Metformin hydrochloride; saxagliptin hydrochloride

What is Metformin hydrochloride; saxagliptin hydrochloride?

• Metformin hydrochloride; saxagliptin hydrochloride (KOMBIGLYZE XR) is a combination of saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and metformin, a biguanide used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type 2 diabetes.

Saxagliptin

Metformin

What are the uses of this medicine?

• Metformin hydrochloride; saxagliptin hydrochloride (KOMBIGLYZE XR) is a prescription medicine that contains saxagliptin and metformin hydrochloride. KOMBIGLYZE XR is used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type 2 diabetes.

Limitations of Use:

• KOMBIGLYZE XR is not for people with type 1 diabetes.
• KOMBIGLYZE XR is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

How does this medicine work?

• KOMBIGLYZE XR combines two antihyperglycemic medications with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes: saxagliptin, a dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin hydrochloride, a biguanide.

Saxagliptin:

• Saxagliptin (sax' a glip' tin) is an inhibitor of dipeptidyl peptidase-4, which is the major enzyme responsible for the degradation of glucagon-like peptide-1 (GLP-1), an important gastrointestinal hormone (incretin) that increases glucose dependent insulin secretion by the pancreas.
• By prolonging the effect of GLP-1, saxagliptin increases insulin levels and lowers blood glucose, thereby improving glycemic control in patients with type 2 diabetes.

Metformin:

• Metformin (met for' min) is a biguanine and acts as an insulin sensitizing agent, probably through activation of adenosine monophosphate dependent (AMP) kinase in liver and muscle tissue.
• Metformin is often associated with weight loss making it a preferred, first line agent for management of overweight patients with type 2 diabetes.
• Initial concerns about the possibility that metformin (like the related biguanine phenformin) could induce lactic acidosis have been largely resolved, although the agent is contraindicated in patients with renal dysfunction because of this reason and should be used with caution in patients with significant liver disease.

Who Should Not Use this medicine ?

This medicine cannot be used in patients who:

• have kidney problems.
• are allergic to metformin hydrochloride, saxagliptin, or any of the ingredients in KOMBIGLYZE XR.
• have a condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine).

What drug interactions can this medicine cause?

• Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole) significantly increases saxagliptin concentrations. Limit KOMBIGLYZE XR dose to 2.5 mg/1000 mg once daily.
• Concomitant use of Carbonic Anhydrase Inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) with KOMBIGLYZE XR may increase the risk for lactic acidosis.
• Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use.
• Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake.

Is this medicine FDA approved?

• Initial U.S. Approval: 2010

How should this medicine be used?

• Assess renal function prior to initiation of KOMBIGLYZE XR and periodically thereafter.
• Do not use in patients with eGFR below 30 mL/min/1.73 m2.
• Initiation is not recommended in patients with eGFR between 30 - 45 mL/min/1.73 m2.
• Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m2.
• Limit the saxagliptin component to 2.5 mg daily if eGFR is less than 45 mL/min/1.73 m2.
• Discontinue if eGFR falls below 30 mL/min/1.73 m2.
• KOMBIGLYZE XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures.

Recommended dosage:

• The dosage of KOMBIGLYZE XR should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability.
• The recommended starting dose of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who are not currently treated with metformin is 5 mg saxagliptin/500 mg metformin extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin.
• Do not exceed a daily dosage of 5 mg saxagliptin/2000 mg metformin HCl extended-release.
• Limit the saxagliptin dosage to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole).

Administration:

• KOMBIGLYZE XR should be taken with meals to help lessen an upset stomach side effect.
• Swallow KOMBIGLYZE XR whole. Do not crush, cut, or chew KOMBIGLYZE XR.
• You may sometimes pass a soft mass in your stools (bowel movement) that looks like KOMBIGLYZE XR tablets.
• When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your healthcare provider right away if you have any of these problems.
• Your healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with KOMBIGLYZE XR.
• Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.
• Follow your healthcare provider’s instructions for treating blood sugar that is too low (hypoglycemia). Talk to your healthcare provider if low blood sugar is a problem for you.
• Check your blood sugar as your healthcare provider tells you to.
• Stay on your prescribed diet and exercise program while taking KOMBIGLYZE XR.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form: As Tablets:

• 5 mg saxagliptin/500 mg metformin HCl extended-release
• 5 mg saxagliptin/1000 mg metformin HCl extended-release
• 2.5 mg saxagliptin/1000 mg metformin HCl extended-release

This medicine is available in fallowing brand namesː

• KOMBIGLYZE XR

What side effects can this medication cause?

The most common side effects of this medicine include:

• upper respiratory tract infection
• stuffy or runny nose and sore throat
• urinary tract infection
• headache
• diarrhea
• nausea and vomiting

• Taking KOMBIGLYZE XR with meals can help lessen the common stomach side effects of metformin.

KOMBIGLYZE XR can cause serious side effects, including:

• Lactic acidosis
• pancreatitis
• Heart failure
• hypersensitivity
• hypoglycemia
• Joint pain
• Skin reaction

What special precautions should I follow?

• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.
• There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin. If pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR.
• Heart Failure may occur with KOMBIGLYZE XR. Consider the risks and benefits of KOMBIGLYZE XR in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms.
• Metformin may lower vitamin B12 levels. Measure hematological parameters annually.
• In the saxagliptin add-on to sulfonylurea, add-on to insulin, and add-on to metformin plus sulfonylurea trials, confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin compared to placebo. When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia.
• More common in patients treated with saxagliptin than in patients treated with placebo; and post-marketing reports of serious hypersensitivity reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions in patients treated with saxagliptin. Promptly discontinue KOMBIGLYZE XR, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• Severe and disabling arthralgia has been reported in patients taking DPP4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate
• There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue KOMBIGLYZE XR.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR.

What to do in case of emergency/overdose?

Symptoms of overdosage may include: Saxagliptin overdose:

• No dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate.

Management:

• In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status.
• Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over 4 hours).

Metformin hydrochloride overdose:

• Hypoglycemia
• Lactic acidosis

Management of overdosage:

• Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.
• Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Can this medicine be used in pregnancy?

• Limited available data with KOMBIGLYZE XR or saxagliptin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.

Can this medicine be used in children?

• Safety and effectiveness of KOMBIGLYZE XR in pediatric patients under 18 years of age have not been established

What are the active and inactive ingredients in this medicine?

• Active ingredients: saxagliptin and metformin hydrochloride.
• Inactive ingredients in each tablet: carboxymethylcellulose sodium, hypromellose 2208, and magnesium stearate.
• The 5 mg/500 mg tablet also contains: microcrystalline cellulose and hypromellose 2910.
• Tablet film coat contains: polyvinyl alcohol, polyethylene glycol 3350, titanium dioxide, talc, and iron oxides.

Who manufactures and distributes this medicine?

• NGLYZA® is a registered trademark of the AstraZeneca group of companies.
• KOMBIGLYZE® XR is a registered trademark of the AstraZeneca group of companies.

Distributed by:

• AstraZeneca Pharmaceuticals LP
• Wilmington, DE

What should I know about storage and disposal of this medication?

• Store KOMBIGLYZE XR between 68°F to 77°F (20°C to 25°C).

• Dailymed label info on Metformin hydrochloride; saxagliptin hydrochloride
• FDA Metformin hydrochloride; saxagliptin hydrochloride

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