RIOMET (metformin hydrochloride oral solution) is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.
RIOMET is contraindicated in patients with:
Diabetic ketoacidosis should be treated with insulin.
Post-marketing 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 characterized by elevated blood lactate levels (>5 mmol/Liter); anion gap acidosis (without evidence of ketonuria or ketonemia); an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [See Dosage and Administration, Contraindications, and Precautions].
If metformin-associated lactic acidosis is suspected, immediately discontinue RIOMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. 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 the 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:
In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anaemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on RIOMET and any apparent abnormalities should be appropriately investigated and managed.
Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.
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 is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with RIOMET or any other oral anti-diabetic drug.
Teratogenic Effects: Pregnancy Category B
Because animal reproduction studies are not always predictive of human response, RIOMET should not be used during pregnancy unless clearly needed.
Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of metformin for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years).
The most common adverse reactions (>5.0 percent) in a placebo-controlled clinical study of Metformin Monotherapy were: Diarrhea, Nausea/Vomiting, Flatulence, Asthenia, Indigestion, Abdominal Discomfort, and Headache. Additionally, the following adverse reactions were reported in ≥1.0 to ≤5.0% of metformin patients and were more commonly reported with metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.
In clinical trials with metformin in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults. Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.
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