JANUVIA 100 MG

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS'

REGULATIONS (PREPARATIONS) – 1986

This medicine can be sold under doctor's prescription only

JANUVIA

®

25 mg JANUVIA

®

50 mg JANUVIA

®

100 mg

Tablets

Tablets Tablets

Each tablet contains:

Sitagliptin (as monohydrate Sitagliptin (as monohydrate Sitagliptin (as monohydrate

phosphate) 25 mg phosphate) 50 mg phosphate) 100 mg

For a list of inactive ingredients please refer to section 6.

Read all of this leaflet carefully before you start using this medicine.

This leaflet contains concise information about JANUVIA. If you have any further questions, ask your

doctor or pharmacist

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if

their ailment seems similar to yours

This medicine is not intended for administration to children and adolescents under 18 years of age

1. WHAT IS JANUVIA USED FOR?

JANUVIA is indicated as an adjunct to diet and exercise, to improve glycemic control in adults with type 2

diabetes mellitus

Important Limitations of Use

JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would

not be effective in these settings.

JANUVIA 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 JANUVIA

THERAPEUTIC GROUP

:

DPP-4 enzyme inhibitors.

JANUVIA is a member of a class of medicines you take by mouth called DPP-4 inhibitors (dipeptidyl

peptidase-4 inhibitors) that lowers blood sugar levels in adult patients with type 2 diabetes mellitus.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your

body produces does not work as well as it should. Your body can also make too much sugar. When this

happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems like: heart

disease, kidney disease, blindness, and amputation.

2. BEFORE YOU TAKE JANUVIA

2.1 Do not take JANUVIA if you:

are allergic (sensitive) to any of the ingredients of JANUVIA (see section 6 for a complete list of

ingredients in JANUVIA).

Symptoms of a serious allergic reaction to JANUVIA 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.

2.2 Special warnings concerning use of JANUVIA

Before starting treatment with JANUVIA, tell your doctor if you:

have or have had in the past pancreatitis (inflammation of the pancreas), gallstones, alcoholism or very

high blood triglyceride levels. These medical conditions can increase your chance of getting pancreatitis

(see “POSSIBLE SIDE EFFECTS”, section 4)

have kidney problems

have any other medical conditions

are pregnant or plan to become pregnant. (See section 2.5 “Pregnancy and breast-feeding”)

are breast-feeding or plan to breast-feed. (See section 2.5 “Pregnancy and breast-feeding”)

Heart failure. Heart failure means your heart does not pump blood well enough.

Before you start taking JANUVIA, tell your doctor if you have ever had heart failure or have problems

with your kidneys.

Contact your doctor 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, ankes or legs

an unusually fast increase in weight

unusual tiredness

These may be symptoms of heart failure.

2.3 Taking other medicines

If you are taking or have recently taken other medicines, including non-prescription medicines and

nutritional supplements, you should inform the attending doctor or pharmacist.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when

you get a new medicine.

2.4 Taking JANUVIA with food and drink

You can take JANUVIA with or without food.

2.5 Pregnancy and breast-feeding

It is not known if JANUVIA will harm your unborn baby. If you are pregnant, or plan to become pregnant, talk

with your doctor about the best way to control your blood sugar while you are pregnant. It is not recommended

to take JANUVIA during pregnancy.

It is not known if JANUVIA will pass into your breast milk. Talk with your doctor about the best way to feed

your baby if you are taking JANUVIA.

2.6 Driving and using machines

This medicine has no known influence on the ability to drive and use machines. However, dizziness and

drowsiness could occur, which may affect your ability to drive or use machines.

Taking JANUVIA in combination with medicines called sulfonylurea or with insulin, can cause hypoglycemia,

which may affect your ability to drive and use machines.

2.7 JANUVIA contains sodium.

This medicinal product contains less than 1 mmol sodium (23 mg) per

tablet, that is to say essentially ‘sodium-free’.

3. HOW DO YOU USE JANUVIA?

Always take JANUVIA exactly as your doctor has told you. You should check with your doctor or pharmacist

if you are not sure.

The dose and way of treatment will be determined by the doctor only. The usually recommended dose is 1

tablet, once a day.

Do not exceed the recommended dose.

You can take JANUVIA with or without food.

Swallow the medicine with a small amount of water.

No information is available regarding crushing/splitting/chewing of the tablets.

Your doctor may do blood tests from time to time to see how well your kidneys are working. Your doctor may

change your dose of JANUVIA based on the results of your blood tests.

Your doctor may tell you to take JANUVIA along with other diabetes medicines. Low blood sugar can happen

more often when JANUVIA is taken with certain other diabetes medicines (see "POSSIBLE SIDE

EFFECTS").

This medicine is not intended for administration to children and adolescents under 18 years of age.

When your body is under some types of stress, such as fever, trauma (such as a car accident), infection or

surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you

have any of these conditions and follow your doctor’s instructions.

Check your blood sugar as your doctor tells you to.

Stay on your prescribed diet and exercise program while taking JANUVIA.

Talk to your doctor about how to prevent, recognize and manage low blood sugar (hypoglycemia), high

blood sugar (hyperglycemia), and problems you have because of your diabetes.

Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your

hemoglobin A1C.

If you have accidentally taken a higher dose of JANUVIA

If you take too much JANUVIA, call your doctor right away.

If you have taken an overdose, or if a child has accidentally swallowed the medicine, proceed immediately to

a hospital emergency room and bring the package of the medicine with you.

If you forget to take JANUVIA

If you miss a dose, take it 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 two doses of JANUVIA at the

same time.

Continue to take this medicine as recommended by the doctor.

How can you contribute to the success of the treatment?

Complete the full course of treatment as instructed by the doctor.

Even if there is an improvement in your health, do not discontinue use of this medicine before consulting your

doctor or pharmacist.

Do not take medicines in the dark! Check the label and the dose each time you take your medicine. Wear

glasses if you need them.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, taking JANUVIA can cause side effects in some of the users.

Do not be alarmed by reading the list of side effects, you may not suffer from any of them.

Serious side effects have happened in people taking JANUVIA:

1. Pancreatitis (inflammation of the pancreas) which may be severe and lead to death.

Certain medical problems make you more likely to get pancreatitis.

Before you start taking JANUVIA, tell your doctor if you have ever had pancreatitis, stones in your

gallbladder (gallstones), a history of alcoholism, high blood triglyceride levels.

Stop taking JANUVIA and call your doctor 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.

2. Low blood sugar (hypoglycemia). Common (may affect up to 1 in 10 people). If you take JANUVIA

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 JANUVIA. Signs and symptoms of low blood sugar may include: headache,

drowsiness, weakness, dizziness, confusion, irritability, hunger, fast heart beat, sweating, feeling jittery.

3. Serious allergic reactions (frequency not known).Allergic reactions, which may be serious, including

rash, hives (raised red patches on your skin), and swelling of the face, lips, tongue and throat that may

cause difficulty in breathing or swallowing. If you have any symptoms of a serious allergic reaction, stop

taking JANUVIA and call your doctor right away. Your doctor may give you a medicine for your allergic

reaction and prescribe a different medicine for your diabetes.

4. Kidney problems (frequency not known), sometimes requiring dialysis.

5. Joint pain (frequency not known). Some people who take medicines called DPP-4 inhibitors like

JANUVIA, may develop joint pain that can be severe. Call your doctor if you have severe joint pain.

6. Skin reaction (frequency not known). Some people who take medicines called DPP-4 inhibitors like

JANUVIA may develop a skin reaction called bullous pemphigoid that can require treatment in a

hospital. Tell your doctor right away if you develop blisters or the breakdown of the outer layer of your

skin (erosion). Your doctor may tell you to stop taking JANUVIA.

The most common side effects of JANUVIA include:

Upper respiratory infection

Stuffy or runny nose and sore throat and headache.

JANUVIA may have other side effects including:

Stomach upset and diarrhea

Swelling of the hands or legs, when JANUVIA is used with rosiglitazone (Avandia

). Rosiglitazone is

another type of diabetes medicine

Constipation

Joint pain

Muscle pain

Arm or leg pain

Back pain

Vomiting

Interstitial lung disease

Osteoarthritis

Dizziness

Itching

Blisters

These are not all the possible side effects of JANUVIA. For more information, ask your doctor or pharmacist.

If you get any side effect, if any of the side effects gets serious or if you notice side effects not mentioned in

this leaflet, consult your doctor.

Side effects can be reported to the Ministry of Health by using the link "Adverse Drug Reactions Report" at

the home page of the Ministry of Health's web site (www.health.gov.il

) which refers to the online side effects

reporting form, or by using the link:

https://sideeffects.health.gov.il/

5. HOW TO STORE JANUVIA?

Avoid Poisoning! This medicine, as all other medicine, must be stored in a safe place out of the reach of

children and/or infants, in order to avoid poisoning. Do not induce vomiting unless explicitly instructed to do

so by a doctor!

Do not use JANUVIA after the expiry date (exp. date) which is stated on the pack. The expiry date refers to

the last day of the indicated month.

Store JANUVIA below 30ºC.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose

of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

6.1 What JANUVIA contains?

In addition to the active ingredient, the medicine also contains:

Microcrystalline

cellulose,

anhydrous dibasic

calcium

phosphate, croscarmellose

sodium,

magnesium

stearate, and sodium stearyl fumarate.

The tablet film coating contains the following inactive ingredients:

Polyvinyl alcohol, macrogol, talc, titanium dioxide, red iron oxide and yellow iron oxide.

6.2 What JANUVIA looks like and contents of the pack

JANUVIA tablets are available in three strengths:

JANUVIA 25 mg are pink, round, biconvex, film-coated tablets, debossed “221” on one side and plain on the

other.

JANUVIA 50 mg are light beige, round, biconvex, film-coated tablets, debossed “112” on one side and plain

on the other.

JANUVIA 100 mg are beige, round, biconvex, film-coated tablets, debossed “277” on one side and plain on

the other.

Pack sizes:

JANUVIA 25 mg: pack sizes of 28, 30 tablets.

JANUVIA 50 mg: pack sizes of 14, 28, 30 tablets.

JANUVIA 100 mg: pack sizes of 14, 28, 30 tablets.

Not all pack sizes may be marketed.

Manufacturer: Merck Sharp & Dohme Corp., NJ, USA.

Marketing authorization holder:

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O. Box 7121 Petah-Tikva 49170.

Revised on June 2020.

Drug registration no. listed in the official registry of the Ministry of Health:

JANUVIA 25 mg: 138.13.31554

JANUVIA 50 mg: 138.14.31555

JANUVIA 100 mg: 138.15.31556

Januvia

®

25 mg, Film coated tablets

Each tablet contains 25 mg Sitagliptin (as monohydrate phosphate)

Januvia

®

50mg, Film coated tablets

Each tablet contains 50 mg Sitagliptin (as monohydrate phosphate)

Januvia

®

100mg, Film coated tablets

Each tablet contains 100 mg Sitagliptin (as monohydrate phosphate)

1 THERAPEUTIC INDICATIONS

JANUVIA

is indicated as an adjunct to diet and exercise to improve glycemic control in adults

with type 2 diabetes mellitus.

Important Limitations of Use

JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic

ketoacidosis, as it would not be effective in these settings.

JANUVIA 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 JANUVIA. [See Warnings and Precautions (5.1).]

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The recommended dose of JANUVIA is 100 mg once daily. JANUVIA can be taken with or

without food.

2.2 Recommendations for Use in Renal Impairment

For patients with an estimated glomerular filtration rate [eGFR] greater than or equal to 45

mL/min/1.73 m² to less than 90 mL/min/1.73 m², no dosage adjustment for JANUVIA is required.

For patients with moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m²

to less than 45 mL/min/1.73 m²), the dose of JANUVIA is 50 mg once daily.

For patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or with end-

stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA

is 25 mg once daily. JANUVIA may be administered without regard to the timing of dialysis.

Because there is a need for dosage adjustment based upon renal function, assessment of renal

function is recommended prior to initiation of JANUVIA and periodically thereafter. There have

been postmarketing reports of worsening renal function in patients with renal impairment, some

of whom were prescribed inappropriate doses of sitagliptin.

2.3 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When JANUVIA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin,

a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.

[See Warnings and Precautions (5.4).]

3 DOSAGE FORMS AND STRENGTHS

100 mg tablets are beige, round, biconvex, film-coated tablets with “277” on one side and plain

on the other.

50 mg tablets are light beige, round, biconvex, film-coated tablets with “112” on one side and

plain on the other.

25 mg tablets are pink, round, biconvex, film-coated tablets with “221” on one side and plain

on the other.

4 CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the excipients listed in section 11.

5 WARNINGS AND PRECAUTIONS

5.1 Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal

hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiation of

JANUVIA, patients should be observed carefully for signs and symptoms of pancreatitis. If

pancreatitis is suspected, JANUVIA should promptly be discontinued and appropriate

management should be initiated. It is unknown whether patients with a history of pancreatitis

are at increased risk for the development of pancreatitis while using JANUVIA.

5.2 Heart Failure

An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure

has been observed in cardiovascular outcomes trials for two other members of the DPP-4

inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic

cardiovascular disease.

Consider the risks and benefits of JANUVIA prior to initiating treatment in patients at risk for

heart failure, such as those with a prior history of heart failure and a history of renal

impairment, and observe these patients for signs and symptoms of heart failure during

therapy. Advise patients of the characteristic symptoms of heart failure and to immediately

report such symptoms. If heart failure develops, evaluate and manage according to current

standards of care and consider discontinuation of JANUVIA.

5.3 Assessment of Renal Function

Assessment of renal function is recommended prior to initiating JANUVIA and periodically

thereafter. A dosage adjustment is recommended in patients with moderate or severe renal

impairment and in patients with ESRD requiring hemodialysis or peritoneal dialysis. [See

Dosage and Administration (2.2); Clinical Pharmacology (12.3).] Caution should be used to

ensure that the correct dose of JANUVIA is prescribed for patients with moderate (eGFR

mL/min/1.73 m² to <45 mL/min/1.73 m²) or severe (GFR <30 mL/min/1.73 m²) renal impairment.

There have been postmarketing reports of worsening renal function, including acute renal

failure, sometimes requiring dialysis. A subset of these reports involved patients with renal

impairment, some of whom were prescribed inappropriate doses of sitagliptin. A return to

baseline

levels

renal

impairment

been

observed

with

supportive

treatment

discontinuation of potentially causative agents. Consideration can be given to cautiously

reinitiating JANUVIA if another etiology is deemed likely to have precipitated the acute

worsening of renal function.

JANUVIA has not been found to be nephrotoxic in preclinical studies at clinically relevant doses,

or in clinical trials.

5.4 Use with Medications Known to Cause Hypoglycemia

When JANUVIA was used in combination with a sulfonylurea or with insulin, medications known

to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used

in combination with a sulfonylurea or with insulin. [See Adverse Reactions (6.1).] Therefore, a

lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. [See

Drug Interactions(7.2)]]

5.5 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated

with

JANUVIA.

These

reactions

include

anaphylaxis,

angioedema,

exfoliative

skin

conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the

first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the

first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other

potential causes for the event, and institute alternative treatment for diabetes. [See Adverse

Reactions (6.2).]

Angioedema has also been reported with other DPP-4 inhibitors. Use caution in a patient with

a history of angioedema with another DPP-4 inhibitor because it is unknown whether such

patients will be predisposed to angioedema with JANUVIA.

5.6 Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking

DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied

from one day to years. Patients experienced relief of symptoms upon discontinuation of the

medication. A subset of patients experienced a recurrence of symptoms when restarting the

same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for

severe joint pain and discontinue drug if appropriate.

5.7 Bullous Pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with

DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic

immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report

development

blisters

erosions

while

receiving

JANUVIA.

bullous

pemphigoid

suspected, JANUVIA should be discontinued and referral to a dermatologist should be

considered for diagnosis and appropriate treatment.

5.8 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk

reduction with JANUVIA

5.9 Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say

essentially ‘sodium-free’.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials

of another drug and may not reflect the rates observed in practice.

In controlled clinical studies as both monotherapy and combination therapy with metformin,

pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions,

hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA

were similar to placebo. In combination with glimepiride, with or without metformin, the overall

incidence of clinical adverse reactions with JANUVIA was higher than with placebo, in part

related to a higher incidence of hypoglycemia (see Table 3); the incidence of discontinuation

due to clinical adverse reactions was similar to placebo.

Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included

patients treated with JANUVIA 100 mg daily, JANUVIA 200 mg daily, and placebo. Five placebo-

controlled add-on combination therapy studies were also conducted: one with metformin; one

with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without

metformin); and one with insulin (with or without metformin). In these trials, patients with

inadequate glycemic control on a stable dose of the background therapy were randomized to

add-on therapy with JANUVIA 100 mg daily or placebo. The adverse reactions, excluding

hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients

treated with JANUVIA 100 mg daily and more commonly than in patients treated with placebo,

are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of

hypoglycemia are shown in Table 3.

Table 1:

Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with

Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/- Metformin: Adverse Reactions (Excluding

Hypoglycemia) Reported in

5% of Patients and More Commonly than in Patients Given Placebo,

Regardless of Investigator Assessment of Causality

*

Number of Patients (%)

Monotherapy (18 or 24 weeks)

JANUVIA 100 mg

Placebo

N = 443

N = 363

Nasopharyngitis

23 (5.2)

12 (3.3)

Combination with Pioglitazone (24

weeks)

JANUVIA 100 mg +

Pioglitazone

Placebo +

Pioglitazone

N = 175

N = 178

Upper Respiratory Tract Infection

11 (6.3)

6 (3.4)

Headache

9 (5.1)

7 (3.9)

Combination with Metformin +

Rosiglitazone (18 weeks)

JANUVIA 100 mg

+ Metformin

+ Rosiglitazone

Placebo

+ Metformin

+ Rosiglitazone

N = 181

N = 97

Upper Respiratory Tract Infection

10 (5.5)

5 (5.2)

Nasopharyngitis

11 (6.1)

4 (4.1)

Combination with Glimepiride

(+/- Metformin) (24 weeks)

JANUVIA 100 mg

+ Glimepiride

(+/- Metformin)

Placebo

+ Glimepiride

(+/- Metformin)

N = 222

N = 219

Nasopharyngitis

14 (6.3)

10 (4.6)

Headache

13 (5.9)

5 (2.3)

Intent-to-treat population

In the 24-week study of patients receiving JANUVIA as add-on combination therapy with

metformin, there were no adverse reactions reported regardless of investigator assessment of

causality in ≥5% of patients and more commonly than in patients given placebo.

In the 24-week study of patients receiving JANUVIA as add-on therapy to insulin (with or without

metformin), there were no adverse reactions reported regardless of investigator assessment of

causality in

5% of patients and more commonly than in patients given placebo, except for

hypoglycemia (see Table 3).

In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone (Table

1), through Week 54 the adverse reactions reported regardless of investigator assessment of

causality in

5% of patients treated with JANUVIA and more commonly than in patients treated

with

placebo

were:

upper

respiratory

tract

infection

(JANUVIA,

15.5%;

placebo,

6.2%),

nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the

add-on to pioglitazone study, the incidence of selected gastrointestinal adverse reactions in

patients treated with JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%;

placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).

In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in

combination

with

metformin,

adverse

reactions

reported

(regardless

investigator

assessment of causality) in ≥5% of patients are shown in Table 2.

Table 2:

Initial Therapy with Combination of Sitagliptin and Metformin:

Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in

5% of Patients

Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin

alone, and Placebo)

*

Number of Patients (%)

Placebo

Sitagliptin

(JANUVIA)

100 mg QD

Metformin

500 or 1000 mg bid

Sitagliptin

50 mg bid +

Metformin

500 or 1000 mg bid

N = 176

N = 179

N = 364

N = 372

Upper Respiratory Infection

9 (5.1)

8 (4.5)

19 (5.2)

23 (6.2)

Headache

5 (2.8)

2 (1.1)

14 (3.8)

22 (5.9)

Intent-to-treat population.

Data pooled for the patients given the lower and higher doses of metformin.

In a 24-week study of initial therapy with JANUVIA in combination with pioglitazone, there were

no adverse reactions reported (regardless of investigator assessment of causality) in

5% of

patients and more commonly than in patients given pioglitazone alone.

No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were

observed in patients treated with JANUVIA.

In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients

randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo)

control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each

group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event

in 3942 patient-years for control). [See Warnings and Precautions (5.1).]

Hypoglycemia

In the above studies (N=9), adverse reactions of hypoglycemia were based on all reports of

symptomatic hypoglycemia. A concurrent blood glucose measurement was not required

although

most

(74%)

reports

hypoglycemia

were

accompanied

blood

glucose

measurement ≤70 mg/dL. When JANUVIA was coadministered with a sulfonylurea or with

insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher

than in the corresponding placebo group (Table 3).

Table 3:

Incidence and Rate of Hypoglycemia

*

in Placebo-Controlled Clinical Studies when JANUVIA was used

as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin),

Regardless of Investigator Assessment of Causality

Add-On to Glimepiride

(+/- Metformin) (24 weeks)

JANUVIA 100 mg

+ Glimepiride

(+/- Metformin)

Placebo

+ Glimepiride

(+/- Metformin)

N = 222

N = 219

Overall (%)

27 (12.2)

4 (1.8)

Rate (episodes/patient-year)

0.59

0.24

Severe (%)

0 (0.0)

0 (0.0)

Add-On to Insulin

(+/- Metformin) (24 weeks)

JANUVIA 100 mg

+ Insulin

(+/- Metformin)

Placebo

+ Insulin

(+/- Metformin)

N = 322

N = 319

Overall (%)

50 (15.5)

25 (7.8)

Rate (episodes/patient-year)

1.06

0.51

Severe (%)

2 (0.6)

1 (0.3)

Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose

measurement was not required; intent-to-treat population.

Based on total number of events (i.e., a single patient may have had multiple events).

Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss

of consciousness or seizure.

In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the

add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was

1.2% in patients treated with JANUVIA 100 mg and 0.9% in patients treated with placebo.

In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone, the

overall incidence of hypoglycemia was 2.2% in patients given add-on JANUVIA and 0.0% in

patients given add-on placebo through Week 18. Through Week 54, the overall incidence of

hypoglycemia was 3.9% in patients given add-on JANUVIA and 1.0% in patients given add-on

placebo.

In the 24-week, placebo-controlled factorial study of initial therapy with JANUVIA in combination

with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in

patients given JANUVIA alone, 0.8% in patients given metformin alone, and 1.6% in patients

given JANUVIA in combination with metformin.

In the study of JANUVIA as initial therapy with pioglitazone, one patient taking JANUVIA

experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes

reported in other studies except in the study involving coadministration with insulin.

In an additional, 30-week placebo-controlled, study of patients with type 2 diabetes

inadequately controlled with metformin comparing the maintenance of sitagliptin 100 mg versus

withdrawal of sitagliptin when initiating basal insulin therapy, the event rate and incidence of

documented symptomatic hypoglycemia (blood glucose measurement ≤70 mg/dL) did not differ

between the sitagliptin and placebo groups.

Laboratory Tests

Across clinical studies, the incidence of laboratory adverse reactions was similar in patients

treated with JANUVIA 100 mg compared to patients treated with placebo. A small increase in

white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in

WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical

studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered

to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37

patients with moderate renal insufficiency were randomized to JANUVIA 50 mg daily, while 14

patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE)

increases in serum creatinine were observed in patients treated with JANUVIA [0.12 mg/dL

(0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this

added increase in serum creatinine relative to placebo is not known.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of JANUVIA as

monotherapy and/or in combination with other antihyperglycemic agents. Because these

reactions are reported voluntarily from a population of uncertain size, it is generally not possible

to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity

reactions

including

anaphylaxis,

angioedema,

rash,

urticaria,

cutaneous

vasculitis

and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings

and Precautions (5.5)]; hepatic enzyme elevations; acute pancreatitis, including fatal and non-

fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1.2); Warnings and

Precautions (5.1)]; worsening renal function, including acute renal failure (sometimes requiring

dialysis) [see Warnings and Precautions (5.3)]; severe and disabling arthralgia [see Warnings

and Precautions (5.6)]; bullous pemphigoid (see Warning and Precautions (5.7)); constipation;

vomiting; headache; myalgia; pain in extremity; back pain;

interstitial l

ung disease; pruritus. ;

mouth ulceration; stomatitis; rhabdomyolysis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

(/https://sideeffects.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

7 DRUG INTERACTIONS

7.1 Digoxin

There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug

concentration (C

, 18%) of digoxin with the coadministration of 100 mg sitagliptin for 10 days.

Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin

or JANUVIA is recommended.

7.2 Insulin Secretagogues or Insulin

Coadministration of JANUVIA with an insulin secretagogue (e.g., sulfonylurea) or insulin may

require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

[see Warnings and Precautions (5.4).]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The limited available data with JANUVIA in pregnant women are not sufficient to inform a drug-

associated risk for major birth defects and miscarriage. There are risks to the mother and fetus

associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. No

adverse developmental effects were observed when sitagliptin was administered to pregnant

rats and rabbits during organogenesis at oral doses up to 30-times and 20-times, respectively,

the 100 mg clinical dose, based on AUC [see Data].

The estimated background risk of major birth defects is 6-10% in women with pre-gestational

diabetes with Hemoglobin A1c >7% and has been reported to be as high as 20-25% in women

with a Hemoglobin A1c >10%.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis,

pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly

controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia

related morbidity.

Data

Animal Data

In embryo-fetal development studies, sitagliptin administered to pregnant rats and rabbits during

organogenesis (gestation day 6 to 20 ) did not adversely affect developmental outcomes at oral

doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100

mg clinical dose, respectively, based on AUC. Higher doses in rats associated with maternal

toxicity increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately

100-times the clinical dose, based on AUC. Placental transfer of sitagliptin was observed in

pregnant rats and rabbits.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no

functional or behavioral toxicity in offspring of rats at doses up to 1000 mg/kg.

8.2 Lactation

Risk Summary

There is no information regarding the presence of JANUVIA in human milk, the effects on the

breastfed infant, or the effects on milk production. Sitagliptin is present in rat milk and therefore

possibly

present

human

milk

[see

Data].

developmental

health

benefits

breastfeeding should be considered along with the mother’s clinical need for JANUVIA and any

potential adverse effects on the breastfed infant from JANUVIA or from the underlying maternal

condition.

Data

Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1.

8.4 Pediatric Use

Safety and effectiveness of JANUVIA in pediatric patients under 18 years of age have not been

established.

8.5 Geriatric Use

Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of

JANUVIA, 725 patients were 65 years and over, while 61 patients were 75 years and over. No

overall differences in safety or effectiveness were observed between subjects 65 years and over

and younger subjects. While this and other reported clinical experience have not identified

differences in responses between the elderly and younger patients, greater sensitivity of some

older individuals cannot be ruled out.

Because sitagliptin is substantially excreted by the kidney, and because aging can be

associated with reduced renal function, renal function

should be assessed more frequently in elderly patients [see Warnings and Precautions (5.3);

Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal

impairment. Lower dosages are recommended in patients with eGFR less than 45 mL/min/1.73

m² (moderate and severe renal impairment, as well as in ESRD patients requiring dialysis). [See

Dosage and Administration (2.2); Clinical Pharmacology (12.3)].

10 OVERDOSAGE

In the event of an overdose, it is reasonable to employ supportive measures, e.g., remove

unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including

obtaining an electrocardiogram), and institute supportive therapy as 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.

11 DESCRIPTION

JANUVIA Tablets contain sitagliptin phosphate, an orally-active inhibitor of the dipeptidyl

peptidase-4 (DPP-4) enzyme.

Sitagliptin phosphate monohydrate 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-a]pyrazine

phosphate (1:1) monohydrate.

The empirical formula is C16H15F6N5OH3PO4H2O and the molecular weight is 523.32. The

structural formula is:

Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder.

It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly

soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.

Each film-coated tablet of JANUVIA contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate

monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base and the

following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate,

croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film

coating

contains

following

inactive

ingredients:

polyvinyl

alcohol,

titanium

dioxide,

polyethylene glycol (macrogol), talc, , iron oxide yellow andiron oxide red .

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2

diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active

intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of

these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-

dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day,

and levels are increased in response to a meal. These hormones are rapidly inactivated by the

enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic

regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated,

GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular

signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic

alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active

incretin levels, sitagliptinincreases insulin release and decreases glucagon levels in the

circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and

does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from

therapeutic doses.

12.2 Pharmacodynamics

General

In patients with type 2 diabetes mellitus, administration of sitagliptin led to inhibition of DPP-4

enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition

resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased

glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting

in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon

was associated with lower fasting glucose concentrations and reduced glucose excursion

following an oral glucose load or a meal.

In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.

Sitagliptin and Metformin hydrochloride Coadministration

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations,

whereas metformin alone increased active and total GLP-1 concentrations to similar extents.

Coadministration

sitagliptin

metformin

additive

effect

active

GLP-1

concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear

how these findings relate to changes in glycemic control in patients with type 2 diabetes mellitus.

Cardiac Electrophysiology

In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a

single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and

placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained

at the peak plasma concentration, or at any other time during the study. Following the 800 mg

dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was

observed at 3 hours postdose and was 8.0 msec. This increase is not considered to be clinically

significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11

times higher than the peak concentrations following a 100 mg dose.

In patients with type 2 diabetes mellitus administered sitagliptin 100 mg (N=81) or sitagliptin 200

mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data

obtained at the time of expected peak plasma concentration.

12.3 Pharmacokinetics

The pharmacokinetics of sitagliptin have been extensively characterized in healthy subjects and

patients with type 2 diabetes mellitus. Following a single oral 100 mg dose to healthy volunteers,

mean plasma AUC of sitagliptin was 8.52 μMhr, C

was 950 nM, and apparent terminal half-

life (t

) was 12.4 hours. Plasma AUC of sitagliptin increased in a dose-proportional manner and

increased approximately 14% following 100 mg doses at steady-state compared to the first

dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small

(5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects

and in patients with type 2 diabetes mellitus.

Absorption

After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed

with peak plasma concentrations (median T

) occurring 1 to 4 hours postdose.The absolute

bioavailability of sitagliptin is approximately 87%.

Effect of Food

Coadministrationof a high-fat meal with sitagliptin had no effect on the pharmacokineticsof

sitagliptin.

Distribution

The mean volume of distribution at steady state following a single 100 mg intravenous dose of

sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly

bound to plasma proteins is low (38%).

Elimination

Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a

minor pathway of elimination. The apparent terminal t

following a 100 mg oral dose of

sitagliptin

approximately

12.4

hours

renal

clearance

approximately

mL/min.Metabolism

Following a [

C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as

metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to

contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the

primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with

contribution from CYP2C8.

Excretion

Following administration of an oral [

C]sitagliptin dose to healthy subjects, approximately 100%

of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week

of dosing. Elimination of sitagliptin occurs primarily via renal excretion and involves active

tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3),

which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in

sitagliptin transport has not been established. Sitagliptin is also a substrate of P-glycoprotein P-

gp), which may also be involved in mediating the renal elimination of sitagliptin. However,

cyclosporine, a P-gp inhibitor, did not reduce the renal clearance of sitagliptin.

Specific Populations

Patients with Renal Impairment

An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with

moderate renal impairment with eGFR of 30 to less than 45 mL/min/1.73 m², and an

approximately 4-fold increase was observed in patients with severe renal impairment, including

patients with ESRD on hemodialysis, as compared to normal healthy control subjects.

Patients with Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and C

sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched

controls following administration of a single 100 mg dose of sitagliptin. These differences are

not considered to be clinically meaningful.

There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score

>9).

Effects of Age Body Mass Index (BMI) , Gender, and Race

Based

population

pharmacokinetic

analysis

composite

analysis

available

pharmacokinetic data, BMI. gender, and race do not have a clinically meaningful effect on the

pharmacokinetics of sitagliptin When the effects of age on renal function are taken into account,

age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin

based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had

approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.

Pediatric Patients

Studies characterizing the pharmacokinetics of sitagliptin in pediatric patients have not been

performed.

Drug Interaction Studies

In Vitro Assessment of Drug Interactions

Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and

is not an inducer of CYP3A4. Sitagliptin is a P-gp substrate, but does not inhibit P-gp mediated

transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause

interactions with other drugs that utilize these pathways.

Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to

be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding

displacement is very low.

In Vivo Assessment of Drug Interactions

Effects of Sitagliptin on Other Drugs

In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin,

glyburide, simvastatin, rosiglitazone, digoxin, warfarin, or an oral contraceptive (ethinyl estradiol

and norethindrone) (Table 4), providing in vivo evidence of a low propensity for causing drug

interactions with substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, and organic cationic

transporter (OCT).

Table 4:

Effect of Sitagliptin on Systemic Exposure of Coadministration Drugs

Coadministered Drug

Dose of

Coadministered

Drug

*

Dose of Sitagliptin*

Geometric Mean Ratio

(ratio with/without sitagliptin)

No Effect = 1.00

AUC

†

C

max

Digoxin

0.25 mg

once daily for

10 days

100 mg

once daily

for 10 days

Digoxin

1.11

1.18

Glyburide

1.25 mg

200 mg

once daily

for 6 days

Glyburide

1.09

1.01

Simvastatin

20 mg

200 mg

once daily

for 5 days

Simvastatin

0.85

0.80

Simvastatin Acid

1.12

1.06

Rosiglitazone

4 mg

200 mg

once daily

for 5 days

Rosiglitazone

0.98

0.99

Warfarin

30 mg single dose on

day 5

200 mg

once daily

for 11 days

S(-) Warfarin

0.95

0.89

R(+) Warfarin

0.99

0.89

Ethinyl estradiol and

norethindrone

21 days once daily of

35 µg ethinyl estradiol

with norethindrone 0.5

mg x 7 days, 0.75 mg x

7 days, 1.0 mg x 7 days

200 mg

once daily

for 21 days

Ethinyl estradiol

0.99

0.97

Norethindrone

1.03

0.98

Metformin

1000 mg

twice daily

for 14 days

50 mg

twice daily

for 7 days

Metformin

1.02

0.97

*

All doses administered as single dose unless otherwise specified

†

AUC is reported as AUC

0-∞

unless otherwise specified

Multiple dose

0-24hr

0-last

0-12hr

Effects of Other Drugs on Sitagliptin

Clinical data described below suggest that sitagliptin is not susceptible to clinically meaningful

interactions by coadministered medications.

Table 5: Effect of Coadministered Drugs on Systemic Exposure of Sitagliptin

Coadministered Drug

Dose of

Coadministered

Drug*

Dose of Sitagliptin*

Geometric Mean Ratio

(ratio with/without coadministered drug)

No Effect = 1.00

AUC

†

C

max

Cyclosporine

600 mg

once daily

100 mg once daily

Sitagliptin

1.29

1.68

Metformin

1000 mg

twice daily

for 14 days

50 mg

twice daily for 7

days

Sitagliptin

1.02

1.05

*

All doses administered as single dose unless otherwise specified

†

AUC is reported as AUC

0-∞

unless otherwise specified

Multiple dose

0-12hr

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 1000 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).

14 CLINICAL STUDIES

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.

14.1 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.

both

monotherapy

studies,

patients

currently

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 6). 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.

Table6:

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

A1C (%)

N = 193

N = 103

N = 229

N = 244

Baseline (mean)

Change from baseline (adjusted mean

-0.5

-0.6

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)

Change from baseline (adjusted mean

Difference from placebo (adjusted

mean

) (95% CI)

(-31, -9)

(-24, -10)

2-hour PPG (mg/dL)

N = 201

N = 204

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo (adjusted

mean

) (95% CI)

(-59, -34)

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.

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).]

14.2 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 7). 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 7:

Glycemic Parameters at Final Visit (24-Week Study)

for JANUVIA in Add-on Combination Therapy with Metformin

*

JANUVIA 100 mg +

Metformin

Placebo +

Metformin

A1C (%)

N = 453

N = 224

Baseline (mean)

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)

Change from baseline (adjusted mean

Difference from placebo + metformin (adjusted

mean

) (95% CI)

(-31, -20)

2-hour PPG (mg/dL)

N = 387

N = 182

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo + metformin (adjusted

mean

) (95% CI)

(-61, -41)

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.

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

combination

JANUVIA

metformin

provided

significant

improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to

JANUVIA 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: 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 8:

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

A1C (%)

N = 165

N = 175

N = 178

N = 177

N = 183

N = 178

Baseline (mean)

Change from baseline (adjusted mean

-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

FPG (mg/dL)

N = 169

N = 178

N = 179

N = 179

N = 183

N = 180

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo (adjusted mean

(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)

Change from baseline (adjusted mean

-117

Difference from placebo (adjusted mean

(95% CI)

(-67, -37)

(-69, -39)

(-93, -63)

(-107, -78)

-117

(-131, -102)

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.

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 9). 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%).

Week

-2.0

-1.5

-1.0

-0.5

LS Mean Change from Baseline

Placebo

Metformin 1000 mg b.i.d.

Sitagliptin 100 mg q.d.

Sitagliptin 50 mg b.i.d. + Metformin 500 mg b.i.d.

Metformin 500 mg b.i.d.

Sitagliptin 50 mg b.i.d. + Metformin 1000 mg b.i.d.

Table 9:

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

A1C (%)

N = 576

N = 559

Baseline (mean)

Change from baseline (adjusted mean

-0.5

-0.6

FPG (mg/dL)

N = 583

N = 568

Baseline (mean)

Change from baseline (adjusted mean

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.

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).

Week

-1.5

-1.2

-0.9

-0.6

-0.3

LS Mean Change from Baseline

Januvia 100 mg

Glipizide

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

PPAR

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 10). 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 10:

Glycemic Parameters at Final Visit (24-Week Study)

for JANUVIA in Add-on Combination Therapy with Pioglitazone

*

JANUVIA 100 mg +

Pioglitazone

Placebo +

Pioglitazone

A1C (%)

N = 163

N = 174

Baseline (mean)

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)

Change from baseline (adjusted mean

Difference from placebo + pioglitazone (adjusted mean

(95% CI)

(-24, -11)

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.

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

combination

JANUVIA

pioglitazone

provided

significant

improvements in A1C, FPG, and 2-hour PPG compared to pioglitazone monotherapy (Table

11). 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 11:

Glycemic Parameters at Final Visit (24-Week Study)

for JANUVIA in Combination with Pioglitazone as Initial Therapy

*

JANUVIA 100 mg +

Pioglitazone

Pioglitazone

A1C (%)

N = 251

N = 246

Baseline (mean)

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)

Change from baseline (adjusted mean

Difference from pioglitazone (adjusted mean

) (95% CI)

(-30, -15)

2-hour PPG (mg/dL)

N = 216

N = 211

Baseline (mean)

Change from baseline (adjusted mean

-114

Difference from pioglitazone (adjusted mean

) (95% CI)

(-57, -32)

Intent-to-treat population using last observation on study.

Least squares means adjusted for baseline value.

p<0.001 compared to placebo + pioglitazone.

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

with

metformin

≥1500 mg/day

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

meet

specific

glycemic

goals

during

study

were

treated

with

glipizide

other

sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week

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 12)

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 12:

Glycemic Parameters at Week 18

for JANUVIA in Add-on Combination Therapy with Metformin and Rosiglitazone

*

JANUVIA

100 mg +

Metformin +

Rosiglitazone

Placebo +

Metformin +

Rosiglitazone

A1C (%)

N = 176

N = 93

Baseline (mean)

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)

Change from baseline (adjusted

mean

Difference from placebo +

rosiglitazone + metformin

(adjusted mean

) (95% CI)

(-26, -10)

2-hour PPG (mg/dL)

N = 152

N = 80

Baseline (mean)

Change from baseline (adjusted

mean

Difference from placebo +

rosiglitazone + metformin

(adjusted mean

) (95% CI)

(-51, -26)

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.

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 13). 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 13:

Glycemic Parameters at Final Visit (24-Week Study)

for JANUVIA as Add-On Combination Therapy with Glimepiride, with or without 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.

JANUVIA 100 mg

+ Glimepiride

Placebo +

Glimepiride

JANUVIA 100 mg

+ Glimepiride

+ Metformin

Placebo

+ Glimepiride

+ Metformin

A1C (%)

N = 102

N = 103

N = 115

N = 105

Baseline (mean)

Change from baseline (adjusted

mean

-0.3

-0.6

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)

Change from baseline (adjusted

mean

Difference from placebo (adjusted

mean

) (95% CI)

(-32, -7)

(-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 14). 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 14:

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)

A1C (%)

N = 305

N = 312

Baseline (mean)

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)

Change from baseline (adjusted mean

Difference from placebo (adjusted mean

) (95% CI)

(-23, -7)

2-hour PPG (mg/dL)

N = 240

N = 257

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo (adjusted mean

) (95% CI)

(-47, -25)

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.

Maintenance of JANUVIA During Initiation and Titration of Insulin Glargine

A total of 746 patients with type 2 diabetes (mean baseline HbA1C 8.8%, disease duration 10.8

years) participated in a 30-week, randomized, double-blind, placebo-controlled study to assess the

efficacy and safety of continuing JANUVIA during the initiation and uptitration of insulin glargine.

Patients who were on a stable dose of metformin (≥1500 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

study. Those on metformin and JANUVIA (100 mg/day) directly entered the double-blind treatment

period; those on another DPP-4 inhibitor and/or on a sulfonylurea entered a 4-8 week run-in period in

which they weremaintained on metformin and switched to JANUVIA (100 mg); other DPP-4 inhibitors

and sulfonylureaswere discontinued. At randomization patients were randomized either to continue

JANUVIA or to discontinue JANUVIA 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 uptitrate their insulin dose in the evening based on fasting blood glucose measurements

to achieve a target of 72- 100 mg/dL.

At 30 weeks, the mean reduction in A1C was greater in the sitagliptin group than in the placebo

group (Table 15). 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 15:

Change from Baseline in A1C and FPG at Week 30 in the Maintenance of Januvia During

Initiation and Titration of Insulin Glargine Study

Sitagliptin 100 mg

+ Metformin

+ Insulin

Placebo

+ Metformin

+ Insulin

A1C (%)

N = 373

N = 370

Baseline (mean)

8.8

8.8

Week 30 (mean)

Change from baseline (adjusted mean)

*

-1.9

-1.4

Difference from placebo (adjusted mean

) (95% CI)

*

-0.4 (-0.6, -0.3)

Patients (%) achieving A1C <7%

202 (54.2%)

131 (35.4%)

FPG (mg/dL)

N = 373

N = 370

Baseline (mean)

Week 30 (mean)

Change from baseline (adjusted mean)

*

*

Analysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates

calculated using multiple imputation to model washout of the treatment effect using placebo data for all subjects having missing

Week 30 data.

N is the number of randomized and treated patients

p<0.001 compared to placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Tablets JANUVIA, 25 mg, are pink, round, biconvex, film-coated tablets with “221” on one side

and plain on the other.

They are supplied as follows: pack sizes of 28, 30 tablets.

Not all pack sizes may be marketed.

Tablets JANUVIA, 50 mg, are light beige, round, biconvex, film-coated tablets with “112” on one

side and plain on the other.

They are supplied as follows: pack sizes of 14, 28, 30 tablets.

Not all pack sizes may be

marketed.

Tablets JANUVIA, 100 mg, are beige, round, biconvex, film-coated tablets with “277” on one

side and plain on the other.

They are supplied as follows: pack sizes of 14, 28, 30 tablets.

Not all pack sizes may be

marketed.

Storage

Store below 30

Manufactured by:

Merck Sharp & Dohme Corp., NJ, USA

For Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O. Box 7121, Petah-Tikva, 49170.

Drug registration no. listed in the official registry of the Ministry of Health:

Januvia 25mg : 139.13.31554

Januvia 50mg : 138.14.31555

Januvia 100mg :138.15.31556

The content of this leaflet was approved by the Ministry of Health in October 2015, and updated

according to the guidelines of the Ministry of Health in June 2020