Linagliptin

  Monotherapy and Combination Therapy

Linagliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

  Important 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.

Linagliptin is used together with proper diet and exercise to treat high blood sugar levels caused by type 2 diabetes. Normally, after you eat, your pancreas releases insulin to help your body store excess sugar for later use. This process occurs during normal digestion of food. In type 2 diabetes, your body does not work properly to store excess sugar and the sugar remains in your blood. Chronic high blood sugar can lead to serious health problems in the future.

Proper diet is the first step in managing type 2 diabetes, but often medicines are needed to help your body. Linagliptin helps to control blood sugar levels by increasing substances in the body that make the pancreas release more insulin. It also signals the liver to stop producing sugar (glucose) when there is too much sugar in the blood.

Linagliptin does not help patients who have insulin-dependent or type 1 diabetes, because they do not produce insulin from the pancreas. The high blood sugar is best controlled with insulin injections in these patients.

Linagliptin is available only with your doctor's prescription.

Recommended Dosing

The recommended dose of Linagliptin is 5 mg once daily.

Linagliptin tablets can be taken with or without food.

Concomitant Use With An Insulin Secretagogue (e.g., Sulfonylurea) Or With Insulin

When Linagliptin is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.

How supplied

Dosage Forms And Strengths

Linagliptin (Linagliptin) 5 mg tablets are light red, round, biconvex, bevel-edged, film-coated tablets with “D5” debossed on one side and the Boehringer Ingelheim logo debossed on the other side.

Storage And Handling

Linagliptin tablets are available as light red, round, biconvex, bevel-edged, film-coated tablets containing 5 mg of Linagliptin. Linagliptin tablets are debossed with “D5” on one side and the Boehringer Ingelheim logo 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 x 10) (NDC 0597-0140-61), institutional pack.

If repackaging is required, dispense in a tight container as defined in USP.

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Store in a safe place out of reach of children.

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA. Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and Company Indianapolis, IN 46285 USA. Revised: July 2015

See also:
What is the most important information I should know about Linagliptin?

Do not use this medication if you are allergic to Linagliptin or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Before you take Linagliptin, tell your doctor if you have high cholesterol or triglycerides, or a history of pancreatitis.

Stop taking Linagliptin and call your doctor at once if you have severe pain in your upper stomach spreading to your back, nausea and vomiting, loss of appetite, or fast heart rate.

Linagliptin is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office.

Use Linagliptin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Linagliptin. Talk to your pharmacist if you have questions about this information.
• Take Linagliptin by mouth with or without food.
• Take Linagliptin on a regular schedule to get the most benefit from it.
• Continue to take Linagliptin even if you feel well. Do not miss any doses.
• If you miss a dose of Linagliptin, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Linagliptin.

Linagliptin is used alone or in combination with other drugs to treat type 2 diabetes mellitus.

See also:
What other drugs will affect Linagliptin?

In vitro Assessment of Drug Interactions: Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes.

Linagliptin is a P-gp substrate, and inhibits P-gp mediated transport of digoxin with low potency. Based on these results and in vivo drug interaction studies, Linagliptin is considered unlikely to cause interactions with other P-gp substrates.

In vivo Assessment of Drug Interactions: Clinical data described as follows suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low. No clinically significant interactions requiring dose adjustment were observed. Linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin or oral contraceptives providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).

Metformin: Co-administration of multiple 3-times-daily doses of metformin 850 mg with a supratherapeutic dose of Linagliptin 10 mg once daily did not clinical meaningfully alter the pharmacokinetics of Linagliptin or metformin in healthy volunteers. Therefore, Linagliptin is not an inhibitor of OCT-mediated transport.

Sulfonylureas: The steady-state pharmacokinetics of Linagliptin 5 mg were not changed by co-administration of a single 1.75-mg glibenclamide (glyburide) dose and multiple oral doses of Linagliptin 5 mg. However, there was a clinically not relevant reduction of 14% of both AUC and C_max of glibenclamide. Because glibenclamide is primarily metabolized by CYP2C9, these data also support the conclusion that Linagliptin is not a CYP2C9 inhibitor. Clinically meaningful interactions would not be expected with other sulfonylureas (eg, glipizide, tolbutamide and glimepiride) which, like glibenclamide, are primarily eliminated by CYP2C9.

Thiazolidinediones: Co-administration of multiple daily doses of Linagliptin 10 mg (supratherapeutic) with multiple daily doses of pioglitazone 45 mg, a CYP2C8 and CYP3A4 substrate, had no clinically relevant effect on the pharmacokinetics of either Linagliptin or pioglitazone or the active metabolites of pioglitazone, indicating that Linagliptin is not an inhibitor of CYP2C8-mediated metabolism in vivo and supporting the conclusion that the in vivo inhibition of CYP3A4 by Linagliptin is negligible.

Ritonavir: A study was conducted to assess the effect of ritonavir, a potent inhibitor of P-gp and CYP3A4, on the pharmacokinetics of Linagliptin. Co-administration of a single 5-mg oral dose of Linagliptin and multiple 200-mg oral doses of ritonavir increased the AUC and C_max of Linagliptin approximately 2-fold and 3-fold, respectively. Simulations of steady-state plasma concentrations of Linagliptin with and without ritonavir indicated that the increase in exposure will be not associated with an increased accumulation. These changes in Linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore, clinically relevant interactions would not be expected with other P-gp/CYP3A4 inhibitors and dose adjustment is not required.

Rifampicin: A study was conducted to assess the effect of rifampicin, a potent inductor of P-gp and CYP3A4, on the pharmacokinetics of Linagliptin 5 mg. Multiple co-administration of Linagliptin with rifampicin, resulted in a 39.6% and 43.8% decreased Linagliptin steady-state AUC and C_max and about 30% decreased DPP-4 inhibition at trough. Thus, Linagliptin in combination with strong P-gp inducers is expected to be clinically efficacious, although full efficacy might not be achieved.

Digoxin: Co-administration of multiple daily doses of Linagliptin 5 mg with multiple doses of digoxin 0.25 mg had no effect on the pharmacokinetics of digoxin in healthy volunteers. Therefore, Linagliptin is not an inhibitor of P-gp-mediated transport in vivo.

Warfarin: Multiple daily doses of Linagliptin 5 mg did not alter the pharmacokinetics of S(-) or R(+) warfarin, a CYP2C9 substrate, showing that Linagliptin is not an inhibitor of CYP2C9.

Simvastatin: Multiple daily doses of Linagliptin 10 mg (supratherapeutic) had a minimal effect on the steady-state pharmacokinetics of simvastatin, a sensitive CYP3A4 substrate, in healthy volunteers. Following administration of Linagliptin 10 mg concomitantly with simvastatin 40 mg daily for 6 days, the plasma AUC of simvastatin was increased by 34%, and the plasma C_max by 10%. Therefore, Linagliptin is considered to be a weak inhibitor of CYP3A4-mediated metabolism, and dosage adjustment of concomitantly administered substances metabolized by CYP3A4 is considered unnecessary.

Oral Contraceptives:

The absolute bioavailability of Linagliptin is approximately 30%. Because co-administration of a high-fat meal with Linagliptin had no clinically relevant effect on the pharmacokinetics, Linagliptin may be administered with or without food.

See also:
What are the possible side effects of Linagliptin?

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

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.

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%).

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. 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

In the placebo-controlled studies, 199 (6.6%) of the total 2994 patients treated with Linagliptin 5 mg reported hypoglycemia compared to 56 patients (3.6%) of 1546 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when Linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When Linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia.

In the study of patients receiving Linagliptin as add-on therapy to a stable dose of insulin for up to 52 weeks (n=1261), no significant difference in the incidence of investigator reported hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self-measured blood glucose ≤ 70 mg/dL, was noted between the Linagliptin-(31.4%) and placebo-(32.9%) treated groups. During the same time period, severe hypoglycemic events, defined as requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 11 (1.7%) of Linagliptin treated patients and 7 (1.1%) of placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 3 (0.5%) patients on Linagliptin and 1 (0.2%) on placebo.

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. 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).

No clinically meaningful changes in vital signs were observed in patients treated with Linagliptin.

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
• Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
• Rash
• Mouth ulceration, stomatitis

Linagliptin is a DPP-4 inhibitor developed by Boehringer Ingelheim for the treatment of type II diabetes [Wikipedia]. Two pharmacological characteristics that sets Linagliptin apart from other DPP-4 inhibitors is that it has a non-linear pharmacokinetic profile and is not primarily eliminated by the renal system. FDA approved on May 2, 2011.