Linagliptin: uses, appearance and warnings

TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . TRADJENTA 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 Not recommended in patients with type 1 diabetes mellitus as it would not be effective ( 1 ) Has not been studied in patients with a history of pancreatitis ( 1 ) Limitations of Use TRADJENTA is not recommended in patients with type 1 diabetes mellitus as it would not be effective. TRADJENTA 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 TRADJENTA [see Warnings and Precautions (5.1) ].

Tablets: 5 mg, light red, round, biconvex, bevel-edged, film-coated tablets with "D5" debossed on one side and the Boehringer Ingelheim symbol debossed on the other side. Tablets: 5 mg ( 3 )

TRADJENTA tablets are available as light red, round, biconvex, bevel-edged, film-coated tablets containing 5 mg of linagliptin. TRADJENTA tablets are debossed with "D5" on one side and the Boehringer Ingelheim symbol on the other side. They are supplied as follows: Bottles of 30 (NDC 0597-0140-30) Bottles of 90 (NDC 0597-0140-90) Cartons containing 10 blister cards of 10 tablets each (10 × 10) (NDC 0597-0140-61), institutional pack. If repackaging is required, dispense in a tight container as defined in USP. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

TRADJENTA is contraindicated in patients with hypersensitivity to linagliptin or any of the excipients in TRADJENTA, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.3) and Adverse Reactions (6) ]. Hypersensitivity to linagliptin or any of the excipients in TRADJENTA ( 4 , 5.3 )

Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA. ( 5.1 ) Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating TRADJENTA ( 5.2 ) Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with TRADJENTA. If hypersensitivity reactions occur, discontinue TRADJENTA, treat promptly, and monitor until signs and symptoms resolve. ( 5.3 ) Arthralgia: Severe and disabling arthralgia has been reported in patients taking TRADJENTA. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.4 ) Bullous pemphigoid: There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue TRADJENTA. ( 5.5 ) Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of TRADJENTA in patients who have known risk factors for heart failure. Monitor for signs and symptoms. ( 5.6 ) 5.1 Pancreatitis Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with TRADJENTA. In the CARMELINA trial [see Clinical Studies (14.2) ] , acute pancreatitis was reported in 9 (0.3%) patients treated with TRADJENTA and in 5 (0.1%) patients treated with placebo. Two patients treated with TRADJENTA in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with TRADJENTA. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using TRADJENTA. 5.2 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when TRADJENTA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1) ] . The use of TRADJENTA in combination with insulin in subjects with severe renal impairment was associated with a higher rate of hypoglycemia [see Adverse Reactions (6.1) ] . Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. 5.3 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with TRADJENTA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with TRADJENTA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue TRADJENTA, assess for other potential causes for the event, and institute alternative treatment for diabetes mellitus. Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with TRADJENTA. 5.4 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking TRADJENTA [see Adverse Reactions (6) ] . The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider the drug as a possible cause for severe joint pain and discontinue drug if appropriate. 5.5 Bullous Pemphigoid Bullous pemphigoid was reported in 7 (0.2%) patients treated with TRADJENTA compared to none in patients treated with placebo in the CARMELINA trial [see Clinical Studies (14.2) ] , and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving TRADJENTA. If bullous pemphigoid is suspected, TRADJENTA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment. 5.6 Heart Failure An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the risks and benefits of TRADJENTA prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of TRADJENTA.

The following serious adverse reactions are described below or elsewhere in the prescribing information: Pancreatitis [see Warnings and Precautions (5.1) ] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.4) ] Bullous Pemphigoid [see Warnings and Precautions (5.5) ] Heart Failure [see Warnings and Precautions (5.6) ] Most common adverse reaction (incidence ≥5% and more often than placebo) was nasopharyngitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . …

Strong P-glycoprotein/CYP3A4 inducer: The efficacy of TRADJENTA 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 TRADJENTA 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 Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when linagliptin is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. …