Sitagliptin/metformin

What is Sitagliptin/metformin?

• Sitagliptin/metformin (JANUMET XR) is a combination of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride (HCl), a biguanide used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.

Sitagliptin

Sitagliptin 3D

What are the uses of this medicine?

• This medicine is used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.

Limitations of Use:

• JANUMET XR is not for people with type 1 diabetes.
• If you have had pancreatitis (inflammation of the pancreas) in the past, it is not known if you have a higher chance of getting pancreatitis while you take JANUMET XR.

How does this medicine work?

• JANUMET XR tablets combine two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes mellitus: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin extended-release, a member of the biguanide class.

Sitagliptin

• Sitagliptin is a DPP-4 inhibitor, which exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones.
• By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.
• Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

Metformin

• Metformin is a biguanide that improves glycemic control in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose.
• Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
• With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

Who Should Not Use this medicine ?

This medicine cannot be used in patients who:

• have severe kidney problems.
• have diabetic ketoacidosis.
• are allergic to any of the ingredients in JANUMET XR. See the end of this Medication Guide for a complete list of ingredients in JANUMET XR.

What drug interactions can this medicine cause?

• Concomitant use of Topiramate, zonisamide, acetazolamide or dichlorphenamide with JANUMET XR may increase the risk for lactic acidosis.
• Concomitant use of Ranolazine, vandetanib, dolutegravir, and cimetidin increase systemic exposure to metformin and may increase the risk for lactic acidosis.
• Alcohol is known to potentiate the effect of metformin on lactate metabolism.
• Coadministration of JANUMET XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.
• Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid tend to produce hyperglycemia and may lead to loss of glycemic control.

Is this medicine FDA approved?

• Initial U.S. Approval: 2012

How should this medicine be used?

• Individualize the dosage of JANUMET XR on the basis of the patient’s current regimen, effectiveness, and tolerability.

Recommended dosage:

• The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin hydrochloride (HCl) extended-release.
• The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl extended-release once daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.
• The starting dose in patients already treated with metformin should provide 100 mg sitagliptin and the previously prescribed dose of metformin.
• For patients taking metformin HCl immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg metformin HCl extended-release tablets taken together once daily.
• Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET and JANUMET XR.

Recommendations for Use in Renal Impairment:

• Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR)
• Do not use in patients with eGFR below 30 mL/min/1.73 m2.
• Discontinue if eGFR later falls 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 dose of sitagliptin to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m2.

• JANUMET XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures.

Administration:

• Take JANUMET XR exactly as your doctor tells you. Your doctor will tell you how many JANUMET XR tablets to take and when you should take them.
• Your doctor may change your dose of JANUMET XR if needed.
• Your doctor may tell you to take JANUMET XR along with certain other diabetes medicines. Low blood sugar (hypoglycemia) can happen more often when JANUMET XR is taken with certain other diabetes medicines.
• Take JANUMET XR 1 time each day with a meal to help to lower your chance of having an upset stomach. It is better to take JANUMET XR with your evening meal.
• Take JANUMET XR tablets whole. Do not break, cut, crush, or chew JANUMET XR tablets before swallowing. If you cannot swallow JANUMET XR tablets whole, tell your doctor.
• You may see something that looks like the JANUMET XR tablet in your stool (bowel movement). If you see tablets in your stool several times, talk to your doctor. Do not stop taking JANUMET XR without talking to your doctor.
• Continue to take JANUMET XR as long as your doctor tells you.
• If you take too much JANUMET XR, call your doctor or local Poison Control Center right away.
• If you miss a dose, take it with food as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take 2 doses of JANUMET XR at the same time.
• You may need to stop taking JANUMET XR for a short time. Call your doctor for instructions if you:
• are dehydrated (have lost too much body fluid). Dehydration can occur if you are sick with severe vomiting, diarrhea or fever, or if you drink a lot less fluid than normal.
• plan to have surgery.
• are going to get an injection of dye or contrast agent for an x-ray procedure.
• 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 doctor right away if you have any of these problems and follow your doctor's instructions.
• Check your blood sugar as your doctor tells you to.
• Stay on your prescribed diet and exercise program while taking JANUMET XR.
• Talk to your doctor about how to prevent, recognize and manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.
• Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.
• Your doctor will do blood tests to check how well your kidneys are working before and during your treatment with JANUMET XR.

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

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

• sitagliptin 100 mg and metformin HCl 1000 mg extended-release
• sitagliptin 50 mg and metformin HCl 500 mg extended-release
• sitagliptin 50 mg and metformin HCl 1000 mg extended-release

This medicine is available in fallowing brand namesː

• JANUMET XR

What side effects can this medication cause?

The most common side effects of this medicine include:

• stuffy or runny nose and sore throat
• gas, upset stomach, indigestion
• headache
• upper respiratory infection
• weakness
• diarrhea
• low blood sugar (hypoglycemia) when used in combination with certain medicines, such as a sulfonylurea or insulin
• nausea and vomiting

JANUMET XR may cause serious side effects, including:

• Lactic Acidosis
• Pancreatitis
• Heart failure
• Kidney problems
• Low vitamin B12 (vitamin B12 deficiency)
• Low blood sugar (hypoglycemia)
• Serious allergic reactions
• Joint pain
• Skin reaction

What special precautions should I follow?

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. If metformin-associated lactic acidosis is suspected, immediately discontinue JANUMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis in patients treated with sitagliptin. If pancreatitis is suspected, promptly discontinue JANUMET XR. An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. Consider risks and benefits of JANUMET XR in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. Acute Renal Failure has been reported postmarketing sometimes requiring dialysis. Before initiating JANUMET XR and at least annually thereafter, assess renal function. Metformin may lower vitamin B12 levels. Measure hematologic parameters annually and vitamin B12 at 2 to 3 year intervals and manage any abnormalities. JANUMET XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue (e.g., sulfonylurea). A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with JANUMET XR. There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Promptly stop JANUMET XR, assess for other potential causes, institute appropriate monitoring and treatment. Severe and Disabling Arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue JANUMET XR.

What to do in case of emergency/overdose?

Symptoms of overdosage may include:

• Hypoglycemia
• Lactic acidosis

Management of overdosage:

• In the event of an overdose, it is reasonable to employ supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status.
• Sitagliptin is modestly dialyzable.
• Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
• 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?

• The limited available data with JANUMET XR in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.
• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to JANUMET XR during pregnancy. Health care providers are encouraged to report any prenatal exposure to JANUMET XR by calling the Pregnancy Registry at 1-800-986-8999.

Can this medicine be used in children?

• The safety and effectiveness of JANUMET XR have not been established in pediatric patients.

What are the active and inactive ingredients in this medicine?

• Active ingredients: sitagliptin and metformin hydrochloride extended-release
• Inactive ingredients:

All doses of JANUMET XR Tablets contain: povidone, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate, propyl gallate, polyethylene glycol, and kaolin. Film coating contains hypromellose, hydroxypropyl cellulose, titanium dioxide, FD&C #2/Indigo Carmine Aluminum Lake and carnauba wax. In addition the JANUMET XR 50 mg/500 mg Tablets also contain: microcrystalline cellulose. In addition the JANUMET XR 50 mg/1000 mg Tablets film coating also contain: yellow iron oxide.

Who manufactures and distributes this medicine?

• Dist. by: Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

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

• Store JANUMET XR at room temperature, between 68°F to 77°F (20°C to 25°C).
• Store in a dry place and keep the cap tightly closed.
• Keep JANUMET XR and all medicines out of the reach of children.

• Dailymed label info on Sitagliptin/metformin
• FDA Sitagliptin/metformin

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