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Eszopiclone is indicated for the treatment of insomnia, including difficulty falling asleep and difficulty maintaining sleep through the night. Eszopiclone is the first sedative approved long-term use

Miscellaneous sedatives & hypnotics

Eszopiclone may interact with Gama-aminobutyric acid (GABA) receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors.

The usual dose to improve or maintain sleep in most adults is 2 or 3 mg. Persons over the age of 65 years usually are treated with 1 or 2 mg. Eszopiclone should be taken immediately before going to bed since the onset of sedation may occur as rapidly as 10 minutes. It should be taken only by individuals who intend to sleep for at least 8 hours since its effects may last up to six hours.

Eszopiclone is generally well tolerated. However few side effects like fatigue, anorexia, nausea, unpleasant taste in the mouth, mood problems, abdominal pain, dyspepsia, asthenia, nervousness, dizziness and confusion have been reported.

Depression, Severe Chronic Obstructive Lung Disease, Severe Liver Disease, Weakened Patient, Having thoughts of Suicide.

Eszopiclone like all sedatives should be taken immediately before bedtime to avoid short-term memory impairment, hallucinations, impaired coordination, dizziness and lightheadedness

Alcohol (which causes sedation) and drugs that have sedating effects should not be used with Eszopiclone since their sedating effects, when added to those of Eszopiclone, may cause excessive sedation.

Pregnancy: Category C. There is no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

Nursing Mothers: It is not known whether the drug is excreted in breast milk. As many drugs are excreted in breast milk, caution should be exercised when Eszopiclone is administered to a nursing mother.

There is limited clinical experience with the overdose of Eszopiclone. In clinical trials one case of overdose with up to 36 mg of Eszopiclone has been reported in which the subject fully recovered. Intravenous fluids should be administered as needed & Flumazenil may be useful.

Store at 25°C.

Eszopiclone is indicated for the treatment of insomnia, including difficulty falling asleep and difficulty maintaining sleep through the night. Eszopiclone is the first sedative approved long-term use

Miscellaneous sedatives & hypnotics

Eszopiclone may interact with Gama-aminobutyric acid (GABA) receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors.

The usual dose to improve or maintain sleep in most adults is 2 or 3 mg. Persons over the age of 65 years usually are treated with 1 or 2 mg. Eszopiclone should be taken immediately before going to bed since the onset of sedation may occur as rapidly as 10 minutes. It should be taken only by individuals who intend to sleep for at least 8 hours since its effects may last up to six hours.

Eszopiclone is generally well tolerated. However few side effects like fatigue, anorexia, nausea, unpleasant taste in the mouth, mood problems, abdominal pain, dyspepsia, asthenia, nervousness, dizziness and confusion have been reported.

Depression, Severe Chronic Obstructive Lung Disease, Severe Liver Disease, Weakened Patient, Having thoughts of Suicide.

Eszopiclone like all sedatives should be taken immediately before bedtime to avoid short-term memory impairment, hallucinations, impaired coordination, dizziness and lightheadedness

Alcohol (which causes sedation) and drugs that have sedating effects should not be used with Eszopiclone since their sedating effects, when added to those of Eszopiclone, may cause excessive sedation.

Pregnancy: Category C. There is no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

Nursing Mothers: It is not known whether the drug is excreted in breast milk. As many drugs are excreted in breast milk, caution should be exercised when Eszopiclone is administered to a nursing mother.

There is limited clinical experience with the overdose of Eszopiclone. In clinical trials one case of overdose with up to 36 mg of Eszopiclone has been reported in which the subject fully recovered. Intravenous fluids should be administered as needed & Flumazenil may be useful.

Store at 25°C.

Eszopiclone is indicated for the treatment of insomnia, including difficulty falling asleep and difficulty maintaining sleep through the night. Eszopiclone is the first sedative approved long-term use

Miscellaneous sedatives & hypnotics

Eszopiclone may interact with Gama-aminobutyric acid (GABA) receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors.

The usual dose to improve or maintain sleep in most adults is 2 or 3 mg. Persons over the age of 65 years usually are treated with 1 or 2 mg. Eszopiclone should be taken immediately before going to bed since the onset of sedation may occur as rapidly as 10 minutes. It should be taken only by individuals who intend to sleep for at least 8 hours since its effects may last up to six hours.

Eszopiclone is generally well tolerated. However few side effects like fatigue, anorexia, nausea, unpleasant taste in the mouth, mood problems, abdominal pain, dyspepsia, asthenia, nervousness, dizziness and confusion have been reported.

Depression, Severe Chronic Obstructive Lung Disease, Severe Liver Disease, Weakened Patient, Having thoughts of Suicide.

Eszopiclone like all sedatives should be taken immediately before bedtime to avoid short-term memory impairment, hallucinations, impaired coordination, dizziness and lightheadedness

Alcohol (which causes sedation) and drugs that have sedating effects should not be used with Eszopiclone since their sedating effects, when added to those of Eszopiclone, may cause excessive sedation.

Pregnancy: Category C. There is no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

Nursing Mothers: It is not known whether the drug is excreted in breast milk. As many drugs are excreted in breast milk, caution should be exercised when Eszopiclone is administered to a nursing mother.

There is limited clinical experience with the overdose of Eszopiclone. In clinical trials one case of overdose with up to 36 mg of Eszopiclone has been reported in which the subject fully recovered. Intravenous fluids should be administered as needed & Flumazenil may be useful.

Store at 25°C.

Eszopiclone is indicated for the treatment of insomnia, including difficulty falling asleep and difficulty maintaining sleep through the night. Eszopiclone is the first sedative approved long-term use

Miscellaneous sedatives & hypnotics

Eszopiclone may interact with Gama-aminobutyric acid (GABA) receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors.

The usual dose to improve or maintain sleep in most adults is 2 or 3 mg. Persons over the age of 65 years usually are treated with 1 or 2 mg. Eszopiclone should be taken immediately before going to bed since the onset of sedation may occur as rapidly as 10 minutes. It should be taken only by individuals who intend to sleep for at least 8 hours since its effects may last up to six hours.

Eszopiclone is generally well tolerated. However few side effects like fatigue, anorexia, nausea, unpleasant taste in the mouth, mood problems, abdominal pain, dyspepsia, asthenia, nervousness, dizziness and confusion have been reported.

Depression, Severe Chronic Obstructive Lung Disease, Severe Liver Disease, Weakened Patient, Having thoughts of Suicide.

Eszopiclone like all sedatives should be taken immediately before bedtime to avoid short-term memory impairment, hallucinations, impaired coordination, dizziness and lightheadedness

Alcohol (which causes sedation) and drugs that have sedating effects should not be used with Eszopiclone since their sedating effects, when added to those of Eszopiclone, may cause excessive sedation.

Pregnancy: Category C. There is no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

Nursing Mothers: It is not known whether the drug is excreted in breast milk. As many drugs are excreted in breast milk, caution should be exercised when Eszopiclone is administered to a nursing mother.

There is limited clinical experience with the overdose of Eszopiclone. In clinical trials one case of overdose with up to 36 mg of Eszopiclone has been reported in which the subject fully recovered. Intravenous fluids should be administered as needed & Flumazenil may be useful.

Store at 25°C.

Appetite suppressant drugs/Anti-obesity drugs

Orlistat is a potent, specific and long-acting lipase inhibitor. It exerts its therapeutic activity in the lumen of the stomach and upper small intestine by forming a covalent bond with the active serine site of gastric and pancreatic lipases. The inactivated enzyme is thus rendered unable to hydrolyze dietary fats in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides can not be absorbed, a caloric deficit arises which has a positive effect on weight control. Systemic absorption of orlistat is therefore not needed for the activity. At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibit dietary fat absorption by approximately 30%.

The recommended dose of Orlistat is one 120 mg capsule to be taken immediately before, during or up to one hour after each main meal. If a meal is missed or contains no fat the dose of Orlistat should be omitted. Doses of Orlistat above 120 mg three times daily have not been shown to provide additional benefits. The effect of Orlistat results in an increase in fecal fat 24-48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48-72 hours.

The safety & efficacy of Orlistat were investigated in clinical studies lasting up to 4 years. The recommended dose of Orlistat for adolescents is as same as adults.

Special dosage instruction: The tolerability and efficacy of Orlistat have not been studied in elderly patients, or patients with hepatic and/ or renal impairments.

Common: Undesirable effects of Orlistat are largely gastrointestinal in nature. Common gastrointestinal side effects are oily spotting from the rectum, flatulence, fecal urgency, oily or fatty stool, abdominal discomfort etc.

Rare: Influenza, anxiety. headache, fatigue etc may rarely occur in some patients. Rare cases of hypersensitivity have been reported. Main clinical symptoms are pruritus, exanthema, urticaria, angioedema and anaphylaxis.

Orlistat is contraindicated in patients with chronic malabsorption syndrome, in patients with cholestasis and in patients who are hypersensitive to orlistat or to any of the other ingredients of the capsules.

Organic causes of obesity (e.g. hypothyroidism) should be excluded before prescribing Orlistat. Orlistat and cyclosporine should not be coadministered. Cyclosporine should be taken at least 2 hours before or after Orlistat in patients taking both drugs. Cyclosporine level should be measured and frequently monitored.

In clinical trial, the decrease in body weight with Orlistat therapy was less in type II diabetic patients than in non-diabetic patients. Antidiabetic drug treatment should be closely monitored during Orlistat therapy. Because of the improvement in glycemic control, the dose of oral antidiabetics or of insulin may need to be adjusted.

Patients should be advised to adhere to the dietary recommendations. The probability of occurrence of gastrointestinal side effects may increase when Orlistat is taken with a fatty meal. The daily intake of fat should be distributed between three main meals. Patients should be strongly encouraged to take a multivitamin supplement that contains fat soluble vitamins to ensure adequate nutrition because orlistat has been shown to reduce the absorption of some fat soluble vitamins & beta-carotene. In addition, the levels of vitamin D & beta carotene may be low in obese patients compared with non-obese patients.

No interactions with commonly prescribed medications such as alcohol, digoxin, nifedipine, oral contraceptives, phenytoin, pravastatin, warfarin, or metformin, glibenclamide, fibrates, furosemide, captopril, or atenolol have been observed in studies.

Use in pregnancy & lactation: No clinical data are available on pregnancy exposed to Orlistat. As it is not known whether Orlistat is excreted in breast milk. Orlistat should not be used during breastfeeding.

Single doses of 800 mg Orlistat and multiple doses of up to 400 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings.

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

Appetite suppressant drugs/Anti-obesity drugs

Orlistat is a potent, specific and long-acting lipase inhibitor. It exerts its therapeutic activity in the lumen of the stomach and upper small intestine by forming a covalent bond with the active serine site of gastric and pancreatic lipases. The inactivated enzyme is thus rendered unable to hydrolyze dietary fats in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides can not be absorbed, a caloric deficit arises which has a positive effect on weight control. Systemic absorption of orlistat is therefore not needed for the activity. At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibit dietary fat absorption by approximately 30%.

The recommended dose of Orlistat is one 120 mg capsule to be taken immediately before, during or up to one hour after each main meal. If a meal is missed or contains no fat the dose of Orlistat should be omitted. Doses of Orlistat above 120 mg three times daily have not been shown to provide additional benefits. The effect of Orlistat results in an increase in fecal fat 24-48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48-72 hours.

The safety & efficacy of Orlistat were investigated in clinical studies lasting up to 4 years. The recommended dose of Orlistat for adolescents is as same as adults.

Special dosage instruction: The tolerability and efficacy of Orlistat have not been studied in elderly patients, or patients with hepatic and/ or renal impairments.

Common: Undesirable effects of Orlistat are largely gastrointestinal in nature. Common gastrointestinal side effects are oily spotting from the rectum, flatulence, fecal urgency, oily or fatty stool, abdominal discomfort etc.

Rare: Influenza, anxiety. headache, fatigue etc may rarely occur in some patients. Rare cases of hypersensitivity have been reported. Main clinical symptoms are pruritus, exanthema, urticaria, angioedema and anaphylaxis.

Orlistat is contraindicated in patients with chronic malabsorption syndrome, in patients with cholestasis and in patients who are hypersensitive to orlistat or to any of the other ingredients of the capsules.

Organic causes of obesity (e.g. hypothyroidism) should be excluded before prescribing Orlistat. Orlistat and cyclosporine should not be coadministered. Cyclosporine should be taken at least 2 hours before or after Orlistat in patients taking both drugs. Cyclosporine level should be measured and frequently monitored.

In clinical trial, the decrease in body weight with Orlistat therapy was less in type II diabetic patients than in non-diabetic patients. Antidiabetic drug treatment should be closely monitored during Orlistat therapy. Because of the improvement in glycemic control, the dose of oral antidiabetics or of insulin may need to be adjusted.

Patients should be advised to adhere to the dietary recommendations. The probability of occurrence of gastrointestinal side effects may increase when Orlistat is taken with a fatty meal. The daily intake of fat should be distributed between three main meals. Patients should be strongly encouraged to take a multivitamin supplement that contains fat soluble vitamins to ensure adequate nutrition because orlistat has been shown to reduce the absorption of some fat soluble vitamins & beta-carotene. In addition, the levels of vitamin D & beta carotene may be low in obese patients compared with non-obese patients.

No interactions with commonly prescribed medications such as alcohol, digoxin, nifedipine, oral contraceptives, phenytoin, pravastatin, warfarin, or metformin, glibenclamide, fibrates, furosemide, captopril, or atenolol have been observed in studies.

Use in pregnancy & lactation: No clinical data are available on pregnancy exposed to Orlistat. As it is not known whether Orlistat is excreted in breast milk. Orlistat should not be used during breastfeeding.

Single doses of 800 mg Orlistat and multiple doses of up to 400 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings.

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

Appetite suppressant drugs/Anti-obesity drugs

Orlistat is a potent, specific and long-acting lipase inhibitor. It exerts its therapeutic activity in the lumen of the stomach and upper small intestine by forming a covalent bond with the active serine site of gastric and pancreatic lipases. The inactivated enzyme is thus rendered unable to hydrolyze dietary fats in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides can not be absorbed, a caloric deficit arises which has a positive effect on weight control. Systemic absorption of orlistat is therefore not needed for the activity. At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibit dietary fat absorption by approximately 30%.

The recommended dose of Orlistat is one 120 mg capsule to be taken immediately before, during or up to one hour after each main meal. If a meal is missed or contains no fat the dose of Orlistat should be omitted. Doses of Orlistat above 120 mg three times daily have not been shown to provide additional benefits. The effect of Orlistat results in an increase in fecal fat 24-48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48-72 hours.

The safety & efficacy of Orlistat were investigated in clinical studies lasting up to 4 years. The recommended dose of Orlistat for adolescents is as same as adults.

Special dosage instruction: The tolerability and efficacy of Orlistat have not been studied in elderly patients, or patients with hepatic and/ or renal impairments.

Common: Undesirable effects of Orlistat are largely gastrointestinal in nature. Common gastrointestinal side effects are oily spotting from the rectum, flatulence, fecal urgency, oily or fatty stool, abdominal discomfort etc.

Rare: Influenza, anxiety. headache, fatigue etc may rarely occur in some patients. Rare cases of hypersensitivity have been reported. Main clinical symptoms are pruritus, exanthema, urticaria, angioedema and anaphylaxis.

Orlistat is contraindicated in patients with chronic malabsorption syndrome, in patients with cholestasis and in patients who are hypersensitive to orlistat or to any of the other ingredients of the capsules.

Organic causes of obesity (e.g. hypothyroidism) should be excluded before prescribing Orlistat. Orlistat and cyclosporine should not be coadministered. Cyclosporine should be taken at least 2 hours before or after Orlistat in patients taking both drugs. Cyclosporine level should be measured and frequently monitored.

In clinical trial, the decrease in body weight with Orlistat therapy was less in type II diabetic patients than in non-diabetic patients. Antidiabetic drug treatment should be closely monitored during Orlistat therapy. Because of the improvement in glycemic control, the dose of oral antidiabetics or of insulin may need to be adjusted.

Patients should be advised to adhere to the dietary recommendations. The probability of occurrence of gastrointestinal side effects may increase when Orlistat is taken with a fatty meal. The daily intake of fat should be distributed between three main meals. Patients should be strongly encouraged to take a multivitamin supplement that contains fat soluble vitamins to ensure adequate nutrition because orlistat has been shown to reduce the absorption of some fat soluble vitamins & beta-carotene. In addition, the levels of vitamin D & beta carotene may be low in obese patients compared with non-obese patients.

No interactions with commonly prescribed medications such as alcohol, digoxin, nifedipine, oral contraceptives, phenytoin, pravastatin, warfarin, or metformin, glibenclamide, fibrates, furosemide, captopril, or atenolol have been observed in studies.

Use in pregnancy & lactation: No clinical data are available on pregnancy exposed to Orlistat. As it is not known whether Orlistat is excreted in breast milk. Orlistat should not be used during breastfeeding.

Single doses of 800 mg Orlistat and multiple doses of up to 400 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings.

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

Doxepin is indicated for the treatment of insomnia characterized by difficulty with sleep maintenance. The clinical trials performed in support of efficacy were up to 3 months in duration.

Tricyclic & related anti-depressant drugs

Doxepin binds with high affinity to the histamine H1 receptor (Ki<1 nM) where it functions as an antagonist. The exact mechanism by which doxepin exerts its sleep maintenance effect is unknown but is believed due to its antagonism of the H1 receptor.

Dosing in Adults: The recommended dose of Doxepin for adults is 6 mg once daily. A 3 mg once daily dose may be appropriate for some patients, if clinically indicated.

Dosing in the Elderly: The recommended starting dose of Doxepin in elderly patients (≥65 years old) is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically indicated.

Administration: Doxepin should be taken within 30 minutes of bedtime. To minimize the potential for next day effects, Doxepin should not be taken within 3 hours of a meal. The total Doxepin dose should not exceed 6 mg per day.

Pediatric Use: The safety and effectiveness of Doxepin in pediatric patients have not been evaluated.

The following serious adverse reactions are as follows:

• Abnormal thinking and behavioral changes 
• Suicide risk and worsening of depression
• CNS Depressant effects

Hypersensitivity: Doxepin is contraindicated in individuals who have shown hypersensitivity to doxepin HCl,
any of its inactive ingredients, or other dibenoxepines.

Co-administration with Monoamine Oxidase Inhibitors (MAOIs): Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Do not administer Doxepin if patient is currently on MAOIs or has used MAOIs within the past two weeks. The exact length of time may vary depending on the particular MAOI dosage and duration of treatment.

Glaucoma and Urinary Retention: Doxepin is contraindicated in individuals with untreated narrow-angle glaucoma or severe urinary retention.

Need to Evaluate for Comorbid Diagnoses: Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Exacerbation of insomnia or the emergence of new cognitive or behavioral abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with hypnotic drugs.

Abnormal Thinking and Behavioral Changes: Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a hypnotic, with amnesia for the event) have been reported with hypnotics. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Although behaviors such as "sleep-driving" may occur with hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with hypnotics appears to increase the risk of such behaviors, as does the use of hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Doxepin should be strongly considered for patients who report a "sleep-driving" episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a hypnotic. As with "sleep-driving", patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.

Suicide Risk and Worsening of Depression: In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of hypnotics. Doxepin, the active ingredient in Doxepin, is an antidepressant at doses 10- to 100-fold higher than in Doxepin. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Risk from the lower dose of doxepin in Doxepin can not be excluded. It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Cytochrome P450 Isozymes: Doxepin is primarily metabolized by hepatic cytochrome P450 isozymes CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. Inhibitors of these isozymes may increase the exposure of doxepin. Doxepin is not an inhibitor of any CYP isozymes at therapeutically relevant concentrations. The ability of Doxepin to induce CYP isozymes is not known.

Cimetidine: Doxepin exposure is doubled with concomitant administration of cimetidine, a nonspecific inhibitor of CYP isozymes. A maximum dose of 3 mg is recommended in adults and elderly when cimetidine is co administered with Doxepin.

Alcohol: When taken with Doxepin, the sedative effects of alcohol may be potentiated.

CNS Depressants and Sedating Antihistamines: When taken with Doxepin, the sedative effects of sedating antihistamines and CNS depressants may be potentiated.

Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 g/day) 11 days after the addition of oral doxepin (75 mg/day).

Pregnancy Category C. There are no adequate and well-controlled studies of Doxepin in pregnant women. Doxepin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of doxepin to pregnant animals resulted in adverse effects on offspring development at doses greater than the maximum recommended human dose (MRHD) of 6 mg/day.

Doxepin is excreted in human milk after oral administration. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking the higher dose of doxepin used to treat depression. Caution should be exercised when Doxepin is administered to nursing women.

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

Doxepin is indicated for the treatment of insomnia characterized by difficulty with sleep maintenance. The clinical trials performed in support of efficacy were up to 3 months in duration.

Tricyclic & related anti-depressant drugs

Doxepin binds with high affinity to the histamine H1 receptor (Ki<1 nM) where it functions as an antagonist. The exact mechanism by which doxepin exerts its sleep maintenance effect is unknown but is believed due to its antagonism of the H1 receptor.

Dosing in Adults: The recommended dose of Doxepin for adults is 6 mg once daily. A 3 mg once daily dose may be appropriate for some patients, if clinically indicated.

Dosing in the Elderly: The recommended starting dose of Doxepin in elderly patients (≥65 years old) is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically indicated.

Administration: Doxepin should be taken within 30 minutes of bedtime. To minimize the potential for next day effects, Doxepin should not be taken within 3 hours of a meal. The total Doxepin dose should not exceed 6 mg per day.

Pediatric Use: The safety and effectiveness of Doxepin in pediatric patients have not been evaluated.

The following serious adverse reactions are as follows:

• Abnormal thinking and behavioral changes 
• Suicide risk and worsening of depression
• CNS Depressant effects

Hypersensitivity: Doxepin is contraindicated in individuals who have shown hypersensitivity to doxepin HCl,
any of its inactive ingredients, or other dibenoxepines.

Co-administration with Monoamine Oxidase Inhibitors (MAOIs): Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Do not administer Doxepin if patient is currently on MAOIs or has used MAOIs within the past two weeks. The exact length of time may vary depending on the particular MAOI dosage and duration of treatment.

Glaucoma and Urinary Retention: Doxepin is contraindicated in individuals with untreated narrow-angle glaucoma or severe urinary retention.

Need to Evaluate for Comorbid Diagnoses: Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Exacerbation of insomnia or the emergence of new cognitive or behavioral abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with hypnotic drugs.

Abnormal Thinking and Behavioral Changes: Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a hypnotic, with amnesia for the event) have been reported with hypnotics. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Although behaviors such as "sleep-driving" may occur with hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with hypnotics appears to increase the risk of such behaviors, as does the use of hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Doxepin should be strongly considered for patients who report a "sleep-driving" episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a hypnotic. As with "sleep-driving", patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.

Suicide Risk and Worsening of Depression: In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of hypnotics. Doxepin, the active ingredient in Doxepin, is an antidepressant at doses 10- to 100-fold higher than in Doxepin. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Risk from the lower dose of doxepin in Doxepin can not be excluded. It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Cytochrome P450 Isozymes: Doxepin is primarily metabolized by hepatic cytochrome P450 isozymes CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. Inhibitors of these isozymes may increase the exposure of doxepin. Doxepin is not an inhibitor of any CYP isozymes at therapeutically relevant concentrations. The ability of Doxepin to induce CYP isozymes is not known.

Cimetidine: Doxepin exposure is doubled with concomitant administration of cimetidine, a nonspecific inhibitor of CYP isozymes. A maximum dose of 3 mg is recommended in adults and elderly when cimetidine is co administered with Doxepin.

Alcohol: When taken with Doxepin, the sedative effects of alcohol may be potentiated.

CNS Depressants and Sedating Antihistamines: When taken with Doxepin, the sedative effects of sedating antihistamines and CNS depressants may be potentiated.

Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 g/day) 11 days after the addition of oral doxepin (75 mg/day).

Pregnancy Category C. There are no adequate and well-controlled studies of Doxepin in pregnant women. Doxepin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of doxepin to pregnant animals resulted in adverse effects on offspring development at doses greater than the maximum recommended human dose (MRHD) of 6 mg/day.

Doxepin is excreted in human milk after oral administration. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking the higher dose of doxepin used to treat depression. Caution should be exercised when Doxepin is administered to nursing women.

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

Flurazepam is indicated in the following conditions-

• Insomnia is characterized by difficulty in falling asleep, frequent nocturnal awakenings or early morning awakenings
• Recurring insomnia or poor sleeping habits
• In acute or chronic medical situations requiring restful sleep.

Benzodiazepine hypnotics

Flurazepam, a benzodiazepine derivative, is a hypnotic agent which does not appear to decrease dream time as measured by rapid eye movements (REM). Furthermore, it decreases sleep latency and number of awakenings for a consequent increase in total sleep time. Flurazepam binds to an allosteric site on GABA-A receptors. Binding potentiates the action of GABA on GABA-A receptors by opening the chloride channel within the receptor, causing chloride influx and hyperpolarization.

Adult: Usual dosage is 30 mg at bedtime. In some patients, 15 mg may sufficient.
Elderly or debilitated: 15 mg is usually sufficient for a therapeutic response.
Children: Not recommended.
In hepatic and renal impairment: Dosage may need to be reduced in patients with impaired hepatic or renal function.

Dizziness, drowsiness, light-headedness, staggering, ataxia have occurred, particularly in elderly or debilitated persons. Severe sedation, lethargy, disorientation and coma have been reported.

Patients with known hypersensitivity to benzodiazepines or any other ingredients of the capsule.

Since the risk of the development of oversedation, dizziness, confusion or ataxia increases substantially with larger doses in elderly and debilitated patients, it is recommended that in such patients the dosage should be limited to 15 mg. The usual precautions are indicated for severely depressed patients or those in whom there is any evidence of latent depression; particularly the recognition that suicidal tendencies may be present and protective measures may be necessary. The usual precautions should be observed in patients with chronic pulmonary insufficiency.

Flurazepam potentiates other CNS depressants such as alcohol, barbiturates, sedative antidepressants, antihistamines and antipsychotic drugs. Cimetidine moderately prolongs the already long half-life of the active metabolite desalkyl flurazepam. Antacids may delay the absorption of benzodiazepines.

Pregnancy category-C. Flurazepam is contraindicated in pregnant women. Lactating mothers should avoid it.

Flurazepam overdosage includes somnolence, confusion and coma. Respiration, pulse and blood pressure should be monitored as in all cases of drug overdosage. General supportive measures should be employed, along with immediate gastric lavage.

Capsules should be stored in a dry place at 20°-25°C temperature.

Flurazepam is indicated in the following conditions-

• Insomnia is characterized by difficulty in falling asleep, frequent nocturnal awakenings or early morning awakenings
• Recurring insomnia or poor sleeping habits
• In acute or chronic medical situations requiring restful sleep.

Benzodiazepine hypnotics

Flurazepam, a benzodiazepine derivative, is a hypnotic agent which does not appear to decrease dream time as measured by rapid eye movements (REM). Furthermore, it decreases sleep latency and number of awakenings for a consequent increase in total sleep time. Flurazepam binds to an allosteric site on GABA-A receptors. Binding potentiates the action of GABA on GABA-A receptors by opening the chloride channel within the receptor, causing chloride influx and hyperpolarization.

Adult: Usual dosage is 30 mg at bedtime. In some patients, 15 mg may sufficient.
Elderly or debilitated: 15 mg is usually sufficient for a therapeutic response.
Children: Not recommended.
In hepatic and renal impairment: Dosage may need to be reduced in patients with impaired hepatic or renal function.

Dizziness, drowsiness, light-headedness, staggering, ataxia have occurred, particularly in elderly or debilitated persons. Severe sedation, lethargy, disorientation and coma have been reported.

Patients with known hypersensitivity to benzodiazepines or any other ingredients of the capsule.

Since the risk of the development of oversedation, dizziness, confusion or ataxia increases substantially with larger doses in elderly and debilitated patients, it is recommended that in such patients the dosage should be limited to 15 mg. The usual precautions are indicated for severely depressed patients or those in whom there is any evidence of latent depression; particularly the recognition that suicidal tendencies may be present and protective measures may be necessary. The usual precautions should be observed in patients with chronic pulmonary insufficiency.

Flurazepam potentiates other CNS depressants such as alcohol, barbiturates, sedative antidepressants, antihistamines and antipsychotic drugs. Cimetidine moderately prolongs the already long half-life of the active metabolite desalkyl flurazepam. Antacids may delay the absorption of benzodiazepines.

Pregnancy category-C. Flurazepam is contraindicated in pregnant women. Lactating mothers should avoid it.

Flurazepam overdosage includes somnolence, confusion and coma. Respiration, pulse and blood pressure should be monitored as in all cases of drug overdosage. General supportive measures should be employed, along with immediate gastric lavage.

Capsules should be stored in a dry place at 20°-25°C temperature.

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with Sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with Sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with Sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

Levothyroxine: Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

Levothyroxine: Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

Levothyroxine: Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

Levothyroxine: Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

Injection:

• Infants and children: half of a vial (0.5 mg) by slow IV injection or by IV infusion.

• Adults: 1 vial (1 mg) by slow IV injection or by IV infusion. This dose can be repeated as required (1-4 mg are usually sufficient to reverse the status). In adults, the rate of injection must not exceed 0.25 - 0.5 mg per minute (0.5-1.0 ml of the prepared solution) and a total dose of 10 mg should not be exceeded.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma.

When used in patients in whom several different types of seizure disorders coexist, Clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures. This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and Clonazepam may produce absence status.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects appear to be greater in elderly patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug–receptor interactions, post-receptor mechanisms and organ function.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

Slow intravenous injection: The contents of the vial must be diluted with 1 ml of water for injection prior to administration so as to avoid local irritation of the veins. The injection solution should be prepared immediately before use. IV injection should be administered slowly with continuous monitoring of EEG, respiration and blood pressure.

Intravenous infusion: Clonazepam (the vial) can be diluted for infusion in a ratio of 1 vial (1 mg) to at least 85 ml diluting media. The diluting media can be any of the following: sodium chloride 0.9%; sodium chloride 0.45% + glucose 2.5%; glucose 5% or glucose 10%. These mixtures are stable for 24 hours at room temperature. Infusion bags other than PVC should be used for infusing Clonazepam. If PVC infusion bags are used then the mixture should be infused immediately or within 4 hours. The infusion time should not exceed 8 hours. Do not prepare Clonazepam infusions using sodium bicarbonate solution, as precipitation of the solution may occur.

Intramuscular injection: The IM route should be used only in exceptional cases or if IV administration is not feasible.

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

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

Injection:

• Infants and children: half of a vial (0.5 mg) by slow IV injection or by IV infusion.

• Adults: 1 vial (1 mg) by slow IV injection or by IV infusion. This dose can be repeated as required (1-4 mg are usually sufficient to reverse the status). In adults, the rate of injection must not exceed 0.25 - 0.5 mg per minute (0.5-1.0 ml of the prepared solution) and a total dose of 10 mg should not be exceeded.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma.

When used in patients in whom several different types of seizure disorders coexist, Clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures. This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and Clonazepam may produce absence status.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects appear to be greater in elderly patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug–receptor interactions, post-receptor mechanisms and organ function.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

Slow intravenous injection: The contents of the vial must be diluted with 1 ml of water for injection prior to administration so as to avoid local irritation of the veins. The injection solution should be prepared immediately before use. IV injection should be administered slowly with continuous monitoring of EEG, respiration and blood pressure.

Intravenous infusion: Clonazepam (the vial) can be diluted for infusion in a ratio of 1 vial (1 mg) to at least 85 ml diluting media. The diluting media can be any of the following: sodium chloride 0.9%; sodium chloride 0.45% + glucose 2.5%; glucose 5% or glucose 10%. These mixtures are stable for 24 hours at room temperature. Infusion bags other than PVC should be used for infusing Clonazepam. If PVC infusion bags are used then the mixture should be infused immediately or within 4 hours. The infusion time should not exceed 8 hours. Do not prepare Clonazepam infusions using sodium bicarbonate solution, as precipitation of the solution may occur.

Intramuscular injection: The IM route should be used only in exceptional cases or if IV administration is not feasible.

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