Janumet

Name: Janumet

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Patient Handout

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Janumet Side Effects

Common Side Effects of Janumet

Tell your doctor if any of the following side effects become severe or don't go away:

Mild nausea, diarrhea, constipation, or upset stomach
Metallic taste in the mouth
Headache
Weakness
Back pain
Joint or muscle pain
Cold symptoms, such as sneezing, runny nose, or sore throat

Serious Side Effects of Janumet

Call your doctor immediately if you experience any of the symptoms listed in the Warning section or any of the following serious side effects:

Little or no urination
Shortness of breath with mild exertion
Rapid weight gain
Swelling
Severe pain in your upper stomach that spreads to your back
Severe skin reaction
Swelling in your face or tongue
Burning in your eyes
Blistering or peeling rash
Fever or sore throat

Janumet Interactions

Tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially:

Asthma medicine
Acetazolamide (Diamox)
Amiloride (Midamor, in Moduretic)
Angiotensin-converting enzyme (ACE) inhibitors, such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik)
Beta-blockers such as atenolol (Tenormin), labetalol (Normodyne), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), and propranolol (Inderal)
Calcium channel blockers, such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor, Tiazac, others), felodipine (Plendil), isradipine (DynaCirc), nicardipine (Cardene), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), and verapamil (Calan, Isoptin, Verelan)
Cimetidine (Tagamet)
Cold medicine
Diabetes medications
Digoxin (Lanoxin)
Diuretics (water pills)
Furosemide (Lasix)
Hormone replacement therapy
Insulin
Isoniazid (Nydrazid)
Mental illness medication
Medications for thyroid disease
Morphine (MS Contin)
Nausea medicine
Niacin
Oral contraceptives (birth control pills)
Phenytoin (Dilantin, Phenytek)
Procainamide (Procanbid)
Quinidine
Quinine
Ranitidine (Zantac)
Steroids such as dexamethasone (Decadron, Dexone), methylprednisolone (Medrol), and prednisone (Deltasone)
Topiramate (Topamax)
Triamterene (Dyazide, Maxzide)
Trimethoprim (Primsol)
Vancomycin (Vancocin)
Zonisamide (Zonegran)

Alcohol and Janumet

Alcohol can cause your blood-sugar levels to decrease.

Ask your doctor if it's safe for you to drink alcohol while taking Janumet.

Uses For Janumet

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.

Before Using Janumet

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of metformin and sitagliptin combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of metformin and sitagliptin combination in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require an adjustment in the dose for patients receiving metformin and sitagliptin combination.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Acetrizoic Acid
Diatrizoate
Ethiodized Oil
Iobenzamic Acid
Iobitridol
Iocarmic Acid
Iocetamic Acid
Iodamide
Iodipamide
Iodixanol
Iodohippuric Acid
Iodopyracet
Iodoxamic Acid
Ioglicic Acid
Ioglycamic Acid
Iohexol
Iomeprol
Iopamidol
Iopanoic Acid
Iopentol
Iophendylate
Iopromide
Iopronic Acid
Ioseric Acid
Iosimide
Iotasul
Iothalamate
Iotrolan
Iotroxic Acid
Ioxaglate
Ioxitalamic Acid
Ipodate
Metrizamide
Metrizoic Acid
Tyropanoate Sodium

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Aspirin
Balofloxacin
Besifloxacin
Bupropion
Ciprofloxacin
Dasabuvir
Dofetilide
Dolutegravir
Eliglustat
Enoxacin
Fleroxacin
Flumequine
Gatifloxacin
Gemifloxacin
Ioversol
Lanreotide
Levofloxacin
Lomefloxacin
Moxifloxacin
Nadifloxacin
Norfloxacin
Octreotide
Ofloxacin
Ombitasvir
Paritaprevir
Pasireotide
Pazufloxacin
Pefloxacin
Pioglitazone
Prulifloxacin
Ritonavir
Rufloxacin
Simeprevir
Sparfloxacin
Thioctic Acid
Tosufloxacin
Vandetanib

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Acebutolol
Atenolol
Betaxolol
Bisoprolol
Bitter Melon
Carteolol
Carvedilol
Celiprolol
Esmolol
Fenugreek
Furazolidone
Glucomannan
Guar Gum
Iproniazid
Isocarboxazid
Labetalol
Levobunolol
Linezolid
Methylene Blue
Metipranolol
Metoprolol
Moclobemide
Nadolol
Nebivolol
Nialamide
Oxprenolol
Patiromer
Penbutolol
Phenelzine
Pindolol
Practolol
Procarbazine
Propranolol
Psyllium
Ranolazine
Rasagiline
Rifampin
Safinamide
Selegiline
Sotalol
Timolol
Tranylcypromine
Verapamil

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

What do I need to tell my doctor BEFORE I take Janumet?

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.

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.

How is this medicine (Janumet) best taken?

Use Janumet as ordered by your doctor. Read all information given to you. Follow all instructions closely.

Take with meals.
Do not split or break tablet.
Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
To gain the most benefit, do not miss doses.

What do I do if I miss a dose?

Take a missed dose as soon as you think about it.
If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
Do not take 2 doses at the same time or extra doses.

Consumer Information Use and Disclaimer

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 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 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. 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

Clinical Studies

The coadministration of sitagliptin and metformin has been studied in patients with type 2 diabetes inadequately controlled on diet and exercise and in combination with other antihyperglycemic agents.

None of the clinical efficacy studies described below was conducted with Janumet; however, bioequivalence of Janumet with coadministered sitagliptin and metformin hydrochloride tablets was demonstrated.

Sitagliptin and Metformin Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise

A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin and metformin 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 study 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 1000 mg of metformin twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Sitagliptin and metformin coadministration provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to sitagliptin alone (Table 8, Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: sitagliptin 100 mg once daily, -1.1%; metformin 500 mg bid, -1.1%; metformin 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin 1000 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 was similar to that in the groups given metformin alone or placebo.

Table 8: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin, Alone and in Combination in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise*

	Placebo	Sitagliptin 100 mg once daily	Metformin 500 mg twice daily	Metformin 1000 mg twice daily	Sitagliptin 50 mg twice daily + Metformin 500 mg twice daily	Sitagliptin 50 mg twice daily + Metformin 1000 mg twice daily
* Intent-to-treat population using last observation on study prior to glyburide (glibenclamide) rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo.
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†) (95% CI)		-0.8‡ (-1.1, -0.6)	-1.0‡ (-1.2, -0.8)	-1.3‡ (-1.5, -1.1)	-1.6‡ (-1.8, -1.3)	-2.1‡ (-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†) (95% CI)		-23‡ (-33, -14)	-33‡ (-43, -24)	-35‡ (-45, -26)	-53‡ (-62, -43)	-70‡ (-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†) (95% CI)		-52‡ (-67, -37)	-54‡ (-69, -39)	-78‡ (-93, -63)	-93‡ (-107, -78)	-117‡ (-131, -102)

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

* 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 Inadequately Controlled on Metformin Alone

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin. Patients already on metformin (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week, single-blind placebo run-in period. Patients on metformin 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 (at a dose of at least 1500 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 studies were treated with pioglitazone rescue.

In combination with metformin, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 9). 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 9: Glycemic Parameters at Final Visit (24-Week Study) of Sitagliptin as Add-on Combination Therapy with Metformin*

	Sitagliptin 100 mg once daily + Metformin	Placebo + Metformin
* Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy and baseline value. ‡ p<0.001 compared to placebo + metformin.
A1C (%)	N = 453	N = 224
Baseline (mean)	8.0	8.0
Change from baseline (adjusted mean†)	-0.7	-0.0
Difference from placebo + metformin (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 (adjusted mean†) (95% CI)	-25‡ (-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 (adjusted mean†) (95% CI)	-51‡ (-61, -41)

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin and Glimepiride

A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with glimepiride, with or without metformin. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin (≥1500 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 studies were treated with pioglitazone rescue.

Patients receiving sitagliptin with metformin and glimepiride had significant improvements in A1C and FPG compared to patients receiving placebo with metformin and glimepiride (Table 10), 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 (5.7); Adverse Reactions (6.1).]

Table 10: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin in Combination with Metformin and Glimepiride*

	Sitagliptin 100 mg + Metformin and Glimepiride	Placebo + Metformin and Glimepiride
* Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo.
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 Inadequately Controlled on the Combination of Metformin and Rosiglitazone

A total of 278 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin and rosiglitazone. Patients on dual therapy with metformin ≥1500 mg/day and rosiglitazone ≥4 mg/day or with metformin ≥1500 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 ≥1500 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 studies were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.

In combination with metformin and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 11) at Week 18. At Week 54, mean reduction in A1C was -1.0% 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 11: Glycemic Parameters at Week 18 for Sitagliptin in Add-on Combination Therapy with Metformin and Rosiglitazone*

	Week 18
	Sitagliptin 100 mg + Metformin + Rosiglitazone	Placebo + Metformin + Rosiglitazone
* Intent-to-treat population using last observation on study prior to glipizide (or other sulfonylurea) rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo + metformin + rosiglitazone.
A1C (%)	N = 176	N = 93
Baseline (mean)	8.8	8.7
Change from baseline (adjusted mean†)	-1.0	-0.4
Difference from placebo + rosiglitazone + metformin (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 (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 (adjusted mean†) (95% CI)	-39‡ (-51, -26)

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

A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin as add-on to insulin therapy. Approximately 75% of patients were also taking metformin. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin (≥1500 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, 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 study. Patients receiving sitagliptin with metformin and insulin had significant improvements in A1C, FPG and 2-hour PPG compared to patients receiving placebo with metformin and insulin (Table 12). The adjusted mean change from baseline in body weight was -0.3 kg in patients receiving sitagliptin with metformin and insulin and -0.2 kg in patients receiving placebo with metformin and insulin. There was an increased rate of hypoglycemia in patients treated with sitagliptin. [See Warnings and Precautions (5.7); Adverse Reactions (6.1).]

Table 12: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin as Add-on Combination Therapy with Metformin and Insulin*

	Sitagliptin 100 mg + Metformin + Insulin	Placebo + Metformin + Insulin
* Intent-to-treat population using last observation on study prior to rescue therapy. † Least squares means adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed 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.
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)

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

The efficacy of sitagliptin was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin monotherapy (dose of ≥1500 mg per day) which included washout of medications other than metformin, 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 13). 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 study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%).

Table 13: Glycemic Parameters in a 52-Week Study Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Intent-to-Treat Population)*

	Sitagliptin 100 mg + Metformin	Glipizide + Metformin
* The intent-to-treat analysis used the patients' last observation in the study prior to discontinuation. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.
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 Study Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Per Protocol Population) *

* 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 (32.0%). 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).

How Supplied/Storage and Handling

No. 6747 Tablets Janumet, 50 mg/500 mg, are light pink, capsule-shaped, film-coated tablets with "575" debossed on one side. They are supplied as follows:

NDC 0006-0575-61 unit-of-use bottles of 60

NDC 0006-0575-62 unit-of-use bottles of 180

NDC 0006-0575-52 unit dose blister packages of 50

NDC 0006-0575-82 bulk bottles of 1000.

No. 6749 Tablets Janumet, 50 mg/1000 mg, are red, capsule-shaped, film-coated tablets with "577" debossed on one side. They are supplied as follows:

NDC 0006-0577-61 unit-of-use bottles of 60

NDC 0006-0577-62 unit-of-use bottles of 180

NDC 0006-0577-52 unit dose blister packages of 50

NDC 0006-0577-82 bulk bottles of 1000.

Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.]

Before taking this medicine

You should not use Janumet if you are allergic to metformin or sitagliptin (Januvia), or if you have severe kidney disease or diabetic ketoacidosis (call your doctor for treatment with insulin).

Some people taking metformin develop a serious condition called lactic acidosis. This may be more likely if you have liver or kidney disease, congestive heart failure, a heart attack or stroke, a severe infection, if you are 65 or older, if you are dehydrated, or if you drink a lot of alcohol. Talk with your doctor about your risk.

To make sure Janumet is safe for you, tell your doctor if you have:

kidney disease (your kidney function may need to be checked before you take this medicine);
liver disease;
a history of heart disease;
pancreatitis;
high triglycerides (a type of fat in the blood);
gallstones;
a history of alcoholism; or
if you are over 80 years old and have not recently had your kidney function checked.

If you need to have surgery or any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking Janumet. Be sure your caregivers know ahead of time that you are using this medication.

It is not known whether Janumet will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether metformin and sitagliptin passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Janumet is not approved for use by anyone younger than 18 years old.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. You may have signs of low blood sugar, such as extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, and seizure (convulsions).

For the Consumer

Applies to metformin / sitagliptin: oral tablet, oral tablet extended release

Along with its needed effects, metformin / sitagliptin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking metformin / sitagliptin:

Less common

Anxiety
blurred vision
chills
cold sweats
confusion
cool, pale skin
depression
dizziness
fast heartbeat
headache
increased hunger
loss of consciousness
mental cloudiness
nausea
nightmares
not thinking clearly
seizures
shakiness
slurred speech
unusual tiredness or weakness

Rare

Abdominal or stomach discomfort
decreased appetite
diarrhea
fast, shallow breathing
general feeling of discomfort
muscle pain or cramping
shortness of breath
sleepiness

Incidence not known

Blistering, peeling, or loosening of the skin
darkened urine
hives or welts, itching, or skin rash
large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
loss of appetite
pains in the stomach, side, or abdomen, possibly radiating to the back
puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
red skin lesions, often with a purple center
severe joint pain
sores, ulcers, or white spots in the mouth or on the lips
vomiting
yellow eyes or skin

Some side effects of metformin / sitagliptin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

Bloated or full feeling
excess air or gas in the stomach or intestines
indigestion
lack or loss of strength
muscle aches
passing gas
sore throat
stuffy or runny nose
vomiting