SOLOSAMET SR 2MG/500MG (TABLET)

Dosage / Direction for Use: Individualized dosage. Initiate the lowest effective dose & increase dose based on patient's blood glucose level. Titrate daily dose in increments of 1 tab only. Max: 8 mg glimepiride/2,000 mg metformin daily. Renal impairment GFR 60-89 mL/min Max: 3,000 mg, 45-59 mL/min Max:2,000 mg, 30-44 mL/min Max: 1,000 mg. Overdosage: Signs and Symptoms: For Glimepiride: Acute overdosage as well as long-term treatment with too high a dose of glimepiride may lead to severe life-threatening hypoglycaemia. Management: As soon as an overdose of glimepiride has been discovered, a physician must be notified without delay. The patient must immediately take sugar, if possible in the form of glucose, unless a physician has already undertaken responsibility for treating the overdose. Careful monitoring is essential until the physician is confident that the patient is out of danger. It must be remembered that hypoglycaemia may recur after initial recovery. Admission to hospital may sometimes be necessary even as a precautionary measure. In particular, significant overdoses and severe reactions with signs such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and admission to hospital. If, for example, the patient is unconscious, an intravenous injection of concentrated glucose solution is indicated (for adults starting with 40 ml of 20% solution, for example). Alternatively in adults, administration of glucagon, e.g. in doses of 0.5 to 1 mg i.v., s.c. or i.m., may be considered. In particular when treating hypoglycaemia due to accidental intake of glimepiride in infants and young children, the dose of glucose given must be very carefully adjusted in view of the possibility of producing dangerous hyperglycaemia, and must be controlled by close monitoring of blood glucose. Patients who have ingested life-threatening amounts of glimepiride require detoxification (e.g. by gastric lavage and medicinal charcoal). After acute glucose replacement has been completed it is usually necessary to give an intravenous glucose infusion in lower concentration so as to ensure that the hypoglycaemia does not recur. The patient's blood glucose level should be carefully monitored for at least 24 hours. In severe cases with a protracted course, hypoglycaemia, or the danger of slipping back into hypoglycaemia, may persist for several days. For Metformin: Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis. Pancreatitis may occur in the context of a metformin overdose. Administration: Should be taken with food: Take during breakfast or the 1st main meal of the day. Swallow whole, do not chew/crush. Contraindications: Hypersensitivity to glimepiride, metformin, other sulfonylureas, other sulfonamides. Lactic acidosis, diabetic ketoacidosis, diabetic pre-coma; acute conditions w/ potential to alter renal function eg, dehydration, severe infection, shock, intravascular administration of iodinated contrast agent. Acute or chronic disease which may cause tissue hypoxia eg, cardiac or resp failure, recent MI. Acute alcohol intoxication, alcoholism. Any type of acute metabolic acidosis eg, lactic acidosis. Hepatic insufficiency; severe renal failure (GFR <30 mL/min). Warnings: For Glimepiride: In exceptional stress situations (e.g. trauma, surgery, febrile infections) blood glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control. For Metformin: Lactic acidosis: Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis. In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended. Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors associated to lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see Contraindications and Interactions). Diagnosis: Patients and/or care-givers should be informed of the risk of lactic acidosis. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (> 5 mmol/L), and an increased anion gap and lactate/pyruvate ratio. Renal function: GFR should be assessed before treatment initiation and regularly thereafter (see Section Dosage and Administration). Metformin is contraindicated in patients with GFR<30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function, see Contraindications. 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 an NSAID. Administration of iodinated contrast agent: Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see Dosage & Administration and Interactions. Surgery: Metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable. Special Precautions: For Glimepiride: In the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates especially careful monitoring. Factors favouring hypoglycaemia include: unwillingness or (more commonly in older patients) incapacity of the patient to co-operate; undernourishment, irregular mealtimes or skipped meals; imbalance between physical exertion and carbohydrate intake; alterations of diet; consumption of alcohol, especially in combination with skipped meals; impaired renal function; severe impairment of liver function; overdosage with glimepiride; certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (as for example in certain disorders of thyroid function and in anterior pituitary or corticoadrenal insufficiency); concurrent administration of certain other medicines (see Interactions); treatment with glimepiride in the absence of any indication. If such risk factors for hypoglycaemia are present, it may be necessary to adjust the dosage of glimepiride or the entire therapy. This also applies whenever illness occurs during therapy or the patient's life-style changes. Those symptoms of hypoglycaemia which reflect the body's adrenergic counter- regulation (see Adverse Reactions) may be milder or absent where hypoglycaemia develops gradually, in the elderly, and where there is autonomic neuropathy or where the patient is receiving concurrent treatment with beta-blockers, clonidine, reserpine, guanethidine or other sympatholytic drugs. Hypoglycaemia can almost always be promptly controlled by immediate intake of carbohydrates (glucose or sugar). It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur. Patients must, therefore, remain under close observation. Severe hypoglycaemia further requires immediate treatment and follow-up by a physician and, in some circumstances, in-patient hospital care. Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to hemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered. For Metformin: Renal function: As metformin is excreted by the kidney, serum creatinine levels 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 serum creatinine levels at the 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 an NSAID. Administration of iodinated contrast agent: As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal. Surgery: Metformin hydrochloride should be discontinued 48 hours before elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hours afterwards. Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism (see Adverse Reactions). Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended (see Adverse Reactions). Other precautions: All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet. The usual laboratory tests for diabetes monitoring should be performed regularly. Metformin alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulfonylureas. Driving a Vehicle or Performing Other Hazardous Tasks: For Glimepiride: Alertness and reactions may be impaired due to hypo- or hyperglycaemia, especially when beginning or after altering treatment or when glimepiride is not taken regularly. This may, for example, affect the ability to drive or to operate machinery. For Metformin: Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines. However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (sulfonylureas, insulin, repaglinide). Use In Pregnancy & Lactation: Pregnancy: For Glimepiride: Glimepiride must not be taken during pregnancy. Otherwise there is risk of harm to the child. The patient must change over to insulin during pregnancy. Patients planning a pregnancy must inform their physician. It is recommended that such patients change over to insulin. For Metformin: To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development. When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels. Lactation: For Glimepiride: To prevent possible ingestion with the breast milk and possible harm to the child, glimepiride must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breast-feeding. For Metformin: Metformin is excreted into milk in lactating rats. Similar data is not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the compound to the mother. Side Effects / Adverse Reactions: Hypoglycemia. GI symptoms eg, nausea, vomiting, abdominal pain, diarrhea. Glimepiride: Headache, ravenous hunger, lassitude, sleepiness, sleep disorder, restlessness, aggressiveness, impaired concentration, alertness & reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, pareses, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence & loss of consciousness, coma, shallow resp & bradycardia. Temporary visual impairment; sensations of pressure or fullness in epigastrium; allergic or pseudoallergic reactions. Metformin: Loss of appetite; metallic taste; decrease of vit B12 absorption w/ decrease of serum levels. Interactions: Glimepiride: May potentiate blood glucose-lowering effect w/ insulin & other oral antidiabetics, ACE inhibitors, anabolic steroids & male sex hormones, chloramphenicol, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluoxetine, guanethidine, ifosfamide, MAOIs, miconazole, fluconazole, para-aminosalicylic acid, pentoxifylline (high dose parenteral), phenylbutazone, azapropazone, oxyphenbutazone, probenecid, quinolones, salicylates, sulfinpyrazone, clarithromycin, sulfonamide antibiotics, tetracyclines, tritoqualine, trofosfamide. May reduce blood glucose-lowering effect w/ acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine (adrenaline) & other sympathomimetic agents, glucagon, laxatives (after protracted use), nicotinic acid (in high doses), oestrogens & progestogens, phenothiazines, phenytoin, rifampicin, thyroid hormones. May potentiate or reduce blood glucose-lowering effect w/ β-blockers, clonidine, reserpine & alcohol. May potentiate or weaken effect of coumarin derivatives. Metformin: Alcohol intoxication. Renal failure w/ intravascular administration of iodinated contrast agents. Caution use w/ glucocorticoids, β2-agonists & diuretics for their intrinsic hyperglycaemic activity. Decreased blood glucose levels w/ ACE inhibitors. Decreased anticoagulant effect of phenprocoumon. Reduced hypoglycaemic effect w/ levothyroxine. Mechanism of Action: Pharmacology: Pharmacodynamics: Clinical Efficacy/Clinical Studies: A 16-week, double-blind, double-dummy, two-arm, parallel group study was conducted to compare the efficacy and safety of glimepiride/metformin SR 2/500 mg daily (OD) versus glimepiride/metformin 1/250 mg twice daily (BID) in patients with type 2 diabetes mellitus (T2DM). 10 Patients (N=207) were randomized to either glimepiride/metformin SR OD administered with the morning meal or glimepiride/metformin BID administered with the morning and evening meal. The primary objective was to demonstrate equivalence, based on the mean change in glycated hemoglobin (HbA1c) from baseline to endpoint (week 16) between glimepiride/metformin SR 2/500 mg OD and glimepiride/metformin 1/250 mg BID. HbA1c at baseline was 8.05% in glimepiride/metformin SR OD group and 8.13% in glimepiride/metformin BID group. At study end, HbA1c was decreased by 0.59% (adjusted mean=0.61%) to a mean value of 7.47% for glimepiride/metformin SR OD and by 0.67% (adjusted mean=0.65%) to 7.46% for glimepiride/metformin BID. Difference in adjusted mean between the two treatment groups was 0.04% with (-0.16%, 0.24%) of its confidence interval. Therefore, 95% two-sided confidence interval for the difference in change of HbA1c existed within the equivalence range (-0.5%, +0.5%). Regarding nocturnal hypoglycemia there was no significant difference between the two treatment groups. Likewise, statistical significance was not observed between treatment groups based on the frequency of hypoglycemia. No statistical significance was observed between the two groups with regard to adverse events, although the occurrence was lower in the glimepiride/metformin SR OD treatment group. Pharmacokinetics: Glimepiride pharmacokinetics (Tmax and AUC) after meal was similar between a sustained- release formulation of Glimepiride + Metformin HCl (Solosamet SR) 2/500 mg and an immediate-release formulation of single Glimepiride + Metformin HCl (Solosamet) 2/500 mg or BID. Glimepiride + Metformin HCl (Solosamet) 1/250 mg. Meanwhile, metformin tmax was delayed in sustained-release formulation compared to immediate-release formulation, but its elimination half-life was not prolonged. The extent of metformin exposure after meal was lower in sustained-release formulation than in immediate-release formulation and its B.I.D. treatment in divided doses by 14% and 23% on average respectively. This effect on exposure is not considered clinically significant as there was no significant difference in safety between treatment groups. An open label, 3-period, 3-treatment, 3-way crossover study was conducted in 12 healthy Korean male subjects to evaluate the pharmacokinetic and safety profiles of Glimepiride + Metformin HCl (Solosamet) and Glimepiride + Metformin HCl (Solosamet SR) tablets. Subjects were randomized to one of 3 treatment arms (Group A, B or C). Subjects in group A received a single Glimepiride + Metformin HCl (Solosamet SR) 2/500 mg after breakfast. Group B received a single Glimepiride + Metformin HCl (Solosamet) 2/500 mg after breakfast. Group C received Glimepiride + Metformin HCl (Solosamet) 1/250 mg after breakfast and 12 hours later after dinner. There was a 7-day washout period between each treatment period.