-blocker administered with caution in patients with a history of bronchospasm.

Keep all medicines out of reach of children. Store in a cool and dry place, protected from light.