Janumet XR

Black Box Warnings

Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast

Lactic acidosis

• Characterized by elevated blood lactate levels (>5 mmol/L)
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment
• Rare but serious complication that can occur because of metformin accumulation; increased risk with sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure
• Subtle onset with nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, nonspecific abdominal distress)
• Monitor lab for decreased serum pH, increased anion gap, and elevated blood lactate If suspected, discontinue drug and hospitalize patient immediately
• Metformin is highly dialyzable (clearance up to 170 mL/min under good hemodynamic conditions); prompt hemodialysis is recommended to correct the acidosis and to remove accumulated metformin

Contraindications

Hypersensitivity, including anaphylaxis or angioedema

Severe renal disease: eGFR <30 ml/min/1.73 m²

Acute/chronic metabolic acidosis, including diabetic ketoacidosis; treat with insulin

Cautions

Risk of lactic acidosis with metformin accumulation

Initiate in patients >80 years only if CrCl indicates no reduction in renal function

Avoid excessive alcohol use

Withhold in presence of any condition associated with hypoxemia, dehydration, or sepsis

Discontinue temporarily prior to any intravascular radiocontrast study with iodine containing materials and for any surgical procedure

Risk of hypoglycemia esp in elderly, debilitated or malnourished, adrenal/pituitary insufficiency, strenuous exercise not compensated by caloric intake, heavy alcohol use, hepatic/renal impairment, beta blockers

May cause acute pancreatitis, including hemorrhagic and necrotizing pancreatitis

Unknown if patients with history of pancreatitis are at increased risk

Angioedema reported with other DPP-4 inhibitors; caution with history of angioedema

Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as a possible cause for severe joint pain and discontinue drug if appropriate

Cases of lactic acidosis reported primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications; monitor renal function of the elderly closely; withhold metformin promptly in presence of any condition associated with hypoxemia, dehydration, or sepsis

The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment; the risk of metformin accumulation and metformin-associated lactic acidosis increases with severity of renal impairment because metformin is substantially excreted by the kidney

Renal impairment

• Clinical recommendations based upon the patient’s renal function include the following
• Before initiating therapy, obtain an estimated glomerular filtration rate (eGFR)
• Not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m(squared) because these patients require a lower dosage of sitagliptin than what is available in the fixed combination product
• Obtain an eGFR at least annually in all patients receiving therapy at increased risk for development of renal impairment (e.g., the elderly); renal function should be assessed more frequently

Iodinated contrast imaging procedures

• Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
• Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable

• Merck Sharp & Dohme Corp.

Serious side effects have happened in people taking Janumet XR (see "Drug Precautions"). 

The most common side effects of Janumet XR include:

• stuffy or runny nose and sore throat
• upper respiratory infection
• diarrhea
• nausea and vomiting
• gas, upset stomach, indigestion
• weakness
• headache

Taking Janumet XR with meals can help lessen the common stomach side effects of metformin that usually happen at the beginning of treatment. If you have unusual or sudden stomach problems, talk with your doctor. Stomach problems that start later during treatment may be a sign of something more serious. Janumet XR may have other side effects, including:

• Swelling of the hands or legs.
• Swelling of the hands and legs can happen if you take Janumet XR in combination with rosiglitazone (Avandia). Rosiglitazone is another type of diabetes medicine.
• Low blood sugar (hypoglycemia). If you take Janumet XR with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you use Janumet XR. Signs and symptoms of low blood sugar may include:
• headache
• drowsiness
• weakness
• dizziness
• confusion
• irritability
• hunger
• fast heart beat
• sweating
• feeling jittery

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you are taking:

• amiloride
• digoxin
• morphine
• procainamide
• quinidine
• quinine
• ranitidine
• triamterene
• trimethoprim
• vancomycin
• other medicines to treat diabetes
• insulin

This is not a complete list of Janumet XR drug interactions. Ask your doctor or pharmacist for more information.

Metformin and sitagliptin combination is used to treat high blood sugar levels caused by type 2 diabetes. Metformin reduces the absorption of sugar from the stomach, reduces the release of stored sugar from the liver, and helps your body use sugar better. Sitagliptin helps to control blood sugar levels by increasing substances in the body that make the pancreas release more insulin. It also signals the liver to stop producing sugar (glucose) when there is too much sugar in the blood. This medicine does not help patients who have insulin-dependent or type 1 diabetes.

This medicine is available only with your doctor's prescription.

• If you have an allergy to sitagliptin, metformin, or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Acidic blood problem, kidney disease, liver disease, or type 1 diabetes.
• If you have had a recent heart attack or stroke.
• If you are not able to eat or drink like normal, including before certain procedures or surgery.

This is not a list of all drugs or health problems that interact with Janumet XR.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Belly pain.
• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Gas.
• Feeling tired or weak.
• Headache.
• Sore throat.
• Stuffy nose.
• Runny nose.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Janumet XR is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Janumet XR or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Janumet XR. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

• 100 mg/1000 mg tablets are blue, bi-convex oval, film-coated tablets with "81" debossed on one side.
• 50 mg/500 mg tablets are light blue, bi-convex oval, film-coated tablets with "78" debossed on one side.
• 50 mg/1000 mg tablets are light green, bi-convex oval, film-coated tablets with "80" debossed on one side.

Sitagliptin

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg sitagliptin, a mean effect that is not considered clinically important [see Clinical Pharmacology (12.2)]. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 400 mg per day for periods of up to 28 days.

In the event of an overdose, it is reasonable to employ the usual 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. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. 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.