Januvia

Pregnancy category: B

Lactation: Not known whether excreted in breast milk: use caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

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AND PRECAUTIONS The most common side effects of sitagliptin are:

• upper respiratory tract infection and
• headache.

Other important side effects of sitagliptin include:

• abdominal pain,
• nausea and
• diarrhea.

There have been reports of fatal and non-fatal pancreatitis following use of sitagliptin. Acute kidney failure and severe hypersensitivity reactions have also been reported during treatment with sitagliptin.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Januvia falls into category B. There are no well-done studies that have been done in humans with Januvia. But in animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication.

Tell your doctor if you are breastfeeding or planning to breastfeed. It is not known if Januvia is excreted in human breast milk or if it will harm your nursing baby.

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 3 4 9

Used in combination with metformin (given separately or as the fixed combination) as initial therapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus1 11 21 when treatment with both sitagliptin and metformin is appropriate.11

Used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a thiazolidinedione [peroxisome proliferator-activated receptor-γ agonist]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with one or more oral antidiabetic agents and/or insulin.1 2 5 9 11

American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) suggests a DPP-4 inhibitor as one of several alternatives for initial monotherapy in patients with metformin contraindications (e.g., renal disease, hepatic disease, GI intolerance, risk of lactic acidosis).29 DPP-4 inhibitors also recommended as part of combination therapy, particularly with both postprandial and fasting plasma glucose elevations.29

Not indicated for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis; insulin is required in these conditions.1 10 11

General

• Individualize dosage of sitagliptin/metformin hydrochloride in fixed combination based on patient's current antidiabetic regimen, clinical response, and tolerability.11

  Use of combination therapy initially or as maintenance therapy may not be appropriate in all patients; use according to clinician discretion.1 11

  Undertake any change in therapy with care and appropriate monitoring because changes in glycemic control can occur.1 11

Administration

Oral Administration

Sitagliptin Monotherapy

Administer orally once daily with or without food.1 10

If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.1 If the missed dose is remembered at time of next dose, skip missed dose and resume the regular schedule.1 Do not double dose to replace missed dose.1

Sitagliptin/Metformin Hydrochloride Fixed Combination

Administer twice daily with meals, increasing dosage gradually to minimize adverse GI effects of metformin hydrochloride component.11 13

If a dose is missed, take missed dose with a meal23 as soon as it is remembered followed by resumption of regular schedule.13 If missed dose is remembered at time of next dose, skip missed dose and resume regular schedule.13 Do not double dose to replace missed dose.13

Dosage

Available as sitagliptin phosphate (as the monohydrate); dosage expressed in terms of sitagliptin.1

Adults

Diabetes Mellitus Monotherapy Oral

100 mg once daily.1 10

Sitagliptin/Metformin Hydrochloride Fixed-combination Therapy Oral

Patients not currently receiving metformin hydrochloride: Initially, 50 mg of sitagliptin and 500 mg of metformin hydrochloride twice daily as the fixed combination.11 Increase dosage gradually to reduce adverse GI effects of metformin.11

Patients currently receiving metformin hydrochloride: Initially, 50 mg of sitagliptin and 500 mg of metformin hydrochloride or 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily as the fixed combination, depending on the patient's existing dosage of metformin hydrochloride.11 23

Patients currently receiving metformin hydrochloride 850 mg twice daily: 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily as the fixed combination.11

Efficacy and safety of switching therapy from oral antidiabetic agents other than sitagliptin or metformin hydrochloride specifically to the fixed combination of sitagliptin and metformin hydrochloride not established.11

Combination Therapy with Sitagliptin and Other Oral Antidiabetic Agents or Insulin Given as Separate Components Oral

Combination therapy with metformin hydrochloride: Sitagliptin 100 mg once daily has been used.5 10 21 24

Combination therapy with an insulin secretagogue (e.g., sulfonylurea) with or without metformin hydrochloride: 100 mg of sitagliptin once daily has been used.1 22 Reduced dosage of concomitant insulin secretagogue may be needed to decrease risk of hypoglycemia.1

Combination therapy with a thiazolidinedione (e.g., pioglitazone, rosiglitazone) with or without metformin hydrochloride: 100 mg of sitagliptin once daily has been used.1 2 10

Combination therapy with insulin with or without metformin hydrochloride: 100 mg of sitagliptin once daily has been used.1 11 Reduced dosage of concomitant insulin may be needed to decrease risk of hypoglycemia.1

Prescribing Limits

Adults

Diabetes Mellitus Oral

Sitagliptin monotherapy: Maximum 100 mg daily.23

Fixed combination with metformin hydrochloride: Maximum 100 mg of sitagliptin and 2 g of metformin hydrochloride daily (in divided doses).11 23

Special Populations

Hepatic Impairment

No dosage adjustments necessary in patients with mild to moderate hepatic impairment (Child-Pugh score ≤9).1 10 23 Efficacy and safety not established in patients with severe hepatic impairment (Child-Pugh score >9).1 10

Renal Impairment

Sitagliptin Monotherapy Oral

Moderate renal impairment (Clcr of 30 to <50 mL/minute, corresponding to Scr of >1.7–3 mg/dL in men or >1.5–2.5 mg/dL in women): 50 mg once daily.1 23 26

Severe renal impairment (Clcr <30 mL/minute, corresponding to Scr of >3 mg/dL in men or >2.5 mg/dL in women): 25 mg once daily.1 26

End-stage renal disease requiring hemodialysis or peritoneal dialysis: 25 mg once daily.1 26

May administer without regard to timing of dialysis.1 10 26 (See Absorption: Special Populations, under Pharmacokinetics.)

Sitagliptin/Metformin Hydrochloride Fixed-combination Therapy Oral

Patients with renal impairment receiving reduced dosages of sitagliptin should not be switched to the fixed combination of sitagliptin and metformin hydrochloride.11 (See Renal Impairment under Cautions.)

Geriatric Patients

Sitagliptin monotherapy: Select dosage with caution because of age-related decreases in renal function.1 11 (See Geriatric Use and also see Renal Impairment under Cautions.)

Sitagliptin in fixed combination with metformin hydrochloride: Select dosage with caution because of age-related decreases in renal function.11 (See Geriatric Use and also see Renal Impairment under Cautions.) Carefully titrate dosage to minimum dosage necessary for adequate glycemic control.11

In the U.S.

• Januvia

Available Dosage Forms:

• Tablet

Therapeutic Class: Antidiabetic

Pharmacologic Class: Dipeptidyl Peptidase IV Inhibitor

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to decide if you should continue to take it. Blood and urine tests may be needed to check for unwanted effects.

This medicine may cause serious allergic reactions, including anaphylaxis, angioedema, or certain skin conditions (Stevens-Johnson syndrome). These reactions can be life-threatening and require immediate medical attention. Call your doctor right away if you have a rash, itching, blistering, peeling, or loose skin, fever or chills, trouble breathing or swallowing, or any swelling of your hands, face, mouth, or throat while you are using this medicine.

Pancreatitis (swelling and inflammation of the pancreas) may occur while you are using this medicine. Check with your doctor right away if you have a sudden and severe stomach pain, chills, constipation, nausea, vomiting, loss of appetite, fever, or lightheadedness.

This medicine may cause hypoglycemia (low blood sugar). This is more common when this medicine is taken together with certain medicines. Low blood sugar must be treated before it causes you to pass out (unconsciousness). People feel different symptoms of low blood sugar. It is important that you learn which symptoms you usually have so you can treat it quickly. Talk to your doctor about the best way to treat low blood sugar.

Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your medicine, overeat or do not follow your meal plan, have a fever or infection, or do not exercise as much as usual. High blood sugar can be very serious and must be treated right away. It is important that you learn which symptoms you have in order to treat it quickly. Talk to your doctor about the best way to treat high blood sugar.

There may be a time when you need emergency help for a problem caused by your diabetes. You need to be prepared for these emergencies. It is a good idea to wear a medical identification (ID) bracelet or neck chain at all times. Also, carry an ID card in your wallet or purse that says you have diabetes with a list of all your medicines.

This medicine may cause bullous pemphigoid. Tell your doctor if you have large, hard skin blisters while using this medicine.

This medicine may cause severe and disabling joint pain. Call your doctor right away if you have severe joint pain while using this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• 100 mg tablets are beige, round, film-coated tablets with "277" on one side.
• 50 mg tablets are light beige, round, film-coated tablets with "112" on one side.
• 25 mg tablets are pink, round, film-coated tablets with "221" on one side.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Januvia were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Januvia, 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 Januvia with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for 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 dictated 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.

There were approximately 5200 patients with type 2 diabetes randomized in nine double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these studies, the ethnic/racial distribution was approximately 59% white, 20% Hispanic, 10% Asian, 6% black, and 6% other groups. Patients had an overall mean age of approximately 55 years (range 18 to 87 years). In addition, an active (glipizide)-controlled study of 52-weeks duration was conducted in 1172 patients with type 2 diabetes who had inadequate glycemic control on metformin.

In patients with type 2 diabetes, treatment with Januvia produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.

Monotherapy

A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of Januvia monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug washout period of about 7 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week single-blind placebo run-in period. In the 18-week study, 521 patients were randomized to placebo, Januvia 100 mg, or Januvia 200 mg, and in the 24-week study 741 patients were randomized to placebo, Januvia 100 mg, or Januvia 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or Januvia.

Treatment with Januvia at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 4). In the 18-week study, 9% of patients receiving Januvia 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving Januvia 100 mg and 21% of patients receiving placebo required rescue therapy. The improvement in A1C compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, or baseline BMI. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with Januvia appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, among patients who were not on an antihyperglycemic agent at study entry, the reductions from baseline in A1C were -0.7% and -0.8%, respectively, for those given Januvia, and -0.1% and -0.2%, respectively, for those given placebo. Overall, the 200 mg daily dose did not provide greater glycemic efficacy than the 100 mg daily dose. The effect of Januvia on lipid endpoints was similar to placebo. Body weight did not increase from baseline with Januvia therapy in either study, compared to a small reduction in patients given placebo.

Table 4: Glycemic Parameters in 18- and 24-Week Placebo-Controlled Studies of Januvia in Patients with Type 2 Diabetes*

	18-Week Study		24-Week Study
	Januvia 100 mg	Placebo	Januvia 100 mg	Placebo
* Intent-to-treat population using last observation on study prior to metformin rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo. § Data not available.
A1C (%)	N = 193	N = 103	N = 229	N = 244
Baseline (mean)	8.0	8.1	8.0	8.0
Change from baseline (adjusted mean†)	-0.5	0.1	-0.6	0.2
Difference from placebo (adjusted mean†)   (95% CI)	-0.6‡ (-0.8, -0.4)		-0.8‡ (-1.0, -0.6)
Patients (%) achieving A1C <7%	69 (36%)	16 (16%)	93 (41%)	41 (17%)
FPG (mg/dL)	N = 201	N = 107	N = 234	N = 247
Baseline (mean)	180	184	170	176
Change from baseline (adjusted mean†)	-13	7	-12	5
Difference from placebo (adjusted mean†)   (95% CI)	-20‡ (‑31, -9)		-17‡ (‑24, -10)
2-hour PPG (mg/dL)	§	§	N = 201	N = 204
Baseline (mean)			257	271
Change from baseline (adjusted mean†)			-49	-2
Difference from placebo (adjusted mean†)   (95% CI)			-47‡ (-59, -34)

Additional Monotherapy Study

A multinational, randomized, double-blind, placebo-controlled study was also conducted to assess the safety and tolerability of Januvia in 91 patients with type 2 diabetes and chronic renal insufficiency (creatinine clearance <50 mL/min). Patients with moderate renal insufficiency received 50 mg daily of Januvia and those with severe renal insufficiency or with ESRD on hemodialysis or peritoneal dialysis received 25 mg daily. In this study, the safety and tolerability of Januvia were generally similar to placebo. A small increase in serum creatinine was reported in patients with moderate renal insufficiency treated with Januvia relative to those on placebo. In addition, the reductions in A1C and FPG with Januvia compared to placebo were generally similar to those observed in other monotherapy studies. [See Clinical Pharmacology (12.3).]

Combination Therapy

Add-on Combination Therapy with Metformin

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 Januvia 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 with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of Januvia 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, Januvia provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 5). Rescue glycemic therapy was used in 5% of patients treated with Januvia 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 5: Glycemic Parameters at Final Visit (24-Week Study) for Januvia in Add-on Combination Therapy with Metformin*

	Januvia 100 mg + 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)

Initial Combination Therapy with Metformin

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 as initial therapy in combination with metformin. Patients on an antihyperglycemic agent (N=541) discontinued the agent, and 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 initial therapy with placebo, 100 mg of Januvia 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.

Initial therapy with the combination of Januvia and metformin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to Januvia alone (Table 6, 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: Januvia 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 6: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin, Alone and in Combination as Initial Therapy*

	Placebo	Sitagliptin (Januvia) 100 mg QD	Metformin 500 mg bid	Metformin 1000 mg bid	Sitagliptin 50 mg bid + Metformin 500 mg bid	Sitagliptin 50 mg bid + Metformin 1000 mg bid
* 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 as Initial Therapy in Patients with Type 2 Diabetes*

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

Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the health care provider.

Active-Controlled Study vs Glipizide in Combination with Metformin

The efficacy of Januvia 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 Januvia 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, Januvia and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 7). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of Januvia 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 7: Glycemic Parameters in a 52-Week Study Comparing Januvia to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Intent-to-Treat Population)*

	Januvia 100 mg	Glipizide
* 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 Januvia 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 Januvia group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with Januvia 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).

Add-on Combination Therapy with Pioglitazone

A total of 353 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia in combination with pioglitazone. Patients on any oral antihyperglycemic agent in monotherapy (N=212) or on a PPARγ agent in combination therapy (N=106) or not on an antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg per day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.

In combination with pioglitazone, Januvia provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 8). Rescue therapy was used in 7% of patients treated with Januvia 100 mg and 14% of patients treated with placebo. There was no significant difference between Januvia and placebo in body weight change.

Table 8: Glycemic Parameters at Final Visit (24-Week Study) for Januvia in Add-on Combination Therapy with Pioglitazone*

	Januvia 100 mg + Pioglitazone	Placebo + Pioglitazone
* Intent-to-treat population using last observation on study prior to metformin rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo + pioglitazone.
A1C (%)	N = 163	N = 174
Baseline (mean)	8.1	8.0
Change from baseline (adjusted mean†)	-0.9	-0.2
Difference from placebo + pioglitazone (adjusted mean†)   (95% CI)	-0.7‡ (-0.9, -0.5)
Patients (%) achieving A1C <7%	74 (45%)	40 (23%)
FPG (mg/dL)	N = 163	N = 174
Baseline (mean)	168	166
Change from baseline (adjusted mean†)	-17	1
Difference from placebo + pioglitazone (adjusted mean†)   (95% CI)	-18‡ (-24, -11)

Initial Combination Therapy with Pioglitazone

A total of 520 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind study designed to assess the efficacy of Januvia as initial therapy in combination with pioglitazone. Patients not on antihyperglycemic agents at study entry (<4 weeks cumulative therapy over the past 2 years, and with no treatment over the prior 4 months) with inadequate glycemic control (A1C 8% to 12%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with 100 mg of Januvia in combination with 30 mg of pioglitazone once daily or 30 mg of pioglitazone once daily as monotherapy. There was no glycemic rescue therapy in this study.

Initial therapy with the combination of Januvia and pioglitazone provided significant improvements in A1C, FPG, and 2-hour PPG compared to pioglitazone monotherapy (Table 9). The improvement in A1C was generally consistent across subgroups defined by gender, age, race, baseline BMI, baseline A1C, or duration of disease. In this study, patients treated with Januvia in combination with pioglitazone had a mean increase in body weight of 1.1 kg compared to pioglitazone alone (3.0 kg vs. 1.9 kg). Lipid effects were generally neutral.

Table 9: Glycemic Parameters at Final Visit (24-Week Study) for Januvia in Combination with Pioglitazone as Initial Therapy*

	Januvia 100 mg + Pioglitazone	Pioglitazone
* Intent-to-treat population using last observation on study. † Least squares means adjusted for baseline value. ‡ p<0.001 compared to placebo + pioglitazone.
A1C (%)	N = 251	N = 246
Baseline (mean)	9.5	9.4
Change from baseline (adjusted mean†)	-2.4	-1.5
Difference from pioglitazone (adjusted mean†) (95% CI)	-0.9‡ (-1.1, -0.7)
Patients (%) achieving A1C <7%	151 (60%)	68 (28%)
FPG (mg/dL)	N = 256	N = 253
Baseline (mean)	203	201
Change from baseline (adjusted mean†)	-63	-40
Difference from pioglitazone (adjusted mean†) (95% CI)	-23‡ (-30, -15)
2-hour PPG (mg/dL)	N = 216	N = 211
Baseline (mean)	283	284
Change from baseline (adjusted mean†)	-114	-69
Difference from pioglitazone (adjusted mean†) (95% CI)	-45‡ (-57, -32)

Add-on Combination Therapy with 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 Januvia 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 Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the study 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, Januvia provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 10) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with Januvia 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 Januvia 100 mg and 40% of patients treated with placebo. There was no significant difference between Januvia and placebo in body weight change. 

Table 10: Glycemic Parameters at Week 18 for Januvia in Add-on Combination Therapy with Metformin and Rosiglitazone*

	Januvia 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)

Add-on Combination Therapy with Glimepiride, with or without Metformin

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 Januvia 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 Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

In combination with glimepiride, with or without metformin, Januvia provided significant improvements in A1C and FPG compared to placebo (Table 11). In the entire study population (patients on Januvia in combination with glimepiride and patients on Januvia in combination with glimepiride and metformin), a mean reduction from baseline relative to placebo in A1C of -0.7% and in FPG of -20 mg/dL was seen. Rescue therapy was used in 12% of patients treated with Januvia 100 mg and 27% of patients treated with placebo. In this study, patients treated with Januvia had a mean increase in body weight of 1.1 kg vs. placebo (+0.8 kg vs. -0.4 kg). In addition, there was an increased rate of hypoglycemia. [See Warnings and Precautions (5.4); Adverse Reactions (6.1).]

Table 11: Glycemic Parameters at Final Visit (24-Week Study) for Januvia as Add-On Combination Therapy with Glimepiride, with or without Metformin*

	Januvia 100 mg + Glimepiride	Placebo + Glimepiride	Januvia 100 mg + Glimepiride + Metformin	Placebo + Glimepiride + Metformin
* 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. § p<0.01 compared to placebo.
A1C (%)	N = 102	N = 103	N = 115	N = 105
Baseline (mean)	8.4	8.5	8.3	8.3
Change from baseline (adjusted mean†)	-0.3	0.3	-0.6	0.3
Difference from placebo (adjusted mean†)   (95% CI)	-0.6‡ (-0.8, -0.3)		-0.9‡ (-1.1, -0.7)
Patients (%) achieving A1C <7%	11 (11%)	9 (9%)	26 (23%)	1 (1%)
FPG (mg/dL)	N = 104	N = 104	N = 115	N = 109
Baseline (mean)	183	185	179	179
Change from baseline (adjusted mean†)	-1	18	-8	13
Difference from placebo (adjusted mean†)   (95% CI)	-19§ (-32, -7)		-21‡ (-32, -10)

Add-on Combination Therapy with Insulin (with or without Metformin)

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 Januvia as add-on to insulin therapy (with or without metformin). The racial distribution in this study was approximately 70% white, 18% Asian, 7% black, and 5% other groups. Approximately 14% of the patients in this study were Hispanic. 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 Januvia or placebo, 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.

The median daily insulin dose at baseline was 42 units in the patients treated with Januvia and 45 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. In combination with insulin (with or without metformin), Januvia provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 12). Both treatment groups had an adjusted mean increase in body weight of 0.1 kg from baseline to Week 24. There was an increased rate of hypoglycemia in patients treated with Januvia. [See Warnings and Precautions (5.4); Adverse Reactions (6.1).]

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

	Januvia 100 mg + Insulin (+/- Metformin)	Placebo + Insulin (+/- Metformin)
* Intent-to-treat population using last observation on study prior to rescue therapy. † Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value. ‡ Treatment by stratum interaction was not significant (p>0.10) for metformin stratum and for insulin stratum. § p<0.001 compared to placebo.
A1C (%)	N = 305	N = 312
Baseline (mean)	8.7	8.6
Change from baseline (adjusted mean†)	-0.6	-0.1
Difference from placebo (adjusted mean†,‡) (95% CI)	-0.6§ (-0.7, -0.4)
Patients (%) achieving A1C <7%	39 (12.8%)	16 (5.1%)
FPG (mg/dL)	N = 310	N = 313
Baseline (mean)	176	179
Change from baseline (adjusted mean†)	-18	-4
Difference from placebo (adjusted mean†) (95% CI)	-15§ (-23, -7)
2-hour PPG (mg/dL)	N = 240	N = 257
Baseline (mean)	291	292
Change from baseline (adjusted mean†)	-31	5
Difference from placebo (adjusted mean†) (95% CI)	-36§ (-47, -25)

No. 6737  Tablets Januvia, 25 mg, are pink, round, film-coated tablets with "221" on one side. They are supplied as follows:

NDC 0006-0221-31 unit-of-use bottles of 30

NDC 0006-0221-54 unit-of-use bottles of 90

NDC 0006-0221-28 unit dose blister packages of 100.

No. 6738  Tablets Januvia, 50 mg, are light beige, round, film-coated tablets with "112" on one side. They are supplied as follows:

NDC 0006-0112-31 unit-of-use bottles of 30

NDC 0006-0112-54 unit-of-use bottles of 90

NDC 0006-0112-28 unit dose blister packages of 100.

No. 6739  Tablets Januvia, 100 mg, are beige, round, film-coated tablets with "277" on one side. They are supplied as follows:

NDC 0006-0277-31 unit-of-use bottles of 30

NDC 0006-0277-54 unit-of-use bottles of 90

NDC 0006-0277-02 unit-of-use blister calendar package of 30

NDC 0006-0277-33 unit-of-use blister calendar package of 30

NDC 0006-0277-28 unit dose blister packages of 100

NDC 0006-0277-82 bottles of 1000.

Storage

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

Take Januvia exactly as it was prescribed for you. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take Januvia with or without food. Follow your doctor's instructions.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office.

Low blood sugar (hypoglycemia) can happen to everyone who has diabetes. Symptoms include headache, hunger, sweating, pale skin, irritability, dizziness, feeling shaky, or trouble concentrating.

Keep a source of sugar with you in case you have low blood sugar. Sugar sources include fruit juice, hard candy, crackers, raisins, and non-diet soda. Be sure your family and close friends know how to help you in an emergency. If you have severe hypoglycemia and cannot eat or drink, use a glucagon injection. Your doctor can prescribe a glucagon emergency injection kit and tell you how to use it.

Also watch for signs of high blood sugar (hyperglycemia) such as increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, and weight loss.

Check your blood sugar carefully during times of stress, travel, illness, surgery or medical emergency, vigorous exercise, or if you drink alcohol or skip meals. These things can affect your glucose levels and your dose needs may also change. Do not change your medication dose or schedule without your doctor's advice.

Januvia is only part of a complete treatment program that may also include diet, exercise, weight control, regular blood sugar testing, and special medical care. Follow your doctor's instructions very closely.

Store Januvia at room temperature away from moisture, heat, and light.

Summary of Use during Lactation

Because no information is available on the use of sitagliptin during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Acarbose, Chlorpropamide, Glyburide, Insulin, Metformin, Tolbutamide

References