Metformin Tablets

• Class: Oral biguanide antidiabetic agent.
• Similarity: Related to phenformin, which was withdrawn in 1977 due to lactic acidosis; metformin has a lower risk of this adverse reaction.

• Action: Metformin works differently from, but complements, sulfonylureas and other antidiabetic medications. It is used to manage type 2 diabetes and has also proven useful for polycystic ovary syndrome (PCOS).
• Glycemic Control: Comparable to glyburide for type 2 diabetes; however, metformin is associated with a higher incidence of digestive complaints.
• PCOS Treatment: Reduces serum androgens, restores menstrual cycles and ovulation, and may improve pregnancy rates.
• Precocious Puberty: Limited evidence suggests it may delay puberty onset in females with precocious puberty and delay menarche in those with early-normal onset.
• Lifestyle vs. Metformin: While lifestyle interventions reduce diabetes incidence, many patients fail to maintain these changes. The ADA and the European Association for the Study of Diabetes recommend combining metformin with lifestyle changes at diagnosis.

• After 10 years, metformin-treated patients had a 33% relative reduction in myocardial infarction risk and a 27% relative reduction in mortality risk compared to those on conventional therapy. These benefits persisted despite similar HbA1c levels between groups after 1 year.

• History: Approved in Europe in the 1950s; FDA approval in December 1994.
• Indications: Approved for type 2 diabetes as monotherapy or in combination with other antidiabetic agents.
• Formulations: Regular-Release Tablets: Approved for children ≥10 years in January 2001. Oral Solution (Riomet): Approved in September 2003. Extended-Release Formulations: Glucophage XR: Approved October 2000. Fortamet: Approved April 2004. Glumetza: Approved June 2005.
• Advantages: Extended-release formulations provide once-daily dosing and may reduce gastrointestinal side effects compared to regular-release metformin, though larger trials are needed for confirmation.

• Extended-release formulations offer similar glycemic control with the convenience of once-daily administration and potential for fewer gastrointestinal adverse events.

• Glucose Tolerance: Improves glucose tolerance by lowering both basal and postprandial plasma glucose levels.
• Hepatic Gluconeogenesis: Decreases hepatic glucose production by reducing gluconeogenesis in the liver.
• Intestinal Absorption: Decreases intestinal absorption of glucose.
• Insulin Sensitivity: Enhances insulin sensitivity, increasing peripheral glucose uptake and utilization.

• Insulin Secretion: Metformin does not significantly affect insulin secretion. Fasting insulin levels and day-long plasma insulin response may decrease.
• Insulin Sensitivity: Improves glucose utilization in skeletal muscle and adipose tissue by increasing cell membrane glucose transport. This may involve improved binding of insulin to its receptors.
• Residual Islet Function: Metformin is more effective in individuals with some residual pancreatic islet cell function.

• Hypoglycemia: Metformin rarely causes hypoglycemia as it does not significantly alter insulin concentrations. Sulfonylureas increase insulin secretion, which can lead to hypoglycemia.
• Obesity: Metformin is particularly effective in addressing insulin resistance in obese patients with type 2 diabetes, whereas sulfonylureas may be more suitable for non-obese patients.

• Fatty-Acid Oxidation: Causes a 10-20% decrease in fatty-acid oxidation.
• Glucose Oxidation: Slightly increases glucose oxidation.
• Mitochondrial Function: Unlike phenformin, metformin does not inhibit mitochondrial lactate oxidation unless plasma concentrations are excessively high (e.g., in renal failure or hypoxic conditions).

• Hyperglycemia: Lowers fasting and postprandial hyperglycemia by approximately 25-30%.
• Weight Impact: Does not cause weight gain and may lead to modest weight loss due to drug-induced anorexia.
• Lipid Profile: Reduces plasma VLDL triglycerides, leading to modest decreases in plasma triglycerides and total cholesterol. Improvements in hemoglobin A1c and lipid profile are observed, especially if baseline values are elevated.

• Insulin Resistance: Reduces insulin resistance in PCOS patients.
• Androgen Levels: Lowers serum androgen concentrations, restores normal menstrual cycles and ovulation, and may improve PCOS-associated infertility.
• Hormonal Effects: Increases follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG), and decreases serum testosterone concentrations by approximately 50%. Also reduces luteinizing hormone (LH) levels.

• Hypersensitivity: Known hypersensitivity to metformin.
• Type 1 Diabetes Mellitus: Not effective for type 1 diabetes and is contraindicated in diabetic ketoacidosis (DKA). DKA should be treated with insulin.
• Metabolic Acidosis: Contraindicated in metabolic acidosis, including lactic acidosis, which is a rare but serious complication of metformin.
• Renal Impairment: Contraindicated in severe renal impairment (serum creatinine ≥ 1.4 mg/dL for females and ≥ 1.5 mg/dL for males; or CrCl < 60 mL/min). Monitoring renal function is crucial.
• Hepatic Disease: Avoid in patients with significant hepatic disease due to the increased risk of lactic acidosis.

• Health Conditions: Anemia, alcohol consumption, dehydration, and severe illness (e.g., heart attack, heart failure, serious infections, or significant injuries).
• Kidney and Liver Disease: Regular assessment of kidney and liver function is required.
• Polycystic Ovary Syndrome (PCOS): Monitor for potential side effects related to PCOS.
• Pregnancy and Breastfeeding: Metformin passes through the placenta and is excreted in breast milk; use with caution and consider alternatives if necessary.

• Furosemide: May increase metformin levels but also decrease its effectiveness. Blood glucose levels should be monitored.
• Torsemide and Bumetanide: Can impact blood glucose control and should be used cautiously with metformin.

• Corticosteroids and Growth Hormones: Can raise blood glucose levels, potentially reducing the effectiveness of antidiabetic agents.
• Oral Contraceptives: May impair glucose tolerance and require monitoring.

• Triamterene and Thiazide Diuretics: Can reduce the effectiveness of antidiabetic agents by increasing blood glucose.
• Sulfonamides: Might cause hypoglycemia in certain patients.
• Fibric Acid Derivatives: Can enhance hypoglycemic effects.
• ACE Inhibitors and Angiotensin II Receptor Antagonists: Might improve insulin sensitivity and reduce the incidence of diabetes.
• Beta-Blockers: Can have complex effects on blood glucose, potentially masking symptoms of hypoglycemia.

• Cimetidine, Digoxin, and Dofetilide: May increase the risk of lactic acidosis or affect drug levels.
• Cyclosporine and Tacrolimus: Can cause hyperglycemia and may affect insulin secretion.
• Alcohol: Can either worsen or improve blood glucose control, depending on various factors.
• Thyroid Hormones and Isoniazid: Can alter blood sugar levels, requiring monitoring and possible dose adjustments.

• Antipsychotics and Lithium: Can affect glycemic control and need careful monitoring.
• Carbonic Anhydrase Inhibitors and Zonisamide: Can increase the risk of lactic acidosis and affect blood glucose.
• Green Tea and Nicotine: May alter blood glucose levels, necessitating close monitoring.

• Diarrhea affects 53.2% of patients on immediate-release metformin; 9.6% on extended-release.
• Nausea and vomiting affect 6.5—25.5% of patients.
• Flatulence: 1—12.1%.
• Indigestion/Dyspepsia: 1—7.1%.
• Abdominal pain/discomfort: 1—6.4%.
• Other GI effects include anorexia, dysgeusia (metallic taste), and stool changes, all in 1—5% of patients.

• Hypoglycemia is rare with metformin alone (1—5% incidence), but more common with other hypoglycemic agents or insufficient caloric intake.
• Vitamin B12 deficiency is reported in 7% of patients and is rarely associated with anemia.
• Weight loss may occur, averaging 1—8.4 lbs with immediate-release and 0.7—2.2 lbs with extended-release formulations.
• Lactic acidosis is rare but serious, occurring in approximately 0.03 cases per 1000 patient-years. Symptoms include malaise, myalgia, respiratory distress, and abdominal discomfort.

• Lightheadedness, nail disorders, rash, increased sweating, chest pain or discomfort, chills, flu syndrome or upper respiratory infections, flushing, and palpitations occur in 1—5% of patients.

• Call your healthcare provider immediately if you experience skin rash, itching, or hives; swelling of face, lips, or tongue; blue tint to skin; chest tightness or pain; difficulty breathing; wheezing; dizziness; or swollen painful areas on the leg.

• Effect on Ovulation and Fertility: Metformin can help women with insulin resistance and polycystic ovary syndrome (PCOS) resume ovulation. This may increase the risk of conception if contraception is not used by those who do not wish to become pregnant.
• FDA Pregnancy Category: Metformin is classified as Category B, which means that studies in animals have not shown harm to the fetus, but there are limited studies in pregnant women. Routine use during pregnancy is not generally recommended.
• Placental Transfer and Fetal Exposure: Metformin does cross the placenta, and therapeutic levels have been detected in the fetus. In a small study, higher metformin concentrations were found in the umbilical vein and artery than in maternal blood. However, no adverse effects on umbilical artery blood pH were noted.
• Outcomes in PCOS Patients: In a study of women with PCOS treated with metformin throughout pregnancy, there were no significant differences in the rates of preeclampsia and a lower incidence of gestational diabetes compared to controls. Some birth defects were reported, but developmental outcomes in infants exposed to metformin were similar to those not exposed.
• Gestational Diabetes: Metformin has been studied for the treatment of gestational diabetes. It did not show significant differences compared to insulin in glycemic control or pregnancy outcomes, though some studies suggested lower weight gain and improved neonatal outcomes with metformin.

• Excretion in Breast Milk: Metformin is excreted into breast milk, reaching levels similar to those in maternal plasma. Small studies suggest that infant exposure is relatively low, ranging from 0.11—1.08% of the maternal dose.
• Infant Safety: While no adverse effects on infant plasma glucose have been reported, hypoglycemia or other side effects are possible. Studies indicate that metformin use during breastfeeding does not affect infant growth, motor, or social development up to 6 months.
• Recommendations: Decisions regarding breastfeeding while on metformin should involve a risk-benefit analysis. If metformin is discontinued and blood glucose control cannot be maintained through diet and exercise alone, insulin therapy may be considered.
• Alternatives: Acarbose, with minimal systemic absorption, and tolbutamide (considered usually compatible with breastfeeding by the American Academy of Pediatrics) are potential alternatives to metformin during breastfeeding.
• Monitoring: Infants should be monitored for signs of hypoglycemia if the mother is taking oral hypoglycemics. Look for increased fussiness or somnolence in the infant. For specific advice and to ensure safety, consult with a healthcare provider.

Upon receipt of medication, immediately store between 35°F to 46°F (2°C – 8°C). Keep all
medicines out of the reach of children. Throw away any unused medicine within 29 days of
puncture or the BUD, whichever comes first. Do not flush unused medications or pour
down a sink or drain.