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Oral Anti-coagulants

Rivaroxaban is a highly selective direct factor Xa inhibitor. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibits thrombin formation. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.

Rivaroxaban 2.5 mg:

• The recommended dose: 2.5 mg twice daily. Patients should also take a daily dose of 75-100 mg Aspirin or a daily dose of 75-100 mg Aspirin in addition to either a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine.

Rivaroxaban 10-20 mg:

• Nonvalvular Atrial Fibrillation: For patients with Creatinin Clearance >50 mL/min: 20 mg orally, once daily with the evening meal. For patients with Creatinin Clearance 15-50 ml/min: 15 mg orally, once daily with the evening meal.
• Treatment of DVT & PE: 15 mg orally twice daily with food for the first 21 days for the initial treatment of acute DVT or PE. After the initial treatment period, 20 mg orally once daily with food for the remaining treatment.
• Prevention in the risk of recurrence of DVT and of PE: 20 mg once daily with food.
• Prophylaxis of DVT following Hip replacement surgery: 10 mg once daily for 35 days.
• Prophylaxis of DVT following knee replacement surgery: 10 mg once daily for 12 days.

May be taken with or without food.

The most common side effects of Rivaroxaban have increased chance of bleeding, spinal or epidural hematoma and increased risk of stroke after discontinuation in nonvalvular atrial fibrillation.

It is contraindicated in patients with known hypersensitivity of Rivaroxaban or any of the excipients of the product. It is also contraindicated in patients with active pathological bleeding.

Early discontinuation of Rivaroxaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. Rivaroxaban increases the risk of bleeding that can be fatal in presence of following risk factors- bleeding disorders, uncontrolled severe arterial hypertension, gastrointestinal disease (e.g., inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease), vascular retinopathy, bronchiectasis, history of pulmonary bleeding. Signs or symptoms of neurological impairment should be monitored in case of neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture as epidural or spinal hematoma can occur. Rivaroxaban is not recommended in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, erythromycin, fluconazole, diltiazem, verapamil, dronedarone) increases in Rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation), that’s why should be avoided. Co-administration of Rivaroxaban with a combined P-gp and strong CYP3A4 inducer (e.g., rifampicin, phenytoin, carbamazepine) decreases the efficacy of Rivaroxaban and also should be avoided. The concomitant use of other drugs like anti-platelet agents, heparin, fibrinolytic therapy, NSAIDs may cause an increased risk of bleeding.

Rivaroxaban is a pregnancy category C drug. There are no adequate or well-controlled studies of Rivaroxaban in pregnant women, and dosing for pregnant women has not been established. It is not known if Rivaroxaban is excreted in human milk. The safety and efficacy of Rivaroxaban has not been established in breastfeeding women.

Overdose of Rivaroxaban may lead to hemorrhage. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. A specific antidote for Rivaroxaban is not available. The use of activated charcoal to reduce absorption in case of Rivaroxaban overdose may be considered. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.

Store in a cool (below 30°C) & dry place protected from light. Keep away from the reach of children.

Oral Anti-coagulants

Rivaroxaban is a highly selective direct factor Xa inhibitor. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibits thrombin formation. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.

Rivaroxaban 2.5 mg:

• The recommended dose: 2.5 mg twice daily. Patients should also take a daily dose of 75-100 mg Aspirin or a daily dose of 75-100 mg Aspirin in addition to either a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine.

Rivaroxaban 10-20 mg:

• Nonvalvular Atrial Fibrillation: For patients with Creatinin Clearance >50 mL/min: 20 mg orally, once daily with the evening meal. For patients with Creatinin Clearance 15-50 ml/min: 15 mg orally, once daily with the evening meal.
• Treatment of DVT & PE: 15 mg orally twice daily with food for the first 21 days for the initial treatment of acute DVT or PE. After the initial treatment period, 20 mg orally once daily with food for the remaining treatment.
• Prevention in the risk of recurrence of DVT and of PE: 20 mg once daily with food.
• Prophylaxis of DVT following Hip replacement surgery: 10 mg once daily for 35 days.
• Prophylaxis of DVT following knee replacement surgery: 10 mg once daily for 12 days.

May be taken with or without food.

The most common side effects of Rivaroxaban have increased chance of bleeding, spinal or epidural hematoma and increased risk of stroke after discontinuation in nonvalvular atrial fibrillation.

It is contraindicated in patients with known hypersensitivity of Rivaroxaban or any of the excipients of the product. It is also contraindicated in patients with active pathological bleeding.

Early discontinuation of Rivaroxaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. Rivaroxaban increases the risk of bleeding that can be fatal in presence of following risk factors- bleeding disorders, uncontrolled severe arterial hypertension, gastrointestinal disease (e.g., inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease), vascular retinopathy, bronchiectasis, history of pulmonary bleeding. Signs or symptoms of neurological impairment should be monitored in case of neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture as epidural or spinal hematoma can occur. Rivaroxaban is not recommended in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, erythromycin, fluconazole, diltiazem, verapamil, dronedarone) increases in Rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation), that’s why should be avoided. Co-administration of Rivaroxaban with a combined P-gp and strong CYP3A4 inducer (e.g., rifampicin, phenytoin, carbamazepine) decreases the efficacy of Rivaroxaban and also should be avoided. The concomitant use of other drugs like anti-platelet agents, heparin, fibrinolytic therapy, NSAIDs may cause an increased risk of bleeding.

Rivaroxaban is a pregnancy category C drug. There are no adequate or well-controlled studies of Rivaroxaban in pregnant women, and dosing for pregnant women has not been established. It is not known if Rivaroxaban is excreted in human milk. The safety and efficacy of Rivaroxaban has not been established in breastfeeding women.

Overdose of Rivaroxaban may lead to hemorrhage. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. A specific antidote for Rivaroxaban is not available. The use of activated charcoal to reduce absorption in case of Rivaroxaban overdose may be considered. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.

Store in a cool (below 30°C) & dry place protected from light. Keep away from the reach of children.

Cough expectorants & mucolytics

Ambroxol is the active metabolite of bromhexine and it has been proven that this metabolite possesses a greater bronchosecretolytic effect than bromhexine. It improves sputum rheology by hydrating mechanism leading to liquefaction of mucus in the lumen of respiratory tract, thus facilitating expectoration of mucus and reducing dyspnea. It stimulates production of phospholipids of surfactant by alveolar cells, thus contributing to the lowering of superficial tension in the alveoli. It also reduces bronchial hyperactivity. Ambroxol has anti inflammatory properties owing to the inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. In patients with COPD it traditionally improves airway patency.

Average daily dose (preferably after meal):

Pediatric Drops:

• 0-6 months: 0.5 ml 2 times a day
• 6-12 months: 1 ml 2 times a day
• 1-2 years: 1.25 ml 2 times a day

Syrup:

• 2-5 years: 2.5 ml (1/2 teaspoonful) 2-3 times a day
• 5-10 years: 5 ml (1 teaspoonful) 2-3 times a day
• 10 years and adults: 10 ml (2 teaspoonful) 3 times a day.

Sustained release capsule: Adult and children over 12 years old: 1 capsule once daily.

Gastrointestinal side effects like epigastric pain, stomach overfill feeling may occur occasionally. Rarely allergic responses such as eruption, urticaria or angioneurotic edema have been reported.

Contraindicated in known hypersensitivity to Ambroxol or Bromhexine.

Ambroxol should be given cautiously to patients with gastric and duodenal ulceration or convulsive disorders. Patients with hepatic and renal insufficiency should take it with caution.

Ambroxol should not be taken simultaneously with antitussives (e.g.Codeine) because phlegm, which has been liquefied by Ambroxol might not be expectorated.

Teratogenic and fetal toxicity studies have shown no harmful effect of Ambroxol. However, it is advised not to use it in pregnancy, especially during the1st trimester. Safety during lactation has not been established yet.

Protect from direct light exposure, Store in a dry place at a temperature not exceeding 30°C, Keep out of the reach of children.

It is indicated for the relief of symptoms associated with seasonal & perennial allergic rhinitis. It is also indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria and allergen induced asthma.

Sedating Anti-histamine

Cetirizine Hydrochloride is a potent H1 receptor antagonist without any significant anticholinergic and antiserotonic effects. At pharmacologically active dose levels, it has almost no drowsiness effect and does not cause behavioral changes. It inhibits the histamine-mediated early phase of the allergic reaction and also reduces the migration of inflammatory cells and the release of mediators associated with the late phase of the allergic reaction.

Pharmacokinetics: Cetirizine 10 mg achieves peak plasma concentrations of 257 mcg/L within one hour of administration (980 mcg/L in children). Food does not affect the extent of absorption, but it may slightly reduce the rate. Peak blood levels 0.3 micrograms/ml are reached between thirty & sixty minutes after administration of 10 mg dose of Cetirizine. Its plasma half-life is approximately 11 hours. Absorption is very consistent from one subject to the next. Its renal clearance is 30 ml/minute and the excretion half-life is approximately nine hours.

Adults and Children 6 years and older: 1 tablet or 2 teaspoonfuls daily (or 1 teaspoonful twice daily).

Children 2-6 years: 1 teaspoonful once daily or 1/2 teaspoonful twice daily.

Children 6 months to 2 years : 1/2 teaspoonful once daily. The dose in children 12-23 months of age can be increased to a maximum dose as 1/2 teaspoonful every 12 hours.

The most common side effects that occurred more frequently on Cetirizine is somnolence.

It is contraindicated in patients with a history of hypersensitivity to Cetirizine or hydroxyzine.

Caution should be exercised when driving a car or operating a heavy machinery.

No clinically significant drug interactions have been found with Theophylline, Azithromycin, Pseudoephedrine, Ketoconazole or Erythromycin and with other drugs.

US FDA Pregnancy Category of Cetirizine Hydrochloride is B. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Cetirizine Hydrochloride has been shown to be excreted in human milk. So, caution should be exercised when Cetirizine Hydrochloride is administered to a nursing woman.

Keep in a dry place away from light and heat. Keep out of the reach of children.

It is indicated for the relief of symptoms associated with seasonal & perennial allergic rhinitis. It is also indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria and allergen induced asthma.

Sedating Anti-histamine

Cetirizine Hydrochloride is a potent H1 receptor antagonist without any significant anticholinergic and antiserotonic effects. At pharmacologically active dose levels, it has almost no drowsiness effect and does not cause behavioral changes. It inhibits the histamine-mediated early phase of the allergic reaction and also reduces the migration of inflammatory cells and the release of mediators associated with the late phase of the allergic reaction.

Pharmacokinetics: Cetirizine 10 mg achieves peak plasma concentrations of 257 mcg/L within one hour of administration (980 mcg/L in children). Food does not affect the extent of absorption, but it may slightly reduce the rate. Peak blood levels 0.3 micrograms/ml are reached between thirty & sixty minutes after administration of 10 mg dose of Cetirizine. Its plasma half-life is approximately 11 hours. Absorption is very consistent from one subject to the next. Its renal clearance is 30 ml/minute and the excretion half-life is approximately nine hours.

Adults and Children 6 years and older: 1 tablet or 2 teaspoonfuls daily (or 1 teaspoonful twice daily).

Children 2-6 years: 1 teaspoonful once daily or 1/2 teaspoonful twice daily.

Children 6 months to 2 years : 1/2 teaspoonful once daily. The dose in children 12-23 months of age can be increased to a maximum dose as 1/2 teaspoonful every 12 hours.

The most common side effects that occurred more frequently on Cetirizine is somnolence.

It is contraindicated in patients with a history of hypersensitivity to Cetirizine or hydroxyzine.

Caution should be exercised when driving a car or operating a heavy machinery.

No clinically significant drug interactions have been found with Theophylline, Azithromycin, Pseudoephedrine, Ketoconazole or Erythromycin and with other drugs.

US FDA Pregnancy Category of Cetirizine Hydrochloride is B. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Cetirizine Hydrochloride has been shown to be excreted in human milk. So, caution should be exercised when Cetirizine Hydrochloride is administered to a nursing woman.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Rizatriptan Benzoate is indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old.

5-HT Agonists

Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Rizatriptan Benzoate presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.

Dosing Information In Adults: The recommended starting dose of Rizatriptan Benzoate is either 5 mg or 10 mg for the acute treatment of migraines in adults. The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions.

Redosing In Adults: Although the effectiveness of a second dose or subsequent doses has not been established in placebocontrolled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose. The maximum daily dose should not exceed 30 mg in any 24-hour period. The safety of treating, on average, more than four headaches in a 30-day period has not been established.

Dosing Information In Pediatric Patients (Age 6 to 17 Years): Dosing in pediatric patients is based on the patient's body weight. The recommended dose of Rizatriptan Benzoate is 5 mg in patients weighing less than 40 kg, and 10 mg in patients weighing 40 kg or more.

The efficacy and safety of treatment with more than one dose of Rizatriptan Benzoate within 24 hours in pediatric patients 6 to 17 years of age have not been established.

Dosage Adjustment For Patients On Propranolol: Sections or subsections omitted from the full prescribing information are not listed.

• Adult Patients: In adult patients taking propranolol, only the 5-mg dose of Rizatriptan Benzoate is recommended, up to a maximum of 3 doses in any 24-hour period (15 mg)
• Pediatric Patients: For pediatric patients weighing 40 kg or more, taking propranolol, only a single 5-mg dose of Rizatriptan Benzoate is recommended (maximum dose of 5 mg in a 24-hour period). Rizatriptan Benzoate should not be prescribed to propranolol-treated pediatric patients who weigh less than 40 kg

Administration of Rizatriptan Benzoate Tablets, administration with liquid is not necessary. Orally disintegrating tablets are packaged in a blister within an outer aluminum pouch and patients should not remove the blister from the outer pouch until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina 
• Arrhythmias 
• Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure 
• Cerebrovascular Events 
• Other Vasospasm Reactions 
• Medication Overuse Headache 
• Serotonin Syndrome 
• Increase in Blood Pressure

Rizatriptan Benzoate is contraindicated in patients with:

• Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease
• Coronary artery vasospasm including Prinzmetal's angina
• History of stroke or transient ischemic attack (TIA) 
• Peripheral vascular disease (PVD) 
• Ischemic bowel disease 
• Uncontrolled hypertension 
• Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) 
• Hemiplegic or basilar migraine
• Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor
• Hypersensitivity to Rizatriptan Benzoate (angioedema and anaphylaxisseen)

Elderly; mild to moderate hepatic or renal impairment; coronary artery disease; pregnancy, lactation. May cause drowsiness. History of seizures. Ensure an interval of at least 24 hr after stopping an ergotamine compound and starting a serotonin (5-HT1) agonist.

Propranolol: The dose of Rizatriptan should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70% 

Ergot-Containing Drugs: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and Rizatriptan within 24 hours is contraindicated

Other 5-HT1 Agonists: Because their vasospastic effects may be additive, co-administration of Rizatriptan and other 5-HT1 agonists within 24 hours of each other is contraindicated 

SSRIs /SNRIs And Serotonin Syndrome: Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) 

Monoamine Oxidase Inhibitors: Rizatriptan is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors. A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite

Pregnancy: Inform patients that Rizatriptan Benzoate should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Rizatriptan Benzoate is administered to a nursing woman. Rizatriptan is extensively excreted in rat milk, with levels in milk at least 5-fold higher than levels in maternal plasma.

Pediatric Use: Safety and effectiveness in pediatric patients under 6 years of age have not been established. The efficacy and safety of Rizatriptan in the acute treatment of migraine in patients aged 6 to 17 years was established in an adequate and well-controlled study. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received Rizatriptan to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

Geriatric Use: Clinical studies of Rizatriptan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Although the pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range. This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving Rizatriptan

Renal Impairment: For mild-moderate impairment, initate with 5 mg. Further dose of 5 mg may be taken after an interval of at least 2 hr. Max: 10 mg/24 hr. Avoid in severe impairment.

Hepatic Impairment: For mild-moderate impairment, initate with 5 mg. Further dose of 5 mg may be taken after an interval of at least 2 hr. Max: 10 mg/24 hr. Avoid in severe impairment.

May cause hypertension and CV symptoms. Gastric lavage using activated charcoal may be considered. Monitor ECG and clinical status of the patient.

Store at 15-30° C.

Rizatriptan Benzoate is indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old.

5-HT Agonists

Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Rizatriptan Benzoate presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.

Dosing Information In Adults: The recommended starting dose of Rizatriptan Benzoate is either 5 mg or 10 mg for the acute treatment of migraines in adults. The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions.

Redosing In Adults: Although the effectiveness of a second dose or subsequent doses has not been established in placebocontrolled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose. The maximum daily dose should not exceed 30 mg in any 24-hour period. The safety of treating, on average, more than four headaches in a 30-day period has not been established.

Dosing Information In Pediatric Patients (Age 6 to 17 Years): Dosing in pediatric patients is based on the patient's body weight. The recommended dose of Rizatriptan Benzoate is 5 mg in patients weighing less than 40 kg, and 10 mg in patients weighing 40 kg or more.

The efficacy and safety of treatment with more than one dose of Rizatriptan Benzoate within 24 hours in pediatric patients 6 to 17 years of age have not been established.

Dosage Adjustment For Patients On Propranolol: Sections or subsections omitted from the full prescribing information are not listed.

• Adult Patients: In adult patients taking propranolol, only the 5-mg dose of Rizatriptan Benzoate is recommended, up to a maximum of 3 doses in any 24-hour period (15 mg)
• Pediatric Patients: For pediatric patients weighing 40 kg or more, taking propranolol, only a single 5-mg dose of Rizatriptan Benzoate is recommended (maximum dose of 5 mg in a 24-hour period). Rizatriptan Benzoate should not be prescribed to propranolol-treated pediatric patients who weigh less than 40 kg

Administration of Rizatriptan Benzoate Tablets, administration with liquid is not necessary. Orally disintegrating tablets are packaged in a blister within an outer aluminum pouch and patients should not remove the blister from the outer pouch until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina 
• Arrhythmias 
• Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure 
• Cerebrovascular Events 
• Other Vasospasm Reactions 
• Medication Overuse Headache 
• Serotonin Syndrome 
• Increase in Blood Pressure

Rizatriptan Benzoate is contraindicated in patients with:

• Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease
• Coronary artery vasospasm including Prinzmetal's angina
• History of stroke or transient ischemic attack (TIA) 
• Peripheral vascular disease (PVD) 
• Ischemic bowel disease 
• Uncontrolled hypertension 
• Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) 
• Hemiplegic or basilar migraine
• Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor
• Hypersensitivity to Rizatriptan Benzoate (angioedema and anaphylaxisseen)

Elderly; mild to moderate hepatic or renal impairment; coronary artery disease; pregnancy, lactation. May cause drowsiness. History of seizures. Ensure an interval of at least 24 hr after stopping an ergotamine compound and starting a serotonin (5-HT1) agonist.

Propranolol: The dose of Rizatriptan should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70% 

Ergot-Containing Drugs: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and Rizatriptan within 24 hours is contraindicated

Other 5-HT1 Agonists: Because their vasospastic effects may be additive, co-administration of Rizatriptan and other 5-HT1 agonists within 24 hours of each other is contraindicated 

SSRIs /SNRIs And Serotonin Syndrome: Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) 

Monoamine Oxidase Inhibitors: Rizatriptan is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors. A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite

Pregnancy: Inform patients that Rizatriptan Benzoate should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Rizatriptan Benzoate is administered to a nursing woman. Rizatriptan is extensively excreted in rat milk, with levels in milk at least 5-fold higher than levels in maternal plasma.

Pediatric Use: Safety and effectiveness in pediatric patients under 6 years of age have not been established. The efficacy and safety of Rizatriptan in the acute treatment of migraine in patients aged 6 to 17 years was established in an adequate and well-controlled study. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received Rizatriptan to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

Geriatric Use: Clinical studies of Rizatriptan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Although the pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range. This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving Rizatriptan

Renal Impairment: For mild-moderate impairment, initate with 5 mg. Further dose of 5 mg may be taken after an interval of at least 2 hr. Max: 10 mg/24 hr. Avoid in severe impairment.

Hepatic Impairment: For mild-moderate impairment, initate with 5 mg. Further dose of 5 mg may be taken after an interval of at least 2 hr. Max: 10 mg/24 hr. Avoid in severe impairment.

May cause hypertension and CV symptoms. Gastric lavage using activated charcoal may be considered. Monitor ECG and clinical status of the patient.

Store at 15-30° C.

Flunarizine is indicated for

• Prophylaxis of classic (with aura) or common (without aura) migraine
• Symptomatic treatment of vestibular vertigo (due to a diagnosed functional disorder of the vestibular system).
• Peripheral Vascular Disease (PVD)
• Motion sickness
• Refractory epilepsy resistant to conventional antiepileptic therapy.

Miscellaneous prophylactic migraine preparations

Flunarizine is the difluorinated derivative of cinnarizine. It is a selective calcium channel antagonist. By reducing excessive transmembrane influx of calcium Flunarizine prevents cellular calcium overload. It does not interfere with normal cellular calcium homeostasis. Flunarizine also has some antihistaminic and sedative properties. It binds at an affinity of 99% to plasma protein.

Migraine Prophylaxis:

• Starting Dose: 10 mg at night in patients less than 65 years of age and 5 mg daily in patients older than 65 years. If, during this treatment depressive, extrapyramidal or other unacceptable symptoms occur, administration should be discontinued. If, after 2 months of this initial treatment, no significant improvement is observed, the patient should be considered a non-responder and administration should be discontinued.
• Maintenance Treatment: If a patient is responding satisfactorily and if a maintenance treatment is needed, the dose should be decreased to 5 days treatment at the same daily dose with two successive medicine free days every week. Even if the prophylactic maintenance treatment is successful and well tolerated, it should be interrupted after 6 months and it should be re-initiated only if the patient relapses.

Peripheral Vascular disease: 10 mg twice daily, up to 30 mg per day if required.

Vertigo & motion sickness: 10-20 mg daily for adults and 5 mg daily for children (> 40 kg).

Epileptic seizure: 15-20 mg daily in adults and 5 to 10 mg daily for children as an add-on therapy

Drowsiness and/or fatigue, as well as weight gain and/or increased appetite may occur. The following adverse experiences have been reported during chronic treatment with Flunarizine: depression, of which female patients with a history of depressive illness may be particularly at risk; extrapyramidal symptoms (such as bradykinesia, rigidity, akathisia, orofacial dyskinesia, tremor), of which elderly patients seem particularly at risk. Infrequently reported adverse reaction are: heartburn; nausea; gastralgia; insomnia; anxiety; galactorrhoea; dry mouth; muscle ache; skin rash.

Hypersensitivity to Flunarizine. Flunarizine is contra-indicated in patients with a history of depressive illness, or with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders.

Flunarizine may lead to drowsiness which is aggravated by the simultaneous intake of alcohol or other central nervous system depressants. Patients should be cautioned against driving motor vehicles or performing other potentially hazardous tasks where a loss of mental alertness may lead to accidents. Flunarizine is not suited for aborting a migraine attack. The possible occurrence of an attack is therefore no reason to increase the dose of Flunarizine. This treatment may give rise to extrapyramidal and depressive symptoms and reveal Parkinsonism, especially in predisposed patients such as the elderly. Flunarizine should therefore be used with caution in such patients.

Galactorrhoea has been reported in few women on oral contraceptives within the first two months of Flunarizine treatment. Hepatic enzyme inducers such as Carbamazepine and Phenytoin may interact with flunarizine by increasing its metabolism. So an increase in dosage of flunarizine may be required.

Safety in pregnancy and lactation has not been established.

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

Flunarizine is indicated for

• Prophylaxis of classic (with aura) or common (without aura) migraine
• Symptomatic treatment of vestibular vertigo (due to a diagnosed functional disorder of the vestibular system).
• Peripheral Vascular Disease (PVD)
• Motion sickness
• Refractory epilepsy resistant to conventional antiepileptic therapy.

Miscellaneous prophylactic migraine preparations

Flunarizine is the difluorinated derivative of cinnarizine. It is a selective calcium channel antagonist. By reducing excessive transmembrane influx of calcium Flunarizine prevents cellular calcium overload. It does not interfere with normal cellular calcium homeostasis. Flunarizine also has some antihistaminic and sedative properties. It binds at an affinity of 99% to plasma protein.

Migraine Prophylaxis:

• Starting Dose: 10 mg at night in patients less than 65 years of age and 5 mg daily in patients older than 65 years. If, during this treatment depressive, extrapyramidal or other unacceptable symptoms occur, administration should be discontinued. If, after 2 months of this initial treatment, no significant improvement is observed, the patient should be considered a non-responder and administration should be discontinued.
• Maintenance Treatment: If a patient is responding satisfactorily and if a maintenance treatment is needed, the dose should be decreased to 5 days treatment at the same daily dose with two successive medicine free days every week. Even if the prophylactic maintenance treatment is successful and well tolerated, it should be interrupted after 6 months and it should be re-initiated only if the patient relapses.

Peripheral Vascular disease: 10 mg twice daily, up to 30 mg per day if required.

Vertigo & motion sickness: 10-20 mg daily for adults and 5 mg daily for children (> 40 kg).

Epileptic seizure: 15-20 mg daily in adults and 5 to 10 mg daily for children as an add-on therapy

Drowsiness and/or fatigue, as well as weight gain and/or increased appetite may occur. The following adverse experiences have been reported during chronic treatment with Flunarizine: depression, of which female patients with a history of depressive illness may be particularly at risk; extrapyramidal symptoms (such as bradykinesia, rigidity, akathisia, orofacial dyskinesia, tremor), of which elderly patients seem particularly at risk. Infrequently reported adverse reaction are: heartburn; nausea; gastralgia; insomnia; anxiety; galactorrhoea; dry mouth; muscle ache; skin rash.

Hypersensitivity to Flunarizine. Flunarizine is contra-indicated in patients with a history of depressive illness, or with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders.

Flunarizine may lead to drowsiness which is aggravated by the simultaneous intake of alcohol or other central nervous system depressants. Patients should be cautioned against driving motor vehicles or performing other potentially hazardous tasks where a loss of mental alertness may lead to accidents. Flunarizine is not suited for aborting a migraine attack. The possible occurrence of an attack is therefore no reason to increase the dose of Flunarizine. This treatment may give rise to extrapyramidal and depressive symptoms and reveal Parkinsonism, especially in predisposed patients such as the elderly. Flunarizine should therefore be used with caution in such patients.

Galactorrhoea has been reported in few women on oral contraceptives within the first two months of Flunarizine treatment. Hepatic enzyme inducers such as Carbamazepine and Phenytoin may interact with flunarizine by increasing its metabolism. So an increase in dosage of flunarizine may be required.

Safety in pregnancy and lactation has not been established.

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

It is indicated for the relief of symptoms associated with seasonal & perennial allergic rhinitis. It is also indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria and allergen induced asthma.

Sedating Anti-histamine

Cetirizine Hydrochloride is a potent H1 receptor antagonist without any significant anticholinergic and antiserotonic effects. At pharmacologically active dose levels, it has almost no drowsiness effect and does not cause behavioral changes. It inhibits the histamine-mediated early phase of the allergic reaction and also reduces the migration of inflammatory cells and the release of mediators associated with the late phase of the allergic reaction.

Pharmacokinetics: Cetirizine 10 mg achieves peak plasma concentrations of 257 mcg/L within one hour of administration (980 mcg/L in children). Food does not affect the extent of absorption, but it may slightly reduce the rate. Peak blood levels 0.3 micrograms/ml are reached between thirty & sixty minutes after administration of 10 mg dose of Cetirizine. Its plasma half-life is approximately 11 hours. Absorption is very consistent from one subject to the next. Its renal clearance is 30 ml/minute and the excretion half-life is approximately nine hours.

Adults and Children 6 years and older: 1 tablet or 2 teaspoonfuls daily (or 1 teaspoonful twice daily).

Children 2-6 years: 1 teaspoonful once daily or 1/2 teaspoonful twice daily.

Children 6 months to 2 years : 1/2 teaspoonful once daily. The dose in children 12-23 months of age can be increased to a maximum dose as 1/2 teaspoonful every 12 hours.

The most common side effects that occurred more frequently on Cetirizine is somnolence.

It is contraindicated in patients with a history of hypersensitivity to Cetirizine or hydroxyzine.

Caution should be exercised when driving a car or operating a heavy machinery.

No clinically significant drug interactions have been found with Theophylline, Azithromycin, Pseudoephedrine, Ketoconazole or Erythromycin and with other drugs.

US FDA Pregnancy Category of Cetirizine Hydrochloride is B. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Cetirizine Hydrochloride has been shown to be excreted in human milk. So, caution should be exercised when Cetirizine Hydrochloride is administered to a nursing woman.

Keep in a dry place away from light and heat. Keep out of the reach of children.

It is indicated for the relief of symptoms associated with seasonal & perennial allergic rhinitis. It is also indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria and allergen induced asthma.

Sedating Anti-histamine

Cetirizine Hydrochloride is a potent H1 receptor antagonist without any significant anticholinergic and antiserotonic effects. At pharmacologically active dose levels, it has almost no drowsiness effect and does not cause behavioral changes. It inhibits the histamine-mediated early phase of the allergic reaction and also reduces the migration of inflammatory cells and the release of mediators associated with the late phase of the allergic reaction.

Pharmacokinetics: Cetirizine 10 mg achieves peak plasma concentrations of 257 mcg/L within one hour of administration (980 mcg/L in children). Food does not affect the extent of absorption, but it may slightly reduce the rate. Peak blood levels 0.3 micrograms/ml are reached between thirty & sixty minutes after administration of 10 mg dose of Cetirizine. Its plasma half-life is approximately 11 hours. Absorption is very consistent from one subject to the next. Its renal clearance is 30 ml/minute and the excretion half-life is approximately nine hours.

Adults and Children 6 years and older: 1 tablet or 2 teaspoonfuls daily (or 1 teaspoonful twice daily).

Children 2-6 years: 1 teaspoonful once daily or 1/2 teaspoonful twice daily.

Children 6 months to 2 years : 1/2 teaspoonful once daily. The dose in children 12-23 months of age can be increased to a maximum dose as 1/2 teaspoonful every 12 hours.

The most common side effects that occurred more frequently on Cetirizine is somnolence.

It is contraindicated in patients with a history of hypersensitivity to Cetirizine or hydroxyzine.

Caution should be exercised when driving a car or operating a heavy machinery.

No clinically significant drug interactions have been found with Theophylline, Azithromycin, Pseudoephedrine, Ketoconazole or Erythromycin and with other drugs.

US FDA Pregnancy Category of Cetirizine Hydrochloride is B. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Cetirizine Hydrochloride has been shown to be excreted in human milk. So, caution should be exercised when Cetirizine Hydrochloride is administered to a nursing woman.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Crizotinib is a kinase inhibitor indicated for the treatment of patients with-

• Metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive
• Metastatic NSCLC whose tumors are ROS1-positive

Targeted Cancer Therapy

Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.

Recommended Dose: 250 mg orally, twice daily 

Geriatric Use: No differences in safety or efficacy were observed between older and younger patients. Clinical studies of Crizotinib in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients

Pediatric Dose: The safety and effectiveness of Crizotinib in pediatric patients have not been established.

Renal impairment: 250 mg orally, once daily in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild (ClCr 60-89 mL/min) or moderate (ClCr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis.

Hepatic Impairment: Caution should be used in patients with hepatic impairment

The most common adverse reactions (≥25%) are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Hepatotoxicity: Patients should undergo periodic liver testing. Crizotinib should be temporarily suspended, dose reduced or permanently suspended

Interstitial lung disease (ILD)/ Pneumonitis: Drug should be permanently discontinued in patients with ILD/ Pneumonitis

QT interval prolongation: Electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT should be monitored. Crizotinib should be temporarily suspended, dose reduced or permanently suspended

Bradycardia: Crizotinib can cause bradycardia. Heart rate and blood pressure should be regularly monitored. Crizotinib should be temporarily suspended, dose reduced or permanently suspended

Severe visual loss: Ophthalmological evaluation should be performed. Crizotinib should be discontinued in severe visual loss

Embryo-fetal toxicity: Crizotinib can cause fetal harm. Females of reproductive potential should be advised of the potential risk to a fetus and use of effective contraception

CYP3A Inhibitors: Concurrent use of Crizotinib should be avoided with strong CYP3A inhibitors including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole

CYP3A Inducers: Concurrent use of Crizotinib should be avoided with strong CYP3A inducers including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort 

CYP3A Substrates: Concurrent use of Crizotinib should be avoided with CYP3A substrates with narrow therapeutic indices including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus

Based on its mechanism of action, Crizotinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Crizotinib during pregnancy. Females of reproductive potential should be advised of the potential risk to a fetus and use of effective contraception.
There is no information regarding the presence of Crizotinib in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants patients should not breastfeed during treatment with Crizotinib and for 45 days after the final dose.

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

Proton Pump Inhibitor

Rabeprazole suppresses gastric acid secretion by inhibiting the gastric H⁺/K⁺-ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, Rabeprazole has been characterized as a gastric proton-pump inhibitor.

Active Duodenal Ulcer and Active Benign Gastric Ulcer: The recommended oral dose for both bioactive duodenal ulcer and active benign gastric ulcer is 20 mg to be taken once daily in the morning. Most patients with active duodenal ulcer heal within four weeks. However, a few patients may require an additional four weeks of therapy to achieve healing. Most patients with active benign gastric ulcer heal within six weeks. However, again a few patients may require an additional six weeks of therapy to achieve healing.

Erosive or Ulcerative Gastro-Esophageal Reflux Disease (GERD): The recommended oral dose for this condition is 20 mg to be taken once daily for four to eight weeks.

Gastro-Esophageal Reflux Disease Long-term Management (GERD Maintenance): For long-term management, a maintenance dose of rabeprazole sodium 20 mg or 10 mg once daily can be used depending upon patient response.

Symptomatic treatment of moderate to very severe Gastro-Esophageal Reflux Disease (symptomatic GERD): 10 mg once daily in patients without oesophagitis. If symptom control has not been achieved during four weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen taking 10 mg once daily when needed.

Treatment of GERD in pediatric patients 1 to 11 years of age (Less than 15 kg): 5 mg once daily for 12 weeks with the option to increase to 10 mg if inadequate response.

Treatment of GERD in pediatric patients 1 to 11 years of age (15 kg or more): 10 mg once daily for 12 weeks. 

Zollinger-Ellison Syndrome: The recommended adult starting dose is 60 mg once a day. The dose may be titrated upwards to 120 mg/day based on individual patient needs. Single daily doses up to 100 mg/day may be given. 120 mg dose may require divided doses, 60 mg twice daily. Treatment should continue for as long as clinically indicated.

Eradication of H. pylori: Patients with H. pylori infection should be treated with eradication therapy. The following combination given for 7 days is recommended. Rabeprazole sodium 20 mg twice daily, clarithromycin 500 mg twice daily and amoxicillin 1g twice daily.

For indications requiring once-daily treatment Rabeprazole tablets should be taken in the morning, before eating; and although neither the time of day nor food intake was shown to have any effect on rabeprazole sodium activity, this regimen will facilitate treatment compliance. Patients should be cautioned that the Rabeprazole tablets should not be chewed or crushed, but should be swallowed whole.

In general, Rabeprazole is well-tolerated in both short-term and long-term studies. Rabeprazole may sometimes cause headache, diarrhoea, abdominal pain, vomiting, constipation, dry mouth, increased or decreased appetite, muscle pain, drowsiness, dizziness.

Hypersensitivity to the active substance or to any of the excipients. Rabeprazole is contra-indicated in pregnancy and during breastfeeding.

• Symptomatic response to therapy with Rabeprazole does not preclude the presence of gastric or oesophageal malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with Rabeprazole 20 mg Gastro-resistant Tablets.
• Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.
• Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10–40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care and they should have an adequate intake of vitamin D and calcium.
• A risk of cross-hypersensitivity reactions with other proton pump inhibitor or substituted benzimidazoles cannot be excluded.
• Patients should be cautioned that Rabeprazole gastro-resistant tablets should not be chewed or crushed, but should be swallowed whole.
• There have been post marketing reports of blood dyscrasias (thrombocytopenia and neutropenia). In the majority of cases where an alternative aetiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.
• Hepatic enzyme abnormalities have been seen in clinical trials and have also been reported since market authorisation. In the majority of cases where an alternative aetiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.
• No evidence of significant drug related safety problems was seen in a study of patients with mild to moderate hepatic impairment versus normal age and sex matched controls. However because there are no clinical data on the use of rabeprazole in the treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with Rabeprazole 20mg Gastro-resistant. Tablets is first initiated in such patients.
• Co-administration of atazanavir with Rabeprazole is not recommended.
• Treatment with proton pump inhibitors, including rabeprazole, may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile.

Hypomagnesaemia: Severe hypomagnesaemia has been reported in patients treated with PPIs like rabeprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Influence on vitamin B12 absorption: Rabeprazole sodium, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or a- chlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.

Subacute cutaneous lupus erythematosus (SCLE): Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping Rabeprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Interference with laboratory tests: Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Rabeprazole 20mg Gastro-resistant Tablets treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

Respite produces a profound and long-lasting inhibition of gastric acid secretion. An interaction with a compound whose absorption is pH dependent may occur. Co-administration of rabeprazole sodium with ketoconazole or itraconazole may result in a significant decrease in antifungal plasma levels. Therefore individual patients may need to be monitored to determine if a dosage adjustment is necessary when ketoconazole or itraconazole are taken concomitantly with Respite. No interaction with liquid antacids was observed. The absorption of atazanavir is pH-dependent. Therefore PPIs, including rabeprazole, should not be co-administered with atazanavir.

US FDA pregnancy category 'C'. Studies have been performed in animals and have revealed no evidence of impaired fertility or harm to the fetus due to Rabeprazole. There are however, no adequate and well-controlled studies in pregnant women. Rabeprazole is likely to be excreted in human milk, 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.

Renal and hepatic impairment: No dosage adjustment is necessary for patients with renal or hepatic impairment.

Pediatric populations: Rabeprazole is not recommended for use in children due to a lack of data on safety and efficacy.

The maximum established exposure has not exceeded 60 mg twice daily, or 160 mg once daily. Effects are  generally minimal, representative of the known adverse event profile and reversible without further medical intervention. No specific antidote is known. Rabeprazole is extensively protein bound and is, therefore, not dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

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

Isotretinoin is indicated in severe forms of acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy.

Oral retinoids for Acne

Isotretinoin produces its effects through altering progress through the cell cycle, cell differentiation, survival, and apoptosis. These actions reduce sebum production, preventing the blockage of pores, and growth of acne causing bacteria. Isotretinoin and 4-oxo-isotretinoin both significantly reduce the production of sebum. Isotretinoin has little to no affinity for retinol binding proteins (RBPs) and retinoic acid nuclear receptors (RARs). Tretinoin and 4-oxo-tretinion bind to the RAR-γ receptor, which is suspected to be part of the action of acne treatment by isotretinoin. Isotretinoin induces apoptosis in sebocytes, leading to a decrease in sebum production. Isotretinoin also reduces the formation of comedones by reducing hyperkeratinization through an unknown mechanism. Isotretinoin does not directly kill bacteria but it does reduce the size of sebum ducts and makes the microenvironment less hospitable to acne causing bacteria. It may also increase immune mechanisms and alter chemotaxis of monocytes to reduce inflammation.

The capsules should be taken with food once or twice daily. Isotretinoin should only be prescribed by or under the supervision of physicians with expertise in the use of systemic retinoids for the treatment of severe acne and a full understanding of the risks of Isotretinoin therapy and monitoring requirements.

Adults including adolescents and the elderly: Isotretinoin therapy should be started at a dose of 0.5 mg/kg daily. The therapeutic response to Isotretinoin and some of the adverse effects are dose-related and vary between patients. This necessitates individual dosage adjustment during therapy. For most patients, the dose ranges from 0.5-1.0 mg/kg per day. Long-term remission and relapse rates are more closely related to the total dose administered than to either duration of treatment or daily dose. It has been shown that no substantial additional benefit is to be expected beyond a cumulative treatment dose of 120-150 mg/kg. The duration of treatment will depend on the individual daily dose. A treatment course of 16-24 weeks is normally sufficient to achieve remission. In the majority of patients, complete clearing of the acne is obtained with a single treatment course. In the event of a definite relapse a further course of Isotretinoin therapy may be considered using the same daily dose and cumulative treatment dose. As further improvement of the acne can be observed up to 8 weeks after discontinuation of treatment, a further course of treatment should not be considered until at least this period has elapsed.

Patients with severe renal insufficiency: In patients with severe renal insufficiency treatment should be started at a lower dose (e.g. 10 mg/day). The dose should then be increased up to 1 mg/kg/day or until the patient is receiving the maximum tolerated dose.

Children: Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended in patients less than 12 years of age due to a lack of data on efficacy and safety.

Patients with intolerance: In patients who show severe intolerance to the recommended dose, treatment may be continued at a lower dose with the consequences of a longer therapy duration and a higher risk of relapse. In order to achieve the maximum possible efficacy in these patients the dose should normally be continued at the highest tolerated dose.

Some of the side effects associated with the use of Isotretinoin are dose-related. The side effects are generally reversible after altering the dose or discontinuation of treatment, however some may persist after treatment has stopped. The following symptoms are the most commonly reported undesirable effects with Isotretinoin: dryness of the skin, dryness of the mucosae e.g. of the lips (cheilitis), the nasal mucosa (epistaxis) and the eyes (conjunctivitis).

The incidence of the adverse events was calculated from pooled clinical trial data involving 824 patients and from post-marketing data. Frequency categories are defined as Very common (³1/10), Common (³1/100 to <1/10), Uncommon (³1/1,000 to <1/100), Rare (³1/10,000 to <1/1,000), Very rare (³1/10,000 to <1/1,000) and not known (cannot be estimated from the available data. Infections: Very Rare: Gram positive (mucocutaneous) bacterial infection Blood and lymphatic system disorders: Very common: Anaemia, red blood cell sedimentation rate increased, thrombocytopenia, thrombocytosis; Common: Neutropenia; Very Rare: Lymphadenopathy Immune system disorders: Rare: Allergic skin reaction, anaphylactic reactions, hypersensitivity Metabolism and nutrition disorders: Very Rare: Diabetes mellitus, hyperuricaemia Psychiatric disorders: Rare: Depression, depression aggravated, aggressive tendencies, anxiety, mood alterations. Very Rare: Abnormal behaviour, psychotic disorder, suicidal ideation suicide attempt, suicide Nervous system disorders: Common: Headache; Very Rare: Benign intracranial hypertension, convulsions, drowsiness, dizziness Eye disorders: Very Common: Blepharitis, conjunctivitis, dry eye, eye irritation; Very Rare: Blurred vision, cataract, colour blindness (colour vision deficiencies), contact lens intolerance, corneal opacity, decreased night vision, keratitis, papilloedema (as sign of benign intracranial hypertension), photophobia, visual disturbances. Ear and labyrinth disorders: Very Rare: Hearing impaired Vascular disorders: Very Rare: Vasculitis (for example Wegener's granulomatosis, allergic vasculitis) Respiratory, thoracic and mediastinal disorders: Common: Epistaxis, nasal dryness, nasopharyngitis, Very Rare: Bronchospasm (particularly in patients with asthma), hoarseness Gastrointestinal disorders: Very Rare: Colitis, ileitis, dry throat, gastrointestinal haemorrhage, haemorrhagic diarrhoea and inflammatory bowel disease, nausea, pancreatitis Hepatobiliary disorders: Very Common: Transaminase increased; Very rare: Hepatitis Skin and subcutaneous tissues disorders: Very Common: Pruritus, rash erythematous, dermatitis, cheilitis, dry skin, localised exfoliation, skin fragility (risk of frictional trauma), Rare: Alopecia, Very Rare: Acne fulminans, acne aggravated (acne flare), erythema (facial), exanthema, hair disorders, hirsutism, nail dystrophy, paronychia, photosensitivity reaction, pyogenic granuloma, skin hyperpigmentation, sweating increased. Musculo-skeletal and connective tissue disorders: Very Common: Arthralgia, myalgia, back pain (particularly in children and adolescent patients), Very Rare: Arthritis, calcinosis (calcification of ligaments and tendons), epiphyses premature fusion, exostosis, (hyperostosis), reduced bone density, tendonitis. Renal and urinary disorders: Very Rare: Glomerulonephritis. General disorders and administration site conditions: Very Rare: Granulation tissue (increased formation of), malaise. Overdose Isotretinoin is a derivative of vitamin A. Although the acute toxicity of Isotretinoin is low, signs of hypervitaminosis A could appear in cases of accidental overdose. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Signs and symptoms of accidental or deliberate overdosage with Isotretinoin would probably be similar. These symptoms would be expected to be reversible and to subside without the need for treatment. Pharmaceutical precautions Store in a cool and dry place protected from light.

Isotretinoin is contraindicated in women who are pregnant or breastfeeding. Isotretinoin is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met. Isotretinoin is also contraindicated in patients with hypersensitivity to Isotretinoin or to any of the excipients. Isotretinoin is also contraindicated in patients with hepatic insufficiency, with excessively elevated blood lipid values, with hypervitaminosis A, receiving concomitant treatment with tetracyclines.

This medicinal product is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Programme are met: She has severe acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic anti-bacterials and topical therapy. She understands the teratogenic risk. She understands the need for rigorous follow-up, on a monthly basis. She understands and accepts the need for effective contraception, without interruption, 1 month before starting treatment, throughout the duration of treatment and 1 month after the end of treatment. At least one and preferably two complementary forms of contraception including a barrier method should be used. Even if she has amenorrhea she must follow all of the advice on effective contraception. She should be capable of complying with effective contraceptive measures. She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy. She understands the need and accepts to undergo pregnancy testing before, during and 5 weeks after the end of treatment. She has acknowledged that she has understood the hazards and necessary precautions associated with the use of Isotretinoin. These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy. The prescriber must ensure that the patient complies with the conditions for pregnancy prevention as listed above, including confirmation that she has an adequate level of understanding. The patient has acknowledged the aforementioned conditions. The patient has used at least one and preferably two methods of effective contraception including a barrier method for at least 1 month prior to starting treatment and is continuing to use effective contraception throughout the treatment period and for at least 1 month after cessation of treatment. Negative pregnancy test results have been obtained before, during and 5 weeks after the end of treatment. The dates and results of pregnancy tests should be documented.

Contraception: Female patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. As a minimum requirement, female patients at potential risk of pregnancy must use at least one effective method of contraception. Preferably the patient should use two complementary forms of contraception including a barrier method. Contraception should be continued for at least 1 month after stopping treatment with Isotretinoin, even in patients with amenorrhea.

Pregnancy testing: According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25mIU/mL are recommended to be performed in the first 3 days of the menstrual cycle, as follows.

Prior to starting therapy: In order to exclude the possibility of pregnancy prior to starting contraception, it is recommended that an initial medically supervised pregnancy test should be performed and its date and result recorded. In patients without regular menses, the timing of this pregnancy test should reflect the sexual activity of the patient and should be undertaken approximately 3 weeks after the patient last had unprotected sexual intercourse. The prescriber should educate the patient about contraception. A medically supervised pregnancy test should also be performed during the consultation when Isotretinoin is prescribed or in the 3 days prior to the visit to the prescriber, and should have been delayed until the patient had been using effective contraception for at least 1 month. This test should ensure the patient is not pregnant when she starts treatment with Isotretinoin.

Follow-up visits: Follow-up visits should be arranged at 28 day intervals. The need for repeated medically supervised pregnancy tests every month should be determined according to local practice including consideration of the patient’s sexual activity and recent menstrual history (abnormal menses, missed periods or amenorrhea). Where indicated, follow-up pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.

End of treatment: Five weeks after stopping treatment, women should undergo a final pregnancy test to exclude pregnancy.

Prescribing and dispensing restrictions: Prescriptions of Isotretinoin for women of childbearing potential should be limited to 30 days of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing of Isotretinoin should occur on the same day. Dispensing of Isotretinoin should occur within a maximum of 7 days of the prescription.

Male patients: The available data suggest that the level of maternal exposure from the semen of the patients receiving Isotretinoin, is not of a sufficient magnitude to be associated with the teratogenic effects of Isotretinoin. Male patients should be reminded that they must not share their medication with anyone, particularly not females.

Additional precautions: Patients should be instructed never to give this medicinal product to another person, and to return any unused capsules to their pharmacist at the end of treatment. Patients should not donate blood during therapy and for 1 month following discontinuation of Isotretinoin because of the potential risk to the foetus of a pregnant transfusion recipient.

Psychiatric disorders: Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with Isotretinoin. Particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression and referred for appropriate treatment if necessary. However, discontinuation of Isotretinoin may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.

Skin and subcutaneous tissues disorders: Acute exacerbation of acne is occasionally seen during the initial period but this subsides with continued treatment, usually within 7-10 days, and usually does not require dose adjustment. Exposure to intense sunlight or to UV rays should be avoided. Where necessary a sun-protection product with a high protection factor of at least SPF 15 should be used. Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in patients on Isotretinoin for a period of 5-6 months after the end of the treatment because of the risk of hypertrophic scarring in atypical areas and more rarely post inflammatory hyper or hypopigmentation in treated areas. Wax depilation should be avoided in patients on Isotretinoin for at least a period of 6 months after treatment because of the risk of epidermal stripping. Concurrent administration of Isotretinoin with topical keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase. Patients should be advised to use a skin moisturising ointment or cream and a lip balm from the start of treatment as Isotretinoin is likely to cause dryness of the skin and lips. There have been post-marketing reports of severe skin reactions (e.g. erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) associated with Isotretinoin use. As these events may be difficult to distinguish from other skin reactions that may occur, patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If a severe skin reaction is suspected, Isotretinoin treatment should be discontinued. Allergic reactions: Anaphylactic reactions have been rarely reported, in some cases after previous topical exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement have been reported. Severe allergic reactions necessitate interruption of therapy and careful monitoring.

Eye disorders: Dry eyes, corneal opacities, decreased night vision and keratitis usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment. Decreased night vision has also been reported and the onset in some patients was sudden. Withdrawal of Isotretinoin may be necessary.

Musculo-skeletal and connective tissue disorders: Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving Isotretinoin, particularly in those undertaking vigorous physical activity. Bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments have occurred after several years of administration at very high doses for treating disorders of keratinisation. The dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.

Benign intracranial hypertension: Cases of benign intracranial hypertension have been reported, some of which involved concomitant use of tetracyclines. Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop benign intracranial hypertension should discontinue Isotretinoin immediately.

Hepatobiliary disorders: Liver enzymes should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Transient and reversible increases in liver transaminases have been reported. In many cases these changes have been within the normal range and values have returned to baseline levels during treatment. However, in the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.

Renal insufficiency: Renal insufficiency and renal failure do not affect the pharmacokinetics of Isotretinoin. Therefore, Isotretinoin can be given to patients with renal insufficiency. However, it is recommended that patients are started on a low dose and titrated up to the maximum tolerated dose.

Lipid Metabolism: Serum lipids (fasting values) should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Elevated serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment and may also respond to dietary measures. Isotretinoin has been associated with an increase in plasma triglyceride levels. Isotretinoin should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Levels in excess of 800mg/dL or 9mmol/L are sometimes associated with acute pancreatitis, which may be fatal.

Gastrointestinal disorders: Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing severe (hemorrhagic) diarrhoea should discontinue Isotretinoin immediately.

High Risk Patients: In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing treatment with Isotretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary. Elevated fasting blood sugars have been reported, and new cases of diabetes have been diagnosed during Isotretinoin therapy.

Additive adverse effects with vit A or its derivatives. Decreased efficacy of microdosed progesterone (use 2 forms of contraception).Increased risk of local irritation with topical keratolytic or exfoliative anti-acne agents. Oxidising agents (e.g. benzoyl peroxide) may reduce the efficacy of topical isotretinoin.

Pregnancy is an absolute contraindication to treatment with Isotretinoin. If pregnancy does occur in spite of these precautions during treatment with Isotretinoin or in the month following, there is a great risk of very severe and serious malformation of the foetus. The foetal malformations associated with exposure to Isotretinoin include central nervous system abnormalities (hydrocephalus, cerebellar malformation/abnormalities, microcephaly), facial dysmorphia, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), eye abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great vessels, septal defects), thymus gland abnormality and parathyroid gland abnormalities. There is also an increased incidence of spontaneous abortion. If pregnancy occurs in a woman treated with Isotretinoin, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice. Isotretinoin is highly lipophilic, therefore the passage of Isotretinoin into human milk is very likely. Due to the potential for adverse effects in the child exposed via mothers’ milk, the use of Isotretinoin is contraindicated in nursing mothers.

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

Isotretinoin is indicated in severe forms of acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy.

Oral retinoids for Acne

Isotretinoin produces its effects through altering progress through the cell cycle, cell differentiation, survival, and apoptosis. These actions reduce sebum production, preventing the blockage of pores, and growth of acne causing bacteria. Isotretinoin and 4-oxo-isotretinoin both significantly reduce the production of sebum. Isotretinoin has little to no affinity for retinol binding proteins (RBPs) and retinoic acid nuclear receptors (RARs). Tretinoin and 4-oxo-tretinion bind to the RAR-γ receptor, which is suspected to be part of the action of acne treatment by isotretinoin. Isotretinoin induces apoptosis in sebocytes, leading to a decrease in sebum production. Isotretinoin also reduces the formation of comedones by reducing hyperkeratinization through an unknown mechanism. Isotretinoin does not directly kill bacteria but it does reduce the size of sebum ducts and makes the microenvironment less hospitable to acne causing bacteria. It may also increase immune mechanisms and alter chemotaxis of monocytes to reduce inflammation.

The capsules should be taken with food once or twice daily. Isotretinoin should only be prescribed by or under the supervision of physicians with expertise in the use of systemic retinoids for the treatment of severe acne and a full understanding of the risks of Isotretinoin therapy and monitoring requirements.

Adults including adolescents and the elderly: Isotretinoin therapy should be started at a dose of 0.5 mg/kg daily. The therapeutic response to Isotretinoin and some of the adverse effects are dose-related and vary between patients. This necessitates individual dosage adjustment during therapy. For most patients, the dose ranges from 0.5-1.0 mg/kg per day. Long-term remission and relapse rates are more closely related to the total dose administered than to either duration of treatment or daily dose. It has been shown that no substantial additional benefit is to be expected beyond a cumulative treatment dose of 120-150 mg/kg. The duration of treatment will depend on the individual daily dose. A treatment course of 16-24 weeks is normally sufficient to achieve remission. In the majority of patients, complete clearing of the acne is obtained with a single treatment course. In the event of a definite relapse a further course of Isotretinoin therapy may be considered using the same daily dose and cumulative treatment dose. As further improvement of the acne can be observed up to 8 weeks after discontinuation of treatment, a further course of treatment should not be considered until at least this period has elapsed.

Patients with severe renal insufficiency: In patients with severe renal insufficiency treatment should be started at a lower dose (e.g. 10 mg/day). The dose should then be increased up to 1 mg/kg/day or until the patient is receiving the maximum tolerated dose.

Children: Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended in patients less than 12 years of age due to a lack of data on efficacy and safety.

Patients with intolerance: In patients who show severe intolerance to the recommended dose, treatment may be continued at a lower dose with the consequences of a longer therapy duration and a higher risk of relapse. In order to achieve the maximum possible efficacy in these patients the dose should normally be continued at the highest tolerated dose.

Some of the side effects associated with the use of Isotretinoin are dose-related. The side effects are generally reversible after altering the dose or discontinuation of treatment, however some may persist after treatment has stopped. The following symptoms are the most commonly reported undesirable effects with Isotretinoin: dryness of the skin, dryness of the mucosae e.g. of the lips (cheilitis), the nasal mucosa (epistaxis) and the eyes (conjunctivitis).

The incidence of the adverse events was calculated from pooled clinical trial data involving 824 patients and from post-marketing data. Frequency categories are defined as Very common (³1/10), Common (³1/100 to <1/10), Uncommon (³1/1,000 to <1/100), Rare (³1/10,000 to <1/1,000), Very rare (³1/10,000 to <1/1,000) and not known (cannot be estimated from the available data. Infections: Very Rare: Gram positive (mucocutaneous) bacterial infection Blood and lymphatic system disorders: Very common: Anaemia, red blood cell sedimentation rate increased, thrombocytopenia, thrombocytosis; Common: Neutropenia; Very Rare: Lymphadenopathy Immune system disorders: Rare: Allergic skin reaction, anaphylactic reactions, hypersensitivity Metabolism and nutrition disorders: Very Rare: Diabetes mellitus, hyperuricaemia Psychiatric disorders: Rare: Depression, depression aggravated, aggressive tendencies, anxiety, mood alterations. Very Rare: Abnormal behaviour, psychotic disorder, suicidal ideation suicide attempt, suicide Nervous system disorders: Common: Headache; Very Rare: Benign intracranial hypertension, convulsions, drowsiness, dizziness Eye disorders: Very Common: Blepharitis, conjunctivitis, dry eye, eye irritation; Very Rare: Blurred vision, cataract, colour blindness (colour vision deficiencies), contact lens intolerance, corneal opacity, decreased night vision, keratitis, papilloedema (as sign of benign intracranial hypertension), photophobia, visual disturbances. Ear and labyrinth disorders: Very Rare: Hearing impaired Vascular disorders: Very Rare: Vasculitis (for example Wegener's granulomatosis, allergic vasculitis) Respiratory, thoracic and mediastinal disorders: Common: Epistaxis, nasal dryness, nasopharyngitis, Very Rare: Bronchospasm (particularly in patients with asthma), hoarseness Gastrointestinal disorders: Very Rare: Colitis, ileitis, dry throat, gastrointestinal haemorrhage, haemorrhagic diarrhoea and inflammatory bowel disease, nausea, pancreatitis Hepatobiliary disorders: Very Common: Transaminase increased; Very rare: Hepatitis Skin and subcutaneous tissues disorders: Very Common: Pruritus, rash erythematous, dermatitis, cheilitis, dry skin, localised exfoliation, skin fragility (risk of frictional trauma), Rare: Alopecia, Very Rare: Acne fulminans, acne aggravated (acne flare), erythema (facial), exanthema, hair disorders, hirsutism, nail dystrophy, paronychia, photosensitivity reaction, pyogenic granuloma, skin hyperpigmentation, sweating increased. Musculo-skeletal and connective tissue disorders: Very Common: Arthralgia, myalgia, back pain (particularly in children and adolescent patients), Very Rare: Arthritis, calcinosis (calcification of ligaments and tendons), epiphyses premature fusion, exostosis, (hyperostosis), reduced bone density, tendonitis. Renal and urinary disorders: Very Rare: Glomerulonephritis. General disorders and administration site conditions: Very Rare: Granulation tissue (increased formation of), malaise. Overdose Isotretinoin is a derivative of vitamin A. Although the acute toxicity of Isotretinoin is low, signs of hypervitaminosis A could appear in cases of accidental overdose. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Signs and symptoms of accidental or deliberate overdosage with Isotretinoin would probably be similar. These symptoms would be expected to be reversible and to subside without the need for treatment. Pharmaceutical precautions Store in a cool and dry place protected from light.

Isotretinoin is contraindicated in women who are pregnant or breastfeeding. Isotretinoin is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met. Isotretinoin is also contraindicated in patients with hypersensitivity to Isotretinoin or to any of the excipients. Isotretinoin is also contraindicated in patients with hepatic insufficiency, with excessively elevated blood lipid values, with hypervitaminosis A, receiving concomitant treatment with tetracyclines.

This medicinal product is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Programme are met: She has severe acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic anti-bacterials and topical therapy. She understands the teratogenic risk. She understands the need for rigorous follow-up, on a monthly basis. She understands and accepts the need for effective contraception, without interruption, 1 month before starting treatment, throughout the duration of treatment and 1 month after the end of treatment. At least one and preferably two complementary forms of contraception including a barrier method should be used. Even if she has amenorrhea she must follow all of the advice on effective contraception. She should be capable of complying with effective contraceptive measures. She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy. She understands the need and accepts to undergo pregnancy testing before, during and 5 weeks after the end of treatment. She has acknowledged that she has understood the hazards and necessary precautions associated with the use of Isotretinoin. These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy. The prescriber must ensure that the patient complies with the conditions for pregnancy prevention as listed above, including confirmation that she has an adequate level of understanding. The patient has acknowledged the aforementioned conditions. The patient has used at least one and preferably two methods of effective contraception including a barrier method for at least 1 month prior to starting treatment and is continuing to use effective contraception throughout the treatment period and for at least 1 month after cessation of treatment. Negative pregnancy test results have been obtained before, during and 5 weeks after the end of treatment. The dates and results of pregnancy tests should be documented.

Contraception: Female patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. As a minimum requirement, female patients at potential risk of pregnancy must use at least one effective method of contraception. Preferably the patient should use two complementary forms of contraception including a barrier method. Contraception should be continued for at least 1 month after stopping treatment with Isotretinoin, even in patients with amenorrhea.

Pregnancy testing: According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25mIU/mL are recommended to be performed in the first 3 days of the menstrual cycle, as follows.

Prior to starting therapy: In order to exclude the possibility of pregnancy prior to starting contraception, it is recommended that an initial medically supervised pregnancy test should be performed and its date and result recorded. In patients without regular menses, the timing of this pregnancy test should reflect the sexual activity of the patient and should be undertaken approximately 3 weeks after the patient last had unprotected sexual intercourse. The prescriber should educate the patient about contraception. A medically supervised pregnancy test should also be performed during the consultation when Isotretinoin is prescribed or in the 3 days prior to the visit to the prescriber, and should have been delayed until the patient had been using effective contraception for at least 1 month. This test should ensure the patient is not pregnant when she starts treatment with Isotretinoin.

Follow-up visits: Follow-up visits should be arranged at 28 day intervals. The need for repeated medically supervised pregnancy tests every month should be determined according to local practice including consideration of the patient’s sexual activity and recent menstrual history (abnormal menses, missed periods or amenorrhea). Where indicated, follow-up pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.

End of treatment: Five weeks after stopping treatment, women should undergo a final pregnancy test to exclude pregnancy.

Prescribing and dispensing restrictions: Prescriptions of Isotretinoin for women of childbearing potential should be limited to 30 days of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing of Isotretinoin should occur on the same day. Dispensing of Isotretinoin should occur within a maximum of 7 days of the prescription.

Male patients: The available data suggest that the level of maternal exposure from the semen of the patients receiving Isotretinoin, is not of a sufficient magnitude to be associated with the teratogenic effects of Isotretinoin. Male patients should be reminded that they must not share their medication with anyone, particularly not females.

Additional precautions: Patients should be instructed never to give this medicinal product to another person, and to return any unused capsules to their pharmacist at the end of treatment. Patients should not donate blood during therapy and for 1 month following discontinuation of Isotretinoin because of the potential risk to the foetus of a pregnant transfusion recipient.

Psychiatric disorders: Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with Isotretinoin. Particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression and referred for appropriate treatment if necessary. However, discontinuation of Isotretinoin may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.

Skin and subcutaneous tissues disorders: Acute exacerbation of acne is occasionally seen during the initial period but this subsides with continued treatment, usually within 7-10 days, and usually does not require dose adjustment. Exposure to intense sunlight or to UV rays should be avoided. Where necessary a sun-protection product with a high protection factor of at least SPF 15 should be used. Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in patients on Isotretinoin for a period of 5-6 months after the end of the treatment because of the risk of hypertrophic scarring in atypical areas and more rarely post inflammatory hyper or hypopigmentation in treated areas. Wax depilation should be avoided in patients on Isotretinoin for at least a period of 6 months after treatment because of the risk of epidermal stripping. Concurrent administration of Isotretinoin with topical keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase. Patients should be advised to use a skin moisturising ointment or cream and a lip balm from the start of treatment as Isotretinoin is likely to cause dryness of the skin and lips. There have been post-marketing reports of severe skin reactions (e.g. erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) associated with Isotretinoin use. As these events may be difficult to distinguish from other skin reactions that may occur, patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If a severe skin reaction is suspected, Isotretinoin treatment should be discontinued. Allergic reactions: Anaphylactic reactions have been rarely reported, in some cases after previous topical exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement have been reported. Severe allergic reactions necessitate interruption of therapy and careful monitoring.

Eye disorders: Dry eyes, corneal opacities, decreased night vision and keratitis usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment. Decreased night vision has also been reported and the onset in some patients was sudden. Withdrawal of Isotretinoin may be necessary.

Musculo-skeletal and connective tissue disorders: Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving Isotretinoin, particularly in those undertaking vigorous physical activity. Bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments have occurred after several years of administration at very high doses for treating disorders of keratinisation. The dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.

Benign intracranial hypertension: Cases of benign intracranial hypertension have been reported, some of which involved concomitant use of tetracyclines. Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop benign intracranial hypertension should discontinue Isotretinoin immediately.

Hepatobiliary disorders: Liver enzymes should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Transient and reversible increases in liver transaminases have been reported. In many cases these changes have been within the normal range and values have returned to baseline levels during treatment. However, in the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.

Renal insufficiency: Renal insufficiency and renal failure do not affect the pharmacokinetics of Isotretinoin. Therefore, Isotretinoin can be given to patients with renal insufficiency. However, it is recommended that patients are started on a low dose and titrated up to the maximum tolerated dose.

Lipid Metabolism: Serum lipids (fasting values) should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Elevated serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment and may also respond to dietary measures. Isotretinoin has been associated with an increase in plasma triglyceride levels. Isotretinoin should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Levels in excess of 800mg/dL or 9mmol/L are sometimes associated with acute pancreatitis, which may be fatal.

Gastrointestinal disorders: Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing severe (hemorrhagic) diarrhoea should discontinue Isotretinoin immediately.

High Risk Patients: In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing treatment with Isotretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary. Elevated fasting blood sugars have been reported, and new cases of diabetes have been diagnosed during Isotretinoin therapy.

Additive adverse effects with vit A or its derivatives. Decreased efficacy of microdosed progesterone (use 2 forms of contraception).Increased risk of local irritation with topical keratolytic or exfoliative anti-acne agents. Oxidising agents (e.g. benzoyl peroxide) may reduce the efficacy of topical isotretinoin.

Pregnancy is an absolute contraindication to treatment with Isotretinoin. If pregnancy does occur in spite of these precautions during treatment with Isotretinoin or in the month following, there is a great risk of very severe and serious malformation of the foetus. The foetal malformations associated with exposure to Isotretinoin include central nervous system abnormalities (hydrocephalus, cerebellar malformation/abnormalities, microcephaly), facial dysmorphia, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), eye abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great vessels, septal defects), thymus gland abnormality and parathyroid gland abnormalities. There is also an increased incidence of spontaneous abortion. If pregnancy occurs in a woman treated with Isotretinoin, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice. Isotretinoin is highly lipophilic, therefore the passage of Isotretinoin into human milk is very likely. Due to the potential for adverse effects in the child exposed via mothers’ milk, the use of Isotretinoin is contraindicated in nursing mothers.

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

Dicycloverine is indicated in:

• Functional bowel/irritable bowel syndrome
• Urinary incontinence secondary to unstable detrusor muscle
• Infantile colic
• GIT spasm
• Colicky abdominal pain
• Diverticulitis
• Abdominal colic

Anticholinergics (antimuscarinics)/ Anti-spasmodics

Dicycloverine hydrochloride is an antispasmodic and anticholinergic (antimuscarinic) agent. Chemically, it is [Bicyclohexyl-]1-carboxylic acid, 2-(diethylammo) ethyl ester, hydrochloride. Dicycloverine relieves smooth muscle spasm of the gastrointestinal tract. Dicycloverine HCl Injection is a sterile, pyrogen-free, aqueous solution for intramuscular injection (Not For Intravenous Use). It works at specific receptors, called cholinergic (or muscarinic) receptors, located on the involuntary muscle in the walls of the gut. By binding to these receptors dicycloverine prevents certain chemicals produced by the body from interacting with these receptors. This causes the gut muscle to relax, relieving the pain of colic produced by gut muscle contraction and spasm.

For oral dosage forms:

• Adults:10 to 20 mg three times a day.
• Children over 6 months of age: 5 to 10 mg three times a day.

For injectable dosage form:

• Adults: Intramuscular injection. Not for intravenous use. The recommended intramuscular dose is 80 mg daily (in 4 equally divided doses).

Oral dicycloverine Hydrochloride should be started as soon as possible and the intramuscular form should not be used for periods longer than 1 or 2 days.

Children: Dose must be determined by the doctor.

Insomnia, mydriasis, cycloplegia, increased ocular tension, urinary hesitancy, palpitations, dyspnea.

Use with caution in patients with autonomic neuropathy, hepatic or renal disease, ulcerative colitis, coronary heart disease, congestive heart failure, cardiac tachyarrhythmia, hiatal hernia, known or suspected prostatic hypertrophy.

Pregnancy Category B. Dicycloverine was neither teratogenic nor embryocidal in animal trial. It, like other drugs should be used during pregnancy only if clearly needed. There are no data on the secretion of this drug into breast milk. Dicycloverine should be used cautiously in case of lactating mother.

Toxic reaction seldom occurs with dicycloverine. The signs and symptoms of overdosage are headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation.

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

Dicycloverine is indicated in:

• Functional bowel/irritable bowel syndrome
• Urinary incontinence secondary to unstable detrusor muscle
• Infantile colic
• GIT spasm
• Colicky abdominal pain
• Diverticulitis
• Abdominal colic

Anticholinergics (antimuscarinics)/ Anti-spasmodics

Dicycloverine hydrochloride is an antispasmodic and anticholinergic (antimuscarinic) agent. Chemically, it is [Bicyclohexyl-]1-carboxylic acid, 2-(diethylammo) ethyl ester, hydrochloride. Dicycloverine relieves smooth muscle spasm of the gastrointestinal tract. Dicycloverine HCl Injection is a sterile, pyrogen-free, aqueous solution for intramuscular injection (Not For Intravenous Use). It works at specific receptors, called cholinergic (or muscarinic) receptors, located on the involuntary muscle in the walls of the gut. By binding to these receptors dicycloverine prevents certain chemicals produced by the body from interacting with these receptors. This causes the gut muscle to relax, relieving the pain of colic produced by gut muscle contraction and spasm.

For oral dosage forms:

• Adults:10 to 20 mg three times a day.
• Children over 6 months of age: 5 to 10 mg three times a day.

For injectable dosage form:

• Adults: Intramuscular injection. Not for intravenous use. The recommended intramuscular dose is 80 mg daily (in 4 equally divided doses).

Oral dicycloverine Hydrochloride should be started as soon as possible and the intramuscular form should not be used for periods longer than 1 or 2 days.

Children: Dose must be determined by the doctor.

Insomnia, mydriasis, cycloplegia, increased ocular tension, urinary hesitancy, palpitations, dyspnea.

Use with caution in patients with autonomic neuropathy, hepatic or renal disease, ulcerative colitis, coronary heart disease, congestive heart failure, cardiac tachyarrhythmia, hiatal hernia, known or suspected prostatic hypertrophy.

Pregnancy Category B. Dicycloverine was neither teratogenic nor embryocidal in animal trial. It, like other drugs should be used during pregnancy only if clearly needed. There are no data on the secretion of this drug into breast milk. Dicycloverine should be used cautiously in case of lactating mother.

Toxic reaction seldom occurs with dicycloverine. The signs and symptoms of overdosage are headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation.

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

Ornidazole is indicated for Amoebiasis (Intestinal and hepatic), Giardiasis, Trichomoniasis, Bacterial vaginosis, Treatment of susceptible anaerobic infections

Amoebicides, Anti-diarrhoeal Antiprotozoal

Ornidazole is a 5-nitroimidazole derivative active against protozoa and anaerobic bacteria. It is converted to reduction products that interact with DNA to cause destruction of helical DNA structure and strand leading to a protein synthesis inhibition and cell death in susceptible organisms.

Amoebiasis:

• Adults: 500 mg twice a day for 5 days.
• Children: 10-25 mg per kg body weight in two divided doses.

Amoebic dysentery:

• Adults: 1.5 gm once a day for 3 days.
• Children: 40 mg per kg body weight, once a day for 3 days.

Giardiasis:

• Adults: 1.5 gm once daily for 1-2 days.
• Children: 40 mg per kg body weight for 2 days.

Trichomoniasis: 1.5 gm once or 500 mg twice a day for 5 days. Sexual partner should also be treated at the same time.

Bacterial vaginosis: 3 tablets of 500 mg each as a single dose or one tablet of 500 mg once daily for 5-7 days.

Side effects of Ornidazole have been mainly limited to the gastrointestinal tract (nausea, vomiting, epigastric pain) and central nervous system (dizziness, headache, lassitude). Unlike other nitroimidazoles, Ornidazole does not interact with alcohol, although this requires further study.

Leukopenia has been described occasionally during therapy. Adverse central nervous system (CNS) effects of Ornidazole have mainly included headache, dizziness, lassitude or somnolence, fatigue and weakness. Adverse CNS effects of Ornidazole may be less than that happens with metronidazole. Seizures have not been reported with Ornidazole in studies available to date.

Previous hypersensitivity to Ornidazole and to other nitroimidazoles. Ornidazole is contraindicated in central nervous system disorders, particularly in epilepsy or in peripheral neuropathy.

In patient with ataxia, vertigo, and mental confusion, Ornidazole should be prescribed with caution. During prolonged treatment with Ornidazole, blood dyscrasia namely mild leukopenia have been reported rarely. In case leukopenia occurs, the decision to discontinue the therapy should depend upon the gravity of infection.

Like other imidazoles, Ornidazole has a mild potential to cause disulfiramlike reactions. Concomitant administration of oral anticoagulants may increase the risk of haemorrhage due to diminished hepatic metabolism. Ornidazole has been reported to decrease the clearance of 5-fluorouracil.

Adequate clinical trials have not been conducted. Ornidazole should be prescribed only if the potential benefit justifies the potential risk to fetus/neonate.

Renal Impairment Haemodialysis patients: Give a supplemental dose (50% of the usual dose) before dialysis.

Hepatic Impairment Severe: Double the interval between doses.

Store at room temperature and protect from light and moisture.

Proton Pump Inhibitor

Rabeprazole suppresses gastric acid secretion by inhibiting the gastric H⁺/K⁺-ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, Rabeprazole has been characterized as a gastric proton-pump inhibitor.

Active Duodenal Ulcer and Active Benign Gastric Ulcer: The recommended oral dose for both bioactive duodenal ulcer and active benign gastric ulcer is 20 mg to be taken once daily in the morning. Most patients with active duodenal ulcer heal within four weeks. However, a few patients may require an additional four weeks of therapy to achieve healing. Most patients with active benign gastric ulcer heal within six weeks. However, again a few patients may require an additional six weeks of therapy to achieve healing.

Erosive or Ulcerative Gastro-Esophageal Reflux Disease (GERD): The recommended oral dose for this condition is 20 mg to be taken once daily for four to eight weeks.

Gastro-Esophageal Reflux Disease Long-term Management (GERD Maintenance): For long-term management, a maintenance dose of rabeprazole sodium 20 mg or 10 mg once daily can be used depending upon patient response.

Symptomatic treatment of moderate to very severe Gastro-Esophageal Reflux Disease (symptomatic GERD): 10 mg once daily in patients without oesophagitis. If symptom control has not been achieved during four weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen taking 10 mg once daily when needed.

Treatment of GERD in pediatric patients 1 to 11 years of age (Less than 15 kg): 5 mg once daily for 12 weeks with the option to increase to 10 mg if inadequate response.

Treatment of GERD in pediatric patients 1 to 11 years of age (15 kg or more): 10 mg once daily for 12 weeks. 

Zollinger-Ellison Syndrome: The recommended adult starting dose is 60 mg once a day. The dose may be titrated upwards to 120 mg/day based on individual patient needs. Single daily doses up to 100 mg/day may be given. 120 mg dose may require divided doses, 60 mg twice daily. Treatment should continue for as long as clinically indicated.

Eradication of H. pylori: Patients with H. pylori infection should be treated with eradication therapy. The following combination given for 7 days is recommended. Rabeprazole sodium 20 mg twice daily, clarithromycin 500 mg twice daily and amoxicillin 1g twice daily.

For indications requiring once-daily treatment Rabeprazole tablets should be taken in the morning, before eating; and although neither the time of day nor food intake was shown to have any effect on rabeprazole sodium activity, this regimen will facilitate treatment compliance. Patients should be cautioned that the Rabeprazole tablets should not be chewed or crushed, but should be swallowed whole.

In general, Rabeprazole is well-tolerated in both short-term and long-term studies. Rabeprazole may sometimes cause headache, diarrhoea, abdominal pain, vomiting, constipation, dry mouth, increased or decreased appetite, muscle pain, drowsiness, dizziness.

Hypersensitivity to the active substance or to any of the excipients. Rabeprazole is contra-indicated in pregnancy and during breastfeeding.

• Symptomatic response to therapy with Rabeprazole does not preclude the presence of gastric or oesophageal malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with Rabeprazole 20 mg Gastro-resistant Tablets.
• Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.
• Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10–40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care and they should have an adequate intake of vitamin D and calcium.
• A risk of cross-hypersensitivity reactions with other proton pump inhibitor or substituted benzimidazoles cannot be excluded.
• Patients should be cautioned that Rabeprazole gastro-resistant tablets should not be chewed or crushed, but should be swallowed whole.
• There have been post marketing reports of blood dyscrasias (thrombocytopenia and neutropenia). In the majority of cases where an alternative aetiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.
• Hepatic enzyme abnormalities have been seen in clinical trials and have also been reported since market authorisation. In the majority of cases where an alternative aetiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.
• No evidence of significant drug related safety problems was seen in a study of patients with mild to moderate hepatic impairment versus normal age and sex matched controls. However because there are no clinical data on the use of rabeprazole in the treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with Rabeprazole 20mg Gastro-resistant. Tablets is first initiated in such patients.
• Co-administration of atazanavir with Rabeprazole is not recommended.
• Treatment with proton pump inhibitors, including rabeprazole, may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile.

Hypomagnesaemia: Severe hypomagnesaemia has been reported in patients treated with PPIs like rabeprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Influence on vitamin B12 absorption: Rabeprazole sodium, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or a- chlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.

Subacute cutaneous lupus erythematosus (SCLE): Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping Rabeprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Interference with laboratory tests: Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Rabeprazole 20mg Gastro-resistant Tablets treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

Respite produces a profound and long-lasting inhibition of gastric acid secretion. An interaction with a compound whose absorption is pH dependent may occur. Co-administration of rabeprazole sodium with ketoconazole or itraconazole may result in a significant decrease in antifungal plasma levels. Therefore individual patients may need to be monitored to determine if a dosage adjustment is necessary when ketoconazole or itraconazole are taken concomitantly with Respite. No interaction with liquid antacids was observed. The absorption of atazanavir is pH-dependent. Therefore PPIs, including rabeprazole, should not be co-administered with atazanavir.

US FDA pregnancy category 'C'. Studies have been performed in animals and have revealed no evidence of impaired fertility or harm to the fetus due to Rabeprazole. There are however, no adequate and well-controlled studies in pregnant women. Rabeprazole is likely to be excreted in human milk, 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.

Renal and hepatic impairment: No dosage adjustment is necessary for patients with renal or hepatic impairment.

Pediatric populations: Rabeprazole is not recommended for use in children due to a lack of data on safety and efficacy.

The maximum established exposure has not exceeded 60 mg twice daily, or 160 mg once daily. Effects are  generally minimal, representative of the known adverse event profile and reversible without further medical intervention. No specific antidote is known. Rabeprazole is extensively protein bound and is, therefore, not dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

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

Minerals in bone formation, Specific mineral preparations

Calcium carbonate reacts with gastric acid to produce a salt and water. For calcium carbonate the postulated chemical reaction is: CaCO₃+2HCl = CaCl₂+H₂O+CO₂. Two grams of calcium carbonate will readily bring 100 ml of hydrochloric acid to a pH above 6. The increase in gastric pH diminishes the activity of pepsin in the gastric secretion. Up to 30% of the oral calcium load may be absorbed.

250 mg or 500 mg tablet: Calcium Carbonate is always used orally and when used as an antacid the recommended doses for adults are equivalent to 540-2000 mg Calcium Carbonate per day, doses for children being half of those for adults. As a dietary supplement, such as for the prevention of osteoporosis, 1250-3750 mg Calcium Carbonate (500-1500 mg calcium) daily is recommended in general, but again this will need to be tailored to the individual patient depending on any specific disease such as Calcium deficiency, malabsorption or parathyroid function. In pregnancy and lactation the recommended daily dose of calcium is 1200-1500 mg. In chronic renal failure the doses used vary from 2.5-9.0 gm Calcium Carbonate per day and need to be adjusted according to the individual patient. To maximize effective phosphate binding in this context the Calcium Carbonate should be given with meals.

1000 mg tablet: 2000-3000 mg tablet when symptoms occur; may be repeated hourly if needed or as directed by the physician.

Orally administered Calcium Carbonate may be irritating to the GI tract. It may also cause constipation. Hypercalcaemia is rarely produced by administration of calcium alone, but may occur when large doses are given to patients with chronic renal failure.

• Hypercalcaemia and hyperparathyroidism
• Hypercalciuria and nephrolithiasis
• Zollinger-Ellison syndrome
• Concomitant digoxin therapy (requires careful monitoring of serum calcium level)

When hypercalcaemia occurs, discontinuation of the drug is usually sufficient to return serum calcium concentrations to normal. Calcium salts should be used cautiously in patients with sarcoidosis, renal or cardiac disease, and in patients receiving cardiac glycosides.

Calcium Carbonate may enhance the cardiac effects of digoxin and other cardiac glycosides, if systemic hypercalcaemia occurs. Calcium Carbonate may interfere with the absorption of concomitantly administered tetracycline preparations and in chronic renal failure modification of vitamin D therapy may be required to avoid hypercalcaemia when Calcium Carbonate is used as the primary phosphate binder.

Calcium containing drugs have been widely used in pregnancy by way of oral calcium supplementation or antacid therapy. Calcium Carbonate can be used in lactating women too.

Use in children: Calcium carbonate has been extensively studied in children and infants with chronic renal failure and is both safe and effective.

Use in elderly: In case of elderly patients with renal failure when calcium carbonate is taken constipation may be troublesome one for this group. For this reason, monitoring of serum calcium and phosphate is of course indicated for elderly patients.

Store in a cool, dry place in controlled room temperature.