Linagliptin/Metformin

Linagliptin/Metformin is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus when treatment with both Linagliptin/Metformin is appropriate, in patients inadequately controlled on metformin alone or those already being treated and well controlled with the free combination of Linagliptin/Metformin.

Linagliptin/Metformin is indicated in combination with a sulphonylurea (ie, triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea.

Linagliptin/Metformin is indicated as add-on to insulin (ie, triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when insulin and metformin alone do not provide adequate glycaemic control.

Limitation of Use: Linagliptin/Metformin must not be used in patients with type 1 diabetes or ketoacidosis due to no clinical effects.

Clinical experience of the use of Linagliptin/Metformin in patients with pancreatitis history is limited. There is no information if patients-risk from pancretitis will be increased by the drug. Therefore, Linagliptin/Metformin should be used in these patients only when necessary and pancreatitis monitoring is required.

Linagliptin/Metformin combination is used 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 the excess sugar and the sugar remains in your blood. Chronic high blood sugar can lead to serious health problems in the future.

Many people can control type 2 diabetes with diet alone or diet and exercise. Following a specially planned diet and exercising will always be important when you have diabetes, even when you are taking medicines. To work properly, the amount of Linagliptin/Metformin combination you take must be balanced against the amount and type of food you eat and the amount of exercise you do. If you change your diet, your exercise, or both, you will want to test your blood sugar to find out if it is too low. Your doctor will teach you what to do if this happens.

Linagliptin/Metformin combination does not help patients who have insulin-dependent or type 1 diabetes, because they cannot produce insulin from their pancreas. Their blood glucose is best controlled by insulin injections.

Linagliptin/Metformin is available only with your doctor's prescription.

Recommended Dosing

The dosage of Linagliptin/Metformin should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended total daily dose of Linagliptin/Metformin 5 mg and metformin hydrochloride 2000 mg. Linagliptin/Metformin should be given once daily with a meal. For available dosage forms and strengths see [Dosage Forms and Strengths (3)].

Recommended starting dose:

• In patients currently not treated with metformin, initiate Linagliptin/Metformin treatment with 5 mg Linagliptin/Metformin/1000 mg metformin hydrochloride extended-release once daily with a meal.
• In patients already treated with metformin, start Linagliptin/Metformin with 5 mg of Linagliptin/Metformin total daily dose and a similar total daily dose of metformin once daily with a meal.
• In patients already treated with Linagliptin/Metformin or Linagliptin/Metformin, switch to Linagliptin/Metformin containing 5 mg of Linagliptin/Metformin total daily dose and a similar total daily dose of metformin once daily with a meal.

Linagliptin/Metformin should be swallowed whole. The tablets must not be split, crushed, dissolved, or chewed before swallowing. There have been reports of incompletely dissolved tablets being eliminated in the feces for other tablets containing metformin extended-release. If a patient reports seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control.

Linagliptin/Metformin 5 mg Linagliptin/Metformin/1000 mg metformin hydrochloride extended-release tablet should be taken as a single tablet once daily. Patients using 2.5 mg Linagliptin/Metformin/1000 mg metformin extended-release tablets should take two tablets together once daily.

No studies have been performed specifically examining the safety and efficacy of Linagliptin/Metformin in patients previously treated with other oral antihyperglycemic agents and switched to Linagliptin/Metformin. Any change in therapy of type 2 diabetes mellitus should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Recommended Dosing in Renal Impairment

Assess renal function prior to initiation of Linagliptin/Metformin and periodically thereafter.

Linagliptin/Metformin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.

Initiation of Linagliptin/Metformin in patients with an eGFR between 30-45 mL/min/1.73 m2 is not recommended.

In patients taking Linagliptin/Metformin whose eGFR later falls below 45 mL/min/1.73 m2, assess benefit risk of continuing therapy.

Discontinue Linagliptin/Metformin if the patient’s eGFR later falls below 30 mL/min/1.73 m2.

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue Linagliptin/Metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Linagliptin/Metformin if renal function is stable.

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

Linagliptin/Metformin is contraindicated in patients with:

• Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin
• A history of hypersensitivity reaction to Linagliptin/Metformin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity
• Hypersensitivity to metformin

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

• Linagliptin/Metformin comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Linagliptin/Metformin refilled.
• Take Linagliptin/Metformin by mouth with meals as directed by your doctor.
• Take Linagliptin/Metformin on a regular schedule to get the most benefit from it.
• Continue to take Linagliptin/Metformin even if you feel well. Do not miss any doses.
• If you miss a dose of Linagliptin/Metformin, 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/Metformin.

Use: Labeled Indications

Diabetes mellitus type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both Linagliptin/Metformin is appropriate.

See also:
What other drugs will affect Linagliptin/Metformin?

Drug Interactions With Metformin

Carbonic Anhydrase Inhibitors

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/Metformin, may increase the risk of lactic acidosis. Consider more frequent monitoring of these patients.

Drugs That Reduce Metformin Clearance

Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine) have the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the accumulation of metformin and the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving Linagliptin/Metformin.

Drug Interactions With Linagliptin/Metformin

Inducers Of P-glycoprotein And CYP3A4 Enzymes

Rifampin decreased Linagliptin/Metformin exposure, suggesting that the efficacy of Linagliptin/Metformin may be reduced when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As Linagliptin/Metformin is a fixed-dose combination of Linagliptin/Metformin, use of alternative treatments (not containing Linagliptin/Metformin) is strongly recommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary.

Insulin Secretagogues Or Insulin

Coadministration of Linagliptin/Metformin 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.

Drugs Affecting Glycemic Control

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Linagliptin/Metformin, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving Linagliptin/Metformin, the patient should be observed closely for hypoglycemia.

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

Summary of the Safety Profile: Fixed Dose Combination: The most frequently reported adverse reaction for Linagliptin/Metformin plus metformin was diarrhoea (0.9%) with a comparable rate on metformin plus placebo (1.2%).

Hypoglycaemia may occur when Linagliptin/Metformin is administered together with sulphonylurea (≥1 case per 10 patients).

The safety of Linagliptin/Metformin 2.5 mg twice daily (or its bioequivalent of 5 mg once daily) in combination with metformin has been evaluated in over 3500 patients with type 2 diabetes mellitus. In placebo-controlled studies, more than 1300 patients were treated with the therapeutic dose of either 2.5 mg Linagliptin/Metformin twice daily (or its bioequivalent of 5 mg Linagliptin/Metformin once daily) in combination with metformin for ≥12/24 weeks.

In the pooled analysis of the four placebo-controlled trials, the overall incidence of adverse reactions in patients treated with placebo and metformin was comparable to that seen with Linagliptin/Metformin 2.5 mg and metformin (50.6 and 47.8%). Discontinuation of therapy due to adverse reactions was comparable in patients who received placebo and metformin to patients treated with Linagliptin/Metformin (2.6% and 2.3%).

Adverse Reactions Reported When Linagliptin/Metformin were Combined with Sulphonylurea: In one study Linagliptin/Metformin was given as add-on to metformin plus sulphonylurea. When Linagliptin/Metformin were administered in combination with a sulphonylurea, hypoglycaemia was the most frequently reported adverse reaction (Linagliptin/Metformin plus metformin plus sulphonylurea 22.9% versus 14.8% in placebo plus metformin plus sulphonylurea).

Adverse Reactions Reported When Linagliptin/Metformin were Combined with Insulin: When Linagliptin/Metformin were administrated in combination with insulin, hypoglycaemia was the most frequently reported adverse reactions, but occurred at comparable rate when placebo and metformin were combined with insulin (Linagliptin/Metformin plus metformin plus insulin 29.5% versus 30.9% in the placebo plus metformin plus insulin group) with a low rate of severe episodes (1.5% versus 0.9%).

Tabulated List of Adverse Reactions: Adverse Reactions Reported with the Fixed Dose Combination: Adverse reactions reported in all clinical trials with Linagliptin/Metformin are shown as follows according to system organ class. Adverse reactions known to occur with each active substance given singly, but which have not been seen in clinical trials with Linagliptin/Metformin, may occur during treatment with this medicinal product.

The adverse reactions are listed by system organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), or very rare (<1/10,000) and not known (cannot be estimated from the available data)..

Adverse Reactions Reported When Linagliptin/Metformin were Combined with Sulphonylurea: When Linagliptin/Metformin were administered in combination with a sulphonylurea, hypoglycaemia was identified as an additional adverse reaction under these conditions..

None of the hypoglycaemias was classified as severe.

Adverse Reactions Reported When Linagliptin/Metformin were Combined with Insulin: When Linagliptin/Metformin were administered in combination with insulin, constipation was identified as an additional adverse reaction under these conditions. The combination of Linagliptin/Metformin when administered in combination with insulin may be associated with an increased risk of hepatic events..

Additional Information on Individual Components: Adverse reactions previously reported with one of the individual active substances may be potential adverse reactions with Linagliptin/Metformin, even if not observed in clinical trials with this medicinal product.

Metformin: Known adverse reactions for metformin, that were not reported in patients who received Linagliptin/Metformin are listed in Table 5..

Description of Selected Adverse Reactions: Gastrointestinal disorders such as, nausea, vomiting, diarrhoea and decreased appetite (Table 2) and abdominal pain (Table 5) occur most frequently during initiation of therapy with Linagliptin/Metformin or metformin hydrochloride and resolve spontaneously in most cases. For prevention, it is recommended that Linagliptin/Metformin be taken in 2 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption (Table 5) which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia).

Each tablet contains 2.5 mg of Linagliptin/Metformin and 500 mg, 850 mg or 1000 mg of metformin hydrochloride.

Excipients/Inactive Ingredients: Tablet Core: Arginine, copovidone, magnesium stearate, maize starch, silica, colloidal anhydrous.

Film Coating: Hypromellose, titanium dioxide (E171), talc, propylene glycol.

Linagliptin/Metformin 2.5mg/500mg: Iron oxide, yellow (E172).

Linagliptin/Metformin 2.5mg/850mg: Iron oxide, yellow (E172), iron oxide, red (E172).

Linagliptin/Metformin 2.5mg/1000mg: Iron oxide, red (E172).