Boxed warningThe FDA label of this medicine carries a boxed warning, the strongest warning the FDA gives. Read it under warnings and precautions.
Indications
RIOMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. RIOMET is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. (1)
Contraindications
1. RIOMET is contraindicated in patients with: 2. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1) ]. 3. Hypersensitivity to metformin. 4. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) (4, 5.1)
Hypersensitivity to metformin (4)
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4)
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)
5.1Lactic
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.
5.2Vitamin 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) ].
5.3Hypoglycemia 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)].
5.4Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with RIOMET.
Interactions
1. Table 2 presents clinically significant drug interactions with RIOMET. 2. Table 2: Clinically Significant Drug Interactions with RIOMET 1. Carbonic Anhydrase Inhibitors 1. Clinical Impact: 1. Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with RIOMET may increase the risk for lactic acidosis. 1.
Intervention: 1. Consider more frequent monitoring of these patients. 1. Examples: 1. Topiramate, zonisamide, acetazolamide or dichlorphenamide. 1. Drugs that Reduce RIOMET Clearance 1. Clinical Impact: 1. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT 2 ] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. 1.
Intervention: 1. Consider the benefits and risks of concomitant use with RIOMET. 1. Examples: 1. Ranolazine, vandetanib, dolutegravir, and cimetidine. 1. Alcohol 1. Clinical Impact: 1. Alcohol is known to potentiate the effect of metformin on lactate metabolism. 1. Intervention: 1. Warn patients against excessive alcohol intake while receiving RIOMET. 1. Insulin Secretagogues or Insulin 1. Clinical Impact: 1. Coadministration of RIOMET with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. 1.
Intervention: 1. Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. 1. Drugs Affecting Glycemic Control 1. Clinical Impact: 1. Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. 1. Intervention: 1. When such drugs are administered to a patient receiving RIOMET, observe the patient closely for loss of blood glucose control.
When such drugs are withdrawn from a patient receiving RIOMET, observe the patient closely for hypoglycemia. 1. Examples: 1. Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.
Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7)
Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use (7)
Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake (7)
Pregnancy and breastfeeding
8.1Pregnancy 1. Risk Summary 2.
Limited data with RIOMET in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations]. 3.
No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5‑ times, respectively, a 2,550 mg clinical dose, based on body surface area [see Data]. 4. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20 to 25% in women with a HbA1C >10.
The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. 5. Clinical Considerations 6. Disease-associated maternal and/or embryo/fetal risk 7. Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications.
Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. 8. Data 9. Human Data 10. Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. 11.
Animal Data 12. Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2,550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Adverse reactions
The following adverse reactions are also discussed elsewhere in the labeling:
Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
Vitamin B 12 Deficiency [see Warnings and Precautions (5.2)]
Hypoglycemia [see Warnings and Precautions (5.3)] The most common adverse reactions are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch
6.1Clinical Studies Experience 1.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 2. In a U.S. clinical trial of metformin HCl tablets in patients with type 2 diabetes mellitus, a total of 141 patients received metformin HCl tablets up to 2,550 mg per day.
Adverse reactions reported in greater than 5% of patients treated with metformin HCl tablets and that were more common than in placebo-treated patients, are listed in Table 1. 3. Table 1: Adverse Reactions from a Clinical Trial of Metformin HCl Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus 1. Metformin HCl Tablets (n = 141) 1. Placebo (n = 145) 1. Diarrhea 1. 53% 1. 12% 1.
Nausea/Vomiting 1. 26% 1. 8% 1. Flatulence 1. 12% 1. 6% 1. Asthenia 1. 9% 1. 6% 1. Indigestion 1. 7% 1. 4% 1. Abdominal Discomfort 1. 6% 1. 5% 1. Headache 1. 6% 1. 5% 1. Diarrhea led to discontinuation of metformin HCl tablets in 6% of patients. Additionally, the following adverse reactions were reported in ≥ 1% to ≤ 5% of patients treated with metformin HCl tablets and were more commonly reported than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. 2.
Pediatric Patients 3. In clinical trials with metformin HCl tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. 4. Laboratory Tests 5. Vitamin B 12 Concentrations 6. In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.
6.2Postmarketing
Experience
The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.
Composition
Active ingredients
METFORMIN HYDROCHLORIDE 500MG/5ML **Federal Register determination that product was not discontinued or withdrawn for safety or effectiveness reasons**
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA021591.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
