This is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.
Combination Oral hypoglycemic preparations
Linagliptin is indicated to improve glycemic control in patients with type 2 diabetes mellitus. Linagliptin is an inhibitor of DPP-4 (dipeptidyl peptidase-4), an enzyme that degrades the incretin hormones GLP-1 (glucagon like peptide-1) and GIP (glucose dependent insulinotropic polypeptide). Thus, Linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin from pancreatic beta (β) cells in a glucose-dependent manner and decreasing the secretion of glucagon from pancreatic alpha (α) cells in the circulation.
Metformin Hydrochloride is a biguanide type oral antihyperglycemic drug used in the management of type 2 diabetes. It lowers both basal and postprandial plasma glucose. Its mechanism of action is different from those of sulfonylureas and it does not produce hypoglycemia. Metformin Hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by an increase in peripheral glucose uptake and utilization.
The dosage should be individualized on the basis of both effectiveness and tolerability. Maximum recommended dose of 2.5 mg Linagliptin and 1000 mg Metformin Hydrochloride twice daily with meals. Dose escalation should be gradual to reduce the gastrointestinal (GI) side effects associated with Metformin use. Recommended starting dose: In patients currently not treated with Metformin, initiate treatment with 2.5 mg Linagliptin and 500 mg Metformin Hydrochloride twice daily. In patients already treated with Metformin, start with 2.5 mg Linagliptin and the current dose of Metformin Hydrochloride twice daily. Patients already treated with linagliptin and metformin, individual components may be switched to this combination containing the same doses of each component.
Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with Metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of this combination and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with this combination, as the risk of lactic acidosis may increase.
Inducers of P-glycoprotein and CYP3A4 Enzymes: Rifampin decreased Linagliptin exposure, suggesting that the efficacy of Linagliptin may be reduced when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As this combination is a fixed-dose combination of Linagliptin and Metformin, use of alternative treatments (not containing Linagliptin) is strongly recommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary.
Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving this combination, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving this combination, the patient should be observed closely for hypoglycemia.
Although Linagliptin undergoes minimal renal excretion, Metformin is known to be substantially excreted by the kidney. The risk of Metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore, this combination is contraindicated in patients with renal impairment. It is also contraindicated in acute or chronic metabolic acidosis (diabetic ketoacidosis) and in hypersensitivity to Linagliptin or Metformin. In a patient with lactic acidosis who is taking Metformin, the drug should be discontinued immediately and supportive therapy promptly instituted. There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue Linagliptin & Metformin. Temporarily discontinue Linagliptin & Metformin in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids. Metformin may lower Vitamin B12 levels; so hematologic parameters shoud be monitored annually.
Most common side effects are nasopharyngitis and diarrhea. Hypoglycemia is more common in patients treated with this combination and sulfonylureas.
Pregnancy category B. There are no adequate and well-controlled studies in pregnant women with this combination or its individual component; so it should be used during pregnancy only if clearly needed. Caution should also be excercised when it is administered to a lactating mother.
In the event of an overdose with this combination the usual supportive measures (i.e. remove unabsorbed material from the gastrointestinal tract, perform clinical monitoring, and institute supportive treatment) should be employed. Removal of Linagliptin by hemodialysis or peritoneal dialysis is unlikely but Metformin Hydrochloride is dialyzable.
During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of Linagliptin (equivalent to 120 times the recommended daily dose), there were no dose-related clinical adverse drug reactions.
Overdose of Metformin Hydrochloride has occurred in case of ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with Metformin Hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of Metformin Hydrochloride overdose cases.
Keep in a cool & dry place (below 30°C), protected from light & moisture. Keep out of the reach of children.
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