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This tablet is indicated as an adjunct to diet and exercise in type 2 diabetes mellitus patients-

• In case that the monotherapy with glimepiride or metformin does not result in adequate glycemic control.
• Replacement of combination therapy of glimepiride and metformin.

Combination Oral hypoglycemic preparations

Glimepiride is a sulfonylurea antidiabetic agent which decreases blood glucose concentration. The primary mechanism of action of Glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. Glimepiride acts in concert with glucose by improving the sensitivity of beta cells to physiological glucose stimulus, resulting in insulin secretion. In addition, extrapancreatic effects like reduction of basal hepatic glucose production, increased peripheral tissue sensitivity to insulin and glucose uptake may also play role in the activity of Glimepiride. In non-fasting diabetic patients, the hypoglycaemic action of a single dose of Glimepiride persists for 24 hours.

Metformin Hydrochloride is a biguanide type oral antihyperglycemic drug used in the management of type 2 diabetes. It lowers both basal and postprandial plasma glucose. Its mechanism of action is different from those of sulfonylureas and it does not produce hypoglycemia. Metformin Hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.

This tablet must be swallowed whole and not crushed or chewed.

For Glimepiride:
Metabolism and nutrition disorders-

• As a result of the blood-glucose-lowering action of glimepiride, Hypoglycaemia which may also be prolonged.
• The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Eye disorders: Especially at the start of treatment, there may be temporary visual impairment due to the change in blood glucose levels. The cause is a temporary alteration in the turgidity and hence the refractive index of the lens, this being dependent on blood glucose level.

Gastrointestinal disorders-

• Occasionally, Gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fulness in the epigastrium, abdominal pain and diarrhea may occur.
• In isolated cases, there may be hepatitis, elevation of liver enzyme levels and/or cholestasis and jaundice, which may progress to life-threatening liver failure.
• Dysgeusia (frequency not known)

Blood and lymphatic system disorders-

• Changes in the blood picture may occur: Rarely, thrombocytopenia and, in isolated cases, leucopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop. Cases of severe thrombocytopenia with platelet count less than 10,000/μl and thrombocytopenic purpura have been reported in post-marketing experience (frequency not known).

Skin and subcutaneous tissue disorders: Alopecia (frequency not known)

General disorders-

• Occasionally, Allergic or pseudo allergic reactions may occur, e.g. in the form of itching, urticaria or rashes. Such mild reactions may develop into serious reactions with dyspnoea and a fall in blood pressure, sometimes progressing to shock.
• In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur.

Investigations: Glimepiride, like all sulfonylureas, can cause weight gain (frequency not known)

For Metformin:

• Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite (>10%) are very common. These occur most frequently during initiation of therapy and resolve spontaneously in most cases.
• Metallic taste (3%) is common
• Decrease of vitamin B12 absorption with decrease of serum levels has been observed in patients treated long-term with metformin and appears generally to be without clinical signifcance (<0.01%). However, Cases of peripheral neuropathy in patients with vitamin B12 defciency have been reported in post-marketing experience (frequency not known). (frequency unknown)
• Lactic acidosis (0.03 cases/1000 patient-years) is very rare
• Hemolytic anemia (frequency unknown)
• Reduction of thyrotropin level in patients with hypothyroidism (frequency unknown)
• Hypomagnesemia in the context of diarrhea (frequency unknown)
• Encephalopathy (frequency unknown)
• Photosensitivity (frequency unknown)
• Hepatobiliary disorders: Reports of liver function tests abnormalities and hepatitis resolving upon metformin discontinuation

For Glimepiride-

• In patients hypersensitive to glimepiride, metformin, other sulfonylureas, other sulfonamides, or any of the excipients of Amaryl M.
• In pregnant women.
• In breastfeeding women.

No experience has been gained concerning the use of glimepiride in patients with severe impairment of liver function and in dialysis patients. In patients with severe impairment of hepatic function, change-over to insulin is indicated, not least to achieve optimal metabolic control.

For Metformin-

• Hypersensitivity to metformin or any of the excipients.
• Any type of acute metabolic acidosis such as lactic acidosis Diabetic ketoacidosis, diabetic pre-coma.
• Severe Renal failure or renal disfunction (e.g., serum creatine levels >135 μmol/L in males and >110 μmol/L in females), GFR < 30 mL/min.
• Acute conditions with the potential to alter renal function such as Dehydration, severe infection, intravascular administration of iodinated contrast agents etc.
• Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock
• Hepatic insufciency.
• Acute alcohol intoxication, alcoholism.
• Lactation.

For Glimepiride: In the initial weeks of treatment, the risk of hypoglycemia may be increased and necessitates especially careful monitoring. If risk factors for hypoglycemia are present, it may be necessary to adjust the dosage of glimepiride or the entire therapy. This also applies whenever illness occurs during therapy or the patient's life-style changes. It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur. Patients must, therefore, remain under close observation. Severe hypoglycaemia further requires immediate treatment and follow-up by a physician and, in some circumstances, in-patient hospital care. Treatment of patients with G6PD-defciency with sulfonylurea agents can lead to hemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-defciency and a non-sulfonylurea alternative should be considered.

For Metformin: Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients withhypothyroidism. Long-term treatment with metformin has been associated with a decrease in vitamin B12 serumlevels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

For Glimepiride:

• Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is coadministered with inducers (e.g. rifampicin) or inhibitors (e.g. fuconazole) of CYP 2C9.
• Potentiation of the blood-glucose-lowering efect and, thus, in some instances hypoglycaemia may occur when one of the following drugs is taken, for example: insulin and other, oral antidiabetics; ACE inhibitors; anabolic steroids and male sex hormones; chloramphenicol; coumarin derivatives; cyclophosphamide; disopyramide; fenfuramine; fenyramidol; fbrates; fuoxetine; guanethidine; ifosfamide; MAO inhibitors; miconazole; fuconazole; para-aminosalicylic acid; pentoxifylline (high dose parenteral); phenylbutazone; azapropazone; oxyphenbutazone; probenecid; quinolones; salicylates; sulfnpyrazone; clarithromycin; sulfonamide antibiotics; tetracyclines; tritoqualine; trofosfamide.
• Weakening of the blood-glucose-lowering efect and, thus raised blood glucose levels may occur when one of the following drugs is taken, for example: acetazolamide; barbiturates; corticosteroids; diazoxide; diuretics; epinephrine (adrenaline) and other sympathomimetic agents; glucagon; laxatives (after protracted use); nicotinic acid (in high doses); oestrogens and progestogens; phenothiazines; phenytoin; rifampicin; thyroid hormones.
• H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering efect. Under the infuence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent.
• Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering action of glimepiride in an unpredictable fashion.
• The efect of coumarin derivatives may be potentiated or weakened.
• Bile acid sequestrant: Colesevelam binds to glimepiride and reduces glimepiride absorption from the gastrointestinal tract. Glimepiride should be administered at least 4 hours prior to colesevelam.

For Metformin: Concomitant use not recommended:

• Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting, malnutrition or hepatic insufciency. Avoid consumption of alcohol and alcohol-containing medications
• Iodinated contrast agents: Metformin must be discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable.
• Combinations requiring precautions for use: Some medicinal products can adversely afect renal function which may increase the risk of lactic Acidosis. When starting or using such products in combination with metformin, close monitoring of renal function is necessary. Glucocorticoids, beta-2-agonists, and diuretics have intrinsic hyperglycemic activity. Inform the patient and perform more frequent blood glucose monitoring. ACE-inhibitors may decrease the blood glucose levels. Metformin may decrease the anticoagulant efect of phenprocoumon. Therefore, a close monitoring of the INR is recommended. Levothyroxine can reduce the hypoglycemic efect 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.

Organic cation transporters (OCT): Metformin is a substrate of both transporters OCT1 and OCT2. Co-administration of metformin with:

• Inhibitors of OCT1 (such as verapamil) may reduce efcacy of metformin.
• Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efcacy of metformin.
• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.
• Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efcacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are coadministered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efcacy of metformin.

Pregnancy-

• For Glimepiride: Glimepiride must not be taken during pregnancy. Otherwise, there is risk of harm to the child. The patient must change over to insulin during pregnancy. Patients planning a pregnancy must inform their physician. It is recommended that such patients change over to insulin.
• For Metformin: When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.

Lactation-

• For Glimepiride: To prevent possible ingestion with the breast milk and possible harm to the child, glimepiride must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breastfeeding.
• For Metformin: Metformin is excreted into milk in lactating rats. Similar data is not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the compound to the mother.

Children: Data is insufficient to recommend pediatric use of this tablet.

Renal impairment: A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering the initiation of metformin in patients with GFR<60 mL/min. If no adequate strength of this tablet is available, individual monocomponents should be used instead of the fixed dose combination.

GFR 60-89 ml/min:

• Metformin: Maximum daily dose is 3000 mg. Dose reduction may be considered in relation to declining renal function.
• Glimepiride: The highest recommended dose per day should be 8 mg of glimepiride.

GFR 45-59 ml/min:

• Metformin: Maximum daily dose is 2000 mg. The starting dose is at most half of the maximum dose.

GFR 30-44 ml/min:

• Metformin: Maximum daily dose is 1000 mg. The starting dose is at most half of the maximum dose.

GFR <30 ml/min:

• Metformin: Metformin is contraindicated
• Glimepiride: Change-over to insulin is indicated, not least to achieve optimal metabolic control.

For Glimepiride: Acute overdosage, as well as long-term treatment with too high a dose of glimepiride, may lead to severe life-threatening hypoglycaemia. As soon as an overdose of glimepiride has been discovered, a physician must be notifed without delay. The patient must immediately take sugar, if possible in the form of glucose unless a physician has already undertaken responsibility for treating the overdose. Careful monitoring is essential until the physician is confdent that the patient is out of danger. It must be remembered that hypoglycaemia may recur after initial recovery. Admission to hospital may sometimes be necessary even as a precautionary measure. In particular, signifcant overdoses and severe reactions with signs such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and admission to hospital. If, for example, the patient is unconscious, an intravenous injection of concentrated glucose solution is indicated (for adults starting with 40 ml of 20% solution, for example). Alternatively in adults, administration of glucagon, e.g. in doses of 0.5 to 1 mg i.v., s.c. or i.m., may be considered. In particular when treating hypoglycaemia due to accidental intake of glimepiride in infants and young children, the dose of glucose given must be very carefully adjusted in view of the possibility of producing dangerous hyperglycaemia, and must be controlled by close monitoring of blood glucose. Patients who have ingested life-threatening amounts of glimepiride require detoxifcation (e.g. by gastric lavage and medicinal charcoal). After acute glucose replacement has been completed it is usually necessary to give an intravenous glucose infusion in lower concentration so as to ensure that the hypoglycaemia does not recur. The patient's blood glucose level should be carefully monitored for at least 24 hours. In severe cases with a protracted course, hypoglycaemia, or the danger of slipping back into hypoglycaemia, may persist for several days.

For Metformin: Hypoglycaemia has not been seen with metformin doses of up to 85 g, although Lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis Lactic acidosis is a medical emergency and must be treated in hospital. The most efective method to remove lactate and metformin is haemodialysis. Pancreatitis may occur in the context of a metformin overdose.

Store in a cool (not exceeding 25°C) and dry place, protected from light.

This tablet is indicated as an adjunct to diet and exercise in type 2 diabetes mellitus patients-

• In case that the monotherapy with glimepiride or metformin does not result in adequate glycemic control.
• Replacement of combination therapy of glimepiride and metformin.

Combination Oral hypoglycemic preparations

Glimepiride is a sulfonylurea antidiabetic agent which decreases blood glucose concentration. The primary mechanism of action of Glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. Glimepiride acts in concert with glucose by improving the sensitivity of beta cells to physiological glucose stimulus, resulting in insulin secretion. In addition, extrapancreatic effects like reduction of basal hepatic glucose production, increased peripheral tissue sensitivity to insulin and glucose uptake may also play role in the activity of Glimepiride. In non-fasting diabetic patients, the hypoglycaemic action of a single dose of Glimepiride persists for 24 hours.

Metformin Hydrochloride is a biguanide type oral antihyperglycemic drug used in the management of type 2 diabetes. It lowers both basal and postprandial plasma glucose. Its mechanism of action is different from those of sulfonylureas and it does not produce hypoglycemia. Metformin Hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.

This tablet must be swallowed whole and not crushed or chewed.

For Glimepiride:
Metabolism and nutrition disorders-

• As a result of the blood-glucose-lowering action of glimepiride, Hypoglycaemia which may also be prolonged.
• The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Eye disorders: Especially at the start of treatment, there may be temporary visual impairment due to the change in blood glucose levels. The cause is a temporary alteration in the turgidity and hence the refractive index of the lens, this being dependent on blood glucose level.

Gastrointestinal disorders-

• Occasionally, Gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fulness in the epigastrium, abdominal pain and diarrhea may occur.
• In isolated cases, there may be hepatitis, elevation of liver enzyme levels and/or cholestasis and jaundice, which may progress to life-threatening liver failure.
• Dysgeusia (frequency not known)

Blood and lymphatic system disorders-

• Changes in the blood picture may occur: Rarely, thrombocytopenia and, in isolated cases, leucopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop. Cases of severe thrombocytopenia with platelet count less than 10,000/μl and thrombocytopenic purpura have been reported in post-marketing experience (frequency not known).

Skin and subcutaneous tissue disorders: Alopecia (frequency not known)

General disorders-

• Occasionally, Allergic or pseudo allergic reactions may occur, e.g. in the form of itching, urticaria or rashes. Such mild reactions may develop into serious reactions with dyspnoea and a fall in blood pressure, sometimes progressing to shock.
• In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur.

Investigations: Glimepiride, like all sulfonylureas, can cause weight gain (frequency not known)

For Metformin:

• Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite (>10%) are very common. These occur most frequently during initiation of therapy and resolve spontaneously in most cases.
• Metallic taste (3%) is common
• Decrease of vitamin B12 absorption with decrease of serum levels has been observed in patients treated long-term with metformin and appears generally to be without clinical signifcance (<0.01%). However, Cases of peripheral neuropathy in patients with vitamin B12 defciency have been reported in post-marketing experience (frequency not known). (frequency unknown)
• Lactic acidosis (0.03 cases/1000 patient-years) is very rare
• Hemolytic anemia (frequency unknown)
• Reduction of thyrotropin level in patients with hypothyroidism (frequency unknown)
• Hypomagnesemia in the context of diarrhea (frequency unknown)
• Encephalopathy (frequency unknown)
• Photosensitivity (frequency unknown)
• Hepatobiliary disorders: Reports of liver function tests abnormalities and hepatitis resolving upon metformin discontinuation

For Glimepiride-

• In patients hypersensitive to glimepiride, metformin, other sulfonylureas, other sulfonamides, or any of the excipients of Amaryl M.
• In pregnant women.
• In breastfeeding women.

No experience has been gained concerning the use of glimepiride in patients with severe impairment of liver function and in dialysis patients. In patients with severe impairment of hepatic function, change-over to insulin is indicated, not least to achieve optimal metabolic control.

For Metformin-

• Hypersensitivity to metformin or any of the excipients.
• Any type of acute metabolic acidosis such as lactic acidosis Diabetic ketoacidosis, diabetic pre-coma.
• Severe Renal failure or renal disfunction (e.g., serum creatine levels >135 μmol/L in males and >110 μmol/L in females), GFR < 30 mL/min.
• Acute conditions with the potential to alter renal function such as Dehydration, severe infection, intravascular administration of iodinated contrast agents etc.
• Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock
• Hepatic insufciency.
• Acute alcohol intoxication, alcoholism.
• Lactation.

For Glimepiride: In the initial weeks of treatment, the risk of hypoglycemia may be increased and necessitates especially careful monitoring. If risk factors for hypoglycemia are present, it may be necessary to adjust the dosage of glimepiride or the entire therapy. This also applies whenever illness occurs during therapy or the patient's life-style changes. It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur. Patients must, therefore, remain under close observation. Severe hypoglycaemia further requires immediate treatment and follow-up by a physician and, in some circumstances, in-patient hospital care. Treatment of patients with G6PD-defciency with sulfonylurea agents can lead to hemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-defciency and a non-sulfonylurea alternative should be considered.

For Metformin: Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients withhypothyroidism. Long-term treatment with metformin has been associated with a decrease in vitamin B12 serumlevels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

For Glimepiride:

• Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is coadministered with inducers (e.g. rifampicin) or inhibitors (e.g. fuconazole) of CYP 2C9.
• Potentiation of the blood-glucose-lowering efect and, thus, in some instances hypoglycaemia may occur when one of the following drugs is taken, for example: insulin and other, oral antidiabetics; ACE inhibitors; anabolic steroids and male sex hormones; chloramphenicol; coumarin derivatives; cyclophosphamide; disopyramide; fenfuramine; fenyramidol; fbrates; fuoxetine; guanethidine; ifosfamide; MAO inhibitors; miconazole; fuconazole; para-aminosalicylic acid; pentoxifylline (high dose parenteral); phenylbutazone; azapropazone; oxyphenbutazone; probenecid; quinolones; salicylates; sulfnpyrazone; clarithromycin; sulfonamide antibiotics; tetracyclines; tritoqualine; trofosfamide.
• Weakening of the blood-glucose-lowering efect and, thus raised blood glucose levels may occur when one of the following drugs is taken, for example: acetazolamide; barbiturates; corticosteroids; diazoxide; diuretics; epinephrine (adrenaline) and other sympathomimetic agents; glucagon; laxatives (after protracted use); nicotinic acid (in high doses); oestrogens and progestogens; phenothiazines; phenytoin; rifampicin; thyroid hormones.
• H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering efect. Under the infuence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent.
• Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering action of glimepiride in an unpredictable fashion.
• The efect of coumarin derivatives may be potentiated or weakened.
• Bile acid sequestrant: Colesevelam binds to glimepiride and reduces glimepiride absorption from the gastrointestinal tract. Glimepiride should be administered at least 4 hours prior to colesevelam.

For Metformin: Concomitant use not recommended:

• Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting, malnutrition or hepatic insufciency. Avoid consumption of alcohol and alcohol-containing medications
• Iodinated contrast agents: Metformin must be discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable.
• Combinations requiring precautions for use: Some medicinal products can adversely afect renal function which may increase the risk of lactic Acidosis. When starting or using such products in combination with metformin, close monitoring of renal function is necessary. Glucocorticoids, beta-2-agonists, and diuretics have intrinsic hyperglycemic activity. Inform the patient and perform more frequent blood glucose monitoring. ACE-inhibitors may decrease the blood glucose levels. Metformin may decrease the anticoagulant efect of phenprocoumon. Therefore, a close monitoring of the INR is recommended. Levothyroxine can reduce the hypoglycemic efect 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.

Organic cation transporters (OCT): Metformin is a substrate of both transporters OCT1 and OCT2. Co-administration of metformin with:

• Inhibitors of OCT1 (such as verapamil) may reduce efcacy of metformin.
• Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efcacy of metformin.
• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.
• Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efcacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are coadministered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efcacy of metformin.

Pregnancy-

• For Glimepiride: Glimepiride must not be taken during pregnancy. Otherwise, there is risk of harm to the child. The patient must change over to insulin during pregnancy. Patients planning a pregnancy must inform their physician. It is recommended that such patients change over to insulin.
• For Metformin: When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.

Lactation-

• For Glimepiride: To prevent possible ingestion with the breast milk and possible harm to the child, glimepiride must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breastfeeding.
• For Metformin: Metformin is excreted into milk in lactating rats. Similar data is not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the compound to the mother.

Children: Data is insufficient to recommend pediatric use of this tablet.

Renal impairment: A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering the initiation of metformin in patients with GFR<60 mL/min. If no adequate strength of this tablet is available, individual monocomponents should be used instead of the fixed dose combination.

GFR 60-89 ml/min:

• Metformin: Maximum daily dose is 3000 mg. Dose reduction may be considered in relation to declining renal function.
• Glimepiride: The highest recommended dose per day should be 8 mg of glimepiride.

GFR 45-59 ml/min:

• Metformin: Maximum daily dose is 2000 mg. The starting dose is at most half of the maximum dose.

GFR 30-44 ml/min:

• Metformin: Maximum daily dose is 1000 mg. The starting dose is at most half of the maximum dose.

GFR <30 ml/min:

• Metformin: Metformin is contraindicated
• Glimepiride: Change-over to insulin is indicated, not least to achieve optimal metabolic control.

For Glimepiride: Acute overdosage, as well as long-term treatment with too high a dose of glimepiride, may lead to severe life-threatening hypoglycaemia. As soon as an overdose of glimepiride has been discovered, a physician must be notifed without delay. The patient must immediately take sugar, if possible in the form of glucose unless a physician has already undertaken responsibility for treating the overdose. Careful monitoring is essential until the physician is confdent that the patient is out of danger. It must be remembered that hypoglycaemia may recur after initial recovery. Admission to hospital may sometimes be necessary even as a precautionary measure. In particular, signifcant overdoses and severe reactions with signs such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and admission to hospital. If, for example, the patient is unconscious, an intravenous injection of concentrated glucose solution is indicated (for adults starting with 40 ml of 20% solution, for example). Alternatively in adults, administration of glucagon, e.g. in doses of 0.5 to 1 mg i.v., s.c. or i.m., may be considered. In particular when treating hypoglycaemia due to accidental intake of glimepiride in infants and young children, the dose of glucose given must be very carefully adjusted in view of the possibility of producing dangerous hyperglycaemia, and must be controlled by close monitoring of blood glucose. Patients who have ingested life-threatening amounts of glimepiride require detoxifcation (e.g. by gastric lavage and medicinal charcoal). After acute glucose replacement has been completed it is usually necessary to give an intravenous glucose infusion in lower concentration so as to ensure that the hypoglycaemia does not recur. The patient's blood glucose level should be carefully monitored for at least 24 hours. In severe cases with a protracted course, hypoglycaemia, or the danger of slipping back into hypoglycaemia, may persist for several days.

For Metformin: Hypoglycaemia has not been seen with metformin doses of up to 85 g, although Lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis Lactic acidosis is a medical emergency and must be treated in hospital. The most efective method to remove lactate and metformin is haemodialysis. Pancreatitis may occur in the context of a metformin overdose.

Store in a cool (not exceeding 25°C) and dry place, protected from light.

Proton Pump Inhibitor

Omeprazole, a substituted benzimidazole, is an inhibitor of gastric acid secretion. It inhibits gastric acid secretion by blocking hydrogen-potassium-adenosine triphosphatase (H⁺/K⁺ ATPase) enzyme system in the gastric parietal cell. After oral administration, the onset of the antisecretory effect occurs within one hour, with the maximum effect occurring within two hours and inhibition of secretion lasts up to 72 hours. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days.

Oral-

• Benign gastric and duodenal ulcer: 20 mg once daily for 4 weeks in duodenal ulceration, 8 weeks in gastric ulceration; in severe or recurrent cases, dose to be increased to 40 mg daily; maintenance dose for recurrent duodenal ulcer, 20 mg once daily; in prevention of relapse in duodenal ulcer, 10-20 mg daily.
• NSAID-associated duodenal or gastric ulcer: 20 mg once daily for 4 weeks, continued for further 4 weeks, if not fully healed. 20 mg once daily is used as prophylaxis in patients with a history of NSAID-associated duodenal or gastric ulcers.
• Gastro-esophageal reflux disease: 20 mg once daily for 4 weeks, continued for further 4-8 weeks, if not fully healed; 40 mg once daily has been given for 8 weeks in gastro-esophageal reflux disease, refractory to other treatment; maintenance dose is 20 mg once daily.
• Long-term management of acid reflux disease: 10-20 mg daily.
• Acid-related dyspepsia: 10-20 mg once daily for 2-4 weeks.
• Prophylaxis of acid aspiration: 40 mg on the preceding evening, then 40 mg 2-6 hours before surgery.
• Zollinger-Ellison syndrome: Initially 60 mg once daily; usual range 20-120 mg daily (If daily dose is more than 80 mg, 2 divided dose should be used).
• Helicobacter pylori eradication regimen in peptic ulcer disease: Omeprazole is recommended at a dose of 20 mg twice daily in association with antimicrobial agents as detailed below: Amoxicillin 500 mg and Metronidazole 400 mg both three times a day for one week, or Clarithromycin 250 mg and Metronidazole 400 mg both twice a day for one week, or Amoxicillin 1 g and Clarithromycin 500 mg both twice a day for one week.
• Paeditaric use in severe ulcerating reflux esophagitis (Child>1 year): If body-weight 10-20 kg, 10-20 -mg once daily for 4-12 weeks; if body-weight over 20 kg, 20-40 mg once daily for 4-12 weeks.

IV Injection-

• Prophylaxis of acid aspiration: Omeprazole 40 mg to be given slowly (over a period of 5 minutes) as an intravenous injection, one hour before surgery.
• Duodenal ulcer, gastric ulcer or reflux oesophagitis: In patients with duodenal ulcer, gastric ulcer or reflux oesophagitis where oral medication is inappropriate, Omeprazole IV 40 mg once daily is recommended.
• Zollinger- Ellison syndrome (ZES): In patients with Zollinger-Ellison Syndrome the recommended initial dose of Omeprazole given intravenously is 60 mg daily. Higher daily doses may be required and the dose should be adjusted individually. When doses exceed 60 mg daily, the dose should be divided & given twice daily.

Direction for use of IV Injection: Omeprazole lyophilized powder and water for injection is for intravenous administration only and must not be given by any other route. Omeprazole IV injection should be given as a slow intravenous injection. The solution for IV injection is obtained by adding 10 ml water for injection to the vial containing powder. After reconstitution the injection should be given slowly over a period of at least 2 to 5 minutes at a maximum rate of 4 ml/minute. Use only freshly prepared solution. The solution should be used within 4 hours of reconstitution.

Direction for use of IV Infusion: Omeprazole IV infusion should be given as an intravenous infusion over a period of 20-30 minutes or more. The contents of one vial must be dissolved in 100 ml saline for infusion or 100 ml 5% Dextrose for infusion. The solution should be used within 12 hours when Omeprazole is dissolved in saline and within 6 hours when dissolved in 5% Dextrose. The reconstituted solution should not be mixed or co-administered in the same infusion set with any other drug.

Omeprazole is generally well tolerated. Nausea, abdominal colic, paresthesia, dizziness and headache have been stated to be generally mild and transient and not requiring a reduction in dosage.

Omeprazole is contraindicated in patients with known hypersensitivity to any of the components of the formulation.

When gastric ulcer is suspected, the possibility of gastric malignancy should be excluded before treatment with Omeprazole is instituted, as treatment may alleviate the symptoms and delay diagnosis.

Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin. So, reduction of warfarin or phenytoin dose may be necessary when Omeprazole is added to the treatment. There is no evidence of an interaction of Omeprazole with theophylline, propranolol or antacids.

US FDA pregnancy category of Omeprazole is C. However, results from three prospective epidemiological studies indicate no adverse effects of Omeprazole on pregnancy or on the health of the fetus/newborn child. There is no information available on the passage of Omeprazole into breast milk or its effects on the neonate. Breast-feeding should, therefore, be discontinued, if the use of Omeprazole is considered essential.

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

Proton Pump Inhibitor

Omeprazole, a substituted benzimidazole, is an inhibitor of gastric acid secretion. It inhibits gastric acid secretion by blocking hydrogen-potassium-adenosine triphosphatase (H⁺/K⁺ ATPase) enzyme system in the gastric parietal cell. After oral administration, the onset of the antisecretory effect occurs within one hour, with the maximum effect occurring within two hours and inhibition of secretion lasts up to 72 hours. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days.

Oral-

• Benign gastric and duodenal ulcer: 20 mg once daily for 4 weeks in duodenal ulceration, 8 weeks in gastric ulceration; in severe or recurrent cases, dose to be increased to 40 mg daily; maintenance dose for recurrent duodenal ulcer, 20 mg once daily; in prevention of relapse in duodenal ulcer, 10-20 mg daily.
• NSAID-associated duodenal or gastric ulcer: 20 mg once daily for 4 weeks, continued for further 4 weeks, if not fully healed. 20 mg once daily is used as prophylaxis in patients with a history of NSAID-associated duodenal or gastric ulcers.
• Gastro-esophageal reflux disease: 20 mg once daily for 4 weeks, continued for further 4-8 weeks, if not fully healed; 40 mg once daily has been given for 8 weeks in gastro-esophageal reflux disease, refractory to other treatment; maintenance dose is 20 mg once daily.
• Long-term management of acid reflux disease: 10-20 mg daily.
• Acid-related dyspepsia: 10-20 mg once daily for 2-4 weeks.
• Prophylaxis of acid aspiration: 40 mg on the preceding evening, then 40 mg 2-6 hours before surgery.
• Zollinger-Ellison syndrome: Initially 60 mg once daily; usual range 20-120 mg daily (If daily dose is more than 80 mg, 2 divided dose should be used).
• Helicobacter pylori eradication regimen in peptic ulcer disease: Omeprazole is recommended at a dose of 20 mg twice daily in association with antimicrobial agents as detailed below: Amoxicillin 500 mg and Metronidazole 400 mg both three times a day for one week, or Clarithromycin 250 mg and Metronidazole 400 mg both twice a day for one week, or Amoxicillin 1 g and Clarithromycin 500 mg both twice a day for one week.
• Paeditaric use in severe ulcerating reflux esophagitis (Child>1 year): If body-weight 10-20 kg, 10-20 -mg once daily for 4-12 weeks; if body-weight over 20 kg, 20-40 mg once daily for 4-12 weeks.

IV Injection-

• Prophylaxis of acid aspiration: Omeprazole 40 mg to be given slowly (over a period of 5 minutes) as an intravenous injection, one hour before surgery.
• Duodenal ulcer, gastric ulcer or reflux oesophagitis: In patients with duodenal ulcer, gastric ulcer or reflux oesophagitis where oral medication is inappropriate, Omeprazole IV 40 mg once daily is recommended.
• Zollinger- Ellison syndrome (ZES): In patients with Zollinger-Ellison Syndrome the recommended initial dose of Omeprazole given intravenously is 60 mg daily. Higher daily doses may be required and the dose should be adjusted individually. When doses exceed 60 mg daily, the dose should be divided & given twice daily.

Direction for use of IV Injection: Omeprazole lyophilized powder and water for injection is for intravenous administration only and must not be given by any other route. Omeprazole IV injection should be given as a slow intravenous injection. The solution for IV injection is obtained by adding 10 ml water for injection to the vial containing powder. After reconstitution the injection should be given slowly over a period of at least 2 to 5 minutes at a maximum rate of 4 ml/minute. Use only freshly prepared solution. The solution should be used within 4 hours of reconstitution.

Direction for use of IV Infusion: Omeprazole IV infusion should be given as an intravenous infusion over a period of 20-30 minutes or more. The contents of one vial must be dissolved in 100 ml saline for infusion or 100 ml 5% Dextrose for infusion. The solution should be used within 12 hours when Omeprazole is dissolved in saline and within 6 hours when dissolved in 5% Dextrose. The reconstituted solution should not be mixed or co-administered in the same infusion set with any other drug.

Omeprazole is generally well tolerated. Nausea, abdominal colic, paresthesia, dizziness and headache have been stated to be generally mild and transient and not requiring a reduction in dosage.

Omeprazole is contraindicated in patients with known hypersensitivity to any of the components of the formulation.

When gastric ulcer is suspected, the possibility of gastric malignancy should be excluded before treatment with Omeprazole is instituted, as treatment may alleviate the symptoms and delay diagnosis.

Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin. So, reduction of warfarin or phenytoin dose may be necessary when Omeprazole is added to the treatment. There is no evidence of an interaction of Omeprazole with theophylline, propranolol or antacids.

US FDA pregnancy category of Omeprazole is C. However, results from three prospective epidemiological studies indicate no adverse effects of Omeprazole on pregnancy or on the health of the fetus/newborn child. There is no information available on the passage of Omeprazole into breast milk or its effects on the neonate. Breast-feeding should, therefore, be discontinued, if the use of Omeprazole is considered essential.

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

Diazepam is indicated for the short-term treatment of mild to moderate anxiety, excitation, agitation, fear, aggressiveness, etc. Anxiety reactions caused by stressed conditions, anxiety states with somatic expression, acute alcohol withdrawal, status epilepticus, premedication for surgical procedures, febrile convulsions, insomnia of hospitalized patients.

Benzodiazepine sedatives, Centrally acting Skeletal Muscle Relaxants, Primary anti-epileptic drugs

Diazepam attaches to the specific site on the GABA receptor and potentiates the effect of GABA, which acts by opening chloride ion channels into cells.

Diazepam is absorbed rapidly and completely after oral administration. Peak Plasma concentration reaches within 15-90 minutes. Mean plasma half-life is 30 hours. Plasma protein binding is 98-99%. Diazepam is metabolized in the liver with only traces of the unchanged drug excreted in urine. A very small proportion of the metabolites is excreted through the bile into the intestine and eliminated with the feces. After rectal administration in suppository form diazepam is significantly absorbed and peak concentration reaches within 1.5-2 hours.

Oral:

• Anxiety: 2 mg thrice daily, increased if necessary to 15-30 mg daily in divided doses. Elderly (or debilitated), half of the adult dose.
• Insomnia associated with anxiety: 5-15 mg at bedtime.
• Night terrors and somnambulism in Child: 1-5 mg at bedtime.

IM/slow IV injection (large vein, a rate below 5 mg/minute):

• For severe acute anxiety, control of acute panic attacks, and acute alcohol withdrawal: 10 mg repeated if necessary after not less than 4 hours.
• Febrile convulsion in children: Slow IV in a dose of 250 mcg/kg.

Rectal:

• In case of children- A dose of 500 mcg/kg (maximum 10 mg), repeated if necessary.

Diazepam is generally well tolerated. Higher doses may cause somnolence, dizziness, light headedness, confusion and ataxia.

Diazepam is contraindicated in myasthenia gravis, pulmonary insufficiency, respiratory depression and hypersensitivity to bezodiazepine.

Prolonged use and abrupt withdrawal should be avoided. Diazepam should be used with caution in respiratory disease, muscle weakness, history of drug or alcohol abuse, in hepatic or renal impairment.

Concomitant intake with alcohol is not recommended. Sedation may be increased due to concomitant use of neuroleptics (antipsychotics), hypnotics, sedative antihistamines and CNS depressants e.g., general anesthetics, narcotic analgesics or antidepressants. Diazepam clearance is increased by concomitant administration of phonobarbitone and is decreased by administration of cimetidine. Omeprazole and isoniazide inhibit diazepam metabolism.

Diazepam and its active metabolites cross the placental barrier and also pass into breast milk. So, it should be avoided if possible during pregnancy and lactation. US FDA pregnancy category D.

Sedation, muscle weakness, profound sleep or paradoxical excitation. In more severe cases symptoms may include ataxia, hypotonia, hypotension, respiratory depression and rarely coma and death.

Store in a cool (below 25˚C temperature) and dry place protected from light.

Midazolam is indicated in-

• Short-term treatment of insomnia.
• Sedation in premedication before surgical or diagnostic procedures.

Benzodiazepine hypnotics, Benzodiazepine sedatives

The actions of benzodiazepines such as midazolam are mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is one of the major inhibitory neurotransmitters in the central nervous system. Benzodiazepines increase the activity of GABA, thereby producing a sedating effect, relaxing skeletal muscles, and inducing sleep, anesthesia, and amnesia. Benzodiazepines bind to the benzodiazepine site on GABA-A receptors, which potentiates the effects of GABA by increasing the frequency of chloride channel opening. These receptors have been identified in different body tissues including the heart and skeletal muscle, although mainly appear to be present in the central nervous system.

Oral dosage:

• For adults: 7.5-15 mg daily.
• In elderly and debilitated patients: The recommended dose is 7.5 mg.
• In premedication: 15 mg of Midazolam should be given 30-60 minutes before the procedure.

Intravenous administration:

• Endoscopic or Cardiovascular Procedures: In healthy adults, the initial dose is approximately 2.5 mg. In cases of severe illness and in elderly patients, the initial dose must be reduced to 1 to 1.5 mg.
• Induction of Anesthesia: The dose is 10-15 mg.

Intramuscular administration:

• Adult: 0.07-0.1 mg/kg body weight. The usual dose is about 5 mg.
• Children: 0.15-0.20 mg/kg
• Elderly and debilitated patients: 0.025-0.05 mg/kg

Rectal administration in children:

• For preoperative sedation: Rectal administration of the ampoule solution (0.35-0.45 mg/kg) 20-30 min. before induction of general anesthesia.

At the start of therapy, drowsiness during daytime, confusion, fatigue, headache and muscle weakness may occur which usually disappear with repeated administration. Following parenteral (IV or IM) administration of Midazolam, fluctuations in vital signs have been noted including respiratory depression, apnea, variations in blood pressure and pulse rate.

Midazolam must not be given to patients with severe respiratory insufficiency, severe hepatic insufficiency, myasthenia gravis, sleep apnea syndrome and with known hypersensitivity to benzodiazepines or to any component of the product

Midazolam IV should be administered very slowly.

Midazolam can enhance the central sedative effect of neuroleptics, tranquillizers, antidepressants, sleep-inducing drugs, analgesics, anaesthetics, antipsychotics, anxiolytics, antiepileptic drugs and sedative antihistamines.

Midazolam should be avoided during pregnancy unless there is no safer alternative. Since Midazolam passes into breast milk, it should not be administered to breast-feeding mothers.

Extreme overdosage may lead to coma, areflexia, cardiorespiratory depression and apnea. The effects of overdosage can be controlled with benzodiazepine antagonist flumazenil.

Protect from light and moisture, store in cool and dry place. Keep out of the reach of children.

Diazepam is indicated for the short-term treatment of mild to moderate anxiety, excitation, agitation, fear, aggressiveness, etc. Anxiety reactions caused by stressed conditions, anxiety states with somatic expression, acute alcohol withdrawal, status epilepticus, premedication for surgical procedures, febrile convulsions, insomnia of hospitalized patients.

Benzodiazepine sedatives, Centrally acting Skeletal Muscle Relaxants, Primary anti-epileptic drugs

Diazepam attaches to the specific site on the GABA receptor and potentiates the effect of GABA, which acts by opening chloride ion channels into cells.

Diazepam is absorbed rapidly and completely after oral administration. Peak Plasma concentration reaches within 15-90 minutes. Mean plasma half-life is 30 hours. Plasma protein binding is 98-99%. Diazepam is metabolized in the liver with only traces of the unchanged drug excreted in urine. A very small proportion of the metabolites is excreted through the bile into the intestine and eliminated with the feces. After rectal administration in suppository form diazepam is significantly absorbed and peak concentration reaches within 1.5-2 hours.

Oral:

• Anxiety: 2 mg thrice daily, increased if necessary to 15-30 mg daily in divided doses. Elderly (or debilitated), half of the adult dose.
• Insomnia associated with anxiety: 5-15 mg at bedtime.
• Night terrors and somnambulism in Child: 1-5 mg at bedtime.

IM/slow IV injection (large vein, a rate below 5 mg/minute):

• For severe acute anxiety, control of acute panic attacks, and acute alcohol withdrawal: 10 mg repeated if necessary after not less than 4 hours.
• Febrile convulsion in children: Slow IV in a dose of 250 mcg/kg.

Rectal:

• In case of children- A dose of 500 mcg/kg (maximum 10 mg), repeated if necessary.

Diazepam is generally well tolerated. Higher doses may cause somnolence, dizziness, light headedness, confusion and ataxia.

Diazepam is contraindicated in myasthenia gravis, pulmonary insufficiency, respiratory depression and hypersensitivity to bezodiazepine.

Prolonged use and abrupt withdrawal should be avoided. Diazepam should be used with caution in respiratory disease, muscle weakness, history of drug or alcohol abuse, in hepatic or renal impairment.

Concomitant intake with alcohol is not recommended. Sedation may be increased due to concomitant use of neuroleptics (antipsychotics), hypnotics, sedative antihistamines and CNS depressants e.g., general anesthetics, narcotic analgesics or antidepressants. Diazepam clearance is increased by concomitant administration of phonobarbitone and is decreased by administration of cimetidine. Omeprazole and isoniazide inhibit diazepam metabolism.

Diazepam and its active metabolites cross the placental barrier and also pass into breast milk. So, it should be avoided if possible during pregnancy and lactation. US FDA pregnancy category D.

Sedation, muscle weakness, profound sleep or paradoxical excitation. In more severe cases symptoms may include ataxia, hypotonia, hypotension, respiratory depression and rarely coma and death.

Store in a cool (below 25˚C temperature) and dry place protected from light.

Diazepam is indicated for the short-term treatment of mild to moderate anxiety, excitation, agitation, fear, aggressiveness, etc. Anxiety reactions caused by stressed conditions, anxiety states with somatic expression, acute alcohol withdrawal, status epilepticus, premedication for surgical procedures, febrile convulsions, insomnia of hospitalized patients.

Benzodiazepine sedatives, Centrally acting Skeletal Muscle Relaxants, Primary anti-epileptic drugs

Diazepam attaches to the specific site on the GABA receptor and potentiates the effect of GABA, which acts by opening chloride ion channels into cells.

Diazepam is absorbed rapidly and completely after oral administration. Peak Plasma concentration reaches within 15-90 minutes. Mean plasma half-life is 30 hours. Plasma protein binding is 98-99%. Diazepam is metabolized in the liver with only traces of the unchanged drug excreted in urine. A very small proportion of the metabolites is excreted through the bile into the intestine and eliminated with the feces. After rectal administration in suppository form diazepam is significantly absorbed and peak concentration reaches within 1.5-2 hours.

Oral:

• Anxiety: 2 mg thrice daily, increased if necessary to 15-30 mg daily in divided doses. Elderly (or debilitated), half of the adult dose.
• Insomnia associated with anxiety: 5-15 mg at bedtime.
• Night terrors and somnambulism in Child: 1-5 mg at bedtime.

IM/slow IV injection (large vein, a rate below 5 mg/minute):

• For severe acute anxiety, control of acute panic attacks, and acute alcohol withdrawal: 10 mg repeated if necessary after not less than 4 hours.
• Febrile convulsion in children: Slow IV in a dose of 250 mcg/kg.

Rectal:

• In case of children- A dose of 500 mcg/kg (maximum 10 mg), repeated if necessary.

Diazepam is generally well tolerated. Higher doses may cause somnolence, dizziness, light headedness, confusion and ataxia.

Diazepam is contraindicated in myasthenia gravis, pulmonary insufficiency, respiratory depression and hypersensitivity to bezodiazepine.

Prolonged use and abrupt withdrawal should be avoided. Diazepam should be used with caution in respiratory disease, muscle weakness, history of drug or alcohol abuse, in hepatic or renal impairment.

Concomitant intake with alcohol is not recommended. Sedation may be increased due to concomitant use of neuroleptics (antipsychotics), hypnotics, sedative antihistamines and CNS depressants e.g., general anesthetics, narcotic analgesics or antidepressants. Diazepam clearance is increased by concomitant administration of phonobarbitone and is decreased by administration of cimetidine. Omeprazole and isoniazide inhibit diazepam metabolism.

Diazepam and its active metabolites cross the placental barrier and also pass into breast milk. So, it should be avoided if possible during pregnancy and lactation. US FDA pregnancy category D.

Sedation, muscle weakness, profound sleep or paradoxical excitation. In more severe cases symptoms may include ataxia, hypotonia, hypotension, respiratory depression and rarely coma and death.

Store in a cool (below 25˚C temperature) and dry place protected from light.

Diazepam is indicated for the short-term treatment of mild to moderate anxiety, excitation, agitation, fear, aggressiveness, etc. Anxiety reactions caused by stressed conditions, anxiety states with somatic expression, acute alcohol withdrawal, status epilepticus, premedication for surgical procedures, febrile convulsions, insomnia of hospitalized patients.

Benzodiazepine sedatives, Centrally acting Skeletal Muscle Relaxants, Primary anti-epileptic drugs

Diazepam attaches to the specific site on the GABA receptor and potentiates the effect of GABA, which acts by opening chloride ion channels into cells.

Diazepam is absorbed rapidly and completely after oral administration. Peak Plasma concentration reaches within 15-90 minutes. Mean plasma half-life is 30 hours. Plasma protein binding is 98-99%. Diazepam is metabolized in the liver with only traces of the unchanged drug excreted in urine. A very small proportion of the metabolites is excreted through the bile into the intestine and eliminated with the feces. After rectal administration in suppository form diazepam is significantly absorbed and peak concentration reaches within 1.5-2 hours.

Oral:

• Anxiety: 2 mg thrice daily, increased if necessary to 15-30 mg daily in divided doses. Elderly (or debilitated), half of the adult dose.
• Insomnia associated with anxiety: 5-15 mg at bedtime.
• Night terrors and somnambulism in Child: 1-5 mg at bedtime.

IM/slow IV injection (large vein, a rate below 5 mg/minute):

• For severe acute anxiety, control of acute panic attacks, and acute alcohol withdrawal: 10 mg repeated if necessary after not less than 4 hours.
• Febrile convulsion in children: Slow IV in a dose of 250 mcg/kg.

Rectal:

• In case of children- A dose of 500 mcg/kg (maximum 10 mg), repeated if necessary.

Diazepam is generally well tolerated. Higher doses may cause somnolence, dizziness, light headedness, confusion and ataxia.

Diazepam is contraindicated in myasthenia gravis, pulmonary insufficiency, respiratory depression and hypersensitivity to bezodiazepine.

Prolonged use and abrupt withdrawal should be avoided. Diazepam should be used with caution in respiratory disease, muscle weakness, history of drug or alcohol abuse, in hepatic or renal impairment.

Concomitant intake with alcohol is not recommended. Sedation may be increased due to concomitant use of neuroleptics (antipsychotics), hypnotics, sedative antihistamines and CNS depressants e.g., general anesthetics, narcotic analgesics or antidepressants. Diazepam clearance is increased by concomitant administration of phonobarbitone and is decreased by administration of cimetidine. Omeprazole and isoniazide inhibit diazepam metabolism.

Diazepam and its active metabolites cross the placental barrier and also pass into breast milk. So, it should be avoided if possible during pregnancy and lactation. US FDA pregnancy category D.

Sedation, muscle weakness, profound sleep or paradoxical excitation. In more severe cases symptoms may include ataxia, hypotonia, hypotension, respiratory depression and rarely coma and death.

Store in a cool (below 25˚C temperature) and dry place protected from light.

Chlorpheniramine Maleate is indicated in the following indications-

• Urticaria
• Sensitivity reactions
• Angioneurotic edema
• Vasomotor rhinitis
• Cough
• Common cold
• Motion sickness and
• Other allergic conditions.

Sedating Anti-histamine

Chlorpheniramine Maleate is an alkylamine antihistamine. It is one of the most potent histamine H1-receptor blocking agents which is used as a potent antihistamine. This generally causes less sedation than promethazine. Chlorpheniramine Maleate exerts its effects by blocking H1-receptor competitively.

Adult- Usual adult dose is 4 mg every 4-6 hours, maximum 24 mg daily.

Child-

• 6-12 years: 2 mg every 4-6 hours, maximum 12 mg daily.
• 2-5 years: 1 mg every 4-6 hours, maximum 6 mg daily.
• 1-2 years: 1 mg twice daily.

Below 1 year the use of Chlorpheniramine Maleate is not recommended.

Chlorpheniramine is well-tolerated, but sometimes drowsiness, dizziness, muscular weakness, and gastrointestinal upset may occur.

Chlorpheniramine is contraindicated in patients hypersensitive to this agent, in newborn or premature infants.

Chlorpheniramine should be used with caution in patients with glaucoma and prostatic hypertrophy. During therapy with chlorpheniramine, caution should be taken in driving vehicles and operating machinery.

Chlorphenamine maleate has been reported to be incompatible with calcium chloride, kanamycin sulfate, noradrenaline acid tartrate, pentobarbital sodium, and meglumine adipiodone.

This drug should not be used in lactating mother and in pregnancy especially during the first trimester of pregnancy.

CNS depression (including sedation, apnea, CV collapse), CNS stimulation (including insomnia, hallucination, tremors, convulsions), tinnitus, blurred vision, dizziness, ataxia, hypotension. Stimulation and atropine-like signs and symptoms (including dry mouth, fixed dilated pupils, flushing, hyperthermia, Gl symptoms) are more likely in children.

Store in a cool (Below 25°C temperature) and dry place protected from light. Keep out of the reach of children.

Chlorpheniramine Maleate is indicated in the following indications-

• Urticaria
• Sensitivity reactions
• Angioneurotic edema
• Vasomotor rhinitis
• Cough
• Common cold
• Motion sickness and
• Other allergic conditions.

Sedating Anti-histamine

Chlorpheniramine Maleate is an alkylamine antihistamine. It is one of the most potent histamine H1-receptor blocking agents which is used as a potent antihistamine. This generally causes less sedation than promethazine. Chlorpheniramine Maleate exerts its effects by blocking H1-receptor competitively.

Adult- Usual adult dose is 4 mg every 4-6 hours, maximum 24 mg daily.

Child-

• 6-12 years: 2 mg every 4-6 hours, maximum 12 mg daily.
• 2-5 years: 1 mg every 4-6 hours, maximum 6 mg daily.
• 1-2 years: 1 mg twice daily.

Below 1 year the use of Chlorpheniramine Maleate is not recommended.

Chlorpheniramine is well-tolerated, but sometimes drowsiness, dizziness, muscular weakness, and gastrointestinal upset may occur.

Chlorpheniramine is contraindicated in patients hypersensitive to this agent, in newborn or premature infants.

Chlorpheniramine should be used with caution in patients with glaucoma and prostatic hypertrophy. During therapy with chlorpheniramine, caution should be taken in driving vehicles and operating machinery.

Chlorphenamine maleate has been reported to be incompatible with calcium chloride, kanamycin sulfate, noradrenaline acid tartrate, pentobarbital sodium, and meglumine adipiodone.

This drug should not be used in lactating mother and in pregnancy especially during the first trimester of pregnancy.

CNS depression (including sedation, apnea, CV collapse), CNS stimulation (including insomnia, hallucination, tremors, convulsions), tinnitus, blurred vision, dizziness, ataxia, hypotension. Stimulation and atropine-like signs and symptoms (including dry mouth, fixed dilated pupils, flushing, hyperthermia, Gl symptoms) are more likely in children.

Store in a cool (Below 25°C temperature) and dry place protected from light. Keep out of the reach of children.

Non-sedating antihistamines

Desloratadine, the major active metabolite of Loratadine, is a non-sedating; long acting tricyclic histamine antagonist with selective H1-receptor histamine antagonist activity. Desloratadine also inhibits histamine release from human mast cell.

Pediatric drops:

• Child 6-11 months of age: 2 ml drops once daily.
• Child 1-2 years of age: 2.5 ml drops once daily.

Syrup:

• Child 6-11 months of age: 2 ml once daily.
• Child 1-5 years of age: 2.5 ml once daily.
• Child 6-11 years of age: 5 ml once daily.
• Adults & >12 years of age: 10 ml once daily.

Tablet:

• Adults and children 12 years of age and over: 1 tablet daily

Less common side effects may include headache, nausea, fatigue, dizziness, pharyngitis, dyspepsia and myalgia.

Desloratadine is contraindicated in patients having hypersensitivity to this medication or to any of its ingredients or Loratadine.

In adult patients with liver or renal impairment: A starting dose of one 5 mg tablet every other day is recommended based on pharmacokinetic data. If the patient has medical or familial history of seizures.

No clinically relevant drug interactions have been reported.

Pregnancy Category C. The safe use of Desloratadine during pregnancy has not been established. Therefore, Desloratadine is not to be used during pregnancy unless clearly indicated. Desloratadine passes into breast milk, therefore a decision should be made whether to discontinue nursing or to discontinue Desloratadine taking into account the importance of the drug to the mother.

Recommended in the use in children & adolescents.

No clinically relevant adverse effects have been reported.

Store in a cool & dry place, protected from light. Store below 30°C. Keep all medicines out of the reach of children.

Third generation Cephalosporins

Cefpodoxime is an oral 3rd generation cephalosporin, which has good stability to beta lactamases and activity against Gram negative and Gram positive bacteria. It is indicated for the treatment of infections either before the infecting organism has been identified. It is a prodrug its active metabolite is Cefpodoxime. Approximately 29 to 33% of Cefpodoxime excreted unchanged in the urine in 12 hours.

Adults and Adolescents (13 years and older)

• Pharyngitis/tonsillitis: 100 mg 12 hourly, 5 to 10 days
• Acute maxillary sinusitis: 200 mg 12 hourly, 10 day
• Community acquired pneumonia: 200 mg 12 hourly, 14 days
• Acute bacterial exacerbations of chronic bronchitis: 200 mg 12 hourly, 10 days
• Skin and skin structure: 400 mg 12 hourly, 7 to 14 days
• Uncomplicated urinary tract infection: 100 mg 12 hourly, 7 days
• Uncomplicated gonorrhea: single dose of 200 mg
• Rectal gonococcal infections in women: single dose of 200 mg

Infants and Pediatric Patients (2 months to 12 years)

• Acute otitis media: 5 mg/kg body weight 12 hourly, 5 days
• Pharyngitis /tonsillitis: 5 mg/kg body weight 12 hourly, 5 to 10 days
• Acute maxillary sinusitis: 5 mg/kg body weight 12 hourly, 10 days

Cefpodoxime has very few side effects. Possible side effects include gastrointestinal disorders (such as- diarrhea, nausea, vomiting and abdominal pain), rash, urticaria and itching.

Cefpodoxime is contraindicated in patients with known allergy to cephalosporins.

In patients with transient or persistent reduction in urinary output due to renal insufficiency, the total daily dose of Cefpodoxime should be reduced. Cefpodoxime should be administered with caution to patients receiving concurrent treatment with potent diuretics. As with other antibiotics, prolonged use of Cefpodoxime may result in overgrowth of non-susceptible organisms.

Cefpodoxime concomitant administration of high doses of antacids (sodium bicarbonate and aluminum hydroxide) or H2 blockers reduces peak plasma levels and the extent of absorption respectively. Renal excretion of Cefpodoxime is inhibit by probenecid.

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

Patients with severe renal impairment (creatinin clearance <30 ml/min) the dosing intervals should be increased to 24 hourly. The dosage adjustment is not require in cases of hepatic impairment.

Step 1: Shake the bottle well to loosen the powder.
Step 2: Add boiled and cooled water in the bottle.
Step 3: Shake until powder is completely mixed with water.

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

Bisphosphonate preparations

Risedronate has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Risedronat inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption.

Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures: The recommended dose is Risedronate Sodium 5 mg once daily or Risedronate Sodium 35 mg once weekly on the same day each week or Risedronate Sodium 150 mg once monthly. 

Prevention of osteoporosis in postmenopausal women with increased risk of osteoporosis: The recommended dose is Risedronate Sodium 5 mg once daily. 

To maintain or increase bone mass in postmenopausal women undergoing long-term (more than 3 months): Systemic corticosteroid treatment at doses 7.5 mg/day prednisone or equivalent. The recommended dose is Risedronate Sodium 5 mg once daily. 

Treatment of osteoporosis in men at high risk of fractures: The recommended dose is Risedronate Sodium 35 mg once weekly. The tablet should be taken on the same day each week.

The absorption of Risedronate Sodium is affected by food, thus to ensure adequate absorption patients should take Risedronate tablets at least 30 minutes before the first food, other medicinal product or drink (other than plain water) of the day. In the particular instances that before breakfast dosing is not practical, Risedronate 5 mg tablet can be taken between meals or in the evening at the same time everyday, with strict adherence to the following instructions, to ensure Risedronate Sodium tablet is taken on an empty stomach-Between meals:

Risedronate Sodium tablet should be taken at least 2 hours before and at least 2 hours after any food, medicinal product or drink (other than plain water). In the evening:

Risedronate Sodium tablet should be taken at least 2 hours after the last food, medicinal product or drink (other than plain water) of the day. If a dose is missed: Risedronate 5 mg tablet: If an occasional dose is missed, Risedronate 5 mg tablet can be taken before breakfast, between meals, or in the evening according to the instructions above.

Risedronate 35 mg tablet: Patients should be instructed that if a dose is missed, just take one Risedronate 35 mg tablet on the morning after remember. Patients should then return to taking one tablet once a week on the day the tablet is normally taken. Two tablets should not be taken on the same day.

Risedronate 150 mg tablet: Patient should be instructed that if a dose is missed and the next month’s schedule dose is more than 7 days away, then should take the missed tablet in the morning after the day it is remembered. Patients should then return to taking one tablet once a month normally taken.The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach Risedronate tablet is to be taken while in an upright position with a glass of plain water (120 ml or more). Patients should not lie down for 30 minutes after taking the tablet. Supplemental calcium and vitamin D should be considered if the dietary intake is inadequate.

Serious side effects:

• chest pain;
• difficulty or pain when swallowing;
• pain or burning under the ribs or in the back;
• new or worsening heartburn;
• severe joint, bone, or muscle pain; or
• jaw pain, numbness, or swelling.

Less serious side effects:

• mild heartburn or stomach upset;
• diarrhea, gas,or constipation;
• mild joint or back pain;
• headache.

Risedronate Sodium tablet is contraindicated in patients with known hypersensitivity to Risedronate Sodium and in patients with hypocalcaemia, severe renal impairment (creatinine clearance lower than 30 ml/min), during pregnancy and lactation.

Take special care with Risedronate if you:

• Have low blood calcium (hypocalcemia)
• Cannot sit or stand up for 30 minutes
• Have kidneys that work poorly
• Have an allergy to Risedronate Sodium

Before taking Risedronate talk to doctor if you:

• Are pregnant or may become pregnant. We do not know if Risedronate Sodium can harm your unborn child.
• Are breast-feeding or plan to breast-feed. We do not know if Risedronate Sodium can passthrough your milk and if it can harm your baby.
• Have kidney problems Risedronate Sodium may not be right for you.
• Risedronate sodium is not intended for use in children.

During treatment, if you experience an allergic reaction (such as swelling of the face, tongue or throat, difficulty in breathing or swallowing, skin rash), you must stop taking Risedronate sodium and seek medical advice immediately. If you have stopped treatment due to hypersensitivity reactions you should not re-start therapy with Risedronate sodium.

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription specially aspirin or other NSAIDs. Antacids, supplements, or medicines that contain aluminum, calcium, magnesium, or other minerals can interfere with how your body absorbs Risedronate Sodium. If you use these other medicines, do not take them for at least 30 minutes after taking a Risedronate Sodium tablet.

Pregnancy: Risedronate Sodium is meant for use only in postmenopausal women. Therefore, Risedronate Sodium should not be taken during pregnancy. If you take it by accident during pregnancy, stop taking it straight away and talk to your doctor.

Breast-feeding: Risedronate Sodium is meant for use only in postmenopausal women. Therefore, breast-feeding women should not take this medicine. If you take it by accident during breast-feeding, stop taking it straight away and talk to your doctor.

Elderly: No dosage adjustment is necessary since bioavailability, distribution and elimination were similar in elderly (60 years of age or older) compared to younger subjects. This has also been shown in the very elderly, 75 years old and above postmenopausal population. 

Renal impairment: No dosage adjustment is required for those patients with mild to moderate renal impairment. The use of Risedronate Sodium is contra-indicated in patients with severe renal impairment (Creatinine clearance lower than 30ml/min).

Seek emergency medical attention if you think you have used too much of this medicine. Drink a full glass of milk right away. Do not make yourself vomit and do not lie down.

Overdose symptoms may include nausea, heartburn, stomach pain, diarrhea, muscle cramps, numbness or tingling, tight muscles in your face, seizure (convulsions), irritability, and unusual thoughts or behavior.

Store in a cool and dry place. Protect from light & moisture. Keep out of the reach of children.

Bisphosphonate preparations

Risedronate has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Risedronat inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption.

Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures: The recommended dose is Risedronate Sodium 5 mg once daily or Risedronate Sodium 35 mg once weekly on the same day each week or Risedronate Sodium 150 mg once monthly. 

Prevention of osteoporosis in postmenopausal women with increased risk of osteoporosis: The recommended dose is Risedronate Sodium 5 mg once daily. 

To maintain or increase bone mass in postmenopausal women undergoing long-term (more than 3 months): Systemic corticosteroid treatment at doses 7.5 mg/day prednisone or equivalent. The recommended dose is Risedronate Sodium 5 mg once daily. 

Treatment of osteoporosis in men at high risk of fractures: The recommended dose is Risedronate Sodium 35 mg once weekly. The tablet should be taken on the same day each week.

The absorption of Risedronate Sodium is affected by food, thus to ensure adequate absorption patients should take Risedronate tablets at least 30 minutes before the first food, other medicinal product or drink (other than plain water) of the day. In the particular instances that before breakfast dosing is not practical, Risedronate 5 mg tablet can be taken between meals or in the evening at the same time everyday, with strict adherence to the following instructions, to ensure Risedronate Sodium tablet is taken on an empty stomach-Between meals:

Risedronate Sodium tablet should be taken at least 2 hours before and at least 2 hours after any food, medicinal product or drink (other than plain water). In the evening:

Risedronate Sodium tablet should be taken at least 2 hours after the last food, medicinal product or drink (other than plain water) of the day. If a dose is missed: Risedronate 5 mg tablet: If an occasional dose is missed, Risedronate 5 mg tablet can be taken before breakfast, between meals, or in the evening according to the instructions above.

Risedronate 35 mg tablet: Patients should be instructed that if a dose is missed, just take one Risedronate 35 mg tablet on the morning after remember. Patients should then return to taking one tablet once a week on the day the tablet is normally taken. Two tablets should not be taken on the same day.

Risedronate 150 mg tablet: Patient should be instructed that if a dose is missed and the next month’s schedule dose is more than 7 days away, then should take the missed tablet in the morning after the day it is remembered. Patients should then return to taking one tablet once a month normally taken.The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach Risedronate tablet is to be taken while in an upright position with a glass of plain water (120 ml or more). Patients should not lie down for 30 minutes after taking the tablet. Supplemental calcium and vitamin D should be considered if the dietary intake is inadequate.

Serious side effects:

• chest pain;
• difficulty or pain when swallowing;
• pain or burning under the ribs or in the back;
• new or worsening heartburn;
• severe joint, bone, or muscle pain; or
• jaw pain, numbness, or swelling.

Less serious side effects:

• mild heartburn or stomach upset;
• diarrhea, gas,or constipation;
• mild joint or back pain;
• headache.

Risedronate Sodium tablet is contraindicated in patients with known hypersensitivity to Risedronate Sodium and in patients with hypocalcaemia, severe renal impairment (creatinine clearance lower than 30 ml/min), during pregnancy and lactation.

Take special care with Risedronate if you:

• Have low blood calcium (hypocalcemia)
• Cannot sit or stand up for 30 minutes
• Have kidneys that work poorly
• Have an allergy to Risedronate Sodium

Before taking Risedronate talk to doctor if you:

• Are pregnant or may become pregnant. We do not know if Risedronate Sodium can harm your unborn child.
• Are breast-feeding or plan to breast-feed. We do not know if Risedronate Sodium can passthrough your milk and if it can harm your baby.
• Have kidney problems Risedronate Sodium may not be right for you.
• Risedronate sodium is not intended for use in children.

During treatment, if you experience an allergic reaction (such as swelling of the face, tongue or throat, difficulty in breathing or swallowing, skin rash), you must stop taking Risedronate sodium and seek medical advice immediately. If you have stopped treatment due to hypersensitivity reactions you should not re-start therapy with Risedronate sodium.

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription specially aspirin or other NSAIDs. Antacids, supplements, or medicines that contain aluminum, calcium, magnesium, or other minerals can interfere with how your body absorbs Risedronate Sodium. If you use these other medicines, do not take them for at least 30 minutes after taking a Risedronate Sodium tablet.

Pregnancy: Risedronate Sodium is meant for use only in postmenopausal women. Therefore, Risedronate Sodium should not be taken during pregnancy. If you take it by accident during pregnancy, stop taking it straight away and talk to your doctor.

Breast-feeding: Risedronate Sodium is meant for use only in postmenopausal women. Therefore, breast-feeding women should not take this medicine. If you take it by accident during breast-feeding, stop taking it straight away and talk to your doctor.

Elderly: No dosage adjustment is necessary since bioavailability, distribution and elimination were similar in elderly (60 years of age or older) compared to younger subjects. This has also been shown in the very elderly, 75 years old and above postmenopausal population. 

Renal impairment: No dosage adjustment is required for those patients with mild to moderate renal impairment. The use of Risedronate Sodium is contra-indicated in patients with severe renal impairment (Creatinine clearance lower than 30ml/min).

Seek emergency medical attention if you think you have used too much of this medicine. Drink a full glass of milk right away. Do not make yourself vomit and do not lie down.

Overdose symptoms may include nausea, heartburn, stomach pain, diarrhea, muscle cramps, numbness or tingling, tight muscles in your face, seizure (convulsions), irritability, and unusual thoughts or behavior.

Store in a cool and dry place. Protect from light & moisture. Keep out of the reach of children.

Diazepam is indicated for the short-term treatment of mild to moderate anxiety, excitation, agitation, fear, aggressiveness, etc. Anxiety reactions caused by stressed conditions, anxiety states with somatic expression, acute alcohol withdrawal, status epilepticus, premedication for surgical procedures, febrile convulsions, insomnia of hospitalized patients.

Benzodiazepine sedatives, Centrally acting Skeletal Muscle Relaxants, Primary anti-epileptic drugs

Diazepam attaches to the specific site on the GABA receptor and potentiates the effect of GABA, which acts by opening chloride ion channels into cells.

Diazepam is absorbed rapidly and completely after oral administration. Peak Plasma concentration reaches within 15-90 minutes. Mean plasma half-life is 30 hours. Plasma protein binding is 98-99%. Diazepam is metabolized in the liver with only traces of the unchanged drug excreted in urine. A very small proportion of the metabolites is excreted through the bile into the intestine and eliminated with the feces. After rectal administration in suppository form diazepam is significantly absorbed and peak concentration reaches within 1.5-2 hours.

Oral:

• Anxiety: 2 mg thrice daily, increased if necessary to 15-30 mg daily in divided doses. Elderly (or debilitated), half of the adult dose.
• Insomnia associated with anxiety: 5-15 mg at bedtime.
• Night terrors and somnambulism in Child: 1-5 mg at bedtime.

IM/slow IV injection (large vein, a rate below 5 mg/minute):

• For severe acute anxiety, control of acute panic attacks, and acute alcohol withdrawal: 10 mg repeated if necessary after not less than 4 hours.
• Febrile convulsion in children: Slow IV in a dose of 250 mcg/kg.

Rectal:

• In case of children- A dose of 500 mcg/kg (maximum 10 mg), repeated if necessary.

Diazepam is generally well tolerated. Higher doses may cause somnolence, dizziness, light headedness, confusion and ataxia.

Diazepam is contraindicated in myasthenia gravis, pulmonary insufficiency, respiratory depression and hypersensitivity to bezodiazepine.

Prolonged use and abrupt withdrawal should be avoided. Diazepam should be used with caution in respiratory disease, muscle weakness, history of drug or alcohol abuse, in hepatic or renal impairment.

Concomitant intake with alcohol is not recommended. Sedation may be increased due to concomitant use of neuroleptics (antipsychotics), hypnotics, sedative antihistamines and CNS depressants e.g., general anesthetics, narcotic analgesics or antidepressants. Diazepam clearance is increased by concomitant administration of phonobarbitone and is decreased by administration of cimetidine. Omeprazole and isoniazide inhibit diazepam metabolism.

Diazepam and its active metabolites cross the placental barrier and also pass into breast milk. So, it should be avoided if possible during pregnancy and lactation. US FDA pregnancy category D.

Sedation, muscle weakness, profound sleep or paradoxical excitation. In more severe cases symptoms may include ataxia, hypotonia, hypotension, respiratory depression and rarely coma and death.

Store in a cool (below 25˚C temperature) and dry place protected from light.

Diazepam is indicated for the short-term treatment of mild to moderate anxiety, excitation, agitation, fear, aggressiveness, etc. Anxiety reactions caused by stressed conditions, anxiety states with somatic expression, acute alcohol withdrawal, status epilepticus, premedication for surgical procedures, febrile convulsions, insomnia of hospitalized patients.

Benzodiazepine sedatives, Centrally acting Skeletal Muscle Relaxants, Primary anti-epileptic drugs

Diazepam attaches to the specific site on the GABA receptor and potentiates the effect of GABA, which acts by opening chloride ion channels into cells.

Diazepam is absorbed rapidly and completely after oral administration. Peak Plasma concentration reaches within 15-90 minutes. Mean plasma half-life is 30 hours. Plasma protein binding is 98-99%. Diazepam is metabolized in the liver with only traces of the unchanged drug excreted in urine. A very small proportion of the metabolites is excreted through the bile into the intestine and eliminated with the feces. After rectal administration in suppository form diazepam is significantly absorbed and peak concentration reaches within 1.5-2 hours.

Oral:

• Anxiety: 2 mg thrice daily, increased if necessary to 15-30 mg daily in divided doses. Elderly (or debilitated), half of the adult dose.
• Insomnia associated with anxiety: 5-15 mg at bedtime.
• Night terrors and somnambulism in Child: 1-5 mg at bedtime.

IM/slow IV injection (large vein, a rate below 5 mg/minute):

• For severe acute anxiety, control of acute panic attacks, and acute alcohol withdrawal: 10 mg repeated if necessary after not less than 4 hours.
• Febrile convulsion in children: Slow IV in a dose of 250 mcg/kg.

Rectal:

• In case of children- A dose of 500 mcg/kg (maximum 10 mg), repeated if necessary.

Diazepam is generally well tolerated. Higher doses may cause somnolence, dizziness, light headedness, confusion and ataxia.

Diazepam is contraindicated in myasthenia gravis, pulmonary insufficiency, respiratory depression and hypersensitivity to bezodiazepine.

Prolonged use and abrupt withdrawal should be avoided. Diazepam should be used with caution in respiratory disease, muscle weakness, history of drug or alcohol abuse, in hepatic or renal impairment.

Concomitant intake with alcohol is not recommended. Sedation may be increased due to concomitant use of neuroleptics (antipsychotics), hypnotics, sedative antihistamines and CNS depressants e.g., general anesthetics, narcotic analgesics or antidepressants. Diazepam clearance is increased by concomitant administration of phonobarbitone and is decreased by administration of cimetidine. Omeprazole and isoniazide inhibit diazepam metabolism.

Diazepam and its active metabolites cross the placental barrier and also pass into breast milk. So, it should be avoided if possible during pregnancy and lactation. US FDA pregnancy category D.

Sedation, muscle weakness, profound sleep or paradoxical excitation. In more severe cases symptoms may include ataxia, hypotonia, hypotension, respiratory depression and rarely coma and death.

Store in a cool (below 25˚C temperature) and dry place protected from light.

Minerals in bone formation, Specific mineral preparations

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

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

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

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

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

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

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

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

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

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

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

Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).

Bronchodilator

Glycopyrronium is a long-acting, specific antimuscarinic agent, in clinical medicine often called an anticholinergic. It has a similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, inhibition of M3-receptors at the smooth muscle results in relaxation. The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.

The recommended dosage of Glycopyrronium is the inhalation of the contents of one capsule once daily with the ConviHaler device at the same time of day.

Inhaled medicines may cause inhalation-induced bronchospasm, dehydration, dry mouth, constipation, dizziness, insomnia, skin and subcutaneous tissue disorders, immune system disorders.

Hypersensitivity to the active substance or to any of the excipients.

Glycopyrronium, as a once-daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy. Immediate hypersensitivity reactions may occur after administration of Glycopyrronium inhalation powder. As with other anticholinergic drugs, Glycopyrronium should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.

Although no formal drug interaction studies have been performed, Glycopyrronium inhalation powder has been used concomitantly with other drugs, commonly used in the treatment of COPD, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids without clinical evidence of drug interactions.

There is a limited amount of data from the use of Glycopyrronium in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses. Glycopyrronium should not be used in pregnant or nursing women unless the expected benefit outweighs any possible risk to the unborn child or the infant.

High doses of Glycopyrronium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 150 micrograms Glycopyrronium in healthy volunteers.

Should be stored at temperature not exceeding 25ºC but do not freeze. Should be stored in cool and dry place, protected from light.

Cough expectorants & mucolytics

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

Average daily dose (preferably after meal):

Pediatric Drops:

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

Syrup:

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

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

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

Contraindicated in known hypersensitivity to Ambroxol or Bromhexine.

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

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

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

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