Linagliptin / Metformin

Pronunciation: LIN-a-GLIP-tin/met-FOR-min
Class: Antidiabetic combination

Trade Names

Jentadueto
- Tablets, oral linagliptin 2.5 mg/metformin hydrochloride 500 mg
- Tablets, oral linagliptin 2.5 mg/metformin hydrochloride 850 mg
- Tablets, oral linagliptin 2.5 mg/metformin hydrochloride 1,000 mg

Pharmacology

Linagliptin

Increases concentrations of active incretin hormones, stimulating the release of insulin and decreasing levels of glucagon in the circulation.

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Metformin

Decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Indications and Usage

Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with both linagliptin and metformin is appropriate.

Contraindications

Renal impairment (eg, serum creatinine levels at least 1.5 mg/dL [men] and at least 1.4 mg/dL [women], abnormal CrCl); acute or chronic metabolic acidosis, including diabetic ketoacidosis; hypersensitivity to linagliptin, metformin, or any component of the product.

Dosage and Administration

Base dosage selection of linagliptin/metformin on the patient's current dose of these agents (max, linagliptin 5 mg/metformin 2,000 mg daily).

Patients currently on metformin
Adults

PO Start with linagliptin 2.5 mg twice daily plus the current dose of metformin. For patients taking metformin 1,000 mg twice daily, the recommended starting dosage is linagliptin 2.5 mg/metformin 1,000 mg twice daily.

Patients not on metformin
Adults

PO Start with linagliptin 2.5 mg/metformin 500 mg twice daily. Dose escalation should be gradual to reduce GI adverse effects associated with metformin.

General Advice

  • Administer twice daily with meals.
  • Individualize the dose based on effectiveness and tolerability.
  • When used in combination with an insulin secretagogue (eg, sulfonylurea), a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia.
  • Do not initiate in any patient unless measurement of CrCl demonstrates that renal function is not reduced.

Storage/Stability

Store between 59°and 86°F. Protect from exposure to high humidity.

Drug Interactions

Alcohol

Alcohol potentiates the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake, short or long term, while receiving metformin.

Carbonic anhydrase inhibitors (eg, acetazolamide, topiramate, zonisamide)

Concomitant use may induce metabolic acidosis. Use with caution because the risk of lactic acidosis may increase.

Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin)

Theoretically, cationic drugs that are eliminated by renal tubular secretion have the potential for interaction with metformin by competing for common renal tubular transport systems. Monitor carefully and adjust the metformin dose and/or the interfering drug dose.

Cimetidine

Coadministration increased metformin C max and AUC. Use with caution. Monitor renal function. Adjust metformin dosage as needed.

CYP3A4 strong inducers (eg, rifampin), P-glycoprotein strong inducers (eg, rifampin)

Linagliptin exposure may be reduced, decreasing the therapeutic effect. Alternative therapy to linagliptin is recommended.

Drugs that produce hyperglycemia (eg, calcium channel blockers [eg, amlodipine], corticosteroids [eg, prednisone], estrogens [eg, estradiol], hormonal contraceptives, isoniazid, nicotinic acid, phenothiazines [eg, thioridazine], phenytoin, sympathomimetics [eg, salmeterol], thiazides and other diuretics [eg, hydrochlorothiazide], thyroid products)

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Monitor closely.

Iodinated contrast material

Parenteral contrast studies with iodinated materials can lead to acute renal failure and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, temporarily discontinue metformin at the time of or prior to the procedure and withhold for 48 hours subsequent to the procedure; reinstitute only after renal function has been reevaluated and found to be healthy.

Ritonavir

Coadministration may increase plasma linagliptin C max and AUC. Dosage adjustment of linagliptin is not required.

Sulfonylureas (eg, glyburide)

The risk of hypoglycemia may be increased. Monitor blood glucose and adjust the sulfonylurea dose as needed.

Adverse Reactions

The following adverse reactions were reported with linagliptin/metformin combination therapy.

EENT

Nasopharyngitis (6%).

GI

Diarrhea (6%); nausea, vomiting.

Hypersensitivity

Hypersensitivity (eg, angioedema, bronchial hyperactivity, urticaria).

Metabolic-Nutritional

Decreased appetite.

Respiratory

Cough.

Miscellaneous

Pancreatitis, pruritus.

Precautions

Warnings

Lactic acidosis is a rare, but serious, complication that can occur because of metformin accumulation. The risk increases with conditions such as dehydration, excess alcohol intake, hepatic and renal impairment, sepsis, and acute CHF. The onset is often subtle and accompanied only by nonspecific symptoms, such as increasing somnolence, malaise, myalgias, nonspecific abdominal distress, and respiratory distress. Abnormal laboratory findings include elevated blood lactate, increased anion gap, and low pH. If acidosis is suspected, discontinue the drug and hospitalize the patient immediately.


Monitor

Measure blood glucose and glycosylated hemoglobin (HbA 1c ) levels periodically; monitor hematologic parameters and renal function initially and at least annually thereafter. For patients in whom development of renal impairment is anticipated (eg, elderly patients), assess renal function more frequently. Measure serum vitamin B 12 levels at 2- to 3-y intervals in patients predisposed to developing subnormal vitamin B 12 levels.


Pregnancy

Category B .

Lactation

Metformin is excreted in human milk; undetermined for linagliptin.

Children

Safety and efficacy are not established.

Elderly

Use with caution because of possible age-related reduction in renal function.

Renal Function

Contraindicated in patients with renal dysfunction. Metformin accumulation and lactic acidosis risk increase with the degree of renal impairment.

Hepatic Function

Avoid metformin in patients with clinical or laboratory evidence of hepatic disease.

Special Risk Patients

Debilitated, malnourished, or elderly patients, and patients with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in elderly patients, and in people who are taking beta-blocking agents.

Hypoxic states

Immediately discontinue therapy in any condition characterized by hypoxemia (eg, acute CHF, MI).

Surgical patients

Temporarily suspend treatment for any surgical procedure, except procedures not associated with restricted intake of food and fluids, and do not restart treatment until oral intake has resumed and renal function has been evaluated as healthy.

Vitamin B 12 levels

Metformin may decrease vitamin B 12 levels.

Overdosage

Symptoms

Linagliptin

No data reported.

Metformin

Hypoglycemia, lactic acidosis.

Patient Information

  • Advise patients to take prescribed dose with meals.
  • Counsel patients against excessive alcohol intake, either short or long term.
  • Instruct patients to take the medication only as prescribed. If a dose is missed, advise patients not to double their next dose.
  • Educate patients, families, or caregivers about symptoms of lactic acidosis. Advise patients to discontinue the drug immediately and promptly notify their health care provider if unexplained hyperventilation, malaise, unusual somnolence, slow or irregular heartbeat, sensation of feeling cold (especially in extremities), or other nonspecific symptoms occur.
  • Educate patients, families, or caregivers regarding type 2 diabetes and its management.
  • Instruct patients that this drug is not a substitute for diet and exercise, and to follow prescribed regimens.
  • Emphasize the importance of regular daily blood glucose monitoring and periodic HbA 1c tests.
  • Advise patients to seek medical advice promptly during periods of stress, such as fever, trauma, infection, or surgery, because medication requirements may change.
  • Review symptoms of hypoglycemia and hyperglycemia, and action plans to undertake in the event either occurs.
  • Inform patients that the risk of hypoglycemia is increased when linagliptin/metformin is used in combination with an insulin secretagogue (eg, sulfonylurea) and that a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia.
  • Inform patients that GI symptoms are common during initiation of therapy with metformin and may occur; however, advise patients to consult their health care provider if they develop unexplained GI symptoms.

Copyright © 2009 Wolters Kluwer Health.

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