These highlights do not include all the information needed to use ZITUVIMET ® XR safely and effectively. See full prescribing information for ZITUVIMET ® XR. ZITUVIMET ® XR (sitagliptin and metformin hydrochloride) extended-release

tablets, for oral useInitial U.S. Approval: 2007 · Zydus Pharmaceuticals USA Inc.

Full label on DailyMed PDF Full label (ZIP)

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].

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.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue ZITUVIMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

ZITUVIMET XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use

ZITUVIMET XR is not recommended in patients with type 1 diabetes mellitus.

ZITUVIMET XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using ZITUVIMET XR [see Warnings and Precautions (5.2)].

Table 4 presents clinically significant drug interactions with ZITUVIMET XR:

Table 4: Clinically Significant Drug Interactions with ZITUVIMET XR

Carbonic Anhydrase Inhibitors
Clinical Impact:	Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with ZITUVIMET XR may increase the risk for lactic acidosis.
Intervention:	Consider more frequent monitoring of these patients.
Examples:	Topiramate, zonisamide, acetazolamide or dichlorphenamide.
Drugs that Reduce Metformin Clearance
Clinical Impact:	Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT₂] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)] .
Intervention:	Consider the benefits and risks of concomitant use with ZITUVIMET XR.
Examples:	Ranolazine, vandetanib, dolutegravir, and cimetidine.
Alcohol
Clinical Impact:	Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention:	Warn patients against alcohol intake while receiving ZITUVIMET XR.
Insulin Secretagogues or Insulin
Clinical Impact:	Coadministration of ZITUVIMET XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.
Intervention:	Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.
Drugs Affecting Glycemic Control
Clinical Impact:	Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
Intervention:	When such drugs are administered to a patient receiving ZITUVIMET XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ZITUVIMET XR, observe the patient closely for hypoglycemia.
Examples:	Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Lactic Acidosis

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue ZITUVIMET XR immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about the importance of regular testing of renal function while receiving ZITUVIMET XR. Instruct patients to inform their doctor that they are taking ZITUVIMET XR prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)].

Pancreatitis

Inform patients that acute pancreatitis has been reported during postmarketing use of ZITUVIMET XR. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to promptly discontinue ZITUVIMET XR and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)].

Heart Failure

Inform patients of the signs and symptoms of heart failure. Before initiating ZITUVIMET XR, ask patients about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their health care provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.3)].

Vitamin B₁₂ Deficiency

Inform patients about the importance of regular monitoring of hematological parameters while receiving ZITUVIMET XR [see Warnings and Precautions (5.5)].

Hypoglycemia

Inform patients that the incidence of hypoglycemia is increased when ZITUVIMET XR is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy. Explain to patients receiving ZITUVIMET XR in combination with these medications the risks of hypoglycemia, its symptoms and treatment and conditions that predispose to its development [see Warnings and Precautions (5.6)].

Hypersensitivity Reactions

Inform patients that allergic reactions have been reported during postmarketing use of sitagliptin, one of the components of ZITUVIMET XR. If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking ZITUVIMET XR and seek medical advice promptly.

Severe and Disabling Arthralgia

Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.8)].

Bullous Pemphigoid

Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.9)].

Administration Instructions

Inform patients that the tablets must be swallowed whole and never split, crushed or chewed.

Incompletely Dissolved Tablets in Feces

Inform patients that incompletely dissolved ZITUVIMET XR tablets may be eliminated in the feces. Tell patients that, if they repeatedly see tablets in feces, they should report this finding to their health care provider. Assess adequacy of glycemic control if a patient reports repeatedly observing tablets in feces.

Females of Reproductive Age:

Inform females that treatment with ZITUVIMET XR may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].

Medication Guide available at www.zydususa.com/medguides or call 1-877-993-8779.

The trademarks depicted herein are owned by their respective companies.

Medication Guide ZITUVIMET ^® XR (zye too' vi met XR) (sitagliptin and metformin hydrochloride extended-release) tablets, for oral use
Read this Medication Guide carefully before you start taking ZITUVIMET XR and each time you get a refill. There may be new information. This information does not take the place of talking with your health care provider about your medical condition or your treatment. If you have any questions about ZITUVIMET XR, ask your health care provider or pharmacist.
What is the most important information I should know about ZITUVIMET XR? ZITUVIMET XR can cause serious side effects, including: Lactic Acidosis. Metformin, one of the medicines in ZITUVIMET XR, can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Stop taking ZITUVIMET XR and call your health care provider right away if you have any of the following symptoms, which could be signs of lactic acidosis: you feel cold in your hands or feet you feel dizzy or lightheaded you have a slow or irregular heartbeat you feel very weak or tired you have unusual (not normal) muscle pain you have trouble breathing you feel sleepy or drowsy you have stomach pains, nausea or vomiting Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your health care provider if you have any of the following, because you have a higher chance for getting lactic acidosis with ZITUVIMET XR if you: have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye have liver problems drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. have surgery have a heart attack, severe infection, or stroke are 65 years of age or older The best way to keep from having a problem with lactic acidosis from metformin is to tell your health care provider if you have any of the problems in the list above. Your health care provider may decide to stop your ZITUVIMET XR for a while if you have any of these things. ZITUVIMET XR can have other serious side effects. See " What are the possible side effects of ZITUVIMET XR? " Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking ZITUVIMET XR, tell your health care provider if you have ever had: pancreatitis stones in your gallbladder (gallstones) high blood triglyceride levels a history of alcoholism kidney problems Stop taking ZITUVIMET XR and call your health care provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis. Heart failure. Heart failure means that your heart does not pump blood well enough. Before you start taking ZITUVIMET XR, tell your health care provider if you have ever had heart failure or have problems with your kidneys. Contact your health care provider right away if you have any of the following symptoms: increasing shortness of breath or trouble breathing, especially when you lie down swelling or fluid retention, especially in the feet, ankles or legs an unusually fast increase in weight unusual tiredness These may be symptoms of heart failure.
What is ZITUVIMET XR? ZITUVIMET XR is a prescription medicine that contains 2 prescription diabetes medicines, sitagliptin and extended-release metformin hydrochloride. ZITUVIMET XR is used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. ZITUVIMET 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 ZITUVIMET XR. It is not known if ZITUVIMET XR is safe and effective in children
Who should not take ZITUVIMET XR? Do not take ZITUVIMET XR if you: have severe kidney problems. have diabetic ketoacidosis. are allergic to any of the ingredients in ZITUVIMET XR. See the end of this Medication Guide for a complete list of ingredients in ZITUVIMET XR. Symptoms of a serious allergic reaction to ZITUVIMET XR may include rash, raised red patches on your skin (hives) or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing.
What should I tell my health care provider before taking ZITUVIMET XR? Before you take ZITUVIMET XR, tell your health care provider about all of your medical conditions, including if you: have or have had inflammation of your pancreas (pancreatitis). have kidney problems. have liver problems. have heart failure. drink alcohol very often or drink a lot of alcohol in short-term "binge" drinking. are going to get an injection of dye or contrast agents for an x-ray procedure. ZITUVIMET XR may need to be stopped for a short time. Talk to your health care provider about when you should stop ZITUVIMET XR and when you should start ZITUVIMET XR again. See "What is the most important information I should know about ZITUVIMET XR?". have low levels of vitamin B₁₂ in your blood. are pregnant, think you may be pregnant, or plan to become pregnant. It is not known if ZITUVIMET XR will harm your unborn baby. If you are pregnant, talk with your health care provider about the best way to control your blood sugar while you are pregnant. are breastfeeding or plan to breastfeed. It is not known if ZITUVIMET XR will pass into your breast milk. Talk with your health care provider about the best way to feed your baby if you are taking ZITUVIMET XR. are a woman who has not gone through menopause (premenopausal) who does not have periods regularly or at all. ZITUVIMET XR can cause the release of an egg from an ovary in a woman (ovulation). This can increase your chance of getting pregnant. Tell your health care provider right away if you become pregnant while taking ZITUVIMET XR. Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ZITUVIMET XR may affect the way other medicines work and other medicines may affect how ZITUVIMET XR works. Know the medicines you take. Keep a list of your medicines and show it to your health care provider and pharmacist when you get a new medicine.
How should I take ZITUVIMET XR? Take ZITUVIMET XR 1 time each day by mouth. Your health care provider will tell you exactly how many ZITUVIMET XR tablets to take and when you should take them. Take ZITUVIMET XR with meals to help to lower your chance of having an upset stomach. Take ZITUVUMET XR tablets whole. Do not break or cut ZITUVIMET XR tablets before swallowing. If you cannot swallow ZITUVIMET XR tablets whole, tell your health care provider. Your health care provider may tell you to take ZITUVIMET XR along with certain other diabetes medicines. Low blood sugar (hypoglycemia) can happen more often when ZITUVIMET XR is taken with certain other diabetes medicines. See "What are the possible side effects of ZITUVIMET XR?" 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 health care provider right away. if you have any of these problems and follow your health care provider's instructions. Your health care provider will do blood tests to check how well your kidneys are working before and during your treatment with ZITUVIMET XR. 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 ZITUVIMET XR at the same time. You may need to stop taking ZITUVIMET XR for a short time. Call your health care provider 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. If you take too much ZITUVIMET XR, call your health care provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away.
What are the possible side effects of ZITUVIMET XR? ZITUVIMET XR may cause serious side effects, including: See "What is the most important information I should know about ZITUVIMET XR?" Kidney problems, sometimes requiring dialysis. Low vitamin B₁₂ (vitamin B₁₂ deficiency). Using metformin for long periods of time may cause a decrease in the amount of vitamin B₁₂ in your blood, especially if you have had low vitamin B₁₂ blood levels before. Your health care provider may do blood tests to check your vitamin B₁₂ levels. Low blood sugar (hypoglycemia). If you take ZITUVIMET 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 ZITUVIMET XR. Signs and symptoms of low blood sugar may include:
headache	irritability	dizziness	sweating	weakness
drowsiness	hunger	confusion	feeling jittery	fast heart beat
Serious allergic reactions. If you have any symptoms of a serious allergic reaction, stop taking ZITUVIMET XR and call your health care provider right away or get emergency medical help. See "Who should not take ZITUVIMET XR?". Your health care provider may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes. Joint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in ZITUVIMET XR, may develop joint pain that can be severe. Call your health care provider if you have severe joint pain. Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in ZITUVIMET XR, may develop a skin reaction called bullous pemphigoid that can require treatment in a hospital. Tell your health care provider right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your health care provider may tell you to stop taking ZITUVIMET XR. The most common side effects of ZITUVIMET XR include:
• diarrhea • upper respiratory infection • headache Taking ZITUVIMET 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 health care provider. Stomach problems that start later during treatment may be a sign of something more serious. ZITUVIMET XR may have other side effects, including swelling of the hands or legs. Swelling of the hands and legs can happen if you take ZITUVIMET XR in combination with rosiglitazone (Avandia). Rosiglitazone is another type of diabetes medicine. Tell your health care provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of ZITUVIMET XR. For more information, ask your health care provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ZITUVIMET XR? Store ZITUVIMET XR in the original container at room temperature, between 68°F to 77°F (20°C to 25°C). Keep ZITUVIMET XR in the original container to protect it from moisture Use ZITUVIMET XR within 1 month of opening the bottle. Keep ZITUVIMET XR and all medicines out of the reach of children.
General information about the safe and effective use of ZITUVIMET XR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZITUVIMET XR for a condition for which it was not prescribed. Do not give ZITUVIMET XR to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about ZITUVIMET XR. If you would like to know more information, talk with your health care provider. You can ask your health care provider or pharmacist for information about ZITUVIMET XR that is written for health professionals.
What are the ingredients in ZITUVIMET XR? Active ingredients: sitagliptin and metformin hydrochloride Inactive ingredients: All doses of ZITUVIMET XR Tablets contain: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate anhydrous, ferric oxide yellow, hypromellose, magnesium stearate, malic acid, microcrystalline cellulose, povidone, pregelatinized starch (maize) and sodium stearyl fumarate. In addition, the film-coating for all doses contains the following inactive ingredients: polyethylene glycol, polyvinyl alcohol-partially hydrolyzed, iron oxide yellow, talc and titanium dioxide. Additionally, ZITUVIMET XR 50 mg/500 mg and 100 mg/1,000 mg tablets film-coating contain the inactive ingredient red iron oxide and 50 mg/1,000 mg and 100 mg/1,000 mg tablets film-coating contain the FD&C yellow#6 Aluminum Lake. For more information, go to MedicalAffairs@zydususa.com or call 1-877-993-8779. Medication Guide available at www.zydususa.com/medguides or call 1-877-993-8779. The trademarks depicted herein are owned by their respective companies.
Manufactured by: Zydus Lifesciences Ltd. Pharmez, Matoda, Ahmedabad, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Route 31 North, Pennington, NJ 08534
Approved.: 07/2025

This Medication Guide has been approved by the U.S. Food and Drug Administration.

ZITUVIMET XR tablets for oral use contain two antihyperglycemic medications: sitagliptin and metformin hydrochloride.

Sitagliptin

Sitagliptin is an orally-active inhibitor of the DPP-4 enzyme. Sitagliptin free base drug substance is used to manufacture ZITUVIMET XR. Sitagliptin free base is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-α]pyrazine with an empirical formula of C₁₆H₁₅F₆N₅O and a molecular weight of 407.31. The structural formula is:

[image: MM1]

Sitagliptin free base is a white to off-white, non-hygroscopic powder. It is soluble in methanol and slightly soluble in water.

Metformin HCl

Metformin HCl (N,N-dimethylimidodicarbonimidic diamide HCl) is a white crystalline powder with a molecular formula of C₄H₁₁N₅•HCl and a molecular weight of 165.62. Metformin HCl is freely soluble in water, slightly soluble in ethanol (95%), practically insoluble in acetone and in methylene chloride. The pK_a of metformin HCl is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula is as shown:

[image: MM2]

ZITUVIMET XR

ZITUVIMET XR is available as film-coated tablets containing:

50 mg sitagliptin and 389.93 mg of metformin equivalent to 500 mg metformin HCl (ZITUVIMET XR 50/500).
50 mg sitagliptin and 779.86 mg of metformin equivalent to 1,000 mg metformin HCl (ZITUVIMET XR 50/1,000).
100 mg sitagliptin and 779.86 mg of metformin equivalent to 1,000 mg metformin HCl (ZITUVIMET XR 100/1,000).

All doses of ZITUVIMET XR contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate anhydrous, ferric oxide yellow, hypromellose, magnesium stearate, malic acid, microcrystalline cellulose, povidone, pregelatinized starch (maize) and sodium stearyl fumarate. In addition, the film-coating for all doses contains the following inactive ingredients: polyethylene glycol, polyvinyl alcohol-partially hydrolyzed, iron oxide yellow, talc and titanium dioxide. Additionally, ZITUVIMET XR 50 mg/500 mg and 100 mg/1,000 mg tablets film-coating contain the inactive ingredient red iron oxide and 50 mg/1,000 mg and 100 mg/1,000 mg tablets film-coating contain the FD&C yellow#6 Aluminum Lake.

Tablets supplied as follows:

Contents	Description	How Supplied	NDC
50 mg sitagliptin and 500 mg metformin HCl extended-release tablets	Light orange to beige colored, oval shaped, film-coated tablets debossed with "1804" on one side and plain on the other side.	Bottles of 60 tablets with child-resistant closure	NDC 70710-1804-6
50 mg sitagliptin and 1,000 mg metformin HCl extended-release tablets	Yellow to beige colored, oval shaped, film-coated tablets debossed with "1805" on one side and plain on the other side.	Bottles of 60 tablets with child-resistant closure	NDC 70710-1805-6
100 mg sitagliptin and 1,000 mg metformin HCl extended-release tablets	Reddish brown to brown colored, oval shaped, film-coated tablets debossed with "1806" on one side and plain on the other side.	Bottles of 30 tablets with child-resistant closure	NDC 70710-1806-3

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in a dry place with cap tightly closed. Keep ZITUVIMET XR in the original container to protect it from moisture. Use ZITUVIMET XR within 1 month of opening the bottle.

What it looks like

Photos of the product and/or packaging supplied by the manufacturer.

Package codes (NDC)

70710-1804-6
70710-1805-6
70710-1806-3

Full prescribing information (for healthcare professionals)

12 CLINICAL PHARMACOLOGY

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

ZITUVIMET XR

No animal studies have been conducted with the combined products in ZITUVIMET XR to evaluate carcinogenesis, mutagenesis or impairment of fertility. The following data are based on the findings in studies with sitagliptin and metformin individually.

Sitagliptin

A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.

In rat fertility studies with oral gavage doses of 125, 250, and 1,000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total), and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).

Metformin

Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1,200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2,000 mg applied dermally. No evidence of

carcinogenicity was observed in male or female mice.

Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at doses up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

14 CLINICAL STUDIES

The coadministration of sitagliptin and metformin immediate-release has been evaluated in patients with type 2 diabetes mellitus inadequately controlled on diet and exercise and in combination with other anti-hyperglycemic medications.

Metformin Extended-Release Compared to Metformin Immediate-Release in Patients with Type 2 Diabetes Mellitus

In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group trial extended-release metformin HCl 1,500 mg once daily, extended-release metformin HCl 1,500 mg per day in divided doses (500 mg in the morning and 1,000 mg in the evening), and extended-release metformin HCl 2,000 mg once daily were compared to immediate-release metformin HCl 1,500 mg per day in divided doses (500 mg in the morning and 1,000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single antidiabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides), and patients (n = 368) receiving metformin HCl up to 1,500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout. Patients randomized to extended-release metformin HCl began titration from 1,000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin HCl initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1,000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. For HbA1c and fasting plasma glucose, each of the extended-release metformin regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of extended-release metformin was as effective as twice daily dosing of the immediate-release metformin formulation.

Sitagliptin and Metformin Immediate-Release Coadministration in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise

A total of 1,091 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial trial designed to assess the efficacy of sitagliptin and metformin immediate-release coadministration. Patients on an antihyperglycemic agent (N=541) underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at trial entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive placebo, 100 mg of sitagliptin once daily, 500 mg or 1,000 mg of metformin HCl immediate-release twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1,000 mg of metformin HCl immediate-release twice daily. Patients who failed to meet specific glycemic goals during the trial were treated with glyburide (glibenclamide) rescue.

Sitagliptin and metformin immediate-release coadministration provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin immediate-release alone, and to sitagliptin alone (Table 9, Figure 1). For patients not on an anti-hyperglycemic agent at trial entry, mean reductions from baseline in A1C were: sitagliptin 100 mg once daily, -1.1%; metformin HCl immediate-release 500 mg bid, -1.1%; metformin HCl immediate-release 1,000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin HCl immediate-release 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin HCl immediate-release 1,000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin immediate-release was similar to that in the groups given metformin alone or placebo.

Table 9: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin and Metformin Immediate-Release, Alone and in Combination in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise

	Placebo	Sitagliptin 100 mg once daily	Metformin HCl Immediate-Release 500 mg twice daily	Metformin HCl Immediate-Release 1,000 mg twice daily	Sitagliptin 50 mg bid + Metformin HCl Immediate-Release 500 mg twice daily	Sitagliptin 50 mg bid + Metformin HCl Immediate-Release 1,000 mg twice daily
A1C (%)	N = 165	N = 175	N = 178	N = 177	N = 183	N = 178
Baseline (mean)	8.7	8.9	8.9	8.7	8.8	8.8
Change from baseline (adjusted mean)	0.2	-0.7	-0.8	-1.1	-1.4	-1.9
Difference from placebo (adjusted mean)		-0.8	-1	-1.3	-1.6	-2.1
(95% CI)	(-1.1, -0.6)	(-1.2, -0.8)	(-1.5, -1.1)	(-1.8, -1.3)	(-2.3, -1.8)
Patients (%) achieving A1C <7%	15 (9%)	35 (20%)	41 (23%)	68 (38%)	79 (43%)	118 (66%)
% Patients receiving rescue medication	32	21	17	12	8	2
FPG (mg/dL)	N = 169	N = 178	N = 179	N = 179	N = 183	N = 180
Baseline (mean)	196	201	205	197	204	197
Change from baseline (adjusted mean)	6	-17	-27	-29	-47	-64
Difference from placebo (adjusted mean)		-23	-33	-35	-53	-70
(95% CI)	(-33, -14)	(-43, -24)	(-45, -26)	(-62, -43)	(-79, -60)
2-hour PPG (mg/dL)	N = 129	N = 136	N = 141	N = 138	N = 147	N = 152
Baseline (mean)	277	285	293	283	292	287
Change from baseline (adjusted mean)	0	-52	-53	-78	-93	-117
Difference from placebo (adjusted mean)		-52	-54	-78	-93	-117
(95% CI)	(-67, -37)	(-69, -39)	(-93, -63)	(-107, -78)	(-131, -102)

Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin Immediate-Release, Alone and in Combination in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise^*

[image: MM3]

^* All Patients Treated Population: least squares means adjusted for prior antihyperglycemic therapy and baseline value.

Initial combination therapy or maintenance of combination therapy should be individualized and are left

to the discretion of the health care provider.

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Immediate-Release Alone

A total of 701 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin in combination with metformin immediate-release. Patients already on metformin HCl immediate-release (N=431) at a dose of at least 1,500 mg per day were randomized after completing a 2-week, single-blind placebo run-in period. Patients on metformin immediate-release and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin HCl immediate-release (at a dose of at least 1,500 mg per day) in monotherapy. Patients were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trials were treated with pioglitazone rescue.

In combination with metformin immediate-release, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin immediate-release (Table 10). Rescue glycemic therapy was used in 5% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 10: Glycemic Parameters at Final Visit (24-Week Trial) of Sitagliptin as Add-on Combination Therapy with Metformin Immediate-Release

	Sitagliptin 100 mg once daily + Metformin Immediate-Release	Placebo + Metformin Immediate-Release
A1C (%)	N = 453	N = 224
Baseline (mean)	8	8
Change from baseline (adjusted mean)	-0.7	-0
Difference from placebo + metformin immediate-release (adjusted mean) (95% CI)	-0.7 (-0.8, -0.5)
Patients (%) achieving A1C <7%	213 (47%)	41 (18%)
FPG (mg/dL)	N = 454	N = 226
Baseline (mean)	170	174
Change from baseline (adjusted mean)	-17	9
Difference from placebo + metformin immediate-release	-25
(adjusted mean) (95% CI)	(-31, -20)
2-hour PPG (mg/dL)	N = 387	N = 182
Baseline (mean)	275	272
Change from baseline (adjusted mean)	-62	-11
Difference from placebo + metformin immediate-release	-51
(adjusted mean) (95% CI)	(-61, -41)

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on the

Combination of Metformin Immediate-Release and Glimepiride

A total of 441 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin in combination with glimepiride, with or without metformin immediate-release. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin HCl immediate-release (≥1,500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trials were treated with pioglitazone rescue.

Patients receiving sitagliptin with metformin immediate-release and glimepiride had significant improvements in A1C and FPG compared to patients receiving placebo with metformin immediate-release and glimepiride (Table 11), with mean reductions from baseline relative to placebo in A1C of -0.9% and in FPG of -21 mg/dL. Rescue therapy was used in 8% of patients treated with add-on sitagliptin 100 mg and 29% of patients treated with add-on placebo. The patients treated with add-on sitagliptin had a mean increase in body weight of 1.1 kg vs. add-on placebo (+0.4 kg vs. -0.7 kg). In addition, add-on sitagliptin resulted in an increased rate of hypoglycemia compared to add-on placebo [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].

Table 11: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin in Combination with Metformin Immediate-Release and Glimepiride

	Sitagliptin 100 mg + Metformin Immediate-Release and Glimepiride	Placebo + Metformin Immediate-Release and Glimepiride
A1C (%)	N = 115	N = 105
Baseline (mean)	8.3	8.3
Change from baseline (adjusted mean)	-0.6	0.3
Difference from placebo (adjusted mean) (95% CI)	-0.9 (-1.1, -0.7)
Patients (%) achieving A1C <7%	26 (23%)	1 (1%)
FPG (mg/dL)	N = 115	N = 109
Baseline (mean)	179	179
Change from baseline (adjusted mean)	-8	13
Difference from placebo (adjusted mean) (95% CI)	-21 (-32, -10)

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on the

Combination of Metformin Immediate-Release and Rosiglitazone

A total of 278 patients with type 2 diabetes mellitus participated in a 54-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin in combination with metformin immediate-release and rosiglitazone. Patients on dual therapy with metformin HCl immediate-release ≥1,500 mg/day and rosiglitazone ≥4 mg/day or with metformin HCl immediate-release ≥1,500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin HCl immediate-release ≥1,500 mg/day and rosiglitazone ≥4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trials were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.

In combination with metformin immediate-release and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin immediate-release and rosiglitazone (Table 12) at Week 18. At Week 54, mean reduction in A1C was -1% for patients treated with sitagliptin and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with sitagliptin 100 mg and 40% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.

Table 12: Glycemic Parameters at Week 18 for Sitagliptin in Add-on Combination Therapy with Metformin Immediate-Release and Rosiglitazone

	Week 18
	Sitagliptin 100 mg + Metformin Immediate- Release + Rosiglitazone	Placebo + Metformin Immediate-Release + Rosiglitazone
A1C (%)	N = 176	N = 93
Baseline (mean)	8.8	8.7
Change from baseline (adjusted mean)	-1	-0.4
Difference from placebo + rosiglitazone + metformin immediate-release (adjusted mean) (95% CI)	-0.7 (-0.9, -0.4)
Patients (%) achieving A1C <7%	39 (22%)	9 (10%)
FPG (mg/dL)	N = 179	N = 94
Baseline (mean)	181	182
Change from baseline (adjusted mean)	-30	-11
Difference from placebo + rosiglitazone + metformin immediate-release (adjusted mean) (95% CI)	-18 (-26, -10)
2-hour PPG (mg/dL)	N = 152	N = 80
Baseline (mean)	256	248
Change from baseline (adjusted mean)	-59	-21
Difference from placebo + rosiglitazone + metformin immediate-release (adjusted mean) (95% CI)	-39 (-51, -26)

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on the Combination of Metformin Immediate-Release and Insulin

A total of 641 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin as add-on to insulin therapy. Approximately 75% of patients were also taking metformin immediate-release. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin HCl immediate-release (≥1,500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of sitagliptin (N=229) or placebo (N=233), administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.

Among patients also receiving metformin immediate-release, the median daily insulin (pre-mixed, intermediate or long acting) dose at baseline was 40 units in the sitagliptin-treated patients and 42 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the trial. Patients receiving sitagliptin with metformin immediate-release and insulin had significant improvements in A1C, FPG and 2-hour PPG compared to patients receiving placebo with metformin immediate-release and insulin (Table 13). The adjusted mean change from baseline in body weight was -0.3 kg in patients receiving sitagliptin with metformin immediate-release and insulin and -0.2 kg in patients receiving placebo with metformin immediate-release and insulin. There was an increased rate of hypoglycemia in patients treated with sitagliptin [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].

Table 13: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin as Add-on Combination Therapy with Metformin Immediate-Release and Insulin^*

^* Intent-to-treat population using last observation in the trial prior to rescue therapy.
^† Least squares means adjusted for insulin use at the screening visit, type of insulin used at the screening visit (premixed vs. non pre-mixed [intermediate- or long-acting]), and baseline value.
^‡Treatment by insulin stratum interaction was not significant (p>0.10).
^@ p<0.001 compared to placebo.
	Sitagliptin 100 mg + Metformin Immediate-Release + Insulin	Placebo + Metformin Immediate-Release + Insulin
A1C (%)	N = 223	N = 229
Baseline (mean)	8.7	8.6
Change from baseline (adjusted mean^{†, ‡)}	-0.7	-0.1
Difference from placebo (adjusted mean^†) (95% CI)	-0.5^@ (-0.7, -0.4)
Patients (%) achieving A1C <7%	32 (14%)	12 (5%)
FPG (mg/dL)	N = 225	N = 229
Baseline (mean)	173	176
Change from baseline (adjusted mean^†)	-22	-4
Difference from placebo (adjusted mean^†) (95% CI)	-18^@ (-28, -8.4)
2-hour PPG (mg/dL)	N = 182	N = 189
Baseline (mean)	281	281
Change from baseline (adjusted mean^†)	-39	1
Difference from placebo (adjusted mean^†) (95% CI)	-40^@ (-53, -28)

Maintenance of Sitagliptin During Initiation and Titration of Insulin Glargine

A total of 746 patients with type 2 diabetes mellitus (mean baseline HbA1C 8.8%, disease duration 10.8 years) participated in a 30-week, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of continuing sitagliptin during the initiation and up-titration of insulin glargine. Patients who were on a stable dose of metformin HCl (≥1,500 mg/day) in combination with a DPP-4 inhibitor and/or sulfonylurea but with inadequate glycemic control (A1C 7.5% to 11%) were enrolled in the trial. Those on metformin and sitagliptin (100 mg/day) directly entered the double-blind treatment period; those on another DPP-4 inhibitor and/or on a sulfonylurea entered a 4 to 8 week run-in period in which they were maintained on metformin and switched to sitagliptin (100 mg); other DPP-4 inhibitors and sulfonylureas were discontinued. At randomization patients were randomized either to continue sitagliptin or to discontinue sitagliptin and switch to a matching placebo. On the day of randomization, insulin glargine was initiated at a dose of 10 units subcutaneously in the evening. Patients were instructed to up-titrate their insulin dose in the evening based on fasting blood glucose measurements to achieve a target of 72 to100 mg/dL.

At 30 weeks, the mean reduction in A1C was greater in the sitagliptin group than in the placebo group (Table 14). At the end of the trial, 27.3% of patients in the sitagliptin group and 27.3% in the placebo group had a fasting plasma glucose (FPG) in the target range; there was no significant difference in insulin dose between arms.

Table 14: Change from Baseline in A1C and FPG at Week 30 in the Maintenance of Sitagliptin During Initiation and Titration of Insulin Glargine Trial

	Sitagliptin 100 mg + Metformin + Insulin Glargine	Placebo + Metformin + Insulin Glargine
A1C (%)	N = 373	N = 370
Baseline (mean)	8.8	8.8
Week 30 (mean)	6.9	7.3
Change from baseline (adjusted mean)	-1.9	-1.4
Difference from placebo (adjusted mean) (95% CI)	-0.4 (-0.6, -0.3)
Patients (%) with A1C <7%	202 (54.2%)	131 (35.4%)
FPG (mg/dL)	N = 373	N = 370
Baseline (mean)	199	201
Week 30 (mean)	118	123
Change from baseline (adjusted mean)	-81	-76

Sitagliptin Add-on Therapy vs. Glipizide Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Immediate-Release

The efficacy of sitagliptin was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes mellitus. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin HCl immediate-release monotherapy (dose of ≥1,500 mg per day) which included washout of medications other than metformin immediate-release, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of sitagliptin 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.

After 52 weeks, sitagliptin and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 15). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of sitagliptin to glipizide may be limited to patients with baseline A1C comparable to those included in the trial (over 70% of patients had baseline A1C less than 8% and over 90% had A1C less than 9%).

Table 15: Glycemic Parameters in a 52-Week Trial Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin Immediate-Release (Intent-to-Treat Population) ^*

^* The intent-to-treat analysis used the patients' last observation in the trial prior to discontinuation.
^† Least squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.
	Sitagliptin 100 mg + Metformin Immediate-Release	Glipizide + Metformin Immediate- Release
A1C (%)	N = 576	N = 559
Baseline (mean)	7.7	7.6
Change from baseline (adjusted mean^†)	-0.5	-0.6
FPG (mg/dL)	N = 583	N = 568
Baseline (mean)	166	164
Change from baseline (adjusted mean^†)	-8	-8

Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a Trial Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin Immediate-Release (Per Protocol Population)^*

[image: MM4]

^* The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had observations at baseline and at Week 52.

The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32%). Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs. + 1.1 kg).

SPL UNCLASSIFIED SECTION

Manufactured by:

Zydus Lifesciences Ltd.

Pharmez, Matoda, Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Route 31 North, Pennington, NJ 08534

Rev:.07/25

Serious warning (boxed)Boxed warningThe FDA's most prominent safety warning.

What this medicine is forThe uses this medicine is approved for.

How to take itDosage and administration instructions.

Available doses and formsTablets: sitagliptin 100 mg and metformin HCl 1,000 mg extended-release tablets are reddish brown to brown colored, oval shaped, film-coated tablets debossed with "1806" on one side and plain on the other side. sitaglipt…

Do not use if…Contraindications.ZITUVIMET XR is contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)]. Acute or chronic metabolic acidosis, including diabetic ketoacidosis. A histo…

Drug interactionsTable 4 presents clinically significant drug interactions with ZITUVIMET XR: Table 4: Clinically Significant Drug Interactions with ZITUVIMET XR Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitor…

Important warnings and precautions

Possible side effectsThe following adverse reactions are also discussed elsewhere in the prescribing information: Lactic Acidosis [see Warnings and Precautions (5.1)] Pancreatitis [see Warnings and Precautions (5.2)] Heart Failure [see Warni…

Use in specific groups

If you take too much (overdose)In the event of overdose with ZITUVIMET XR, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ supportive measures dictated by…

Patient informationAdvise the patient to read the FDA-approved patient labeling (Medication Guide). Lactic Acidosis Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to d…

Medication GuideMedication Guide ZITUVIMET ® XR (zye too' vi met XR) (sitagliptin and metformin hydrochloride extended-release) tablets, for oral use Read this Medication Guide carefully before you start taking ZITUVIMET XR and each tim…

What's in this medicineZITUVIMET XR tablets for oral use contain two antihyperglycemic medications: sitagliptin and metformin hydrochloride. Sitagliptin Sitagliptin is an orally-active inhibitor of the DPP-4 enzyme. Sitagliptin free base drug…

Package labelNDC 70710-1804-6 ZITUVIMET XR (sitagliptin and metformin hydrochloride extended-release) tablets 50 mg/500 mg 60 Tablets Rx only NDC 70710-1805-6 ZITUVIMET XR (sitagliptin and metformin hydrochloride extended-release) ta…

How it's suppliedTablets supplied as follows: Contents Description How Supplied NDC 50 mg sitagliptin and 500 mg metformin HCl extended-release tablets Light orange to beige colored, oval shaped, film-coated tablets debossed with "1804"…