In metformin hydrochloride clinical trials of 29-week duration, 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 hydrochloride 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 and manage any abnormalities [see Adverse Reactions (6.1)].
Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride 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 [see Drug Interactions (7)].
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride.
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 a U.S. clinical trial of metformin hydrochloride in patients with type 2 diabetes mellitus, a total of 141 patients received metformin hydrochloride up to 2,550 mg per day. Adverse reactions reported in greater than 5% of metformin hydrochloride treated patients and that were more common than in placebo-treated patients, are listed in Table 1.
|Metformin Hydrochloride (n=141)||Placebo (n=145)|
Diarrhea led to discontinuation of metformin hydrochloride in 6% of patients. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of metformin hydrochloride treated patients and were more commonly reported with metformin hydrochloride than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.
In metformin hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.
In clinical trials with metformin hydrochloride in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.
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 3 presents clinically significant drug interactions with metformin hydrochloride.
|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 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 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.|
|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.|
|Insulin Secretagogues or Insulin|
|Clinical Impact:||Coadministration of metformin hydrochloride 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, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride, 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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