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. 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 metformin hydrochloride extended-release tablets and manage any abnormalities [ see Adverse Reactions (6.1) ].
Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets 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 metformin hydrochloride extended-release tablets [ see Drug Interactions (7) ].
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets.
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) ]
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.
In placebo-controlled trials, 781 patients were administered metformin HCl extended-release tablets. Adverse reactions reported in greater than 5% of the patients treated with metformin HCl extended-release tablets and that were more common than in placebo-treated patients are listed in Table 1.
Table 1:Adverse Reactions from Clinical Trials of Metformin HCl Extended-Release Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus
|Adverse Reaction||Metformin HCl Extended-Release Tablets (n=781)||Placebo (n=195)|
Diarrhea led to the discontinuation of metformin HCl extended-release tablets in 0.6% of patients. Additionally, the following adverse reactions were reported in 1.0% to 5.0% of patients treated with metformin HCl extended-release tablets and were more commonly reported than in placebo-treated patients: abdominal pain, constipation, abdomen distention, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.
Vitamin B 12 Concentrations
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.
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.
Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets.
Table 2: Clinically Significant Drug Interactions with Metformin Hydrochloride Extended-Release Tablets
|Carbonic Anhydrase Inhibitors|
|Clinical Impact:||Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis.|
|Intervention:||Consider more frequent monitoring of these patients.|
|Examples:||Topiramate, zonisamide, acetazolamide or dichlorphenamide.|
|Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance|
|Clinical Impact:||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 [OCT2] / 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) ].|
|Intervention:||Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets.|
|Examples:||Ranolazine, vandetanib, dolutegravir, and cimetidine.|
|Clinical Impact:||Alcohol is known to potentiate the effect of metformin on lactate metabolism.|
|Intervention:||Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.|
|Insulin Secretagogues or Insulin|
|Clinical Impact:||Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.|
|Intervention:||Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.|
|Drugs Affecting Glycemic Control|
|Clinical Impact:||Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.|
|Intervention:||When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia.|
|Examples:||Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.|
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