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Biguanides

Metformin 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 decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.

Metformin immediate release tablet: Dosage of Metformin Hydrochloride must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses.

• Adult: The usual starting dose of Metformin is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. For those patients requiring additional glycemic control, Glucomin may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.
• Children: The usual starting dose of Metformin is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.

Metformin extended release tablet: Swallow Metformin XR tablet whole and never crush, cut or chew.

• Adult: The usual starting dose of Metformin XR is 500 mg once daily with the evening meal. Dose should be increased in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal, alternatively increased to 1000 mg twice daily taken with meal. Patient receiving Metformin immediate release tablet may be switched to Metformin extended release tablet up to a maximum recommended daily dose.
• Children: Metformin extended release tablet has not been studied in children.
• Renal impaired patient: Do not use Metformin in patients with eGFR below 30 mL/min/1.73 m². Asses risk/benefit of counting if eGFR falls below 45 mL/min/1.73 m².

Blood and lymphatic system disorders: Not known: Hemolytic anemia

Metabolism and nutrition disorders: Very rare: Lactic acidosis. Decrease of vitamin B12 absorption with a decrease of serum levels during long-term use of metformin. Consideration of such etiology is recommended if a patient presents with megaloblastic anemia. Cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post-marketing experience (frequency not known)

Nervous system disorders: Common: Taste disturbance. Not known: Encephalopathy

Gastrointestinal disorders: Very common: Gastrointestinal disorders, such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These undesirable effects occur most frequently during the initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders: Very rare: Isolated reports of liver function test abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders: Very rare: Skin reactions, such as erythema, pruritus, urticaria.

Metformin Hydrochloride is known to be substantially excreted by the kidney and the risk of Metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Metformin may lower vitamin B12 level. It also increases risk of hypoglycemia when use in combination with insulin or insulin secretagogue.

Co-administration with Carbonic anhydrase (Topiramate, Zonisamide) may increase risk of lactic acidosis. Drugs (Ranolazine, Dolutegravir, Cimetidine) that reduce Metformin clearance may increase the accumulation of Metformin. Alcohol can potentiate the effect of Metformin on lactate metabolism.

Pregnancy: Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with an increased risk of congenital abnormalities and perinatal mortality. When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.

Breastfeeding: Metformin is excreted into human breast milk. No adverse efects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breastfeeding should be made, taking into account the benefit of breastfeeding and the potential risk to adverse effects on the child.

Elderly: Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Pediatric population: The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated. No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially prepubescent children, is recommended.

Children aged between 10 and 12 years: Particular caution is recommended when prescribing to children aged between 10 and 12 years.

Renal function: As metformin is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) should be determined before initiating treatment and regularly thereafter:

• At least annually in patients with normal renal function,
• At least two to four times a year in patients with creatinine clearance at the lower limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID). GFR should be assessed before treatment initiation and regularly thereafter. Metformin is contraindicate in patients with GFR<30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function.

Hypoglycemia has not been seen with Metformin doses up to 85 gm, although lactic acidosis has occurred in such circumstances. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and Metformin is hemodialysis.

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

Biguanides

Metformin 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 decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.

Metformin immediate release tablet: Dosage of Metformin Hydrochloride must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses.

• Adult: The usual starting dose of Metformin is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. For those patients requiring additional glycemic control, Glucomin may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.
• Children: The usual starting dose of Metformin is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.

Metformin extended release tablet: Swallow Metformin XR tablet whole and never crush, cut or chew.

• Adult: The usual starting dose of Metformin XR is 500 mg once daily with the evening meal. Dose should be increased in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal, alternatively increased to 1000 mg twice daily taken with meal. Patient receiving Metformin immediate release tablet may be switched to Metformin extended release tablet up to a maximum recommended daily dose.
• Children: Metformin extended release tablet has not been studied in children.
• Renal impaired patient: Do not use Metformin in patients with eGFR below 30 mL/min/1.73 m². Asses risk/benefit of counting if eGFR falls below 45 mL/min/1.73 m².

Blood and lymphatic system disorders: Not known: Hemolytic anemia

Metabolism and nutrition disorders: Very rare: Lactic acidosis. Decrease of vitamin B12 absorption with a decrease of serum levels during long-term use of metformin. Consideration of such etiology is recommended if a patient presents with megaloblastic anemia. Cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post-marketing experience (frequency not known)

Nervous system disorders: Common: Taste disturbance. Not known: Encephalopathy

Gastrointestinal disorders: Very common: Gastrointestinal disorders, such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These undesirable effects occur most frequently during the initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders: Very rare: Isolated reports of liver function test abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders: Very rare: Skin reactions, such as erythema, pruritus, urticaria.

Metformin Hydrochloride is known to be substantially excreted by the kidney and the risk of Metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Metformin may lower vitamin B12 level. It also increases risk of hypoglycemia when use in combination with insulin or insulin secretagogue.

Co-administration with Carbonic anhydrase (Topiramate, Zonisamide) may increase risk of lactic acidosis. Drugs (Ranolazine, Dolutegravir, Cimetidine) that reduce Metformin clearance may increase the accumulation of Metformin. Alcohol can potentiate the effect of Metformin on lactate metabolism.

Pregnancy: Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with an increased risk of congenital abnormalities and perinatal mortality. When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.

Breastfeeding: Metformin is excreted into human breast milk. No adverse efects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breastfeeding should be made, taking into account the benefit of breastfeeding and the potential risk to adverse effects on the child.

Elderly: Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Pediatric population: The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated. No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially prepubescent children, is recommended.

Children aged between 10 and 12 years: Particular caution is recommended when prescribing to children aged between 10 and 12 years.

Renal function: As metformin is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) should be determined before initiating treatment and regularly thereafter:

• At least annually in patients with normal renal function,
• At least two to four times a year in patients with creatinine clearance at the lower limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID). GFR should be assessed before treatment initiation and regularly thereafter. Metformin is contraindicate in patients with GFR<30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function.

Hypoglycemia has not been seen with Metformin doses up to 85 gm, although lactic acidosis has occurred in such circumstances. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and Metformin is hemodialysis.

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

Diltiazem Hydrochloride film coated tablet is used for the prophylaxis and treatment of chronic stable (classical) and vasopastic angina pectoris and has also been used alone or in combination in the management of hypertension, also, Diltiazem is effective in myocardial infarction, coronary artery spasm, arrhythmias, Raynaud's phenomenon, oesophageal motility disorder and migraine.

Calcium-channel blockers

Diltiazem is a calcium-channel blocker with peripheral and coronary vasodilator properties. It lowers blood pressure and has some effect on cardiac conduction. Diltiazem interferes with the influx of calcium ions through the channels of active cell membranes.

Adult: The usual dose of Diltiazem Hydrochloride film coated tablet is 60 mg thrice daily. However patient's response may vary and dosage requirements can differ significantly between individual patients. If necessary, the divided dose may be increased to 180-300 mg/day. Dosage may be started as 30 mg four times daily and increasing at 1 to 2 days intervals until the optimum response is achieved. Higher doses upto 480 mg/day have been used with benefit in some patients especially in unstable angina. Elderly and patients with impaired hepatic or renal function: The recommended starting dose is 60 mg twice daily. The heart rate should be measured regularly and the dose should not be increased if the heart rate falls below 50 beats per minute.

Children: Not recommended.

With Diltiazem headache, ankle oedema, hypertension, dizziness, flushing, rashes (toxic erythema), nausea and Gl disturbances may occur. Transient elevation in liver enzyme values and occasionally hepatitis have been reported. Diltiazem may depress cardiac conduction and has occasionally led to AV block, bradycardia and rarely asystoleor sinus arrest.

Diltiazem is contraindicated to the patients of severe bradycardia, sick sinus syndrome, pregnancy, second or third degree AV block.

Diltiazem should be used with care in patients with lesser degrees of AV block or bradycardia; also in patients with impaired left ventricular function. Caution should be required in patients with impaired liver or kidney function.

Digoxin, Propranolol, Cyclosporin, Theophylline, Cimetidine, Lithium & Carbamazepine.

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

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Linagliptin is indicated to improve glycemic control in patients with type 2 diabetes mellitus. Linagliptin is an inhibitor of DPP-4 (dipeptidyl peptidase-4), an enzyme that degrades the incretin hormones GLP-1 (glucagon like peptide-1) and GIP (glucose dependent insulinotropic polypeptide). Thus, Linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin from pancreatic beta (β) cells in a glucose-dependent manner and decreasing the secretion of glucagon from pancreatic alpha (α) cells in the circulation.

Linagliptin 5 mg once daily. If added to metformin, the dose of metformin should be maintained and linagliptin administered concomitantly. When used in combination with a sulfonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia.

Patients with renal impairment: No dose adjustment required. Linagliptin can be taken with or without a meal at any time of the day.

There may be hypoglycaemia, nasopharyngitis, cough and pancreatitis in combination with metformin and sulfonylurea.

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

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

Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. The risk for clinically meaningful interactions by other medicinal products on linagliptin is low and in clinical studies linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glyburide, simvastatin, warfarin, digoxin or oral contraceptives.

Pregnancy category B. There are no adequate and well controlled studies in pregnant women. So, Linagliptin tablets should be used during pregnancy only if clearly needed. It is not known whether Linagliptin passes into breast milk or not.

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

Vildagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus as monotherapy and in dual combination with Metformin, a Sulphonylurea, a Thiazolidinedione, or Insulin when diet, exercise and a single antidiabetic agent do not result in adequate glycemic control.

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Vildagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Vildagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.

The recommended dose of Vildagliptin is-

• 50 mg or 100 mg daily for monotherapy.
• 50 mg twice daily (morning and evening) when used in dual combination with Metformin or a Thiazolidinedione;
• 50 mg once daily in the morning when used in dual combination with a Sulphonylurea.

Vildagliptin may be taken with or without a meal. No dosage adjustment is required in the elderly, or in patients with mild renal impairment.

Pediatric use: Vildagliptin is not recommended in patients 18 years of age.

The majority of adverse reactions were mild and transient, not requiring treatment discontinuations. A rare case of hepatic dysfunction is seen. Clinical trials of up to and more than 2 years duration did not show any additional safety signals or unforeseen risks when using this combination.

Vildagliptin is contraindicated in patients with:

• Hypersensitivity to the active substance or to any of the excipients
• Patients with moderate to severe renalImpairment
• Patients with Hepatic Impairment: patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotrasferase (AST) >3 times the upper limit of normal (ULN).
• Patients with type 1 diabetes

Caution should be exercised in patients aged 75 years and older due to limited clinical experience. It is recommended that LFTs are monitored prior to initiation of Vildagliptin, at three-monthly intervals in the first year and periodically thereafter. If transaminase levels are increased, patients should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality returns to normal. If AST or ALT persists at 3xULN, Vildagliptin treatment should be stopped. Patients who develop jaundice or other signs of liver dysfunction should discontinue Vildagliptin. Following the withdrawal of treatment with Vildagliptin and LFT normalization, treatment with Vildagliptin should not be reinitiated. Due to limited clinical experience, use with caution in patients with congestive heart failure of New York Heart Association (NYHA) functional class I-II, and do not use in patients with NYHA functional class III IV.

In pharmacokinetic studies, no interactions were seen with pioglitazone, metformin, glibenclamide, digoxin, warfarin, amlodipine, ramipril, valsartan or simvastatin. As with other oral antidiabetic medicinal products the glucose-lowering effect of Vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics.

Vildagliptin should not be used in pregnancy. Vildagliptin should not be used during lactation.

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

This tablet is indicated as an adjunct to diet and exercises to improve glycaemic control in patients with type 2 diabetes mellitus whose diabetes is not adequately controlled on Metformin Hydrochloride or Vildagliptin alone or who are already treated with the combination of Vildagliptin and Metformin Hydrochloride, as separate tablets.

Combination Oral hypoglycemic preparations

Vildagliptin acts primarily by inhibiting DPP-4 (Dipeptidyl peptidase-4), the enzyme responsible for the degradation of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). The administration of Vildagliptin results in a rapid and complete inhibition of DPP-4 activity resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 and GIP. By increasing the endogenous levels of these incretin hormones, Vildagliptin increases insulin secretion from the pancreatic beta cell and decreases glucagon secretion from alpha cell. The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycaemia.

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. Glucomin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.

Adults: Based on the patient's current dose of Metformin, this combination may be initiated at twice daily, 1 tablet in the morning and the other in the evening. Patients receiving Vildagliptin and Metformin from separate tablets may be switched to this combination containing the same doses of each component. Doses higher than 100 mg of vildagliptin are not recommended. There is no clinical experience of Vildagliptin and Metformin in triple combination with other antidiabetic agents. Taking this combination with or just after food may reduce gastrointestinal symptoms associated with Metformin.

The most common side effects are headache, tremor, dizziness, nausea, hypoglycaemia etc.

This combination is contraindicated in patients with known hypersensitivity to Vildagliptin or Metformin Hydrochloride or to any of the excipients. It is contraindicated in patients with renal disease or renal dysfunction, acute myocardial infarction, and septicaemia. It is also contraindicated in patients with congestive heart failure patients and in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. It should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic acidosis can occur due to Metformin accumulation. If metabolic acidosis is suspected, treatment should be discontinued and the patient should be hospitalized immediately. Serum creatinine should be monitored at least once a year in patients with normal renal function and 2–4 times a year in patients with serum creatinine levels at the upper limit of normal and in elderly patients. Special caution should be exercised in elderly patients where renal function may become impaired (e.g. when initiating antihypertensives, diuretics or NSAIDs). It is recommended that Liver Function Tests (LFTs) are monitored prior to initiation of this drug, at three-monthly intervals in the first year and periodically thereafter. If transaminase levels are increased, patients should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality return to normal. If AST or ALT persist at 3 x ULN, Vildagliptin & Metformin tablets should be stopped Patients who develop jaundice or other signs of liver dysfunction. Following withdrawal of treatment with Vildagliptin & Metformin and LFT normalization, treatment with Vildagliptin & Metformin should not be reinitiated. Vildagliptin & Metformin tablets should be discontinued 48 hours before elective surgery with general anaesthesia and should not usually be resumed earlier than 48 hours afterwards.

No clinically relevant pharmacokinetic interaction was observed when Vildagliptin (100 mg once daily) was co-administered with Metformin Hydrochloride (1,000 mg once daily). Vildagliptin has a low potential for drug interactions. Since Vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate nor does it inhibit nor induces CYP 450 enzymes, it is not likely to interact with co-medications that are substrates, inhibitors or inducers of these enzymes. As a result of these studies no clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin hydrochloride), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin. On the other hand, furosemide, nifedipine and glyburide increase Cmax and blood AUC of Metformin with no change in renal clearance of Metformin.

There are no adequate and well controlled studies in pregnant women and therefore, this combination should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus. No studies have been conducted with the components of this combination. As it is not known whether Vildagliptin and/or Metformin Hydrochloride is excreted in human milk this combination should not be administered to breast-feeding women.

Use in pediatric patients: The safety and effectiveness of this combination in pediatric patients have not been established. Therefore, this combination is not recommended for use in children below 18 years of age.

Use in geriatric patients: As Metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking this combination should have their renal function monitored regularly. This combination should only be used in elderly patients with normal renal function.

Patients with renal impairment: This combination should not be used in patients with renal failure or renal dysfunction, e.g. serum creatinine levels > 1.5 mg/dl (>135 micro mol/L) in males and > 1.4 mg/dl (>110 micro mol/L) in females.

Patients with hepatic impairment: This combination is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >3 X the upper limit of normal.

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

This tablet is indicated as an adjunct to diet and exercises to improve glycaemic control in patients with type 2 diabetes mellitus whose diabetes is not adequately controlled on Metformin Hydrochloride or Vildagliptin alone or who are already treated with the combination of Vildagliptin and Metformin Hydrochloride, as separate tablets.

Combination Oral hypoglycemic preparations

Vildagliptin acts primarily by inhibiting DPP-4 (Dipeptidyl peptidase-4), the enzyme responsible for the degradation of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). The administration of Vildagliptin results in a rapid and complete inhibition of DPP-4 activity resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 and GIP. By increasing the endogenous levels of these incretin hormones, Vildagliptin increases insulin secretion from the pancreatic beta cell and decreases glucagon secretion from alpha cell. The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycaemia.

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. Glucomin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.

Adults: Based on the patient's current dose of Metformin, this combination may be initiated at twice daily, 1 tablet in the morning and the other in the evening. Patients receiving Vildagliptin and Metformin from separate tablets may be switched to this combination containing the same doses of each component. Doses higher than 100 mg of vildagliptin are not recommended. There is no clinical experience of Vildagliptin and Metformin in triple combination with other antidiabetic agents. Taking this combination with or just after food may reduce gastrointestinal symptoms associated with Metformin.

The most common side effects are headache, tremor, dizziness, nausea, hypoglycaemia etc.

This combination is contraindicated in patients with known hypersensitivity to Vildagliptin or Metformin Hydrochloride or to any of the excipients. It is contraindicated in patients with renal disease or renal dysfunction, acute myocardial infarction, and septicaemia. It is also contraindicated in patients with congestive heart failure patients and in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. It should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic acidosis can occur due to Metformin accumulation. If metabolic acidosis is suspected, treatment should be discontinued and the patient should be hospitalized immediately. Serum creatinine should be monitored at least once a year in patients with normal renal function and 2–4 times a year in patients with serum creatinine levels at the upper limit of normal and in elderly patients. Special caution should be exercised in elderly patients where renal function may become impaired (e.g. when initiating antihypertensives, diuretics or NSAIDs). It is recommended that Liver Function Tests (LFTs) are monitored prior to initiation of this drug, at three-monthly intervals in the first year and periodically thereafter. If transaminase levels are increased, patients should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality return to normal. If AST or ALT persist at 3 x ULN, Vildagliptin & Metformin tablets should be stopped Patients who develop jaundice or other signs of liver dysfunction. Following withdrawal of treatment with Vildagliptin & Metformin and LFT normalization, treatment with Vildagliptin & Metformin should not be reinitiated. Vildagliptin & Metformin tablets should be discontinued 48 hours before elective surgery with general anaesthesia and should not usually be resumed earlier than 48 hours afterwards.

No clinically relevant pharmacokinetic interaction was observed when Vildagliptin (100 mg once daily) was co-administered with Metformin Hydrochloride (1,000 mg once daily). Vildagliptin has a low potential for drug interactions. Since Vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate nor does it inhibit nor induces CYP 450 enzymes, it is not likely to interact with co-medications that are substrates, inhibitors or inducers of these enzymes. As a result of these studies no clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin hydrochloride), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin. On the other hand, furosemide, nifedipine and glyburide increase Cmax and blood AUC of Metformin with no change in renal clearance of Metformin.

There are no adequate and well controlled studies in pregnant women and therefore, this combination should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus. No studies have been conducted with the components of this combination. As it is not known whether Vildagliptin and/or Metformin Hydrochloride is excreted in human milk this combination should not be administered to breast-feeding women.

Use in pediatric patients: The safety and effectiveness of this combination in pediatric patients have not been established. Therefore, this combination is not recommended for use in children below 18 years of age.

Use in geriatric patients: As Metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking this combination should have their renal function monitored regularly. This combination should only be used in elderly patients with normal renal function.

Patients with renal impairment: This combination should not be used in patients with renal failure or renal dysfunction, e.g. serum creatinine levels > 1.5 mg/dl (>135 micro mol/L) in males and > 1.4 mg/dl (>110 micro mol/L) in females.

Patients with hepatic impairment: This combination is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >3 X the upper limit of normal.

Keep in a dry place away from light and heat. Keep 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.

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.

Dapagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors

Dapagliflozin is a highly potent, selective, and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2) that improves glycemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary excretion of excess glucose (glucuresis).

5 mg orally once a day. May increase to 10 mg orally once a day in patients tolerating therapy with 5 mg and requiring additional glycemic control

Renal impairment, Female genital mycotic infections, Urinary tract infection, Increased urination, Male genital mycotic infections, Dyslipidemia, Constipation, Discomfort with urination, Extremity pain, Volume depletion, Hypersensitivity

Hypersensitivity to dapagliflozin propanediol or to any of the excipients. Moderate to severe renal impairment; end-stage renal disease; active bladder cancer. Pregnancy (2nd & 3rd trimester) & lactation.

CV disease, history of hypotension, UTI, Children, Elderly. Unknown whether distributed in human breast milk; breastfeeding women should discontinue dapagliflozin or nursing taking into account the importance of the drug to the mother

Hypoglycemia may occur with concomitant use with insulin & insulin secretagogues eg sulfonylureas. Decrease in Cmax & AUC with rifampin. Increase in Cmax & AUC with mefenamic acid. Increased thiazide & loop diuretic effects; may increase risk of dehydration & hypotension. Pioglitazone.

Pregnancy Category-C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Renal Impairment: No dosage adjustment is indicated based on renal function. The efficacy is dependent on renal function. lt is not recommended for use in patients with moderate to severe renal impairment (patients with CrCI <60 mL/min or eGFR <60 mL/min/1.73 m²).

This solution is used in Haemodialysis.

Haemodialysis solutions

Calcium chloride is used to prevent or treat negative calcium balance. It also regulates action potential excitation threshold to facilitate nerve and muscle performance.

Potassium chloride is a major cation of the intracellular fluid. It plays an active role in the conduction of nerve impulses in the heart, brain and skeletal muscle; contraction of cardiac skeletal and smooth muscles; maintenance of normal renal function, acid-base balance, carbohydrate metabolism and gastric secretion.

Sodium chloride is the major extracellular cation. It is important in electrolyte and fluid balance, osmotic pressure control and water distribution as it restores sodium ions. It is used as a source of electrolytes and water for hydration, treatment of metabolic acidosis, priming solution in haemodialysis and treatment of hyperosmolar diabetes. It is also used as diluents for infusion of compatible drug additives.

Magnessium Chloride acts as cofactor in numerous enzymatic reactions involving protein synthesis and carbohydrate metabolism; depresses CNS, blocks peripheral neuromuscular transmission, produces anticonvulsant effects.

Recommended dose: 5 liters concentrate per dialysis or as required.

Fluid and electrolyte imbalance, hypovolemia, hypotension or muscle cramping may occur.

Known hypersensitivity to any of the ingredients of this preparation.

It is used for hemodialysis purposes only. Do not use solution A or B alone. Discard container in case visible solid particles inside.

There are no known drug interactions and none well documented.

Pregnancy Category is not Classified. FDA has not yet classified the drug into a specified pregnancy category.

This solution is used for haemodialysis.

Haemodialysis solutions

Calcium chloride is used to prevent or treat negative calcium balance. It also regulates action potential excitation threshold to facilitate nerve and muscle performance.

Potassium chloride is a major cation of the intracellular fluid. It plays an active role in the conduction of nerve impulses in the heart, brain and skeletal muscle; contraction of cardiac skeletal and smooth muscles; maintenance of normal renal function, acid-base balance, carbohydrate metabolism and gastric secretion.

Magnessium Chloride acts as cofactor in numerous enzymatic reactions involving protein synthesis and carbohydrate metabolism; depresses CNS, blocks peripheral neuromuscular transmission, produces anticonvulsant effects.

Sodium chloride is the major extracellular cation. It is important in electrolyte and fluid balance, osmotic pressure control and water distribution as it restores sodium ions. It is used as a source of electrolytes and water for hydration, treatment of metabolic acidosis, priming solution in haemodialysis and treatment of hyperosmolar diabetes. It is also used as diluents for infusion of compatible drug additives.

Recommended dose: 5 liters concentrate per dialysis or as required.

Fluid and electrolyte imbalance, hypovolemia, hypotension or muscle cramping may occur.

Known hypersensitivity to any of the ingredients of this preparation

It is used for haemodialysis purposes only.

There are no known drug interactions and none well documented.

Pregnancy Category-not Classified. FDA has not yet classified the drug into a specified pregnancy category.

Bicarbonate Component [HCO3 Hemodialysis Solution] solution is indicated in renal failure, Chronic renal failure and Haemodialysis. Bicarbonate serves a crucial biochemical role in the physiological pH buffering system.

Haemodialysis solutions

Sodium chloride is the major extracellular cation. It is important in electrolyte and fluid balance, osmotic pressure control and water distribution as it restores sodium ions. It is used as a source of electrolytes and water for hydration, treatment of metabolic acidosis, priming solution in haemodialysis and treatment of hyperosmolar diabetes. It is also used as diluents for infusion of compatible drug additives. Sodium bicarbonate raises blood and urinary pH by dissociation to provide bicarbonate ions, which neutralises the hydrogen ion concentration. It also neutralises gastric acid via production of carbon dioxide.

Acidic component & Bicarbonate Component should be used in the dilution ratio of-

• Acidic component: 1.00 Volume
• Bicarbonate Component: 1.83 Volume
• Purified Water: 34.00 Volume

Known hypersensitivity to any of the ingredients of this preparation.

Sodium bicarbonate: Increases toxicity of amphetamines, ephedrine, pseudoephedrine, flecainide, quinidine and quinine. Decreases effects of lithium, chlorpropamide and salicylates due to increased clearance. May affect the absorption of certain drugs due to raised intra-gastric pH. Sodium chloride: May affect serum concentrations of lithium.

Keep out of reach of children. Not for Injection. Store below 30°C.

Gliclazide is a medicine that reduces blood sugar levels (oral antidiabetic medicine belonging to the sulphonylurea group). Gliclazide is used in a certain form of diabetes (type 2 diabetes Mellitus) in adults, when diet, exercise and weight loss alone do not have an adequate effect on keeping blood sugar at the correct level.

Sulfonylureas

Gliclazide is a second generation sulfonylurea drug that has hypoglycaemic and potentially useful hematological properties. It stimulates the release of insulin from pancreatic β-cells by facilitating Ca⁺²  transport across the β-cell membranes and decreases hepatic glucose output.

Film-coated tablet: The usual initial dose is 40 to 80 mg daily. The dose can be increased up to 320 mg daily in divided doses when needed. The drug should be taken before meal. For children, Gliclazide is not used because it is contraindicated in juvenile-onset diabetes.

Modified release preparation: Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The dose is determined by the doctor, depending on your blood and possibly urine sugar levels. Change in external factors (weight reduction, lifestyle, stress) or improvements in the blood sugar control may require changed gliclazide doses.

The recommended daily dose is one to four tablets (maximum 120 mg) in a single intake at breakfast time. This depends on the response to treatment. Gliclazide MR tablet is for oral use. Take your tablet(s) with a glass of water at breakfast time (and preferably at the same time each day). Swallow your whole tablet(s) in one piece. Do not chew or crush. You must always eat a meal after taking your tablet(s).

If a combination therapy of gliclazide with metformin, an alpha-glucosidase inhibitor, a thiazolidinedione, a dipeptidyl peptidase-4 inhibitor a GLP-1 receptor agonist or insulin is initiated your doctor will determine the proper dose of each medicine individually for you. If you notice that your blood sugar levels are high although you are taking the medicine as prescribed, you should contact your doctor or pharmacist.

If you take more Gliclazide tablets than you should: If you take too many tablets, contact your doctor or the nearest hospital Accident & Emergency department immediately. The signs of overdose are those of low blood sugar (hypoglycaemia). The symptoms can be helped by taking sugar (4 to 6 lumps) or sugary drinks straight away, followed by a substantial snack or meal. If the patient is unconscious immediately inform a doctor and call the emergency services. The same should be done if somebody, (for instance a child), has taken the product unintentionally. Unconscious patients must not be given food or drink. It should be ensured that there is always a pre-informed person that can call a doctor in case of emergency.

If you forget to take Gliclazide tablet: It is important to take your medicine every day as regular treatment works better. However, if you forget to take a dose of Gliclazide MR tablet, take the next dose at the usual time. Do not take a double dose to make up for a forgotten dose.

If you stop taking Gliclazide MR tablet: As the treatment for diabetes is usually lifelong, you should discuss with your doctor before stopping this medicinal product. Stopping could cause high blood sugar (hyperglycaemia) which increases the risk of developing complications of diabetes. If you have any further questions on the use of this product, ask your doctor or pharmacist.

Like all medicines, Gliclazide can cause side effects, although not everybody gets them. The most commonly observed side effect is low blood sugar (hypoglycaemia). If left untreated these symptoms could progress to drowsiness, loss of consciousness or possibly coma. If an episode of low blood sugar is severe or prolonged, even if it is temporarily controlled by eating sugar, you should seek immediate medical attention.

Liver disorders: There have been isolated reports of abnormal iiver function, which can cause yellow skin and eyes. If you get this, see your doctor immediately. The symptoms generally disappear if the medicine is stopped. Your doctor will decide whether to stop your treatment.

Skin disorders: Skin reactions such as rash, redness, itching, hives, blisters, angioedema (rapid swelling of tissues such as eyelids, face, lips, mouth, tongue or throat that may result in breathing difficulty) have been reported. Rash may progress to widespread blistering or peeling of the skin. If you develop this, stop taking, seek urgent advice from a doctor and tell him that you are taking this medicine. Exceptionally, signs of severe hypersensitivity reactions have been reported: initially as flu-like symptoms and a rash on the face then an extended rash with a high temperature.

Blood disorders: Decrease in the number of cells in the blood (e.g. platelets, red and white blood cells) which may cause paleness, prolonged bleeding, bruising, sore throat and fever have been reported. These symptoms usually vanish when the treatment is discontinued.

Digestive disorders: Abdominal pain, nausea, vomiting, indigestion, diarrhoea, and constipation. These effects are reduced when Gliclazide is taken with a meal as recommended.

Eye disorders: Your vision may be affected for a short time especially at the start of treatment. This effect is due to changes in blood sugar levels.

As for another sulfonylurea, the following adverse events have been observed: cases of severe changes in the number of blood cells and allergic inflammation of the wall of blood vessels, reduction in blood sodium (hyponatraemia), symptoms of liver impairment (for instance jaundice) which in most cases disappeared after withdrawal of the sulfonylurea, but may lead to life-threatening liver failure in isolated cases.

Reporting of side effects: If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects, you can help provide more information on the safety of this medicine.

Do not take Gliclazide:

• if you are allergic to gliclazide or to other medicines of the same group (sulfonylurea), or to other related medicines (hypoglycaemic sulfonamides)
• if you have insulin-dependent diabetes (type 1)
• if you have ketone bodies and sugar in your urine (this may mean you have diabetic ketoacidosis), a diabetic pre-coma or coma
• if you have severe kidney or liver disease
• if you are taking medicines to treat fungal infections
• if you are breastfeeding

Talk to your doctor before taking Gliclazide. You should observe the treatment plan prescribed by your doctor to achieve proper blood sugar levels. This means, apart from regular tablet intake, to observe the dietary regimen, have physical exercise and, where necessary, reduce weight During gliclazide treatment regular monitoring of your blood (and possibly urine) sugar level and also your glycated haemoglobin (HbA1c) is necessary. In the first few weeks of treatment, the risk of having reduced blood sugar levels (hypoglycaemia) may be increased. So particularly close medical monitoring is necessary.

Low blood sugar (Hypoglycaemia) may occur:

• if you take meals irregularly or skip meals altogether,
• if you are fasting
• if you are malnourished
• if you change your diet
• if you increase your physical activity and carbohydrate intake does not match this increase,
• if you drink alcohol, especially in combination with skipped meals,
• if you take other medicines or natural remedies at the same time,
• if you take too high doses of gliclazide,
• if you suffer from particular hormone-induced disorders (functional disorders of the thyroid gland, pituitary gland or adrenal cortex),
• if your kidney function or liver function is severely decreased.

if you have low blood sugar you may have the following symptoms: headache, intense hunger, nausea, vomiting, weariness, sleep disorders, restlessness, aggressiveness, poor concentration, reduced alertness and reaction time, depression, confusion, speech or visual disorders, tremor, sensory disturbances, dizziness and helplessness.

The following signs and symptoms may also occur: sweating, clammy skin, anxiety, fast or irregular heartbeat, high blood pressure, sudden strong pain in the chest that may radiate into nearby areas (angina pectoris).

If blood sugar levels continue to drop you may suffer from considerable confusion (delirium), develop convulsions, lose self-control, your breathing may be shallow and your heartbeat slowed down, you may become unconscious.

In most cases the symptoms of low blood sugar vanish very quickly when you consume .some form of sugar, (for instance, glucose tablets, sugar cubes, sweet juice, sweetened tea).

You should therefore always carry some form of sugar with you (glucose tablets, sugar cubes). Remember that artificial sweeteners are not effective. Please contact your doctor or the nearest hospital if taking sugar does not help or if the symptoms recur.

Symptoms of low blood sugar may be absent, less obvious or develop very slowly or you are not aware in time that your blood sugar level has dropped. This may happen if you are an elderly patient taking certain medicines (for instance those acting on the central nervous system and beta-blockers).

If you are in stressful situations (e.g. accidents, surgical operations, fever etc.) your doctor may temporarily switch you to insulin therapy.

Symptoms of high blood sugar (hyperglycaemia) may occur when gliclazide has not yet sufficiently reduced the blood sugar when you have not complied with the treatment plan prescribed by your doctor if you take St. John’s Wort (Hypericum perforatum) preparations or in special stress situations. These may include thirst, frequent urination, dry mouth, dry itchy skin, skin infections and reduced performance.

Blood glucose disturbances (low blood sugar and high bold sugar) can occur when Gliclazide is prescribed at the same time as medicines to a class of antibiotics called fluoroquinolone, especially in elderly patients. In this case, your doctor will remind you of the importance of monitoring your blood glucose.

If you have a family history of or know you have the hereditary condition glucose-6-phosphate dehydrogenase (G6PD) deficiency (abnormality of red blood cells), lowering of the haemoglobin level and breakdown of red blood cells (haemolytic anaemia) can occur. Contact your doctor before taking this medicinal product.

Gliclazide is not recommended for use in children due to lack of data.

Other medicines and Gliclazide: Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

The blood sugar lowering effect of gliclazide may be strengthened and signs of low blood sugar levels may occur when one of the follow ng medicines is taken:

• other medicines used to treat high blood sugar (oral antidiabetics, GLP-1 receptor agonists or insulin),
• antibiotics (sulphonamides, clarithromycin)
• medicines to treat high blood pressure or heart failure (beta-blockers. ACE-inhibitors such as captopril, or enalapril)
• medicines to treat fungal infections (miconazole, fluconazole)
• medicines to treat ulcers in the stomach or duodenum (H2 receptor antagonists),
• medicines to treat depression (monoamine oxidase inhibitors)
• painkiller or antirheumatics (phenylbutazone, ibuprofen)
• medicines containing alcohol

The blood-glucose-lowering effect of gliclazide may be weakened and raised blood sugar levels may occur when one of the following medicines is taken:

• medicines to treat disorders of the central nervous system (chlorpromazine)
• medicines reducing inflammation (corticosteroids)
• medicines to treat asthma or used during labour (intravenous salbutamol, ritodrine and terbutaline)
• medicines to treat breast disorders, heavy menstrual bleeding and endometriosis (danazol)
• St John's Wort- Hypericum perforatum- preparations

Blood glucose disturbance (low blood sugar and high blood sugar) can occur when a medicine belonging to a class of antibiotics called fluoroquinolones is taken at the same time as gliclazide especially in elderly patients.

Gliclazide may increase the effects of medicines that reduce blood clotting (warfarin).

Consult your doctor before you start taking another medicinal product. If you go into hospital tell the medical staff you are taking gliclazide.

Gliclazide with food and drink: Gliclazide can be taken with food and non-alcoholic drinks. Drinking alcohol is not recommended as it can alter the control of your diabetes in an unpredictable manner.

Driving and using machines: Your ability to concentrate or react may be impaired if your blood sugar is too low (hypoglycaemia), or too high (hyperglycaemia) or if you develop visual problems as a result of such conditions. Bear in mind that you could endanger yourself or others (for instance when driving a car or using machines). Please ask your doctor whether you can drive a car if you:

• have frequent episodes of low blood sugar (hypoglycaemia)
• have few or no warning signals of low blood sugar (hypoglycaemia)

Gliclazide contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Gliclazide is not recommended for use during pregnancy. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. You must not take Gliclazide while you are breastfeeding.

Keep out of the reach and sight of children. Do not use this medicine after the expiry date which is stated on the carton and the blister. The expiry date refers to the last day of that month. Store below 30°C. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Gliclazide is a medicine that reduces blood sugar levels (oral antidiabetic medicine belonging to the sulphonylurea group). Gliclazide is used in a certain form of diabetes (type 2 diabetes Mellitus) in adults, when diet, exercise and weight loss alone do not have an adequate effect on keeping blood sugar at the correct level.

Sulfonylureas

Gliclazide is a second generation sulfonylurea drug that has hypoglycaemic and potentially useful hematological properties. It stimulates the release of insulin from pancreatic β-cells by facilitating Ca⁺²  transport across the β-cell membranes and decreases hepatic glucose output.

Film-coated tablet: The usual initial dose is 40 to 80 mg daily. The dose can be increased up to 320 mg daily in divided doses when needed. The drug should be taken before meal. For children, Gliclazide is not used because it is contraindicated in juvenile-onset diabetes.

Modified release preparation: Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The dose is determined by the doctor, depending on your blood and possibly urine sugar levels. Change in external factors (weight reduction, lifestyle, stress) or improvements in the blood sugar control may require changed gliclazide doses.

The recommended daily dose is one to four tablets (maximum 120 mg) in a single intake at breakfast time. This depends on the response to treatment. Gliclazide MR tablet is for oral use. Take your tablet(s) with a glass of water at breakfast time (and preferably at the same time each day). Swallow your whole tablet(s) in one piece. Do not chew or crush. You must always eat a meal after taking your tablet(s).

If a combination therapy of gliclazide with metformin, an alpha-glucosidase inhibitor, a thiazolidinedione, a dipeptidyl peptidase-4 inhibitor a GLP-1 receptor agonist or insulin is initiated your doctor will determine the proper dose of each medicine individually for you. If you notice that your blood sugar levels are high although you are taking the medicine as prescribed, you should contact your doctor or pharmacist.

If you take more Gliclazide tablets than you should: If you take too many tablets, contact your doctor or the nearest hospital Accident & Emergency department immediately. The signs of overdose are those of low blood sugar (hypoglycaemia). The symptoms can be helped by taking sugar (4 to 6 lumps) or sugary drinks straight away, followed by a substantial snack or meal. If the patient is unconscious immediately inform a doctor and call the emergency services. The same should be done if somebody, (for instance a child), has taken the product unintentionally. Unconscious patients must not be given food or drink. It should be ensured that there is always a pre-informed person that can call a doctor in case of emergency.

If you forget to take Gliclazide tablet: It is important to take your medicine every day as regular treatment works better. However, if you forget to take a dose of Gliclazide MR tablet, take the next dose at the usual time. Do not take a double dose to make up for a forgotten dose.

If you stop taking Gliclazide MR tablet: As the treatment for diabetes is usually lifelong, you should discuss with your doctor before stopping this medicinal product. Stopping could cause high blood sugar (hyperglycaemia) which increases the risk of developing complications of diabetes. If you have any further questions on the use of this product, ask your doctor or pharmacist.

Like all medicines, Gliclazide can cause side effects, although not everybody gets them. The most commonly observed side effect is low blood sugar (hypoglycaemia). If left untreated these symptoms could progress to drowsiness, loss of consciousness or possibly coma. If an episode of low blood sugar is severe or prolonged, even if it is temporarily controlled by eating sugar, you should seek immediate medical attention.

Liver disorders: There have been isolated reports of abnormal iiver function, which can cause yellow skin and eyes. If you get this, see your doctor immediately. The symptoms generally disappear if the medicine is stopped. Your doctor will decide whether to stop your treatment.

Skin disorders: Skin reactions such as rash, redness, itching, hives, blisters, angioedema (rapid swelling of tissues such as eyelids, face, lips, mouth, tongue or throat that may result in breathing difficulty) have been reported. Rash may progress to widespread blistering or peeling of the skin. If you develop this, stop taking, seek urgent advice from a doctor and tell him that you are taking this medicine. Exceptionally, signs of severe hypersensitivity reactions have been reported: initially as flu-like symptoms and a rash on the face then an extended rash with a high temperature.

Blood disorders: Decrease in the number of cells in the blood (e.g. platelets, red and white blood cells) which may cause paleness, prolonged bleeding, bruising, sore throat and fever have been reported. These symptoms usually vanish when the treatment is discontinued.

Digestive disorders: Abdominal pain, nausea, vomiting, indigestion, diarrhoea, and constipation. These effects are reduced when Gliclazide is taken with a meal as recommended.

Eye disorders: Your vision may be affected for a short time especially at the start of treatment. This effect is due to changes in blood sugar levels.

As for another sulfonylurea, the following adverse events have been observed: cases of severe changes in the number of blood cells and allergic inflammation of the wall of blood vessels, reduction in blood sodium (hyponatraemia), symptoms of liver impairment (for instance jaundice) which in most cases disappeared after withdrawal of the sulfonylurea, but may lead to life-threatening liver failure in isolated cases.

Reporting of side effects: If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects, you can help provide more information on the safety of this medicine.

Do not take Gliclazide:

• if you are allergic to gliclazide or to other medicines of the same group (sulfonylurea), or to other related medicines (hypoglycaemic sulfonamides)
• if you have insulin-dependent diabetes (type 1)
• if you have ketone bodies and sugar in your urine (this may mean you have diabetic ketoacidosis), a diabetic pre-coma or coma
• if you have severe kidney or liver disease
• if you are taking medicines to treat fungal infections
• if you are breastfeeding

Talk to your doctor before taking Gliclazide. You should observe the treatment plan prescribed by your doctor to achieve proper blood sugar levels. This means, apart from regular tablet intake, to observe the dietary regimen, have physical exercise and, where necessary, reduce weight During gliclazide treatment regular monitoring of your blood (and possibly urine) sugar level and also your glycated haemoglobin (HbA1c) is necessary. In the first few weeks of treatment, the risk of having reduced blood sugar levels (hypoglycaemia) may be increased. So particularly close medical monitoring is necessary.

Low blood sugar (Hypoglycaemia) may occur:

• if you take meals irregularly or skip meals altogether,
• if you are fasting
• if you are malnourished
• if you change your diet
• if you increase your physical activity and carbohydrate intake does not match this increase,
• if you drink alcohol, especially in combination with skipped meals,
• if you take other medicines or natural remedies at the same time,
• if you take too high doses of gliclazide,
• if you suffer from particular hormone-induced disorders (functional disorders of the thyroid gland, pituitary gland or adrenal cortex),
• if your kidney function or liver function is severely decreased.

if you have low blood sugar you may have the following symptoms: headache, intense hunger, nausea, vomiting, weariness, sleep disorders, restlessness, aggressiveness, poor concentration, reduced alertness and reaction time, depression, confusion, speech or visual disorders, tremor, sensory disturbances, dizziness and helplessness.

The following signs and symptoms may also occur: sweating, clammy skin, anxiety, fast or irregular heartbeat, high blood pressure, sudden strong pain in the chest that may radiate into nearby areas (angina pectoris).

If blood sugar levels continue to drop you may suffer from considerable confusion (delirium), develop convulsions, lose self-control, your breathing may be shallow and your heartbeat slowed down, you may become unconscious.

In most cases the symptoms of low blood sugar vanish very quickly when you consume .some form of sugar, (for instance, glucose tablets, sugar cubes, sweet juice, sweetened tea).

You should therefore always carry some form of sugar with you (glucose tablets, sugar cubes). Remember that artificial sweeteners are not effective. Please contact your doctor or the nearest hospital if taking sugar does not help or if the symptoms recur.

Symptoms of low blood sugar may be absent, less obvious or develop very slowly or you are not aware in time that your blood sugar level has dropped. This may happen if you are an elderly patient taking certain medicines (for instance those acting on the central nervous system and beta-blockers).

If you are in stressful situations (e.g. accidents, surgical operations, fever etc.) your doctor may temporarily switch you to insulin therapy.

Symptoms of high blood sugar (hyperglycaemia) may occur when gliclazide has not yet sufficiently reduced the blood sugar when you have not complied with the treatment plan prescribed by your doctor if you take St. John’s Wort (Hypericum perforatum) preparations or in special stress situations. These may include thirst, frequent urination, dry mouth, dry itchy skin, skin infections and reduced performance.

Blood glucose disturbances (low blood sugar and high bold sugar) can occur when Gliclazide is prescribed at the same time as medicines to a class of antibiotics called fluoroquinolone, especially in elderly patients. In this case, your doctor will remind you of the importance of monitoring your blood glucose.

If you have a family history of or know you have the hereditary condition glucose-6-phosphate dehydrogenase (G6PD) deficiency (abnormality of red blood cells), lowering of the haemoglobin level and breakdown of red blood cells (haemolytic anaemia) can occur. Contact your doctor before taking this medicinal product.

Gliclazide is not recommended for use in children due to lack of data.

Other medicines and Gliclazide: Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

The blood sugar lowering effect of gliclazide may be strengthened and signs of low blood sugar levels may occur when one of the follow ng medicines is taken:

• other medicines used to treat high blood sugar (oral antidiabetics, GLP-1 receptor agonists or insulin),
• antibiotics (sulphonamides, clarithromycin)
• medicines to treat high blood pressure or heart failure (beta-blockers. ACE-inhibitors such as captopril, or enalapril)
• medicines to treat fungal infections (miconazole, fluconazole)
• medicines to treat ulcers in the stomach or duodenum (H2 receptor antagonists),
• medicines to treat depression (monoamine oxidase inhibitors)
• painkiller or antirheumatics (phenylbutazone, ibuprofen)
• medicines containing alcohol

The blood-glucose-lowering effect of gliclazide may be weakened and raised blood sugar levels may occur when one of the following medicines is taken:

• medicines to treat disorders of the central nervous system (chlorpromazine)
• medicines reducing inflammation (corticosteroids)
• medicines to treat asthma or used during labour (intravenous salbutamol, ritodrine and terbutaline)
• medicines to treat breast disorders, heavy menstrual bleeding and endometriosis (danazol)
• St John's Wort- Hypericum perforatum- preparations

Blood glucose disturbance (low blood sugar and high blood sugar) can occur when a medicine belonging to a class of antibiotics called fluoroquinolones is taken at the same time as gliclazide especially in elderly patients.

Gliclazide may increase the effects of medicines that reduce blood clotting (warfarin).

Consult your doctor before you start taking another medicinal product. If you go into hospital tell the medical staff you are taking gliclazide.

Gliclazide with food and drink: Gliclazide can be taken with food and non-alcoholic drinks. Drinking alcohol is not recommended as it can alter the control of your diabetes in an unpredictable manner.

Driving and using machines: Your ability to concentrate or react may be impaired if your blood sugar is too low (hypoglycaemia), or too high (hyperglycaemia) or if you develop visual problems as a result of such conditions. Bear in mind that you could endanger yourself or others (for instance when driving a car or using machines). Please ask your doctor whether you can drive a car if you:

• have frequent episodes of low blood sugar (hypoglycaemia)
• have few or no warning signals of low blood sugar (hypoglycaemia)

Gliclazide contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Gliclazide is not recommended for use during pregnancy. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. You must not take Gliclazide while you are breastfeeding.

Keep out of the reach and sight of children. Do not use this medicine after the expiry date which is stated on the carton and the blister. The expiry date refers to the last day of that month. Store below 30°C. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Biguanides

Metformin 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 decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.

Metformin immediate release tablet: Dosage of Metformin Hydrochloride must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses.

• Adult: The usual starting dose of Metformin is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. For those patients requiring additional glycemic control, Glucomin may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.
• Children: The usual starting dose of Metformin is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.

Metformin extended release tablet: Swallow Metformin XR tablet whole and never crush, cut or chew.

• Adult: The usual starting dose of Metformin XR is 500 mg once daily with the evening meal. Dose should be increased in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal, alternatively increased to 1000 mg twice daily taken with meal. Patient receiving Metformin immediate release tablet may be switched to Metformin extended release tablet up to a maximum recommended daily dose.
• Children: Metformin extended release tablet has not been studied in children.
• Renal impaired patient: Do not use Metformin in patients with eGFR below 30 mL/min/1.73 m². Asses risk/benefit of counting if eGFR falls below 45 mL/min/1.73 m².

Blood and lymphatic system disorders: Not known: Hemolytic anemia

Metabolism and nutrition disorders: Very rare: Lactic acidosis. Decrease of vitamin B12 absorption with a decrease of serum levels during long-term use of metformin. Consideration of such etiology is recommended if a patient presents with megaloblastic anemia. Cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post-marketing experience (frequency not known)

Nervous system disorders: Common: Taste disturbance. Not known: Encephalopathy

Gastrointestinal disorders: Very common: Gastrointestinal disorders, such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These undesirable effects occur most frequently during the initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders: Very rare: Isolated reports of liver function test abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders: Very rare: Skin reactions, such as erythema, pruritus, urticaria.

Metformin Hydrochloride is known to be substantially excreted by the kidney and the risk of Metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Metformin may lower vitamin B12 level. It also increases risk of hypoglycemia when use in combination with insulin or insulin secretagogue.

Co-administration with Carbonic anhydrase (Topiramate, Zonisamide) may increase risk of lactic acidosis. Drugs (Ranolazine, Dolutegravir, Cimetidine) that reduce Metformin clearance may increase the accumulation of Metformin. Alcohol can potentiate the effect of Metformin on lactate metabolism.

Pregnancy: Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with an increased risk of congenital abnormalities and perinatal mortality. When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.

Breastfeeding: Metformin is excreted into human breast milk. No adverse efects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breastfeeding should be made, taking into account the benefit of breastfeeding and the potential risk to adverse effects on the child.

Elderly: Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Pediatric population: The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated. No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially prepubescent children, is recommended.

Children aged between 10 and 12 years: Particular caution is recommended when prescribing to children aged between 10 and 12 years.

Renal function: As metformin is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) should be determined before initiating treatment and regularly thereafter:

• At least annually in patients with normal renal function,
• At least two to four times a year in patients with creatinine clearance at the lower limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID). GFR should be assessed before treatment initiation and regularly thereafter. Metformin is contraindicate in patients with GFR<30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function.

Hypoglycemia has not been seen with Metformin doses up to 85 gm, although lactic acidosis has occurred in such circumstances. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and Metformin is hemodialysis.

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

Biguanides

Metformin 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 decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.

Metformin immediate release tablet: Dosage of Metformin Hydrochloride must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses.

• Adult: The usual starting dose of Metformin is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. For those patients requiring additional glycemic control, Glucomin may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.
• Children: The usual starting dose of Metformin is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.

Metformin extended release tablet: Swallow Metformin XR tablet whole and never crush, cut or chew.

• Adult: The usual starting dose of Metformin XR is 500 mg once daily with the evening meal. Dose should be increased in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal, alternatively increased to 1000 mg twice daily taken with meal. Patient receiving Metformin immediate release tablet may be switched to Metformin extended release tablet up to a maximum recommended daily dose.
• Children: Metformin extended release tablet has not been studied in children.
• Renal impaired patient: Do not use Metformin in patients with eGFR below 30 mL/min/1.73 m². Asses risk/benefit of counting if eGFR falls below 45 mL/min/1.73 m².

Blood and lymphatic system disorders: Not known: Hemolytic anemia

Metabolism and nutrition disorders: Very rare: Lactic acidosis. Decrease of vitamin B12 absorption with a decrease of serum levels during long-term use of metformin. Consideration of such etiology is recommended if a patient presents with megaloblastic anemia. Cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post-marketing experience (frequency not known)

Nervous system disorders: Common: Taste disturbance. Not known: Encephalopathy

Gastrointestinal disorders: Very common: Gastrointestinal disorders, such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These undesirable effects occur most frequently during the initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders: Very rare: Isolated reports of liver function test abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders: Very rare: Skin reactions, such as erythema, pruritus, urticaria.

Metformin Hydrochloride is known to be substantially excreted by the kidney and the risk of Metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Metformin may lower vitamin B12 level. It also increases risk of hypoglycemia when use in combination with insulin or insulin secretagogue.

Co-administration with Carbonic anhydrase (Topiramate, Zonisamide) may increase risk of lactic acidosis. Drugs (Ranolazine, Dolutegravir, Cimetidine) that reduce Metformin clearance may increase the accumulation of Metformin. Alcohol can potentiate the effect of Metformin on lactate metabolism.

Pregnancy: Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with an increased risk of congenital abnormalities and perinatal mortality. When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.

Breastfeeding: Metformin is excreted into human breast milk. No adverse efects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breastfeeding should be made, taking into account the benefit of breastfeeding and the potential risk to adverse effects on the child.

Elderly: Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Pediatric population: The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated. No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially prepubescent children, is recommended.

Children aged between 10 and 12 years: Particular caution is recommended when prescribing to children aged between 10 and 12 years.

Renal function: As metformin is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) should be determined before initiating treatment and regularly thereafter:

• At least annually in patients with normal renal function,
• At least two to four times a year in patients with creatinine clearance at the lower limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID). GFR should be assessed before treatment initiation and regularly thereafter. Metformin is contraindicate in patients with GFR<30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function.

Hypoglycemia has not been seen with Metformin doses up to 85 gm, although lactic acidosis has occurred in such circumstances. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and Metformin is hemodialysis.

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

Long acting penicillin

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs); which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Treatment of infection: 0.3 to 1.2 million units repeated every five to seven days.

Prophylaxis of rheumatic fever: 1.2 million units every three weeks.

Specific dosage schedule: Treatment of group-A β-haemolytic streptococcal infections: A single intramuscular dose of 600,000 units.

Prevention of rheumatic fever: Monthly injection of a single dose of 1.2 million units is the most effective regimen for preventing further attacks of rheumatic fever.

Treatment of acute otitis media: A single injection of 6 million units.

• Early syphilis- 2.4 million units as a single dose.
• Late syphilis: 2.4 million units weekly for three successive weeks.
• Neurosyphilis: Benzylpenicillin, intravenously, 2 to 4 million units every 4 hours for 10 days, followed by benzathine penicillin intramuscularly, 2.4 million units weekly for three successive weeks.
• Congenital syphilis: Asymptomatic infants with normal cerebrospinal fluid, intramuscularly 50,000 units per kg in a single dose.

Primary and secondary syphilis have been treated with single injections of 2.4 million units of long acting benzathine penicillin (Benzapen) weekly for 2 to 4 weeks with satisfactory results.

The toxicity of penicillins is generally low, but in a small number of patients penicillin can cause sensitization and allergic reactions. Acute, lifethreatening anaphylactic reactions are rare, but they do occur.

Intramuscular injection of benzathine penicillin can cause moderate burning discomfort, local pain, and deep muscle soreness and tenderness at the site of injection, lasting for one to three days in about 10% of patients. Some patients had low-grade fever (102˚F) associated with local pain and tenderness. This febrile reaction disappeared within 24 to 48 hours.

Hypersensitivity to penicillins

Patient with previous hypersensitivity reactions to cephalosporins, history of allergy, asthma, seizure disorder. Not intended for IV or intra-arterial admin or inj near major peripheral nerves of blood vessels. Prolonged use may result in bacterial or fungal superinfection. Renal impairment.

No potentially hazardous interactions have been described.

Pregnancy category B. Benzathine Penicillin should not be administered during pregnancy unless in the judgment of the physician such administration is clinically justifiable. Special care should be taken in the first three months of pregnancy.

As penicillin appears in breast milk, it is probably best for a mother to stop breast-feeding while being given penicillin to avoid exposing the infant to the drug unnecessarily.

Store between 2-8°C. Do not freeze.

Empagliflozin is indicated in:

• As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
• To reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.

Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors

Empagliflozin is a sodium glucose co-transporter-2 (SGLT-2) inhibitor. SGLT2 co-transporters are responsible for reabsorption of glucose from the glomerular filtrate in the kidney. The glucuretic effect resulting from SGLT2 inhibition reduces renal absorption and lowers the renal threshold for glucose, resulting in increased glucose excretion. Additionally, it contributes to reduced hyperglycaemia, assists weight loss, and reduces blood pressure.

The recommended dose of Empagliflozin is 10 mg once daily, taken in the morning, with or without food. In patients tolerating Empagliflozin, the dose may be increased to 25 mg once daily. In patients with volume depletion, correcting this condition prior to initiation of Empagliflozin is recommended.

The most common adverse reactions associated with Empagliflozin are urinary tract infections and female genital mycotic infections. Others common side effects includes dehydration, hypotension, weakness, dizziness and increased thirstiness.

Empagliflozin is contraindicated in patients with history of serious hypersensitivity reaction to Empagliflozin or any of its ingredients, severe renal impairment, end-stage renal disease, or dialysis.

Assessment of renal function is recommended prior to initiation of Empagliflozin and periodically thereafter. Empagliflozin should not initiated in patients with an eGFR less than 45 ml/min/1.73 m². No dose adjustment is needed in patients with an eGFR greater than or equal to 45 ml/min/1.73 m².

Diuretics: Co-administration of Empagliflozin with diuretics resulted in increased urine volume. 

Insulin or Insulin Secretagogues: Co-administration of Empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia. 

Positive Urine Glucose Test: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control. 

Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

There are no adequate and well-controlled studies of Empagliflozin in pregnant women. Empagliflozin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known if Empagliflozin is excreted in human milk. It is not recommended when breastfeeding.

In the event of an overdose with Empagliflozin the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, perform clinical monitoring, and institute supportive treatment) should be employed. Removal of Empagliflozin by hemodialysis has not been studied.

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