Saxagliptin / Metformin Hydrochloride

Pronunciation: SAX-a-GLIP-tin/met-FOR-min HYE-droe-KLOR-ide
Class: Antidiabetic combination

Trade Names

Kombiglyze XR
- Tablets, ER, oral saxagliptin 5 mg/metformin hydrochloride ER 500 mg
- Tablets, ER, oral saxagliptin 5 mg/metformin hydrochloride ER 1,000 mg
- Tablets, ER, oral saxagliptin 2.5 mg/metformin hydrochloride ER 1,000 mg

Pharmacology

Saxagliptin

Competitive dipeptidyl peptidase-4 (DPP4) inhibitor that slows the inactivation of incretin hormones, thereby reducing fasting and postprandial glucose concentrations.

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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 saxagliptin and metformin is appropriate.

Contraindications

Renal impairment (eg, serum creatinine levels of 1.5 mg/dL or higher in men or 1.4 mg/dL or higher in women, abnormal CrCl); acute or chronic metabolic acidosis, including diabetic ketoacidosis; hypersensitivity to any component of the product.

Dosage and Administration

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

Patients Currently on Metformin
Adults

PO The dose of saxagliptin/metformin ER should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose.

Patients Requiring Saxagliptin 5 mg Who Are Not Currently Treated With Metformin
Adults

PO Start with saxagliptin 5 mg/metformin ER 500 mg once daily. Gradually escalate dose to reduce the GI adverse effects of metformin.

Patients Requiring Saxagliptin 2.5 mg in Combination With Metformin
Adults

PO Saxagliptin 2.5 mg/metformin ER 1,000 mg once daily. Patients who need saxagliptin 2.5 mg who are either metformin-naive or who require a dose of metformin higher than 1,000 mg should use the individual components.

Elderly

Use conservative initial and maintenance dosing of metformin.

CYP3A4/5 strong inhibitor coadministration

When coadministered with strong CYP3A4/5 inhibitors, limit the dosage to saxagliptin 2.5 mg/metformin ER 1,000 mg once daily.

General Advice

  • In general, administer once daily with the evening meal. Tablets should be swallowed whole and never crushed, cut, or chewed.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Alcohol

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

Aluminum hydroxide/magnesium hydroxide/simethicone

Coadministration may decrease the C max of saxagliptin but not alter the AUC. No dosage adjustment is required.

Antidiabetic agents (eg, sulfonylureas)

The risk of hypoglycemia may be increased when used with other antidiabetic agents. A lower dose of the antidiabetic agent may be needed.

Cationic drugs (eg, amiloride, cimetidine, 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. Careful patient monitoring and dose adjustment of saxagliptin/metformin and/or the interfering drug is recommended in patients who are taking cationic medications excreted via the proximal renal tubular secretory system.

CYP3A4/5 strong inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin)

Saxagliptin plasma concentrations may be increased by strong CYP3A4/5 inhibitors. Limit the dosage to saxagliptin 2.5 mg/metformin 1,000 mg once daily when coadministered with a strong CYP3A4/5 inhibitor.

Diltiazem

Coadministration may increase diltiazem C max and AUC slightly. The saxagliptin C max and AUC may be increased, while the C max and AUC of the 5-hydroxy saxagliptin metabolite may be decreased. No dosage adjustment is required.

Iodinated contrast materials

Parenteral contrast studies with iodinated materials can lead to acute renal failure and have been associated with lactic acidosis in patients receiving metformin. Therefore, temporarily discontinue saxagliptin/metformin prior to, and withhold for 48 hours subsequent to, any such study. Reinstitute saxagliptin/metformin only after renal function has been reevaluated and found to be normal.

NSAIDs (eg, ibuprofen)

NSAIDs may decrease glomerular filtration, increasing metformin concentrations and the risk of acute renal failure and lactic acidosis. Use with caution. Closely monitor renal function and for lactic acidosis. If an interaction is suspected, consider discontinuing the NSAID.

Rifampin

Exposure to saxagliptin may be decreased, while plasma concentrations of the saxagliptin active metabolite may be increased. However, dosage adjustment is not recommended. Monitor the clinical response of the patient. If an interaction is suspected, adjust the saxagliptin dose as needed.

Adverse Reactions

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

CNS

Headache (8%).

EENT

Nasopharyngitis (7%).

GI

Diarrhea (10%).

Hematologic

Decreased lymphocyte count (2%).

Hypersensitivity

Hypersensitivity-related reactions, such as urticaria and facial edema (2%).

Metabolic-Nutritional

Hypoglycemia (8%).

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 of lactic acidosis 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 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. Promptly evaluate patients with previously well-controlled type 2 diabetes who develop laboratory abnormalities or clinical illness for ketoacidosis or lactic acidosis. Evaluate serum electrolytes and ketones, as well as blood glucose, and, if indicated, blood pH, lactate, pyruvate, and metformin levels. Carefully observe patients for signs and symptoms of pancreatitis.


Pregnancy

Category B .

Lactation

Metformin is excreted in breast milk; excretion for saxagliptin is undetermined.

Children

Safety and efficacy have not been established.

Elderly

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

Hypersensitivity

Serious hypersensitivity reactions (eg, anaphylaxis, angioedema, exfoliative skin conditions) have been reported with saxagliptin.

Renal Function

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

Hepatic Function

Not recommended in patients with hepatic impairment.

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 patients who are taking beta-blocking agents.

Hypoxemia

CV collapse (shock), acute CHF, acute MI, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia.

Pancreatitis

Has been reported. If pancreatitis is suspected, promptly discontinue therapy and initiate appropriate management.

Surgical procedures

Temporarily suspend treatment for any surgical procedure, except in 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

Metformin

Hypoglycemia, lactic acidosis.

Saxagliptin

None documented.

Patient Information

  • Advise patients to read the Medication Guide before using product the first time and with each refill.
  • Advise patients or caregiver to take or administer prescribed dose once daily with the evening meal. Instruct patients to swallow tablets whole and never to crush, cut, or chew the tablets. Inform patients that the inactive ingredients from the tablet may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
  • Counsel patients against excessive alcohol intake, either short or long term.
  • Educate patients, families, or caregivers about symptoms of lactic acidosis. Advise patients to discontinue saxagliptin/metformin ER immediately and to promptly notify their health care provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heart beat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur.
  • Educate patients, families, or caregivers regarding type 2 diabetes and its management.
  • Advise patients that this drug is not a substitute for diet and exercise, and instruct them to follow prescribed regimens.
  • Emphasize the importance of regular daily blood glucose monitoring and periodic HbA 1c tests. Review symptoms of hypoglycemia and hyperglycemia, and action plans to undertake in the event either occurs. Instruct patients to report hypoglycemic or hyperglycemic episodes to their health care provider.
  • Advise patients that, during periods of stress (eg, fever, infection, surgery, trauma), medication requirements may change and to seek medical advice promptly.
  • 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.
  • Inform patients that acute pancreatitis has been reported and to report symptoms such as severe abdominal pain, sometimes radiating to the back, which may be accompanied by vomiting, to their health care provider.
  • Inform patients if symptoms of hypersensitivity (eg, rash; skin flaking or peeling; urticaria; swelling of the skin; swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, to stop taking the medication and seek medical advice promptly.

Copyright © 2009 Wolters Kluwer Health.

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