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Sulfonylureas

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.

In principle, the dosage of Glimepiride is governed by the desired blood sugar level. The dosage of Glimepiride must be the lowest which is sufficient to achieve the desired metabolic control. The initial and the maintenance doses are set based on the results of regular check of glucose in blood and urine. Monitoring of glucose levels in blood and urine also serves to detect either primary or secondary failure of therapy.

Initial dose and dose titration: the usual initial dose is 1 mg once daily, if necessary, the daily dose can be increased. Any increase can be based on regular blood sugar monitoring, and should be gradual, i.e., at intervals of 1 to 2 weeks, and carried out stepwise, as follows: 1 mg -> 2 mg -> 3 mg -> 4 mg -> 6 mg.

Dose in patients with well controlled diabetes: the usual dose range in patients with well controlled diabetes is 1 to 4 mg daily.

Distribution of doses: Timing and distribution of doses are decided by the physician, in consideration of the patient's current life-style. Normally, a single daily dose is sufficient. This should be taken immediately before a substantial breakfast or if none is taken immediately before the first main meal. It is very important not to skip meals after taking the drug.

Secondary dosage adjustment: As control of diabetes improves, sensitivity to insuiin increases; therefore, Glimepiride requirement may fall as treatment proceeds. To avoid hypoglycaemia, timely dose reduction or cessation of Glimepiride therapy must be considered. A dose adjustment must also be considered whenever the patient's weight or life-styie changes, or other factors arise which cause an increased susceptibility to hypo or hyperglycaemia.

Changeover from other oral antidiabetics to Glimepiride: There is no exact dosage relationship between Glimepiride and other oral blood sugar lowering agents. When substituting Glimepiride for other such agents, the initial daily dose is 1 mg; this applies even in changeover from maximum dose of other oral blood sugar lowering agents. Any dose increase should be in accordance with guideline given above in 'initial dose and dose titration'. Consideration must be given to the potency and duration of action of the previous blood sugar lowering agent. It may be necessary to interrupt treatment to avoid additive effects which would increase the risk of hypoglycaemia.

Glimepiride tablet must be swallowed with sufficient amount of liquid.

Hypoglycaemia, temporary visual impairment, nausea, vomiting, diarrhoea, abdominal pain, urticaria, fall in blood pressure.

Glimepiride is not suitable for the treatment of insulin dependent (type I) diabetes mellitus, or for the treatment of diabetic ketoacidosis, nor for the treatment of diabetic coma. Glimepiride must not be used in patients hypersensitive to Glimepiride, other sulfonylureas, other sulfonamides, severe hepatic dysfunction, severe impairment of renal function and dialysis patients.

in the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates careful monitoring. If such risk present it may be necessary to adjust the dosage of Glimepiride, Hypoglycaemia can almost be promptly controlled by immediate intake of carbohydrates (glucose or sugar).

Based on experience with Glimepiride and known interactions for other sulfonylureas, the following interactions must be considered.

In addition to insulin and other oral antidiabetic agents, drugs which may potentiate the hypoglycaemic action of Glimepiride include: ACE inhibitors, aminosalicylic acid, anabolic steroids and male sex hormones, azapropazone, chloramphenicol, ciofibrate, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluconazole, fluoxetine, guanethidine, ifosfamide, MAO-inhibitors, miconazole, oxpentifylline (high dose parenteral), oxyphenbutazone, para-aminosalicylic acid, phenylbutazone, probenecid, quinolones, salicylates, sulphinpyrazone, sulfonamide antibiotics, tetracyclines, tritoqualine, trofosfamide.

Drugs which may attenuate the hypoglycaemic action of Glimepiride include:

• Acetazoiamide, barbiturates, calcium channel blockers, corticosteroids, diazoxide, diuretics, glucagon, isoniazid, laxatives, nicotinic acid (high doses), oestrogens, phenothiazines, phenytoin, progestagens, rifampicin, sympathomimetic agents, thyroid hormones.
• H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.
• Concomitant treatment with a beta-receptor blocker, clonidine, guanethidine or reserpine may mask the warning symptoms of a hypoglycaemic attack.
• Acute and chronic aicohol intake may either potentiate or attenuate the activity of Glimepiride in an unpredictable fashion.

Glimepiride must not be taken during pregnancy; a changeover to insulin is necessary. Patients planning a pregnancy must inform their physician, and should change over to insulin. Ingestion of Glimepiride with breast milk feeding may harm the child. Therefore, Glimepiride must not be taken by breastfeeding women. Either a changeover or complete discontinuation of breastfeeding is necessary.

Overdosage of sulfonylureas, including Glimepiride, can produce hypoglycaemia. Mild hypoglycaemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycaemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medicai emergencies requiring immediate hospitalization. If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of  concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dl. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycaemia may recur after apparent clinical recovery.

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

Sulfonylureas

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.

In principle, the dosage of Glimepiride is governed by the desired blood sugar level. The dosage of Glimepiride must be the lowest which is sufficient to achieve the desired metabolic control. The initial and the maintenance doses are set based on the results of regular check of glucose in blood and urine. Monitoring of glucose levels in blood and urine also serves to detect either primary or secondary failure of therapy.

Initial dose and dose titration: the usual initial dose is 1 mg once daily, if necessary, the daily dose can be increased. Any increase can be based on regular blood sugar monitoring, and should be gradual, i.e., at intervals of 1 to 2 weeks, and carried out stepwise, as follows: 1 mg -> 2 mg -> 3 mg -> 4 mg -> 6 mg.

Dose in patients with well controlled diabetes: the usual dose range in patients with well controlled diabetes is 1 to 4 mg daily.

Distribution of doses: Timing and distribution of doses are decided by the physician, in consideration of the patient's current life-style. Normally, a single daily dose is sufficient. This should be taken immediately before a substantial breakfast or if none is taken immediately before the first main meal. It is very important not to skip meals after taking the drug.

Secondary dosage adjustment: As control of diabetes improves, sensitivity to insuiin increases; therefore, Glimepiride requirement may fall as treatment proceeds. To avoid hypoglycaemia, timely dose reduction or cessation of Glimepiride therapy must be considered. A dose adjustment must also be considered whenever the patient's weight or life-styie changes, or other factors arise which cause an increased susceptibility to hypo or hyperglycaemia.

Changeover from other oral antidiabetics to Glimepiride: There is no exact dosage relationship between Glimepiride and other oral blood sugar lowering agents. When substituting Glimepiride for other such agents, the initial daily dose is 1 mg; this applies even in changeover from maximum dose of other oral blood sugar lowering agents. Any dose increase should be in accordance with guideline given above in 'initial dose and dose titration'. Consideration must be given to the potency and duration of action of the previous blood sugar lowering agent. It may be necessary to interrupt treatment to avoid additive effects which would increase the risk of hypoglycaemia.

Glimepiride tablet must be swallowed with sufficient amount of liquid.

Hypoglycaemia, temporary visual impairment, nausea, vomiting, diarrhoea, abdominal pain, urticaria, fall in blood pressure.

Glimepiride is not suitable for the treatment of insulin dependent (type I) diabetes mellitus, or for the treatment of diabetic ketoacidosis, nor for the treatment of diabetic coma. Glimepiride must not be used in patients hypersensitive to Glimepiride, other sulfonylureas, other sulfonamides, severe hepatic dysfunction, severe impairment of renal function and dialysis patients.

in the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates careful monitoring. If such risk present it may be necessary to adjust the dosage of Glimepiride, Hypoglycaemia can almost be promptly controlled by immediate intake of carbohydrates (glucose or sugar).

Based on experience with Glimepiride and known interactions for other sulfonylureas, the following interactions must be considered.

In addition to insulin and other oral antidiabetic agents, drugs which may potentiate the hypoglycaemic action of Glimepiride include: ACE inhibitors, aminosalicylic acid, anabolic steroids and male sex hormones, azapropazone, chloramphenicol, ciofibrate, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluconazole, fluoxetine, guanethidine, ifosfamide, MAO-inhibitors, miconazole, oxpentifylline (high dose parenteral), oxyphenbutazone, para-aminosalicylic acid, phenylbutazone, probenecid, quinolones, salicylates, sulphinpyrazone, sulfonamide antibiotics, tetracyclines, tritoqualine, trofosfamide.

Drugs which may attenuate the hypoglycaemic action of Glimepiride include:

• Acetazoiamide, barbiturates, calcium channel blockers, corticosteroids, diazoxide, diuretics, glucagon, isoniazid, laxatives, nicotinic acid (high doses), oestrogens, phenothiazines, phenytoin, progestagens, rifampicin, sympathomimetic agents, thyroid hormones.
• H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.
• Concomitant treatment with a beta-receptor blocker, clonidine, guanethidine or reserpine may mask the warning symptoms of a hypoglycaemic attack.
• Acute and chronic aicohol intake may either potentiate or attenuate the activity of Glimepiride in an unpredictable fashion.

Glimepiride must not be taken during pregnancy; a changeover to insulin is necessary. Patients planning a pregnancy must inform their physician, and should change over to insulin. Ingestion of Glimepiride with breast milk feeding may harm the child. Therefore, Glimepiride must not be taken by breastfeeding women. Either a changeover or complete discontinuation of breastfeeding is necessary.

Overdosage of sulfonylureas, including Glimepiride, can produce hypoglycaemia. Mild hypoglycaemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycaemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medicai emergencies requiring immediate hospitalization. If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of  concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dl. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycaemia may recur after apparent clinical recovery.

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

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.

Combination Oral hypoglycemic preparations

Pioglitazone & Glimepiride combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Pioglitazone, a member of the thiazolidinedione class, and Glimepiride, a member of the sulfonylurea class.

Pioglitazone is an insulin-sensitizing agent that acts primarily by enhancing peripheral glucose utilization. It depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

The primary mechanism of action of Glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as Glimepiride. This is supported by both preclinical and clinical studies demonstrating that Glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin.

Selecting the starting dose of Glimepiride & Pioglitazone should be based on the patient's current regimen of Pioglitazone and/or sulfonylurea. Those patients who may be more sensitive to antihyperglycemic drugs should be monitored carefully during dose adjustment. It is recommended that a single dose of Pioglitazone & Glimepiride be administered once daily with the first main meal.

Starting dose for patients currently on Glimepiride monotherapy: Based on the usual starting dose of Pioglitazone (15 mg or 30 mg daily), Pioglitazone & Glimepiride may be initiated at 30 mg/2 mg or 30 mg/4 mg tablet strengths once daily, and adjusted after assessing adequacy of therapeutic response.

Starting dose for patients currently on Pioglitazone monotherapy: Based on the usual starting doses of Glimepiride (1 mg or 2 mg once daily), and Pioglitazone 15 mg or 30 mg, Pioglitazone & Glimepiride may be initiated at 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

Starting dose for patients switching from combination therapy of Pioglitazone plus Glimepiride as separate tablets: Pioglitazone & Glimepiride may be initiated with 30 mg/2 mg or 30 mg/4 mg tablet strengths based on the dose of Pioglitazone and Glimepiride already being taken. Patients who are not controlled with 15 mg of Pioglitazone in combination with Glimepiride should be carefully monitored when switched to  Pioglitazone & Glimepiride.

Starting dose for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of Pioglitazone plus a different sulfonylurea: No exact dosage relationship exists between Glimepiride and the other sulfonylurea agents. Therefore, based on the maximum starting dose of 2 mg Glimepiride, Pioglitazone & Glimepiride should be limited initially to a starting dose of 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

Pioglitazone: The most common adverse experiences with Pioglitazone monotherapy (≥5%) were upper respiratory tract infection, injury, and headache. Overall, the types of adverse experiences reported when Pioglitazone was used in combination with a sulfonylurea were similar to those during monotherapy with Pioglitazone. Other adverse events reported in at least 5% of patients in controlled clinical studies between placebo and Pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively. In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with Pioglitazone versus 1.2% of placebo treated patients.

Glimepiride: Hypoglycemia: The incidence of hypoglycemia with Glimepiride is documented. In patients treated with Glimepiride, adverse events, other than hypoglycemia, considered to be possibly or probably related to study drug that occurred in more than 1% of patients included dizziness (1.7%), asthenia (1.6%), headache (1.5%), and nausea (1.1%). Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of Glimepiride.

Combination of Pioglitazone and Glimepiride is contraindicated in patients with:

• Known hypersensitivity to Pioglitazone or Glimepiride or any of the components of combination of Pioglitazone or Glimepiride.
• Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

General: Due to the mechanisms of action, Pioglitazone is active only in the presence of endogenous insulin. Therefore, combination of Pioglitazone and Glimepiride should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic action of glucose lowering drugs. Debilitated or malnourished patients and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose lowering drugs.

Loss of Control of Blood Glucose: When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold combination of Pioglitazone and Glimepiride and temporarily administer insulin. Combination of Pioglitazone and Glimepiride may be reinstituted after the acute episode is resolved.

Edema: Combination of Pioglitazone and Glimepiride should be used with caution in patients with edema. Since thiazolidinediones, including Pioglitazone can cause fluid retention, which can exacerbate or lead to congestive heart failure, combination of Pioglitazone and Glimepiride should be used with caution in patients at risk for heart failure.

Weight Gain: Dose-related weight gain was seen with Pioglitazone alone and in combination with other hypoglycemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Hepatic Effects: Liver enzymes should be checked prior to the initiation of therapy with combination of Pioglitazone and Glimepiride in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with combination of Pioglitazone and Glimepiride should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with combination of Pioglitazone and Glimepiride, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with combination of Pioglitazone and Glimepiride should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, and anorexia, and/or dark urine, liver enzymes should be checked.

Glimepiride: Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these drugs are administered to a patient receiving Glimepiride, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving Glimepiride, the patient should be observed closely for hypoglycemia. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the IV, topical, or vaginal preparations of miconazole is not known. Potential interactions of Glimepiride with other drugs metabolized by cytochrome P450 2C9 also include phenytoin, diclofenac, ibuprofen, naproxen, and mefenamic acid.

Pioglitazone: Co-administration of Pioglitazone and an oral contraceptive resulted in decrease in ethinyl estradiol plasma concentrations. There were no significant changes in norethindrone AUC (0-24h) and Cmax. In other drug-drug interaction studies, Pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, metformin, digoxin, warfarin, ranitidine, or theophylline.

Pregnancy category C. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. Combination of Pioglitazone and Glimepiride should not be used during pregnancy.

Nursing mothers: No studies have been conducted with combination of Pioglitazone and Glimepiride. It is not known whether Pioglitazone and/or Glimepiride are excreted in human milk. Because many drugs are excreted in human milk, combination of Pioglitazone and Glimepiride should not be administered to a nursing woman.

Pediatric Uses: Safety and effectiveness of combination of Pioglitazone and Glimepiride in pediatric patients have not been established.

Geriatric use:

• Pioglitazone: Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of Pioglitazone. Therefore, no dosage adjustments are required for the elderly.
• Glimepiride: The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Symptoms: Severe hypoglycaemia with coma, seizure, or neurological impairment.

Management: Admin glucagon or IV glucose. Additional carbohydrate intake may be necessary as hypoglycaemia may recur after apparent clinical recovery.

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

Combination Oral hypoglycemic preparations

Pioglitazone & Glimepiride combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Pioglitazone, a member of the thiazolidinedione class, and Glimepiride, a member of the sulfonylurea class.

Pioglitazone is an insulin-sensitizing agent that acts primarily by enhancing peripheral glucose utilization. It depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

The primary mechanism of action of Glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as Glimepiride. This is supported by both preclinical and clinical studies demonstrating that Glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin.

Selecting the starting dose of Glimepiride & Pioglitazone should be based on the patient's current regimen of Pioglitazone and/or sulfonylurea. Those patients who may be more sensitive to antihyperglycemic drugs should be monitored carefully during dose adjustment. It is recommended that a single dose of Pioglitazone & Glimepiride be administered once daily with the first main meal.

Starting dose for patients currently on Glimepiride monotherapy: Based on the usual starting dose of Pioglitazone (15 mg or 30 mg daily), Pioglitazone & Glimepiride may be initiated at 30 mg/2 mg or 30 mg/4 mg tablet strengths once daily, and adjusted after assessing adequacy of therapeutic response.

Starting dose for patients currently on Pioglitazone monotherapy: Based on the usual starting doses of Glimepiride (1 mg or 2 mg once daily), and Pioglitazone 15 mg or 30 mg, Pioglitazone & Glimepiride may be initiated at 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

Starting dose for patients switching from combination therapy of Pioglitazone plus Glimepiride as separate tablets: Pioglitazone & Glimepiride may be initiated with 30 mg/2 mg or 30 mg/4 mg tablet strengths based on the dose of Pioglitazone and Glimepiride already being taken. Patients who are not controlled with 15 mg of Pioglitazone in combination with Glimepiride should be carefully monitored when switched to  Pioglitazone & Glimepiride.

Starting dose for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of Pioglitazone plus a different sulfonylurea: No exact dosage relationship exists between Glimepiride and the other sulfonylurea agents. Therefore, based on the maximum starting dose of 2 mg Glimepiride, Pioglitazone & Glimepiride should be limited initially to a starting dose of 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

Pioglitazone: The most common adverse experiences with Pioglitazone monotherapy (≥5%) were upper respiratory tract infection, injury, and headache. Overall, the types of adverse experiences reported when Pioglitazone was used in combination with a sulfonylurea were similar to those during monotherapy with Pioglitazone. Other adverse events reported in at least 5% of patients in controlled clinical studies between placebo and Pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively. In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with Pioglitazone versus 1.2% of placebo treated patients.

Glimepiride: Hypoglycemia: The incidence of hypoglycemia with Glimepiride is documented. In patients treated with Glimepiride, adverse events, other than hypoglycemia, considered to be possibly or probably related to study drug that occurred in more than 1% of patients included dizziness (1.7%), asthenia (1.6%), headache (1.5%), and nausea (1.1%). Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of Glimepiride.

Combination of Pioglitazone and Glimepiride is contraindicated in patients with:

• Known hypersensitivity to Pioglitazone or Glimepiride or any of the components of combination of Pioglitazone or Glimepiride.
• Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

General: Due to the mechanisms of action, Pioglitazone is active only in the presence of endogenous insulin. Therefore, combination of Pioglitazone and Glimepiride should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic action of glucose lowering drugs. Debilitated or malnourished patients and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose lowering drugs.

Loss of Control of Blood Glucose: When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold combination of Pioglitazone and Glimepiride and temporarily administer insulin. Combination of Pioglitazone and Glimepiride may be reinstituted after the acute episode is resolved.

Edema: Combination of Pioglitazone and Glimepiride should be used with caution in patients with edema. Since thiazolidinediones, including Pioglitazone can cause fluid retention, which can exacerbate or lead to congestive heart failure, combination of Pioglitazone and Glimepiride should be used with caution in patients at risk for heart failure.

Weight Gain: Dose-related weight gain was seen with Pioglitazone alone and in combination with other hypoglycemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Hepatic Effects: Liver enzymes should be checked prior to the initiation of therapy with combination of Pioglitazone and Glimepiride in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with combination of Pioglitazone and Glimepiride should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with combination of Pioglitazone and Glimepiride, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with combination of Pioglitazone and Glimepiride should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, and anorexia, and/or dark urine, liver enzymes should be checked.

Glimepiride: Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these drugs are administered to a patient receiving Glimepiride, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving Glimepiride, the patient should be observed closely for hypoglycemia. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the IV, topical, or vaginal preparations of miconazole is not known. Potential interactions of Glimepiride with other drugs metabolized by cytochrome P450 2C9 also include phenytoin, diclofenac, ibuprofen, naproxen, and mefenamic acid.

Pioglitazone: Co-administration of Pioglitazone and an oral contraceptive resulted in decrease in ethinyl estradiol plasma concentrations. There were no significant changes in norethindrone AUC (0-24h) and Cmax. In other drug-drug interaction studies, Pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, metformin, digoxin, warfarin, ranitidine, or theophylline.

Pregnancy category C. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. Combination of Pioglitazone and Glimepiride should not be used during pregnancy.

Nursing mothers: No studies have been conducted with combination of Pioglitazone and Glimepiride. It is not known whether Pioglitazone and/or Glimepiride are excreted in human milk. Because many drugs are excreted in human milk, combination of Pioglitazone and Glimepiride should not be administered to a nursing woman.

Pediatric Uses: Safety and effectiveness of combination of Pioglitazone and Glimepiride in pediatric patients have not been established.

Geriatric use:

• Pioglitazone: Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of Pioglitazone. Therefore, no dosage adjustments are required for the elderly.
• Glimepiride: The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Symptoms: Severe hypoglycaemia with coma, seizure, or neurological impairment.

Management: Admin glucagon or IV glucose. Additional carbohydrate intake may be necessary as hypoglycaemia may recur after apparent clinical recovery.

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

Appetite suppressant drugs/Anti-obesity drugs

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Digestive and carminative to correct indigestion, dyspepsia, flatulence, constipation, abdominal pain due to gases, stomach and liver disorders.

Herbal and Nutraceuticals

Hazmina is a specialized formulation of several herbs and natural ingredients that helps to control acidity, flatulence, and indigestion. It even tones up the digestive system as a whole. It also makes a fine balance between liver function and gastric activities.

Adults: 2 teaspoonfuls 2-3 times daily.
Children: 1⁄2-1 teaspoonful 2-3 times daily or as directed by the registered physician.

No significant side effect has been observed in proper dosages.

No report is available on contraindication.

No report is available.

The safety of Hazmina in pregnancy has not been established. Therefore, it should be used with caution during pregnancy.

Store in a cool & dry place away from direct sunlight. Keep it out of reach of children.

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

Dilofenac Sodium is a potent non-steroidal anti-inflammatory drug (NSAID) with pronounced anti-rheumatic, anti-inflammatory, analgesic and antipyretic properties. It has also some uricosuric effect. Diclofenac exerts its effect by inhibiting prostaglandin biosynthesis which plays a major role in causing inflammation, pain and fever. Diclofenac is rapidly and completely absorbed from the gastro-intestinal tract when taken with or after meal. Peak plasma concentrations are reached within an average of 2 hours after ingestion of it. At therapeutic concentrations, it is 99.7% bound to plasma proteins. Diclofenac is metabolized in the liver and undergoes first pass metabolism.

Diclofenac FC Tablet: Adults: 75-150 mg daily in 2 to 3 divided doses, preferably after food. Dose should be reduced in long term use.

Diclofenac SR Tablet:

• Adult: 1 tablet daily, taken whole with liquid, preferably at meal times. If necessary, the daily dose can be increased to 150 mg by supplementation with conventional tablets.
• Children: 1-3 mg of diclofenac/kg body wt. daily in divided doses.
• Elderly patients: In elderly or debilitated patients, the lowest effective dosage is recommended, although the pharmacokinetics of diclofenac sodium is not impaired to any clinically relevant extent in elderly patients.

Diclofenac Dispersible Tablet:

• Adults: The recommended daily dosage is 2-3 tablets and the maximum daily dose is 150 mg. In milder cases, 2 tablets of Diclofenac DT per day are sufficient. Diclofenac DT should preferably be taken before meals.
• Children: Diclofenac is not recommended in children for other indications except juvenile rheumatoid arthritis where the recommended dose is 1-3 mg/kg body weight. Diclofenac DT is to be dropped into a half-glass of water and the liquid is to be stirred to aid dispersion before swallowing. There is no information on the use of Diclofenac DT for more than 03 months.

Diclofenac TR Capsule: One capsule daily. Diclofenac TR should be taken preferably after mealtimes.

Diclofenac Suppository: For adults: 50 mg suppository 2-3 times daily. Maximum daily dose is 150 mg.

Diclofenac injection: For adults the usual dose is 1 ampoule daily. In serious cases this dose may be increased up to 2 ampoules daily.

Diclofenac Gel: For external use only. Depending on the size of area to be treated, 2-4 g of Diclofenac gel should be applied to the skin 3-4 times daily. To the affected area gel should be rubbed in lightly. This gel may also be given in addition to further treatment with other dosage forms of Diclofenac.

Diclofenac Sodium is generally well tolerated. Adverse effects are mild, rare and transient. At the starting of the treatment, however, patients may be sometimes complaining of epigastric pain, eructation, nausea and diarrhea or dizziness or headache. These effects are usually mild in nature. Peripheral edema and skin reactions, such as rash and eczema have also been encountered. Diclofenac Sodium Gel may cause local irritation and reddening of the skin and skin rash.

Contraindicated to the patients hypersensitive to any ingredient of the products. Peptic ulcer, hypersensitivity to Diclofenac like other non-steroid anti-inflammatory agents, Diclofenac is also contra-indicated in asthmatic patient in whom attack with asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or by other drugs with prostaglandin synthetase inhibitor. This Gel should not be used under occlusive airtight dressings.

In rare instances where peptic ulceration or gastrointestinal bleeding occurs in patients under treatment with Diclofenac. In patients with advanced age should be kept under close observation. Diclofenac Sodium Gel should not be allowed to come in contact with the eyes or mucus membranes, after application the hands should be washed properly and not to be taken by mouth.

During pregnancy, Diclofenac should be employed only for compelling reasons. The lowest effective dose should be used. These types of drugs are not recommended during the first trimester of pregnancy. In view of insufficient clinical data, Diclofenac Sodium Gel is not recommended during pregnancy. A very insignificant quantity of Diclofenac may be detected in breast milk but no undesirable effects on the infant to be expected.

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

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

Diclofenac Sodium is a potent nonsteroidal antiinflammatory drug (NSAID) with marked analgesic and antipyretic properties. It also has some uricosuric effects. The action of Diclofenac appeared to be associated with the inhibition of prostaglandin synthesis. Diclofenac may inhibit synthesis of prostaglandins by inhibiting cyclooxygenase, an enzyme that catalyses the formation of prostaglandin precursors from arachidonic acid. Peak plasma concentration is achieved within half an hour following injection. Lidocaine is the most widely used local anaesthetic drug. It acts more rapidly and is more stable than most other local anaesthetics. It is a very useful surface anaesthetic. Like other local anaesthetics, Lidocaine impairs the generation and conduction of nerve impulses by slowing depolarization. The onset of anaesthesia of Lidocaine Hydrochloride is more rapid and the duration is 1-2 hours.

Adult: One ampoule once (or in severe cases, twice) daily by intramuscular injection.

Renal colic: One ampoule once daily intramuscularly. A second dose may be administered after 30 minutes if necessary.

Children: In Juvenile chronic arthritis, 1-3 mg of Diclofenac Sodium per kg body weight daily in divided doses.

Elderly patients: In elderly or debilitated patients, the lowest effective dosage is recommended, commensurate with age and physical status, or as prescribed by the physician.

Side effects to Diclofenac Sodium and Lidocaine injection are usually mild and transient. However if serious side effects occur the injection should be discontinued. Gastrointestinal discomfort, nausea, diarrhea and occasionally bleeding may occur. In very rare instances, injection site disorder may occur. In isolated cases, abscesses and local necrosis may occur. The adverse effects due to Lidocaine mainly involve the CNS, are usually of short duration, and are dose related. The CNS reactions may be manifested by drowsiness, dizziness, disorientation, confusion, lightheadedness etc.

It is contraindicated for those patients who are hypersensitive to Diclofenac. In patients with active or suspected peptic ulcer or gastrointestinal bleeding or for those patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by Aspirin or other NSAIDs possessing prostaglandin synthetase inhibiting activity Diclofenac is also contraindicated. Because of the presence of Lidocaine, this injection is also contraindicated for those patients who are hypersensitive to local anaesthetics of the amide type, although the incidence is very rare. In patients with Adams-Stokes syndrome or with severe degrees of SA, AV, or intraventricular heart block in the absence of an artificial pacemaker, and for those patients who are hypersensitive to any of the excipients used in the formulation (Sodium Metabisulphite, Disodium Edetate, Benzyl Alcohol, Sodium Hydroxide, Propylene Glycol), this injection is also contraindicated.

Renal: Patients with severe hepatic, cardiac or renal insufficiency or the elderly should be kept under close observation, since the use of NSAIDs may result in deterioration of renal function. The lowest effective dose should be used and renal function should be monitored.

Hepatic: If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Diclofenac should be discontinued. All patients who are receiving long term treatment with NSAIDs should be monitored as a precautionary measure (e.g., renal, hepatic function and blood counts).

Lithium and Digoxin: Diclofenac may increase plasma concentrations of Lithium and Digoxin.

Anticoagulants: There are isolated reports of an increased risk of haemorrhage with the combined use of Diclofenac and anticoagulant therapy, although clinical investigations do not appear to indicate any influence on anticoagulant effect.

Antidiabetic agents: Clinical studies have shown that Diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect.

Cyclosporin: Cases of nephrotoxicity have been reported in patients receiving Cyclosporin and Diclofenac concomitantly.

Methotrexate: Cases of serious toxicity have been reported when Methotrexate and NSAIDs are given within 24 hours of each other.

Quinolone antimicrobials: Convulsions may occur due to an interaction between quinolones and NSAIDs. Therefore, caution should be exercised when considering concomitant therapy of NSAIDs and quinolones.

Other NSAIDs and steroids: Co-administration of Diclofenac with other systemic NSAIDs and steroids may increase the frequency of unwanted effects. With Aspirin, the plasma levels of each are lowered, although no clinical significance is known.

Diuretics: Various NSAIDs are liable to inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels. So, serum potassium should be monitored.

It should not be prescribed during pregnancy unless there are compelling reasons for doing so. The lowest effective dosage should be used. These types of drugs are not recommended during the last trimester of pregnancy. Very small quantities of Diclofenac may be detected in breast milk, but no undesirable effects on the infant are to be expected.

Store at temparature not exceeding 30°C in a dry place. Protected from light.

Diphenhydramine is indicated for the treatment of followings:

• Seasonal, perennial, vasomotor rhinitis
• Urticaria, angioneurotic oedema, anaphylaxis
• Pruiritic conditions
• Premedication for emesis and motion sickness
• Miscellaneous like meniere's disease and parkinsonism

Sedating Anti-histamine

Diphenhydramine is an antihistamine with anticholinergic and sedative effects. It competes with histamine for H1-receptor sites on effector cells in the GI tract, blood vessels and respiratory tract.

Adult-

• Most allergic conditions: 25-50 mg three times a day with a further 50 mg at night.

Children-

• 1 to 5 years of age: 5 mg i.e., 2.5 ml of elixir 4 times a day
• More than 6 years of age: 10 mg i.e. 5 ml of elixir 4 times a day

Side effect includes sedation, dizziness, tinnitus, fatigue, ataxia, blurred vision, diplopia, euphoria, and epigastric discomfort.

Known hypersensitivity to Diphenhydramine Hydrochloride, Ammonium chloride is contra-indicated in presence of impaired hepatic or renal function.

Caution should be exercised with patients in whom drowsiness is undesirable e.g., drivers, machine operators. Concomitant consumption of alcohol or central nervous system (CNS) depressants will potentiate drowsiness.

Diphenhydramine administration significantly reduces the absorption of the antituberculous agent para-aminosalicyclic acid (PAS) from the gastrointestinal tract. CNS depressants may potentiate the sedative action of Diphenhydramine. Anticholinergic drugs may potentiate Diphenhydramine’s anticholinergic side effects.

Category B: There are no adequate and well controlled studies in pregnant women using diphenhydramine hydrochloride. Therefore, diphenhydramine hydrochloride should be used in pregnancy only if clearly needed. Diphenhydramine hydrochloride has been reported to be excreted in breast milk and thus, use of diphenhydramine hydrochloride in lactating mother is not recommended.

Symptoms: Impaired consciousness; psychosis, seizures, antimuscarinic symptoms (e.g. mydriasis, tachycardia, tachyarrhythmias), resp failure, rhabdomyolysis; acute delirium with visual and auditory hallucination (topical).

Management: Supportive and symptomatic treatment. Convulsions and marked CNS stimulation may be treated with IV diazepam.

Store between 15-30° C. Protect from moisture.

Tetracycline group of drugs

Doxycycline Hydrochloride is a semisynthetic tetracycline antibiotic with broad spectrum activity. It is primarily a bacteriostatic antibiotic. It has a similar spectrum of activity to other tetracyclines but in particular is more active against Staphylococcus aureus and Nocardia. The drug is often active against penicillin-resistant strains of Staphylococcus aureus and against strains of those organisms that are resistant to other Tetracyclines. Certain Gram-negative strains of E. coli, Proteus mirabilis and Klebsiella, which are often resistant to Tetracycline, may be sensitive to Doxycycline. In addition, 70-90% of the various anaerobes are sensitive to Doxycycline and Bacteroides fragilis is more likely to be sensitive to Doxycycline than to other tetracyclines.

Doxycycline is active against most strains of Haemophilus influenzaeand is particularly useful for infections with H. ducreyi, Actinomyces, Brucella and Vibrio cholerae. It is also active against Nocardia, Chlamydia, Mycoplasma and a wide range of Rickettsiae. Doxycycline is active against spirochetes such as Borellia recurrentis, Treponema pallidum and Treponema pertenue. It is also active against Plasmodium falciparum.

Usual dose: 200 mg on first day, then 100 mg daily for 7-10 days.
Severe infections (including refractory urinary tract infections): 200 mg daily for 10 days.
Acne: 100 mg daily.
Uncomplicated genital chlamydia, non-gonococcal urethritis: 100 mg twice daily for 7-21 days (14-21 days in pelvic inflammatory disease).

Capsules should be swallowed whole with plenty of fluid during meals while sitting or standing.

Nausea, vomiting, diarrhoea, skin rashes, hemolytic anaemia, eosinophilia may be reported.

Doxycycline is contraindicated to the patients who have shown hypersensitivity to any of the tetracyclines. Doxycycline is contraindicated to the children under 8 years of age. It is also contraindicated to pregnant women and to the lactating mothers.

The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of teeth. Tetracyclines drugs, therefore should not be used in this age group.

Absorption of tetracyclines is impaired by antacid containing aluminium, calcium or magnesium, and iron containing preparation. Absorption of tetracyclines is also impaired by bismuth salicylate. Barbiturates, carbamazepine and phenytoin decrease half-life of doxycycline. Concurrent use of tetracyclines may render oral contraceptive less effective. Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosages. It is advisable to avoid giving tetracyclines in conjunction with penicillin.

Doxycycline should be avoided in pregnant women, because of the risk of both staining and effect on bone growth in the foetus. Doxycyclines enter breast milk, and mothers taking these drugs should not breastfeed their child.

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

Fluconazole is indicated for the treatment of vaginal candidiasis, oropharyngeal & esophageal candidiasis and cryptococcal meningitis. It is also effective for the treatment of urinary tract infection caused by candida, peritonitis and systemic candida infections (including candidemia, disseminated candidiasis and pneumonia).

Drugs for subcutaneous and mycoses

Fluconazole is a triazole antifungal agent. It is a potent inhibitor of fungal cytochrome P-450 dependent enzymes. Cytochrome P-450 enzyme system is essential component of fungal cell membrane which is responsible for the synthesis of ergosterol.

Adult (oral)-

• Vaginal candidiasis: 150 mg as a single dose.
• Oropharyngeal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of this infection generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.
• Esophageal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used. Patients should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.
• Systemic candida infections: Optimal therapeutic dosage and duration of therapy have not been established. Sometimes, doses of up to 400 mg daily have been used.
• Urinary tract infections caused by candida and peritonitis: 50-200 mg daily have been used.
• Cryptococcal meningitis: 400 mg on the first day, followed by 200 mg once daily.
• Prophylaxis in patients undergoing bone marrow transplantation: 400 mg once daily.

Child (oral):

• Doses of 3-6 mg/kg daily have been used. Doses up to 12 mg/kg is recommended.

Intravenous-

• Adult: Invasive candidal infections including candidaemia and disseminated candidiasis and cryptococcal infections including meningitis, by IV, 400 mg initially then 200 mg daily, increased if necessary to 400 mg daily, treatment continued according to response (at least 6-8 weeks for cryptococcal meningitis)
• Child: 6-12 mg/kg daily (every 72 hours in neonate up to 2 weeks old, every 48 hours in neonate 2-4 weeks old); maximum 400 mg daily. Prevention of relapse of cryptococcal meningitis, by IV, 100-200 mg daily.

Fluconazole is well tolerated. Most common side effects of using Fluconazole includes nausea, vomiting, abdominal pain, diarrhoea, headache and skin rash.

Fluconazole should not be used in patients with known hypersensitivity to Fluconazole or to related triazole compounds.

Fluconazole should be administered with caution to patients having proarrhythmic conditions.

Concomitant use of cyclosporin or phenytoin with Fluconazole increases the plasma level of cyclosporin or phenytoin. Concomitant use of Fluconazole & warfarin prolongs the prothrombin time. Rifampicin level is decreased when used with Fluconazole.

US FDA Pregnancy category of Fluconazole is C. So, Fluconazole should be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the fetus.

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

For the treatment of fungal corneal ulcers/ keratitis.

Ophthalmic Anti-fungal Products

Fluconazole is fungistatic in action. It inhibits cytochrome P-450 14-α demethylase in susceptible fungi which leads to accumulation of lanosterol and decreased concentration of ergosterol thereby altering cellular membrane resulting in increased membrane permeability, leakage of essential elements and impaired uptake of precursor molecules to DNA.

Instill 1 drop to be instilled into the affected eye(s) 5 times daily.

This drug is generally well tolerated. Eosinophillia has been reported in some patients.

The drug is contraindicated in patients with hypersensitivity to azoles.

Use of fluconazole may result in overgrowth of non-susceptible strains of candida other than Candida albicans

Fluconazole can alter pharmacokinetics of certain drugs undergoing hepatic metabolism.

Use in pregnancy: Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Fluconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation: Nursing mother should not be given as the drug is excreted in breast milk in concentration similar to plasma.

Keep out of the reach of children. Store in a cool, dry place, away from heat and direct light. Do not use more than 4 weeks after opening the bottle

Fluconazole is indicated for the treatment of vaginal candidiasis, oropharyngeal & esophageal candidiasis and cryptococcal meningitis. It is also effective for the treatment of urinary tract infection caused by candida, peritonitis and systemic candida infections (including candidemia, disseminated candidiasis and pneumonia).

Drugs for subcutaneous and mycoses

Fluconazole is a triazole antifungal agent. It is a potent inhibitor of fungal cytochrome P-450 dependent enzymes. Cytochrome P-450 enzyme system is essential component of fungal cell membrane which is responsible for the synthesis of ergosterol.

Adult (oral)-

• Vaginal candidiasis: 150 mg as a single dose.
• Oropharyngeal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of this infection generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.
• Esophageal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used. Patients should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.
• Systemic candida infections: Optimal therapeutic dosage and duration of therapy have not been established. Sometimes, doses of up to 400 mg daily have been used.
• Urinary tract infections caused by candida and peritonitis: 50-200 mg daily have been used.
• Cryptococcal meningitis: 400 mg on the first day, followed by 200 mg once daily.
• Prophylaxis in patients undergoing bone marrow transplantation: 400 mg once daily.

Child (oral):

• Doses of 3-6 mg/kg daily have been used. Doses up to 12 mg/kg is recommended.

Intravenous-

• Adult: Invasive candidal infections including candidaemia and disseminated candidiasis and cryptococcal infections including meningitis, by IV, 400 mg initially then 200 mg daily, increased if necessary to 400 mg daily, treatment continued according to response (at least 6-8 weeks for cryptococcal meningitis)
• Child: 6-12 mg/kg daily (every 72 hours in neonate up to 2 weeks old, every 48 hours in neonate 2-4 weeks old); maximum 400 mg daily. Prevention of relapse of cryptococcal meningitis, by IV, 100-200 mg daily.

Fluconazole is well tolerated. Most common side effects of using Fluconazole includes nausea, vomiting, abdominal pain, diarrhoea, headache and skin rash.

Fluconazole should not be used in patients with known hypersensitivity to Fluconazole or to related triazole compounds.

Fluconazole should be administered with caution to patients having proarrhythmic conditions.

Concomitant use of cyclosporin or phenytoin with Fluconazole increases the plasma level of cyclosporin or phenytoin. Concomitant use of Fluconazole & warfarin prolongs the prothrombin time. Rifampicin level is decreased when used with Fluconazole.

US FDA Pregnancy category of Fluconazole is C. So, Fluconazole should be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the fetus.

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

Fluconazole is indicated for the treatment of vaginal candidiasis, oropharyngeal & esophageal candidiasis and cryptococcal meningitis. It is also effective for the treatment of urinary tract infection caused by candida, peritonitis and systemic candida infections (including candidemia, disseminated candidiasis and pneumonia).

Drugs for subcutaneous and mycoses

Fluconazole is a triazole antifungal agent. It is a potent inhibitor of fungal cytochrome P-450 dependent enzymes. Cytochrome P-450 enzyme system is essential component of fungal cell membrane which is responsible for the synthesis of ergosterol.

Adult (oral)-

• Vaginal candidiasis: 150 mg as a single dose.
• Oropharyngeal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of this infection generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.
• Esophageal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used. Patients should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.
• Systemic candida infections: Optimal therapeutic dosage and duration of therapy have not been established. Sometimes, doses of up to 400 mg daily have been used.
• Urinary tract infections caused by candida and peritonitis: 50-200 mg daily have been used.
• Cryptococcal meningitis: 400 mg on the first day, followed by 200 mg once daily.
• Prophylaxis in patients undergoing bone marrow transplantation: 400 mg once daily.

Child (oral):

• Doses of 3-6 mg/kg daily have been used. Doses up to 12 mg/kg is recommended.

Intravenous-

• Adult: Invasive candidal infections including candidaemia and disseminated candidiasis and cryptococcal infections including meningitis, by IV, 400 mg initially then 200 mg daily, increased if necessary to 400 mg daily, treatment continued according to response (at least 6-8 weeks for cryptococcal meningitis)
• Child: 6-12 mg/kg daily (every 72 hours in neonate up to 2 weeks old, every 48 hours in neonate 2-4 weeks old); maximum 400 mg daily. Prevention of relapse of cryptococcal meningitis, by IV, 100-200 mg daily.

Fluconazole is well tolerated. Most common side effects of using Fluconazole includes nausea, vomiting, abdominal pain, diarrhoea, headache and skin rash.

Fluconazole should not be used in patients with known hypersensitivity to Fluconazole or to related triazole compounds.

Fluconazole should be administered with caution to patients having proarrhythmic conditions.

Concomitant use of cyclosporin or phenytoin with Fluconazole increases the plasma level of cyclosporin or phenytoin. Concomitant use of Fluconazole & warfarin prolongs the prothrombin time. Rifampicin level is decreased when used with Fluconazole.

US FDA Pregnancy category of Fluconazole is C. So, Fluconazole should be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the fetus.

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

Fluconazole is indicated for the treatment of vaginal candidiasis, oropharyngeal & esophageal candidiasis and cryptococcal meningitis. It is also effective for the treatment of urinary tract infection caused by candida, peritonitis and systemic candida infections (including candidemia, disseminated candidiasis and pneumonia).

Drugs for subcutaneous and mycoses

Fluconazole is a triazole antifungal agent. It is a potent inhibitor of fungal cytochrome P-450 dependent enzymes. Cytochrome P-450 enzyme system is essential component of fungal cell membrane which is responsible for the synthesis of ergosterol.

Adult (oral)-

• Vaginal candidiasis: 150 mg as a single dose.
• Oropharyngeal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of this infection generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.
• Esophageal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used. Patients should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.
• Systemic candida infections: Optimal therapeutic dosage and duration of therapy have not been established. Sometimes, doses of up to 400 mg daily have been used.
• Urinary tract infections caused by candida and peritonitis: 50-200 mg daily have been used.
• Cryptococcal meningitis: 400 mg on the first day, followed by 200 mg once daily.
• Prophylaxis in patients undergoing bone marrow transplantation: 400 mg once daily.

Child (oral):

• Doses of 3-6 mg/kg daily have been used. Doses up to 12 mg/kg is recommended.

Intravenous-

• Adult: Invasive candidal infections including candidaemia and disseminated candidiasis and cryptococcal infections including meningitis, by IV, 400 mg initially then 200 mg daily, increased if necessary to 400 mg daily, treatment continued according to response (at least 6-8 weeks for cryptococcal meningitis)
• Child: 6-12 mg/kg daily (every 72 hours in neonate up to 2 weeks old, every 48 hours in neonate 2-4 weeks old); maximum 400 mg daily. Prevention of relapse of cryptococcal meningitis, by IV, 100-200 mg daily.

Fluconazole is well tolerated. Most common side effects of using Fluconazole includes nausea, vomiting, abdominal pain, diarrhoea, headache and skin rash.

Fluconazole should not be used in patients with known hypersensitivity to Fluconazole or to related triazole compounds.

Fluconazole should be administered with caution to patients having proarrhythmic conditions.

Concomitant use of cyclosporin or phenytoin with Fluconazole increases the plasma level of cyclosporin or phenytoin. Concomitant use of Fluconazole & warfarin prolongs the prothrombin time. Rifampicin level is decreased when used with Fluconazole.

US FDA Pregnancy category of Fluconazole is C. So, Fluconazole should be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the fetus.

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

Fluconazole is indicated for the treatment of vaginal candidiasis, oropharyngeal & esophageal candidiasis and cryptococcal meningitis. It is also effective for the treatment of urinary tract infection caused by candida, peritonitis and systemic candida infections (including candidemia, disseminated candidiasis and pneumonia).

Drugs for subcutaneous and mycoses

Fluconazole is a triazole antifungal agent. It is a potent inhibitor of fungal cytochrome P-450 dependent enzymes. Cytochrome P-450 enzyme system is essential component of fungal cell membrane which is responsible for the synthesis of ergosterol.

Adult (oral)-

• Vaginal candidiasis: 150 mg as a single dose.
• Oropharyngeal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of this infection generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.
• Esophageal candidiasis: 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used. Patients should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.
• Systemic candida infections: Optimal therapeutic dosage and duration of therapy have not been established. Sometimes, doses of up to 400 mg daily have been used.
• Urinary tract infections caused by candida and peritonitis: 50-200 mg daily have been used.
• Cryptococcal meningitis: 400 mg on the first day, followed by 200 mg once daily.
• Prophylaxis in patients undergoing bone marrow transplantation: 400 mg once daily.

Child (oral):

• Doses of 3-6 mg/kg daily have been used. Doses up to 12 mg/kg is recommended.

Intravenous-

• Adult: Invasive candidal infections including candidaemia and disseminated candidiasis and cryptococcal infections including meningitis, by IV, 400 mg initially then 200 mg daily, increased if necessary to 400 mg daily, treatment continued according to response (at least 6-8 weeks for cryptococcal meningitis)
• Child: 6-12 mg/kg daily (every 72 hours in neonate up to 2 weeks old, every 48 hours in neonate 2-4 weeks old); maximum 400 mg daily. Prevention of relapse of cryptococcal meningitis, by IV, 100-200 mg daily.

Fluconazole is well tolerated. Most common side effects of using Fluconazole includes nausea, vomiting, abdominal pain, diarrhoea, headache and skin rash.

Fluconazole should not be used in patients with known hypersensitivity to Fluconazole or to related triazole compounds.

Fluconazole should be administered with caution to patients having proarrhythmic conditions.

Concomitant use of cyclosporin or phenytoin with Fluconazole increases the plasma level of cyclosporin or phenytoin. Concomitant use of Fluconazole & warfarin prolongs the prothrombin time. Rifampicin level is decreased when used with Fluconazole.

US FDA Pregnancy category of Fluconazole is C. So, Fluconazole should be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the fetus.

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

Difluprednate is indicated for the treatment of inflammation and pain associated with ocular surgery. It is also indicated for the treatment of uveitis, pseudophakic cystoid macular edema(CME), ocular surface diseases, e.g. blepharitis & corneal inflammation.

Ophthalmic Steroid preparations

Corticosteroids inhibit the inflammatory response to a variety of inciting agents and may delay or slow healing. They inhibit edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Difluprednate is structurally similar to other corticosteroids.

For the treatment of inflammation and pain associated with ocular surgery: Instill 1 drop into the conjunctival sac of the affected eye 4 times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the post-operative period, followed by 2 times daily for a week and then a taper based on the response.

For the treatment of endogenous anterior uveitis: Instill 1 drop into the conjunctival sac of the affected eye 4 times daily for 14 days followed by tapering as clinically indicated.

For blepharitis: Instill 1 drop into the conjunctival sac of the affected eyes 2 times daily for 1 week & then once daily for 1 week.

For pseudophakic cystoid macular edema: Instill 1 drop into the conjunctival sac of the affected eyes 2 times daily.

Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects; posterior subcapsular cataract formation; secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. Ocular adverse reactions occurring with Difluprednate included corneal edema, ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule opacification, anterior chamber cells, anterior chamber flare, conjunctival edema, and blepharitis for patient with ocular surgery.

Difluprednate is contraindicated in most active viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures.

Specific drug interaction studies have not been conducted with Difluprednate 0.05% ophthalmic emulsion.

Pregnancy Category C. Difluprednate has been shown to be embryotoxic and teratogenic when administered subcutaneously to rabbits. Since use of Difluprednate during human pregnancy has not been evaluated so Difluprednate should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus. It is not known whether use of Difluprednate passes into breast milk. Caution should be exercised when it is administered to a nursing mothers.

Pediatric Use: Difluprednate was evaluated in 0 to 3 years of age for the treatment of inflammation following cataract surgery. A similar safety profile was observed in pediatric patients comparing Difluprednate to Prednisolone Acetate ophthalmic suspension 1%.

Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Overdosage will not ordinarily cause acute problems. If accidentally ingested, drink fluids to dilute.

Store at room temperature, protect from light and freezing. It is desirable that the contents should not be used more than 1 month after first opening of the bottle.

This capsule is a haematinic preparation for the treatment and prophylaxis of iron and folic acid deficiency, especially during pregnancy and lactation.

Iron & Vitamin Combined preparations

Iron is an essential constituent of the body, being necessary for haemoglobin formation and for the oxidative processes of living tissues. Iron is primarily absorbed from the duodenum and upper jejunum. The ferrous salt form is absorbed three times more readily than the ferric salt form. The adult male has a requirement of only 13 µg/kg per day (about 1 mg), whereas the menstruating female requires about 21 µg/kg per day (about 1.4 mg). In the last two trimesters of pregnancy, requirements increase to about 80 µg/kg per day (5 to 6 mg). Folic acid is an important factor in cell division and without it, division stops. Adequate folic acid is required for normal erythropoiesis. Deficiency of Folic Acid causes megaloblastic anaemia

1 (one) capsule a day, throughout pregnancy and lactation. Some patients may need a higher dose because of dietary or other factors.

Because iron salts are astringent, gastrointestinal irritation may occur. Nausea and epigastric pain are dose related.

Contraindicated in patients receiving repeated blood transfusions or in patients with anaemias not produced by iron deficiency unless iron deficiency is also present.

Iron chelates with antacid and tetracycline and absorption of all these may be impaired if taken concurrently. However, the administration of tetracycline during pregnancy is contraindicated.

The absorption of both iron salts and tetracyclines is diminished when they are taken concomitantly by mouth. The absorption of iron salts may also be decreased by magnesium trisilicate-containing antacid.

Symptoms of overdosage with iron salts include epigastric pain, nausea and vomiting, haematemesis and circulatory collapse. In severe cases encephalopathy, acute hepatic necrosis and acute renal failure may develop after a latent period. The timed release capsule presentation of ferrous sulfate may delay excessive absorption of iron and allow more time for the initiation of appropriate counter measures. Treatment consists of gastric lavage followed by the introduction of 5 gm desferrioxamine into the stomach. Serum iron levels should be monitored, in severe cases intravenous desferrioxamine should be given together with supportive and symptomatic measures as required.

Do not store above 25°C temperature, keep away from light and wet place. Keep out of reach of children.

This is indicated in Indigestion, Dyspepsia, Flatulence, Colic, Constipation.

Herbal and Nutraceuticals

This is an Ayurvedic liquid digestive medicine which is formulated from Jamani seed (Trachyspermum ammi) in a scientific manner. It provides quick relief from several digestive problems like indigestion, dyspepsia, flatulence, abdominal pain constipation.

Trachyspermum ammi- It contains essential oil (2-3.5%), phenol, thymol (35-60%), carvacrol, y terpinene, α and β pinenes, dipentene. It is antispasmodic, antimicrobial, antiseptic, stomachic, carminative and tonic. It is used in indigestion, dyspepsia, flatulence, colic, and constipation.

Adult: 2-4 tea-spoonful to be taken with an equal quantity of water 2-3 times daily after meal.
Children: 1-2 tea-spoonful to be taken with an equal quantity of water 2-3 times daily after meal.

Not yet known.

There is no major contraindication.

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