Riomet

Warnings

5 WARNINGS AND PRECAUTIONS • Lactic acidosis: See boxed warning. (5.1) • Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. (5.2) • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required (5.3) 5.1 Lactic Acidosis • There have been postmarketing 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, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin‑associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were 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 RIOMET. In RIOMET 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/min 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 RIOMET 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: • Before initiating RIOMET, obtain an estimated glomerular filtration rate (eGFR). • RIOMET is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) ]. • Initiation of RIOMET is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 . • Obtain an eGFR at least annually in all patients taking RIOMET. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. • In patients taking RIOMET whose eGFR falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy. • 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 (2.3), Clinical Pharmacology (12.3) ]: • Before initiating RIOMET, obtain an estimated glomerular filtration rate (eGFR). • RIOMET is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) ]. • Initiation of RIOMET is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 . • Obtain an eGFR at least annually in all patients taking RIOMET. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. • In patients taking RIOMET whose eGFR falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy. • Drug interactions — The concomitant use of RIOMET 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. Consider more frequent monitoring of patients [see Drug Interactions (7)] . • 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. • Radiologic 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 RIOMET 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 RIOMET 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. RIOMET 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 cause prerenal azotemia. When such an event occurs, discontinue RIOMET. • Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving RIOMET. • Hepatic impairment — Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of RIOMET in patients with clinical or laboratory evidence of hepatic disease. 5.2 Vitamin B 12 Deficiency 1. In clinical trials of 29-week duration with metformin hydrochloride (HCl) tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on RIOMET and manage any abnormalities [see Adverse Reactions (6.1) ]. 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. RIOMET may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with RIOMET [see Drug Interactions (7)]. 5.4 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with RIOMET.