RI Metformin HCI Glumet® Glumet®-XR 500 mg & 19 Tablet 500 mg Extended-ReleaseTablet oral hypoglycemic FORMULATION Each tablet contains: Metformin hydrochlotde ..uaisisnnsiniminninmnninimininaninnmnininnnnnmnsnnnnsmnsnnns SOOM Each tablet contains: Metformin nydrochioride 49 Each extended-release (XR) tablet contains: Melforminhydrochioide 500 mg PRODUCT DESCRIPTION Metformin hydrochloride 500 mg (Glumet* tablet is @ white, round, 7/16" in diameter, shallow biconvex tablet, with ‘LRI"lago on one side and plain on the othe side. Metformin hydrochloride 1 g (Glumet tablets a white to owt, cepsule-shaped tablet, bisected on one side ad plain on the other side, Metformin hydrochloride 500 mg extended-release (Glumet®-XR} tablets a white elipical, plain, biconvex table. CLINICAL PHARMACOLOGY Pharmacodynamics Metformin is abiguanide antelabetic agent that reduces both basal and postprandial plasma glucose concentrationsin patients wth type 2 diabetes melitus byimproving both peripheral and hepatic sensivty to insulin. Itdoesnot stimulate insulin Secretion and therefore doesnot produce hypoglycemia when Used alone, Fasting insulin levels and daylong insulin respanse remain the same or may even decrease wih metfonin therapy. Metformin may aca three mechanisms: Iteduces hepatc glucose producton by inhibiting gluconeogenesis and glycogenolysisinoreases insulin senstvty in the skeletal muscles and adipocytes, improving peripheral ucose uplake and utiizaton; delays intestinal glucose absorption ‘Metformin simulates intracellular glycogen synthesis by acting on glycagen synthase. It also increases the transport capacity of al lypes of memirane lucose transporters. Metormin has demonstrated modest favorable ffecs on lid metabolsm in paints with type 2dabetes I lowers ttl cholesterol, mean fasting serum tiglycerdes and low density Ipoprotin cholesterol levels thas no adverse eects on other ip levels. Pharmacokinetics Metorminis slowly andincomplealy absorbed fom the gastrointestinal ac ater orl ainistation. The asolue bioavailly of metformin abel under fasting condions is approximately 80% to 60% with metformin hyGrochlorde doses of 500 mg o 1,500 mg. Single doses of metformin 500 mg to 1,500 1m show lack of dose proportonaly with increasing doses whichis due to decreased absorption rather than altered elimination, Metionin hydrochloride (Glumet®-XR) 500 mq tablets an extended lease formulation intended for once daly dosing. Once-daly dosing is possible through contol of meonmin release rete prolonging absorpton nthe upper gastrintestal tac. The folowing are important pharmacokinetic parameters of metformin in adult volunteers who recived immediateelease metformin 500 mg and 1 9 (Glumet® 500 mg and 1 g) tablets (as a single oral dose), and extended-release metformin (Glumet?-XR) 500 mg tablet (two 500 mg tablets given once Gal or tree days) under fed condos, Pharmacokinetic Parameters Metformin (Glumet®) 500 mg Tablet 4. Tmax (hour) 1.7941 + 0.5607 2. Cmax + $.D. (megiml) 4.4472 + 0,3073 3.AUC, 445.0. (mog-himL} 5.1467 + 1.3651 Tmax = time the drug reached is maximum concentration in the blood (Cmax = maximum plasma concentration of the drug al peak time AUC =_area under the concentation-time curve Pharmacokinetic Parameters Metformin (Glumet®) 1 g Tablet Tmax (out) 169407 2. Cmax + $.D. (regimb) 2.29 + 06257 SAUC, ,. + SD. (mog-himl) 1145 £3.94 4, AUC, SD. (mog-himl) 12.124 3.94 .Kel (mogimLthour) 0.24 + 0.06 T, (hour) 3234182 Tmax= time the drug reached its maximum concentration in the blood Cmax = maximum plasma concentration of the drug at peak time AUC, ,,= area under the curve from blood level profile (rom zero to sampling me point) ‘AUC, = area under the curve from blood level profile (extrapolated to inrity) Kel = elimination rate constant T,,= elimination hatte Pharmacokinetic Parameters Metformin Extended-Release (Glumet™-XR) Tablet 2x 500mg 1. Tmax, (hour) 3 2. Cmax, # SD. (moginL) 1322047 3.Cave,, = SD_(meginc] AVEDA TAU, ,., SD. (mora) B6E ITS ime the drug reached its maximum concentration n blood at steady state average plasma concentration at steady state = area under the concentration-ime curve at steady state for one dosing interval Metformin distbutes rapidly to peripheral body tissues and fluids. It also appears to distribute slowly info erythrocytes and info a deep tissue ‘compartment. Metformin is negligibly bound to plasma proteins. Steady-state plasma concentration of metformin is generally <1 mogimL and is reached within 24-48 hours at usual cinical doses and dosing schedules, Metformin is not metabolized in the lver or Gl tract. Renal elimination of metformin is via glomerular fitration and secretion by the proximal convoluted tubules as unchanged drug. About 80% ofthe total dose being cleared within 24 hours in patients with normal renal function ‘SPECIAL POPULATIONS Pationt with Type 2 Diabetes ‘There areno differences between singl-or mutiple-dose pharmacokinetics of metformin between normal subjects and patients with type 2 diabetes rors there any accumulation of metformin in either group at usual clinical doses inthe presence of normal renal function Renal Insufficiency The plasma and blood halt fe of metformin s prolonged and the renal clearance decreased in proportion to the decrease in creatinine clearance in patients with decreased renal function (based on measured creatinine levels) Geriatrics The limited pharmacokinetic data of metformin in healthy elderly subjects sugges that total plasma clearance of metformin s decreased, hal-ife is prolonged, and C.,, is increased, compared to heatty young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily related {6'a change in renal function. Pediatrics ‘After oral administration ofa single metformin 500 mg tablet with food, C.., and AUC differed less than 5% between pediatric ype 2 diabetic patients (12 to 16 years old) compared with heathy adults (20 -45 years of), all with normal renal function. INDICATIONS. + As an adjunct to diet and exercise to improve glycemic contral in patients with type 2 diabetes melitus + Metformin may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin DOSAGE AND ADMINISTRATION «There is usually no fixed dosage regimen with any antidiabetic agent for the management of hyperglycemia in patients with diabetes mellitus Dosage of metformin HC! tablets must be individualized based on both effectiveness and tolerance while not exceeding the maximum recommended daily doses, + During treatment initiation and dose titration, fasting plasma glucose should be used to determine the therapeutic response to metformin hydrochloride tablet and identify the minimum effective dose. Thereafter, ycosylated nemoglobin (HDA...) should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to1normal or near normal by using the lowest effective dose of metformin when used as monotherapy or in combination with other oral antgiabetc agents or insulin + Monitoring of glycemic control through frequent measurements of fasting blood glucose and periodic testing of HDA... will detect primary failure (i, inadequate lowering of blood glucose al the maximum recommended dose of medication), and secondary fllure (Le. loss of adequate blood glucose lowering response after an inital period of effectiveness). 1.5 mg/dL (males) - Serum creatinine levels > 1.4 mgldl. (females) + Abnormal creatinine clearance (< 60 mL/minute) + Acute conditions withthe potential to alter renal function such as: - Dehydration due to persistent or severe diarrhea, recurrent vomiting - Severe infection + Diagnostic examinations (e.g. intravenous urography, angiography) that would involve the use of iodinated contrast agentsimedia + Acute or chronic disease which may cause tissue hypoxia such as: + Cardiac or respiratory failure - Recent myocardial infarction = Shock + In chronic alcoholism with hepatic damage + Presence of severe iver disease + Pregnancy or breastfeeding WARNINGS AND PRECAUTIONS: Warning on Lactic Acidosis Lactic acidosis is arare, but serious (high mortalty in the absence of promot reatment), metabolic complication that can occur due to metformin accumulation, Reported cases of lactic acidosis in patents on metformin have occurred primarly in diabetic patients wit significant renal failure. ‘The incidence of lactic acidosis can be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, and any condition associated with hypoxia, Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol), reduced blood pH, electrolyte disturbance with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >SygimL are generally found Lactic acidosis usually accompanied by nonspecic symptoms such as acdatic dyspnea, vomiting, abdominal pain with muscle cramps, andlor ‘a general feeling of malaise with severe fatigue. Hypothermia followed by coma, hypotension, and resistant bradyarthiythmias maybe seen with marked acidosis. Instruct patients to immediately alert their physicians if these symptoms occur, Serum electrolytes, Ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful, Lactic acidosis is a medical emergency that must be treated in a hospital setting. Ina patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable, prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. Do not use metformin in patients with congestive heart failure receiving drugs such as digoxin and furosemide because of the risk for hypoperfusion and hypoxemia which may lead to lactic acidosis. Monitoring of Renal Function Impaired renal function would increase the risk of metformin accumulation and lactic acidosis. Patients with serum creatinine levels higher than the normal range should not initate therapy with metformin hydrochloride Renal function should be assessed and verfied as normal before initiation of metformin hydrochloride therapy especialy in elderly patients because aging is associated with reduced renal function, Medications which may affect renal function or result significant hemodynamic change or interfere wih the disposition of metformin (cationic drugs) should be used with caution since these drugs are eliminated by renal tubular secretion Macrovascular Outcomes Macrovascular risk reduction with the use of metformin or any anti-diabetic drug has not been established in clinical studies. Radiologic Studies Parenteral iodinated contrast media may alter renal function and increase the risk f lactic acidosis in patients receiving metformin. Temporariy discontinue metformin prior to or atthe time of any procedure requiring parenteral iodine contrast media. Do not reinsttute metformin until 48 hours after such procedures and unt renal function has been reevaluated and found to be normal Hypoxic States Cardiovascular collapse (shock) ftom whatever cause, acute congestive heart fallure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia, Promptly discontinue metformin ‘when such events occur in patients on metformin hydrochloride therapy. ‘Surgical Procedures Temporarily discontinue metformin use in patients undergoing surgery associated with restricted food or uid intake. Metformin therapy may be reinstituted when the patients oral intake has resumed and renal function has been found normal. {Impaired Hepatic Function Metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease since impaired hepatic function has been associated with lactic acidosis. Alcohol Combined use of alcohol and metformin may increase the risk of hypoglycemia and lactic acidosis since alcohol decreases lactate clearance and hepatic gluconeogenesis and may increase insulin secretion, Excessive alcohol intake on an acute or chronic basis should be avoided in patients receiving metformin, Vitamin B,, Levels Evaluate nematologic parameters prior to initiation of metformin therapy and at least annually since decreases in serum vitamin B,, have been associated with metformin use Hypoglycemia Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise isnot compensated by caloric supplementation, or during concomitant use with other lucose-lowering agents (such as sulfonylureas and insulin) or ethanol Elderly, debiltated or malnourished patients, and those with adrenal or pituitary insufficiency or aloohol intoxication are particularly susceptible to hypoglycemia. It maybe dificul to recognize hypoglycemic states inthe elderly and in people who are taking beta-adrenergic blocking drugs. Maintaining Adequate Glycemic Control During Periods of Stress Temporary discontinuation of metformin and administration of insulin may be necessary in periods of stress such as fever, trauma, infection, or surgery to maintain adequate glucose control. Metformin may be reinttuted ate the acute episode is resolved INTERACTIONS WITH OTHER MEDICAMENTS Cationic Drugs: Cationic drugs such as amiloride, digoxin, morphine, procainamide, quinine, quinine, ranitidine, triamterene, trimethoprim, and ‘vancomycin that are eliminated by renal tubular secretion, theoretically may cause an increase in metformin peak plasma concentrations, ‘hole blood concentrations and whole blood AUC by competing with metformin for common renal tubular transport systems. Concomitant administration of metformin and cimetidine has been observed to result in reduced urinary metformin excretion and increased plasma metformin concentration. Other Antidiabetic Agents: Hypoglycemia may occur when metformin is used concomitantly with other antdabetic agents such as sulfonylureas gitazones or insulin, Diuretics: Thiazide diuretics may exacerbate diabetes mellius and may resul in increased requirements of oral antidiabetic agents, metformin included, Temporary loss of glycemic control, or secondary failure to the antidiabetic agent may also occur, Potassium-sparing diuretics, which are less diabetogenic, may be considered as substitute. Furosemide may increase metformin plasma and blood concentrations and blood AUC without significantly affecting metformin renal clearance. ‘Nifedipine: Concomitant administration of metformin and nifedipine may resul in increased plasma metformin concentration due to enhanced absorption. Nifedipine may also increase urinary metformin excretion, Adrenergic Blocking Agents: Beta-adrenergic blocking agents may impair glucose tolerance and mask the true frequency or severity of hypoglycemia, block hypoglycemia-induced tachycardia but not hypoglycemic sweating, delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia, and impair peripheral circulation. Use these drugs with caution in patients with type 2 diabetes. Protein-Bound Drugs: Interaction of metformin and highly protein-bound drugs (e.g, salicylates, sufonamides, chloramphenicol, probenecid) is unlikely because metformin is negligibly bound to plasma proteins. ‘Angiotensin-Converting Enzyme (ACE) Inhibitors: ACE inhibitors such as captopril and enalapril may reduce fasting blood glucose concentrations. These drugs have also been associated with unexplained nypoglycemia in ciabetic patients. Caution should be exercised when administering metformin together with ACE inhibitors to prevent severe hypoglycemia Clomiphene: Ovulatory response may be increased when clomiphene and metformin are used concomitantly in premenopausal patients with polycystic ovary syndrome. Coumarin Anticoagulants: Metformin may affect the pharmacokinetic properties of coumarin anticoagulants when administered concomitantly with metformin, An increase in prothrombin time may occur upon cessation of metformin therapy, with an increased risk of hemorrhage, Patients receiving phenprocoumon or other vitamin K anticoagulants snould be carefully monitored. Others: Drugs that may cause and exacerbate hyperglycemia or loss of glycemic control in patients with type 2 diabetes melitus include corticosteroids, estrogen plus progestogen, oral contraceptives, phenytoin, thyroid products, sympathomimetics, phenothiazines, nicotinic acid, calcium-channel blocking agents, and isoniazid. When such drugs are added to or withdrawn from therapy inpatients receiving oral antciabetic agents including metformin, patients should be observed closely for evidence of altered glycemic control The pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when co-administered in single dose. ‘STATEMENT ON USAGE FOR HIGH-RISK GROUPS Pregnancy: Pregnancy Category B Oral hypoglycemic agents (including metformin) are not recommended during pregnancy. Maintaining blood glucose levels as close to normal as possible is necessary during pregnancy since abnormal blood glucose levels are associated with a higher incidence of congenital abnormaites. Insulin s recommended during pregnancy. Lactation: Metformin is excreted into human milk and should therefore not be used by breastfeeding mothers, The importance of metformin hydrochloride tothe mother should be considered when deciding whether to ciscontinue breastfeeding or discontinue metformin because the potential orhypoglycemiain breastfeeding infants may exist, Consider insulin therapy for adequate glycemic contralf metformin hydrochlorides discontinued Elderly: Aging is associated with reduced renal function and metformin is known to be substantally excreted inthe kidney. The risk of serious adverse reactions to metformin is greater in patients with reduced/impaired renal function especially in the elderly. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, dose in elderly natients should not be tiated tothe maximum dose. Metformin treatment should not be inated in patients >80 years old unless creatinine clearance demonstrates that renal function is not reduced Infants and Children: The use of metformin hydrochloride immediate-elease tablet has been established in pediatric patents 10 to 16 years old with type 2 diabetes. Studies have not been conducted with metformin extended-release tablets in these pation. UNDESIRABLE EFFECTS Metformin may provoke of augment lactic acidosis particularly if itis present in high concentrations in the blood. Some of the symptoms of lactic acidosis may mimic certain adverse effects of metformin. Physicians should instruct their patients to recognize the onset of symptoms of lactic acidosis to avoid this adverse reaction Reported adverse events are as follows: Gastrointestinal: Adverse effecs with metformin are principally gastrointestinal and appear tobe dose-related and include, darthea, loose stools, nausea, vomiting, abdominal discomfort (e.9., abdominal cramps or pain), abnormal stools, constipation, abdominal distention, dyspepsia, epigastric discomfor, flatulence, gastroenteritis (viral), taste disturbance specifically metalic taste in the mouth, toothache, tooth abscess, Most ofthese reactions are transient and can be controlled by taking metformin with meals, or by a temporary reduction in dosage. Body as a Whole: Chills, fu syndrome, fatigue, lethargy, asthenia, accidental injury, headache, infection Cardiovascular: Chest discomfortichest pain, hypertension, palpitations Hematologic: Vitamin B,, and folate malabsorption, thrombocytopenia, neutropenia and rare reports of megaloblastic anemia Hepatic: Severe acute hepattis associated with liver function tests abnormalities and cholestasis have been associated with long-term metformin therapy resolving upon discontinuation of metformin. Endocrine Effects: Hypoglycemia may occur when metformin is given concomitantly with sulfonylureas andlor alcohol; hyperglycemia (NOS) and sexual dysfunction Musculoskeletal: Asteria, muscle cramp, muscle strain, myalgia, pin in limb Nervous System: Agjlaton, dizziness, migraine, paresthesia, syncope, sinus headache, hypoesthesia, lightheadedness, tremor Respiratory: Dyspnea, fu syndrome, nasal congestion, sinus congestion, rhinorrhea chins, tonsils, upper respiratory infection Skin and Appendages: Rash, erythema, pruritus, urticaria, increased sweating, contusion Others: Pneumoniis with vasculitis, edema (aggravated), peripheral edema, ear pain, blurred vision, fungal infection, fushing, nail cisorder and seasonal allergy ‘The profile of adverse reactions in pediatric patents is similar to those observed in adults Laboratory Findings: Decreased blood glucose, abnormal ver function test and increased white blood cell count OVERDOSAGE AND TREATMENT ‘There were no cases of overdose reported in clinical studies. Symptoms of metformin overdose include extensions of the common undesirable effects (e.g, epigastric discomfort, nausea, vomiting, darthea, drowsiness, weakness, dizziness, malaise, and headache). Should these symptoms ‘occur, lactic acidosis should be excluded. Metformin therapy should be discontinued and proper supportive therapy should be instituted Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mLimin under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected, CAUTION Foods, Drugs, Devices, and Cosmetics Act prohibits dispensing without prescription AVAILABILITY Metformin hydrochloride 500 mg (Glumet*) tablet, in flex fol x 4s (box of 100) Metformin hydrochloride 1 g (Glumet®) tablet, in flex fol x 4s (pox of 100s), Metformin hydrochloride 500 mg extended-release (Glumet®-XR) tablet, i lex fll x 4s (box of 100s). STORE AT TEMPERATURES NOT EXCEEDING 30°C KEEP OUT OF SIGHT AND REACH OF CHILDREN Manufactured by IB AMHERST LABORATORIES, INC. UNILAB Pharma Campus, Barangay Mamplasan, Bifian, Laguna, Philippines for L.R. IMPERIAL, INC. 2IF, Bonaventure Plaza, Orligas Ave., Greenhills, San Juan City, Philippines Trusted Quality Healthcare 30000008000 Date of Revision : October 2071 Reg. IPOPHIL