Linagliptin And Metformin Hydrochloride (1 brand name, 1 dosage form, 1 route)
Available dosage forms: TABLET.
Routes of administration: ORAL.
Brand Names
- LINAGLIPTIN AND METFORMIN HYDROCHLORIDE
Boxed Warning
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)]. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)]. If metformin-associated lactic acidosis is suspected, immediately discontinue linagliptin and metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].
Indications and Usage
Linagliptin and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Linagliptin and metformin hydrochloride tablets are not recommended in patients with type 1 diabetes mellitus. Linagliptin and metformin hydrochloride tablets have not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using linagliptin and metformin hydrochloride tablets [see Warnings and Precautions (5.2)].
Contraindications
Linagliptin and metformin hydrochloride are contraindicated in patients with: • severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)]. • acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)]. • hypersensitivity to linagliptin, metformin, or any of the excipients in linagliptin and metformin hydrochloride, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin [seeWarnings and Precautions (5.4) and Adverse Reactions (6.1)].
Adverse Reactions
The following serious adverse reactions are described below or elsewhere in the prescribing information: • Lactic Acidosis [see Warnings and Precautions (5.1)] • Pancreatitis [see Warnings and Precautions (5.2)] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions [see Warnings and Precautions (5.4)] • Vitamin B12 Deficiency [see Warnings and Precautions (5.5)] • Severe and Disabling Arthralgia [see Warnings and Precautions (5.6)] • Bullous Pemphigoid [see Warnings and Precautions (5.7)] • Heart Failure [see Warnings and Precautions (5.8)]
Drug Interactions
Table 2 describes clinically relevant interactions with linagliptin and metformin hydrochloride. Table 2 Clinically Relevant Interactions with linagliptin and metformin hydrochloride Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with linagliptin and metformin hydrochloride may increase the risk of lactic acidosis. Intervention Consider more frequent monitoring of these patients. Drugs that Reduce Metformin 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 such as ranolazine, vandetanib, dolutegravir, and cimetidine) 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. Alcohol Clinical Impact Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention Warn patients against excessive alcohol intake while receiving linagliptin and metformin hydrochloride. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when linagliptin and metformin hydrochloride is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Intervention Coadministration of linagliptin and metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazide
Mechanism of Action
Linagliptin and Metformin Hydrochloride Linagliptin and metformin hydrochloride contains: linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin, a biguanide. Linagliptin Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Metformin HCl Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.
Overdosage
In the event of an overdose with linagliptin and metformin hydrochloride, consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations. Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.