brand glyxambi 25 mg-5 mg tablet

Uses

Diabetes Mellitus

Linagliptin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Linagliptin also is used as initial therapy in combination with metformin hydrochloride as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Linagliptin also is used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptor_γ [PPAR_γ] agonist [ thiazolidinedione]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with oral antidiabetic agent monotherapy.

While metformin generally is the preferred antidiabetic agent for initial therapy in patients with type 2 diabetes mellitus, the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) suggests a DPP-4 inhibitor as one of several alternative antidiabetic agents for initial monotherapy in patients with a contraindication to metformin (e.g., renal disease, hepatic disease, GI intolerance, risk of lactic acidosis). DPP-4 inhibitors are also recommended by AACE/ACE as part of combination therapy, particularly when both postprandial and fasting plasma glucose concentrations are elevated.

Linagliptin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Linagliptin Monotherapy

Efficacy of linagliptin as monotherapy for the management of type 2 diabetes mellitus has been established in 2 double-blind, placebo-controlled studies of 18 or 24 weeks' duration. Linagliptin (5 mg once daily) improved glycemic control as evidenced by reductions in glycosylated hemoglobin (HbA_1c) as well as in fasting and 2-hour postprandial plasma glucose concentrations. HbA_1c was reduced by a mean of 0.4% (from a mean baseline concentration of about 8%) in patients receiving linagliptin 5 mg daily, compared with an increase in HbA_1c of 0.1-0.3% in those receiving placebo.

Combination Therapy

Efficacy of linagliptin in combination with metformin, a sulfonylurea, or a thiazolidinedione in the management of type 2 diabetes mellitus has been established in several randomized, placebo- or active-controlled, double-blind studies. In these studies, the addition of linagliptin (5 mg once daily) to therapy with metformin and/or a sulfonylurea or to pioglitazone therapy improved glycemic control as evidenced by reductions in HbA_1c as well as in fasting and/or 2-hour postprandial plasma glucose concentrations.

Efficacy of the combination of linagliptin and metformin as initial therapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise is supported by results of a 24-week, randomized, double-blind trial. In this trial, concurrent therapy with linagliptin and metformin hydrochloride improved glycemic control (as evidenced by reductions in HbA_1c and fasting plasma glucose) compared with linagliptin or metformin hydrochloride monotherapy or placebo. Reductions in HbA_1c were 1.2 or 1.6% with linagliptin 2.5 mg plus metformin hydrochloride 0.5 or 1 g twice daily, respectively; 0.5% with linagliptin 5 mg once daily; 0.6 or 1.1% with metformin hydrochloride 0.5 or 1 g twice daily, respectively; and 0.1% with placebo.

In a 24-week study in patients receiving metformin hydrochloride monotherapy (>=1.5 g daily), add-on therapy with linagliptin resulted in a reduction of 0.5% in HbA_1c compared with an increase of 0.15% in patients receiving metformin hydrochloride and add-on placebo. In a 104-week, active-controlled, noninferiority study in patients receiving metformin hydrochloride monotherapy (>=1.5 g daily), add-on therapy with linagliptin was noninferior at 52 weeks and resulted in a reduction of 0.4% in HbA_1c from baseline, compared with a reduction of 0.6% from baseline in patients receiving add-on therapy with glimepiride (initiated at 1 mg daily and titrated over 12 weeks to a maximum dosage of 4 mg daily [ mean dosage: 3 mg daily]). At 104 weeks, add-on therapy with linagliptin resulted in a reduction of 0.2% in HbA_1c from baseline, compared with a reduction of 0.4% from baseline in those receiving add-on glimepiride therapy. Patients receiving add-on linagliptin therapy had a mean decrease in body weight (loss of 1.1 kg), while those receiving add-on glimepiride had a mean increase in body weight (gain of 1.4 kg).

In a 24-week study in patients receiving pioglitazone monotherapy (30 mg daily), add-on linagliptin or placebo resulted in a reduction of 1.1 or 0.6%, respectively, in HbA_1c.

In an 18-week study in patients receiving a sulfonylurea antidiabetic agent (sulfonylurea not specified), add-on therapy with linagliptin resulted in a reduction of 0.5% in HbA_1c compared with a reduction of 0.1% in patients receiving add-on placebo.

In a 24-week study in patients receiving metformin and a sulfonylurea (generally glimepiride, glyburide [glibenclamide], or gliclazide [not commercially available in the US]), add-on therapy with linagliptin or placebo resulted in a reduction of 0.7 or 0.1%, respectively, in HbA_1c.

Efficacy of linagliptin in combination with insulin in patients with type 2 diabetes mellitus inadequately controlled with insulin (with or without oral antidiabetic agents) is supported by the results of a 24-week randomized, placebo-controlled trial. In this trial, addition of linagliptin (5 mg once daily) to existing stable therapy with insulin resulted in improvements in HbA_1c and fasting plasma glucose concentrations at week 24 compared with addition of placebo. Mean reductions in HbA_1c were 0.6% in patients receiving linagliptin and 0.1% in those receiving placebo.

Dosage and Administration

Administration

When administered as monotherapy, linagliptin may be administered orally once daily without regard to meals. If a dose is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule. If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed. The dose should not be doubled to replace a missed dose.

Dosage

Linagliptin Monotherapy

When used as monotherapy for the management of type 2 diabetes mellitus, the recommended dosage of linagliptin is 5 mg once daily.

Combination Therapy with a Sulfonylurea

When used concomitantly with a sulfonylurea for the management of type 2 diabetes mellitus, the recommended dosage of linagliptin is 5 mg once daily; dosage of the sulfonylurea may need to be reduced to decrease risk of hypoglycemia.

Special Populations

Dosage adjustment is not routinely required based on age or renal or hepatic impairment.

Cautions

Contraindications

Linagliptin is contraindicated in patients with a history of hypersensitivity reaction (e.g., urticaria, angioedema, bronchial hyperreactivity) to linagliptin.

Warnings/Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal pancreatitis, has been reported during postmarketing experience in patients receiving linagliptin therapy. FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cell changes (pancreatic duct metaplasia) in patients with type 2 diabetes mellitus receiving incretin mimetics (alogliptin, exenatide, linagliptin, liraglutide, saxagliptin, and sitagliptin). These findings are based on examination of a small number of pancreatic tissue specimens taken from patients who died from unspecified causes while receiving an incretin mimetic. FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete, or when the agency has additional information to report.

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics. The manufacturer states that patients receiving linagliptin therapy should be monitored for signs and symptoms of pancreatitis.(See Advice to Patients.) If pancreatitis is suspected, linagliptin should be promptly discontinued and appropriate management instituted. Safety and efficacy of linagliptin have not been established in patients with a history of pancreatitis and it is not known whether such patients are at increased risk for pancreatitis with linagliptin therapy.

Severe Arthralgia

Severe, disabling joint pain has been reported during postmarketing experience in patients receiving DPP-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin). Onset of such symptoms has ranged from 1 day to years following initiation of therapy. Fever, chills, rash, and swelling accompanied joint pain in some patients, suggesting an immunologic reaction; some patients required hospitalization. Symptoms resolved upon discontinuance of the DPP-4 inhibitor, usually in less than a month. In some patients, symptoms recurred when the same or another DPP-4 inhibitor was restarted. DPP-4 inhibitors should be considered as a possible cause of severe joint pain and should be discontinued if appropriate.(See Advice to Patients.)

Concomitant Therapy with Hypoglycemic Agents

Use of linagliptin in combination with an insulin secretagogue (e.g., a sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. Use of linagliptin in combination with insulin in patients with severe renal impairment also was associated with a higher rate of hypoglycemia compared with placebo in another clinical trial. A reduced dosage of an insulin secretagogue or insulin may be required to decrease the risk of hypoglycemia when used in combination with linagliptin.

Macrovascular Outcomes

Evidence of macrovascular risk reduction with linagliptin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.

Specific Populations

Pregnancy

Category B.

Lactation

Linagliptin is distributed into milk in animals at a milk-to-plasma ratio of 4:1; it is not known whether the drug is distributed into human milk. Caution is advised if linagliptin is administered in nursing women.

Pediatric Use

Safety and efficacy have not been established in patients younger than 18 years of age.

Geriatric Use

Of 4040 patients in clinical studies of linagliptin, 27% were 65 years of age and older and 3% were 75 years of age and older. No substantial differences in safety and efficacy relative to younger adults were observed, but increased sensitivity cannot be ruled out.

Hepatic Impairment

In patients with mild hepatic impairment (Child-Pugh class A), linagliptin area under the concentration-time curve (AUC) and peak plasma concentration were reduced by 25 and 36%, respectively, compared with values in healthy individuals. In patients with moderate hepatic impairment (Child-Pugh class B), linagliptin AUC and peak plasma concentration were reduced by 14 and 8%, respectively, compared with values in healthy individuals. In patients with severe hepatic impairment (Child-Pugh class C), linagliptin AUC was comparable to that in healthy individuals, and peak plasma concentration was reduced by 23% relative to that in healthy individuals.

Renal Impairment

In patients with mild renal impairment (creatinine clearance 50 to less than 80 mL/minute), linagliptin exposure was comparable to that in healthy individuals. In patients with moderate renal impairment (creatinine clearance 30 to less than 50 mL/minute), linagliptin AUC and peak plasma concentration were increased by 71 and 46%, respectively, compared with values in healthy individuals. In patients with severe renal impairment (creatinine clearance less than 30 mL/minute) and type 2 diabetes mellitus, linagliptin AUC and peak plasma concentration were increased by 42 and 35%, respectively, compared with those values in patients with type 2 diabetes mellitus and normal renal function.

Common Adverse Effects

Adverse effects reported in at least 5% of patients receiving linagliptin monotherapy include nasopharyngitis.

Adverse effects reported in at least 2% of patients receiving linagliptin concomitantly with pioglitazone, a sulfonylurea, metformin, or basal insulin include nasopharyngitis, hyperlipidemia, cough, hypertriglyceridemia, weight gain, urinary tract infection, constipation, back pain, arthralgia, upper respiratory tract infection, headache, and pain in extremity.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Linagliptin is a weak to moderate inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4; however, it does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 4A11 in vitro.

In vivo studies indicate that drug interactions are unlikely with substrates of CYP isoenzymes 3A4, 2C9, or 2C8. No adjustment of linagliptin dosage is recommended based on results of pharmacokinetic studies.

Inducers of CYP3A4 (e.g., rifampin) decrease exposure to linagliptin, resulting in subtherapeutic and likely ineffective concentrations. The manufacturer states that alternatives to linagliptin are strongly recommended in patients who require therapy with potent CYP3A4 inducers.

Drugs Affecting or Affected by P-glycoprotein Transport

Linagliptin is a P-glycoprotein substrate and inhibits P-glycoprotein-mediated transport of digoxin at high concentrations. At therapeutic concentrations, linagliptin is considered unlikely to cause interactions with other P-glycoprotein substrates; no adjustment of linagliptin dosage is recommended based on results of pharmacokinetic studies.

Inducers of P-glycoprotein (e.g., rifampin) decrease exposure to linagliptin, resulting in subtherapeutic and likely ineffective concentrations. The manufacturer states that alternatives to linagliptin are strongly recommended in patients who require therapy with potent P-glycoprotein inducers.

Drugs Affected by Organic Cation Transporter

In vivo studies indicate that drug interactions are unlikely with substrates of organic cation transporter (OCT). No adjustment of linagliptin dosage is recommended based on results of pharmacokinetic studies.

Digoxin

Concomitant use of linagliptin (5 mg once daily) and digoxin (0.25 mg once daily) in healthy individuals did not appreciably alter the pharmacokinetics of digoxin (e.g., a 2% increase in area under the concentration-time curve [AUC] and a 6% decrease in peak plasma concentration with concomitant use); no digoxin dosage adjustment is necessary.

Estrogens or Progestins

Concomitant use of linagliptin (5 mg once daily) and an estrogen-progestin contraceptive (ethinyl estradiol 30 mcg with levonorgestrel 0.15 mg once daily) increased AUC and peak plasma concentration by 1 and 8%, respectively, for ethinyl estradiol and by 9 and 13%, respectively, for levonorgestrel. No dosage adjustments are necessary for ethinyl estradiol or levonorgestrel when given concomitantly with linagliptin.

Metformin

Concomitant use of linagliptin (10 mg once daily) and metformin hydrochloride (850 mg 3 times daily) in healthy individuals increased linagliptin AUC and peak plasma concentration by 20 and 3%, respectively. Such concomitant use did not affect metformin AUC but reduced metformin peak plasma concentration by 11%. These alterations in pharmacokinetic parameters were not associated with clinically relevant effects (e.g., hypoglycemia), and no dosage adjustments are necessary for either drug.

Pioglitazone

Concomitant use of linagliptin (10 mg once daily) and pioglitazone (45 mg once daily) in healthy individuals increased linagliptin AUC and peak plasma concentration by 13 and 7%, respectively. Pioglitazone AUC and peak plasma concentration were reduced by 6 and 14%, respectively, during concomitant linagliptin therapy; small changes (5% or less) in AUC and peak plasma concentrations of 2 pioglitazone active metabolites also occurred with such concomitant therapy. No dosage adjustments are necessary for either drug when given concomitantly.

Rifampin

Concomitant use of linagliptin (5 mg once daily) and rifampin (600 mg once daily) reduced linagliptin AUC and peak plasma concentration by 40 and 44%, respectively; such concomitant therapy is not recommended.(See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes and see Drugs Affecting P-glycoprotein Transport under Drug Interactions.)

Ritonavir

Administration of a single dose of linagliptin (5 mg) to patients receiving ritonavir (200 mg twice daily) resulted in approximately a twofold increase in linagliptin AUC and approximately a threefold increase in linagliptin peak plasma concentration. The increase in exposure was not associated with an increase in linagliptin accumulation. No adjustment of linagliptin dosage is necessary when linagliptin is administered concurrently with ritonavir.

Simvastatin

Concomitant use of linagliptin (10 mg once daily) and simvastatin (40 mg once daily) in healthy individuals increased simvastatin AUC and peak plasma concentration by 34 and 10%, respectively; these changes were not considered clinically important. No simvastatin dosage adjustment is necessary when given concomitantly with linagliptin.

Sulfonylureas

When a sulfonylurea is administered concomitantly with linagliptin, reduction in the dosage of the sulfonylurea may be required to reduce the risk of hypoglycemia.

A single dose of glyburide (1.75 mg) given on day 6 to healthy individuals receiving linagliptin therapy (5 mg once daily for 6 days) decreased glyburide exposure (AUC and peak plasma concentration) by about 14%; these changes were not considered clinically important. No dosage adjustments are necessary for either drug when given concomitantly.

Warfarin

Administration of a single dose of warfarin sodium (10 mg) to healthy individuals receiving linagliptin (5 mg once daily) had no apparent effect (i.e., change of 3% or less) on R- or S-warfarin AUC and peak plasma concentration and no clinically relevant effect on international normalized ratio (INR) or prothrombin time (PT); no warfarin dosage adjustment is necessary.