The following adverse reactions are also discussed elsewhere in the labeling:
- Lactic Acidosis [ see Boxed Warning and Warnings and Precautions (5.1)]
- Vitamin B12 Deficiency [ see Warnings and Precautions (5.2)]
- Hypoglycemia [ see Warnings and Precautions (5.3)]
6.1 Clinical Studies Experience
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.
Metformin Hydrochloride Tablets
In a U.S. clinical trial of metformin hydrochloride tablets in patients with type 2 diabetes mellitus, a total of 141 patients received metformin hydrochloride tablets up to 2550 mg per day. Adverse reactions reported in greater than 5% of metformin hydrochloride tablets treated patients and that were more common than in placebo-treated patients, are listed in Table 1. Table 1: Adverse Reactions from Clinical Trial of Metformin Hydrochloride Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus
|Metformin Hydrochloride Tablet (n=141)||Placebo (n=145)|
Diarrhea led to discontinuation of metformin hydrochloride tablets in 6% of patients. Additionally, the following adverse reactions were reported in ≥1% to ≤5.0% of metformin hydrochloride tablets treated patients and were more commonly reported with metformin hydrochloride tablets 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 tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.
In clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.
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.
Table 2 presents clinically significant drug interactions with metformin hydrochloride tablets.
Table 2: Clinically Significant Drug Interactions with Metformin Hydrochloride 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 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 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 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 tablets.|
|Insulin Secretagogues or Insulin|
|Clinical Impact:||Coadministration of metformin hydrochloride 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 metformin hydrochloride tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride 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.|
Limited data with metformin hydrochloride tablets 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].
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 2550 mg clinical dose, based on body surface area [see Data].
The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20–25% 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 2–4% and 15–20%, respectively.
Disease-associated maternal and/or embryo/fetal risk
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.
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.
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 2550 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.
Limited published studies report that metformin is present in human milk [see Data].
However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride tablets and any potential adverse effects on the breastfed child from metformin hydrochloride tablets or from the underlying maternal condition.
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to
definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.
8.3 Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride tablets may result in ovulation in some anovulatory women.
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