LINAGLIPTIN

Linagliptin tablets contain, as the active ingredient, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Linagliptin is described chemically as 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]- The empirical formula is C 25 H 28 N 8 O 2 and the molecular weight is 472.54 g/mol. The structural formula is: Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1 mg/mL), and very slightly soluble in acetone (ca. 1 mg/mL). Each film-coated tablet of linagliptin contains 5 mg of linagliptin free base and the following inactive ingredients: mannitol, pregelatinized starch, copovidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide and polyethylene glycol. Linagliptin structure

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1 ) Limitations of Use Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis ( 1 ) Has not been studied in patients with a history of pancreatitis ( 1 ) Linagliptin tablet is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14.1) ] . Limitations of Use Linagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. Linagliptin has 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 [see Warnings and Precautions (5.1) ].

The recommended dose of linagliptin is 5 mg once daily (2.1) Linagliptin can be taken with or without food (2.1) 2.1 Recommended Dosing The recommended dose of linagliptin is 5 mg once daily. Linagliptin tablets can be taken with or without food.

Linagliptin is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial Linagliptin is contraindicated in patients with hypersensitivity to linagliptin or any of the excipients in linagliptin tablets, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.4) and Adverse Reactions (6) ] . Hypersensitivity to linagliptin or any of the excipients in linagliptin tablets. ( 4 , 5.4 )

The following serious adverse reactions are described below or elsewhere in the prescribing information: Pancreatitis [see Warnings and Precautions (5.1) ] Heart Failure [see Warnings and Precautions (5.2) ] Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.5) ] Bullous Pemphigoid [see Warnings and Precautions (5.6) ] Adverse reactions reported in ≥5% of patients treated with linagliptin and more commonly than in patients treated with placebo included nasopharyngitis (6.1) To report SUSPECTED ADVERSE REACTIONS, contact HEC Pharm USA Inc. at 1-267-348-3664 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. The safety evaluation of linagliptin 5 mg once daily in patients with type 2 diabetes is based on 14 placebo-controlled trials, 1 active-controlled study, and one study in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated with linagliptin 5 mg daily and 2176 with placebo. The mean exposure in patients treated with linagliptin across studies was 29.6 weeks. The maximum follow-up was 78 weeks. Linagliptin 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks’ duration and in five additional placebo-controlled studies lasting ≤18 weeks. The use of linagliptin in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); one with pioglitazone (24 weeks’ treatment duration); and one with insulin (primary endpoint at 24 weeks). In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of patients receiving linagliptin (n = 3625) and more commonly than in patients given placebo (n = 2176), are shown in Table 1. The overall incidence of adverse events with linagliptin were similar to placebo. Table 1 Adverse Reactions Reported in ≥2% of Patients Treated with Linagliptin and Greater than Placebo in Placebo-Controlled Clinical Studies of Linagliptin Monotherapy or Combination Therapy Number (%) of Patients Linagliptin 5 mg n = 3625 Placebo n = 2176 Nasopharyngitis 254 (7.0) 132 (6.1) Diarrhea 119 (3.3) 65 (3.0) Cough 76 (2.1) 30 (1.4) Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when linagliptin was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal insulin therapy. Other adverse reactions reported in clinical studies with treatment of linagliptin were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia. Following 104 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%). In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Hypoglycemia Table 2 summarizes the incidence of hypoglycemia in placebo-controlled studies of linagliptin. The incidence of hypoglycemia increased when linagliptin was administered with sulfonylurea or insulin. Table 2: Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of Linagliptin in Patients with Type 2 Diabetes Mellitus *Hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Add-on to Sulfonylurea (18 Weeks) Placebo (N=84) Linagliptin (N=161) Hypoglycemia with plasma glucose <54 mg/dL 1.2% 1.9% Severe* hypoglycemia (%) 0% 0% Add-on to Metformin and Sulfonylurea (24 Weeks) Placebo (N=263) Linagliptin (N=792) Hypoglycemia with plasma glucose <54 mg/dL 5.3% 8.1% Severe* hypoglycemia (%) 0.8% 0.6% Add-on to Basal Insulin (52 Weeks) Placebo (N=630) Linagliptin (N=631) Hypoglycemia with plasma glucose <54 mg/dL 21.6% 19.8% Severe* hypoglycemia (%) 1.1% 1.7% Use in Renal Impairment Linagliptin was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other linagliptin trials. The observed incidence of hypoglycemia was higher (linagliptin, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten linagliptin-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) linagliptin-treated patients and 3 (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on linagliptin and 1 (1.5%) patient on placebo. Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks' treatment compared to placebo. Laboratory Tests Changes in laboratory findings were similar in patients treated with linagliptin 5 mg compared to patients treated with placebo. Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and > 1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group). Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively. The clinical significance of elevations in lipase with linagliptin is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (5.1) ]. Vital Signs No clinically meaningful changes in vital signs were observed in patients treated with linagliptin. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of linagliptin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1) ] Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions Severe and disabling arthralgia Bullous pemphigoid Rash Mouth ulceration, stomatitis Rhabdomyolysis

Strong P-glycoprotein/CYP3A4 inducer: The efficacy of linagliptin may be reduced when administered in combination (e.g., with rifampin). Use of alternative treatments is strongly recommended. (7.1) 7.1 Inducers of P-glycoprotein or CYP3A4 Enzymes Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer [see Clinical Pharmacology (12.3) ] . 7.2 Insulin Secretagogues or Insulin Coadministration of linagliptin with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3) ] .