Boxed Warning (Black Box)
WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. 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...
RIOMET
METFORMIN HYDROCHLORIDE
Manufacturer: Sun Pharmaceutical Industries, Inc.
Clinical information
Indications & Usage
1 INDICATIONS AND USAGE 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)
Dosage & Administration
2 DOSAGE AND ADMINISTRATION Adult Dosage for RIOMET : • Starting dose: 500 mg (5 mL) orally twice a day or 850 mg (8.5 mL) once a day, with meals (2.1) • Increase the dose in increments of 500 mg (5 mL) weekly or 850 mg (8.5 mL) every 2 weeks, up to a maximum dose of 2,550 mg (25.5 mL) per day, given in divided doses (2.1) • Doses above 2,000 mg (20 mL) may be better tolerated given in divided doses 3 times a day with meals (2.1) Pediatric Dosage for RIOMET : • Starting dose: 500 mg (5 mL) orally twice a day, with meals (2.2) • Increase dosage in increments of 500 mg (5 mL) weekly up to a maximum of 2,000 mg (20 mL) per day, given in divided doses twice daily (2.2) Renal Impairment : • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3) • Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 (2.3) • Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 (2.3) • Assess risk/benefit of continuing RIOMET if eGFR falls below 45 mL/minute/1.73 m 2 (2.3) • Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 (2.3) Discontinuation for Iodinated Contrast Imaging Procedures: • RIOMET may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4) 2.1 Adult Dosage • Measure the RIOMET dose in the RIOMET specific dosing cup. • The recommended starting dose of RIOMET is 500 mg (5 mL) orally twice a day or 850 mg (8.5 mL) once a day, given with meals. • Increase the dose in increments of 500 mg (5 mL) weekly or 850 mg (8.5 mL) every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2,550 mg (25.5 mL) per day, given in divided doses. • Doses above 2,000 mg (20 mL) may be better tolerated given in divided doses 3 times a day with meals. 2.2 Pediatric Dosage • Measure the RIOMET dose in the RIOMET specific dosing cup. • The recommended starting dose of RIOMET for pediatric patients 10 years of age and older is 500 mg (5 mL) orally twice a day, given with meals. • Increase dosage in increments of 500 mg (5 mL) weekly on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg (20 mL) per day, given in divided doses twice daily. 2.3 Recommendations for Use in Renal Impairment • Assess renal function prior to initiation of RIOMET and periodically thereafter. • RIOMET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . • Initiation of RIOMET in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. • In patients taking RIOMET whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. • Discontinue RIOMET if the patient’s eGFR later falls below 30 mL/minute/1.73 m 2 [see Warnings and Precautions (5.1) ]. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures • Discontinue 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 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 RIOMET if renal function is stable.
Contraindications
4 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)
Safety
Adverse Reactions
6 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 6.1 Clinical 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. 6.2 Postmarketing 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.
Drug Interactions
7 DRUG 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)
Additional information
Description
11 DESCRIPTION RIOMET oral solution contains the biguanidine antihyperglycemic agent metformin in the form of monohydrochloride salt. Metformin hydrochloride, is N , N -dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is shown as: Metformin hydrochloride, USP is a white crystalline powder with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62. Metformin hydrochloride, USP 2.0 g is soluble in 20 mL of water. The pK a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. It is freely soluble in water; slightly soluble in alcohol; practically insoluble in acetone and in methylene chloride. RIOMET (Cherry Flavor) contains 500 mg of metformin hydrochloride (the equivalent of 389.93 mg metformin) per 5 mL and the following inactive ingredients: Artificial cherry flavor, hydrochloric acid, potassium bicarbonate, purified water, saccharin calcium, and xylitol. RIOMET (Strawberry Flavor) contains 500 mg of metformin hydrochloride (the equivalent of 389.93 mg metformin) per 5 mL and the following inactive ingredients: Hydrochloric acid, N&A strawberry flavor (propylene glycol and glycerin), potassium bicarbonate, purified water, sucralose, and xylitol. structure
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied 1. RIOMET 500 mg per 5 mL (100 mg/mL) oral solution is supplied in bottles with child-resistant caps and a dosing cup as follows: Flavor Appearance Size NDC Cherry clear, colorless solution 4 ounce (118 mL) 10631-206-01 16 ounce (473 mL) 10631-206-02 Strawberry clear, colorless to light yellow solution 4 ounce (118 mL) 10631-238-01 16 ounce (473 mL) 10631-238-02 Storage 1. Store at 15 ° - 30 ° C (59 ° - 86 ° F) [See USP Controlled Room Temperature].
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Frequently Asked Questions
What is RIOMET used for?+
RIOMET, also known as metformin hydrochloride, is used to improve blood sugar control in adults and children 10 years and older with type 2 diabetes. It works by decreasing glucose production in the liver and increasing the body's sensitivity to insulin. Consult a doctor for more information on how RIOMET can help manage your diabetes.
Can I take RIOMET if I have kidney problems?+
If you have kidney problems, you should use RIOMET with caution, as it can increase the risk of lactic acidosis, a serious condition. Your doctor may need to adjust your dose or monitor your kidney function while taking RIOMET. Consult a doctor to discuss the potential risks and benefits of taking RIOMET with kidney problems.
How should I take RIOMET?+
RIOMET should be taken orally with meals to help reduce stomach upset. The usual starting dose is 500 mg twice daily, but your doctor may adjust the dose based on your individual needs. Consult a doctor for specific instructions on taking RIOMET and to discuss any questions or concerns you may have.
What are the common side effects of RIOMET?+
Common side effects of RIOMET include diarrhea, nausea, vomiting, and stomach upset. These side effects are usually mild and temporary, but if they persist or worsen, you should consult a doctor. Consult a doctor if you experience any side effects while taking RIOMET to determine the best course of action.
Can I stop taking RIOMET if my blood sugar levels are under control?+
Even if your blood sugar levels are under control, you should not stop taking RIOMET without consulting a doctor. Stopping the medication abruptly can cause your blood sugar levels to rise again, and you may experience withdrawal symptoms. Consult a doctor to discuss the best way to manage your diabetes and determine if any changes to your treatment plan are needed.
MEDICAL DISCLAIMER
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