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warnings and cautions
5 WARNINGS AND PRECAUTIONS Lactic acidosis : See boxed warning. ( 4 , 5.1 ) Hypoglycemia : Repaglinide and metformin hydrochloride tablets may cause hypoglycemia. Skip the scheduled dose if a meal is skipped to reduce the risk of hypoglycemia. Reduce the dose if hypoglycemia occurs. ( 5.2 ) Vitamin B 12 deficiency : Metformin can lower vitamin B 12 levels. Monitor hematological parameters annually. ( 5.3 ) Serious Cardiovascular Adverse Reactions with Concomitant NPH-insulin : Repaglinide and metformin hydrochloride tablets are not indicated for use with NPH insulin. ( 5.4 ) Macrovascular outcomes : There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide and metformin hydrochloride tablets. ( 5.5 ) 5.1 Lactic Acidosis There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of repaglinide and metformin hydrochloride tablets. In repaglinide and metformin hydrochloride tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin 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 repaglinide and metformin hydrochloride tablets 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 post-marketing 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 CLINICAL PHARMACOLOGY ( 12.3 )]: Before initiating repaglinide and metformin hydrochloride tablets, obtain an estimated glomerular filtration rate (eGFR). Repaglinide and metformin hydrochloride tablets is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m 2 [see CONTRAINDICATIONS ( 4 )]. Initiation of repaglinide and metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 . Obtain an eGFR at least annually in all patients taking repaglinide and metformin hydrochloride tablets. 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 repaglinide and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy . Drug Interactions The concomitant use of repaglinide and metformin hydrochloride tablets 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 ( 7 )]. 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 [see USE IN SPECIFIC POPULATIONS ( 8.5 )]. 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 repaglinide and metformin hydrochloride tablets 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 m 2 ; 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 repaglinide and metformin hydrochloride tablets 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. Repaglinide and metformin hydrochloride tablets 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 repaglinide and metformin hydrochloride tablets. 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 repaglinide and metformin hydrochloride tablets. 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 repaglinide and metformin hydrochloride tablets in patients with clinical or laboratory evidence of hepatic disease. 5.2 Hypoglycemia All glinides, including repaglinide and metformin hydrochloride tablets, can cause hypoglycemia [ see ADVERSE REACTIONS ( 6.1 )] . Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see DRUG INTERACTIONS ( 7 )], or in patients who experience recurrent hypoglycemia. Factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in level of physical activity, changes to co-administered medication [see DRUG INTERACTIONS ( 7 )] , and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see USE IN SPECIFIC POPULATIONS ( 8.6 , 8.7 )] . Patients should administer repaglinide and metformin hydrochloride tablets before meals and be instructed to skip the dose of repaglinide and metformin hydrochloride tablets if a meal is skipped. In patients who experience hypoglycemia, the dose of repaglinide and metformin hydrochloride tablets should be reduced [see DOSAGE AND ADMINISTRATION ( 2.1 )] . Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 5.3 Vitamin B12 Levels In controlled clinical trials of metformin of 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. This finding, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, is rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on repaglinide and metformin hydrochloride tablets and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. In these patients, routine serum vitamin B 12 measurements at 2- to 3- year intervals may be useful. 5.4 Serious Cardiovascular Adverse Reactions with Concomitant Use with NPH-insulin Across seven controlled trials, there were six serious adverse events of myocardial ischemia in patients treated with repaglanide plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [see ADVERSE REACTIONS ( 6.1 )]. repaglinide and metformin hydrochloride tablets is not indicated for use in combination with NPH-insulin. 5.5 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide and metformin hydrochloride tablets.