GLIRITDHG 500/2.5

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COMPOSITION:
Metformin HCl ........................................................................................... 500 mg
Glibenclamide ............................................................................................ 2.5 mg
Excipients q.s............................................................................................. 1 tablet
(Avicel, lactose, PVP K30, croscarmellose sodium, magnesium stearate, HPMC, PVA, PEG 6000, titanium dioxide, talc, yellow ferric oxide, red ferric oxide).
DOSAGE FORM: Film coated tablet.
PRESENTATION: Box of 3 blisters x 10 tablets.
PHARMACODYNAMICS: GliritDHG 500mg/2,5mg, a combination of metformin and glibenclamide, is a type 2 antihyperglycemic agent. Metformin belongs to biguanide class with mechanism of peripheral actions. Metformin increases cellular glucose utilization, improves insulin binding to receptors, inhibits hepatic glucose production, and decreases intestinal absorption of glucose. Metformin does not produce hypoglycemia on normal subjects. In diabetic patients, metformin reduces hyperglycemia but does not produce hypoglycemic accidents except for fasting cases or combination of synergistic drugs. Glibenclamide is a sulfonylurea which appears to lower blood glucose concentrations by stimulating pancreatic beta cells, resulting in increase in endogenous insulin secretion. At the start of treatment with glibenclamide, hypoglycaemia is also caused by decreasing hepatic glucose flow to blood and increasing effect of insulin on peripheral target cells. When used for a long time, blood insulin concentrations decrease the level as before treatment; but plasma glucose concentrations remain low. Metformin and glibenclamide have different mechanism and sites of action, but their action is complementary; and may give synergistic effects to control well blood glucose in case monotherapy does not control blood glucose as required.
PHARMACOKINETICS: Metformin is slowly, incompletely absorbed from gastrointestinal tract. The absolute bioavailability of a 500 mg metformin given under fasting conditions is approximately 50 - 60%. There is a lack of dose proportionality with increasing doses, which due to decreased absorption. Food decreases the extent of and slightly delays the absorption of metformin. Metformin is not metabolized in the liver and is not excreted in the bile. Metformin is eliminated unchanged in the kidney. It has a plasma half-life of about 1.5 - 4.5 hrs.
Glibenclamide is readily absorbed from the gastrointestinal tract. Food does not affect the absorption of glibenclamide. Glibenclamide action shows from 45 - 60 minutes and obtains an optimal plasma concentration within 1.5 - 3 hours. The volume of distribution of glibenclamide is about 0.125 liter/kg; the half-life is 1.4 - 1.8 hours, and prolonged in patients with renal or hepatic impairment. Glibenclamide can be used once during the day. Glibenclamide is completely metabolized to active metabolites in the liver and is excreted via urine and faeces.
INDICATIONS: Treatment of type 2 diabetes to control blood glucose levels, combining with diet and physical exercise.
CONTRAINDICATIONS: Patients known to have sensitivity to metformin, glibenclamide, sulfonamide, diuretics containing sulfonamide or probenecid or to any components of the drug.
Insulin-dependent diabetes mellitus (type 1 diabetes). Type 2 diabetes for patients aged < 18 years. Complicated diabetes. Diabetes during stress.
Patients with acute catabolism state, severe infections, septicemia, trauma, serious respiratory diseases associated with hypoxia, hyperglycemia with or without coma, severe blood acidification due to hyperglycemia, congestive heart failure, cardiovascular collapse, acute myocardial infraction.
Severely impaired renal or hepatic function. Severe malnutrition, acute course of chronic diseases.
Severe renal failure (eGFR below 30 mL/min/1.73m2) [see Warnings and precautions].
Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
WARNINGS AND PRECAUTIONS: A standard diet and regular use of drug are extremely important to treat successfully and prevent changes in adverse effects of blood glucose levels.
The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol.
Patients who suffer from malnutrition, cerebral arterial sclerosis.
Lactic acidosis: Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmia. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 µg/mL.
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration, Contraindications, Warnings and Precautions, Interactions and Use in specific populations).
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin. In metformin treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/ minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue metformin and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration, Clinical Pharmacology]:
- Before initiating metformin, obtain an estimated glomerular filtration rate (eGFR).
- Metformin is contraindicated in patients with an eGFR less than 30 mL/ minute/1.73 m2 [see Contraindiations].
- Initiation of metformin is not recommended in patients with eGFR between 30 - 45 mL/minute/1.73 m2.
- Obtain an eGFR at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
- In patients taking metformin whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
Drug interactions: The concomitant use of metformin with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions]. Therefore, consider more frequent monitoring of patients.
Age 65 or greater: The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
Radiological studies with contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin if renal function is stable.
Surgery and other procedures:
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Metformin should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic states: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue metformin.
Excessive alcohol intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving metformin.
Hepatic impairment: Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin in patients with clinical or laboratory evidence of hepatic disease.
PREGNANCY AND LACTATION:
The drug is contraindicated in pregnant and nursing women.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES:
The drug should be used with caution in drivers and machinery operators because of risk of hypoglycemia.
INTERACTIONS:
The hypoglycemic action may be potentiated when GliritDHG 500mg/2,5mg is used concurrently with agents such as sulfonamide, salicylates, phenylbutazone, nonsteroidal anti-inflammatory drugs, fluoroquinolone, coumarin derivatives, beta blockers, monoaminoxydase inhibitors, perhexiline, chloramphenicol, clofibrate and fenofibrate, sulfinpyrazone, probenecid, pentoxifylline, cyclophosphamide, azapropazone, tetracyclines, angiotensin-converting enzyme inhibitors, alcohol, fluconazole, miconazole, ciprofloxacin, enoxacin.
The hypoglycemic action may be diminished when GliritDHG 500mg/2,5mg is used concurrently with agents such as thiazide diuretics, ethacrynic acid, estrogen/gestagen oral contraceptives, phenothiazine derivatives, isoniazid, nicotinic acid (high doses), sympathomimetics, thyroid preparations and corticosteroids, salbutamol or terbutaline (intravenous injection).
The toxicity may be increased when GliritDHG 500mg/2,5mg is used concurrently with cationic (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin), cimetidine.
ADVERSE EFFECTS:
Adverse effects are generally concerning with initial treatment and during dose titration:
Frequently: anorexia, nausea, vomiting, diarrhoea, epigastric pain, constipation, heartburn; rash, urticaria, photosensitization.
Infrequently: blood dysplasia, aplastic anemia, hemolytic anemia, marrow impairment, thrombocytopenia, agranulocytosis, lactic acidosis.
Rarely: temporarily impaired vision.
Inform your physician about any adverse effects occur during the treatment.
OVERDOSAGE:
Hypoglycemic reactions may be reported by overdosage, drug interactions, or diet mistake. Signs include headache, irritation, anxiety, excessive sweating, insomnia, tremble, behaviour disorders, poor nimbleness.
The solution is showed by eating sugar (about 20 - 30 g) and informing the physician immediately. In case of patients with coma, it is advised to pump saccharose or glucose solutions into the stomach or transfuse glucose by intravenous route.
DOSAGE & ADMINISTRATION:
The drug should be taken 30 minutes before meals.
Recommended dosage of metformin
The starting dose of metformin in patients who are not currently taking metformin is 500 mg orally, once daily. Increase the dose in 500 mg increments every 1-2 weeks if a higher dose of metformin is needed and there are no gastrointestinal adverse reactions. The dosage of metformin must be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2000 mg.
Dosage of GliritDHG
The therapy should be initiated with one tablet GliritDHG 500mg/2,5mg before breakfast 30 minutes. Dosage increases should be made in increments of one tablet GliritDHG 500mg/5mg per day after 2 weeks.
The maximum recommended dose is 2000 mg/20 mg/day (4 tablets of GliritDHG 500mg/5mg/day), given before meals.
The dose should be determined in each patient to avoid hypoglycemia.
Patients should apply a strict diet as directed by the physician.
Recommendations for use in renal impairment
Assess renal function prior to initiation of metformin and periodically thereafter.
Metformin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2.
Initiation of metformin in patients with an eGFR between 30-45 mL/minute/1.73 m2 is not recommended.
In patients taking metformin whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefit risk of continuing therapy.
Discontinue metformin if the patient's eGFR later falls below 30 mL/minute/1.73 m2 [see Contraindications and Warnings and Precautions].
Discontinuation for iodinated contrast imaging procedures
Discontinue metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin if renal function is stable [see Warnings and Precautions].
Or as directed by physician.
Read the directions carefully before use.
Consult the physician for more information.
This drug is for prescriptions only.
Shelf-life: 36 months from the manufacturing date.
Storage conditions: Store in dry places, not exceeding 30oC, protect from light.
Specifications: Manufacturer's.

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