JANUET 50 MG500 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
METFORMIN HYDROCHLORIDE; SITAGLIPTIN AS MONOHYDRATE PHOSPHATE
Available from:
MERCK SHARP & DOHME ISRAEL LTD
ATC code:
A10BA02
Pharmaceutical form:
TABLETS
Composition:
SITAGLIPTIN AS MONOHYDRATE PHOSPHATE 50 MG; METFORMIN HYDROCHLORIDE 500 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
MERCK SHARP & DOHME CORP., USA
Therapeutic group:
METFORMIN
Therapeutic area:
METFORMIN
Therapeutic indications:
Januet is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus. Important limitations of use:Januet 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.Januet 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 Januet.
Authorization number:
139 89 31706 12
Authorization date:
2013-11-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

15-09-2020

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS'

REGULATIONS (PREPARATIONS) – 1986

This medicine can be sold under doctor’s prescription only

JANUET

®

50 mg/500 mg

Tablets

Each tablet contains:

Sitagliptin (as monohydrate phosphate) 50 mg

Metformin Hydrochloride 500 mg

JANUET

®

50 mg/850 mg

Tablets

Each tablet contains:

Sitagliptin (as monohydrate phosphate) 50 mg

Metformin Hydrochloride 850 mg

JANUET

®

50 mg/1000 mg

Tablets

Each tablet contains:

Sitagliptin (as monohydrate phosphate) 50 mg

Metformin Hydrochloride 1000 mg

For a list of inactive ingredients please refer to section 6.1.

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

This leaflet contains concise information about JANUET. 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 under 18 years of age.

1. WHAT JANUET IS AND WHAT IT IS USED FOR?

1.1 What is JANUET?

THERAPEUTIC GROUP:

Sitagliptin: DPP-4 enzyme inhibitor. Metformin: biguanide.

1.2 What is JANUET used for?

JANUET is a tablet that contains 2 prescription medicines, sitagliptin phosphate (JANUVIA

) and

metformin, which lower blood sugar. Sitagliptin, a member of a class of medicines called DPP-4 inhibitors

(dipeptidyl peptidase-4 inhibitors), and metformin, a member of the biguanide class of medicines, work

together to control blood sugar levels in patients with type 2 diabetes mellitus, in whom this combination is

appropriate.

JANUET, along with a recommended diet and exercise program is intended to lower blood sugar in patients

with type 2 diabetes.

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.

High blood

sugar can be lowered by diet and exercise, and by certain medicines when necessary.

2. BEFORE YOU TAKE JANUET

2.1 Do not take JANUET if:

2.2 Special warnings concerning use of JANUET

Before you take JANUET, tell your doctor if you:

have or have had inflammation of your pancreas (pancreatitis). If you have had pancreatitis in the past, it

is not known if you have a higher chance of getting pancreatitis while you take JANUET (see section 4

”Possible side effects”)

have severe kidney problems

have liver problems

have or have had stones in your gallbladder

have high blood triglyceride levels

have heart problems, including congestive heart failure

drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking. If you are or were addicted

to alcohol

are going to get an injection of dye or contrast agents for an x-ray procedure, JANUET may need to be

stopped for a short time. Talk to your doctor about when you should stop JANUET and when you should

start JANUET again. (See section 4 ”Possible side effects”)

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”)

Stop taking JANUET 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.

2.3 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. Especially if you are

taking:

Topiramate (for the treatment of convulsions and migranes)

Acetazolamide (for the treatment of edema, glaucoma and relief of mountain sickness)

Dolutegravir (for the treatment of HIV infection)

Cimetidine (for the treatment of ulcers)

Ranolazine

Vandetanib

JANUET may affect how well other drugs work and some drugs can affect how well JANUET works.

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 JANUET with food and drink

Take JANUET with meals to help to lower your chance of having an upset stomach.

2.5 Pregnancy and breast-feeding

Do not use this medicine if you:

have type 1 diabetes mellitus.

have severely impaired renal function (your doctor will determine the level of impairment in

your renal function)

have diabetic ketoacidosis (increased ketones in your blood or urine: diabetes complication

which includes high blood sugar, rapid weight loss, nausea or vomiting).

are allergic to any of the ingredients in JANUET (see section 6 for a complete list of ingredients

in JANUET). Symptoms of a serious allergic reaction to JANUET 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.

If you are pregnant or plan to become pregnant: It is not known if JANUET will harm your unborn baby.

If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are

pregnant.

If you are breast-feeding or plan to breast-feed: It is not known if JANUET will pass into your breast milk.

Talk with your doctor about the best way to feed your baby if you are taking JANUET.

3. HOW DO YOU USE JANUET?

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

if you are not sure.

Your doctor will tell you how many JANUET tablets to take and when you should take them.

Your doctor may change your dose of JANUET if needed.

Take JANUET with meals to help to

lower your chance of an upset stomach.

Your doctor may tell you to take JANUET along with certain other diabetes medicines. Low blood sugar

(hypoglycemia) can happen more often when JANUET is taken with certain other diabetes medicines (see

section 4 “Possible side effects”).

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

There is no information about crushing, splitting, or chewing these tablets. If you cannot swallow JANUET

tablets whole, tell your doctor.

If you have reduced kidney function, your doctor may prescribe a lower dose.

If you take too much JANUET, 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 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 2 doses of JANUET at

the same time

You may need to stop taking JANUET for a short time. Call your doctor for instructions if you:

are dehydrated (have lost too much body fluid). Dehydration can occur if you are sick with severe

vomiting, diarrhea or fever, or if you drink a lot less fluid than normal

plan to have surgery

are going to get an injection of dye or contrast agent for an x-ray procedure. (See section 2.2 “Special

warnings concerning use of JANUET” and section 4 “Possible Side Effects”)

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 problems 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 JANUET.

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.

Continue to take JANUET as long as your doctor tells you.

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

doctor.

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, JANUET 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 can happen in people taking JANUET or the individual medicines in JANUET, including:

4.1 Lactic Acidosis. Metformin, one of the medicines in JANUET, can cause a rare (may affect up to 1 in

10,000 people), but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause

death. Lactic acidosis is a medical emergency and must be treated in the hospital.

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:

you feel cold in your hands or feet

you feel dizzy or lightheaded

you have a slow or irregular heartbeat

you feel very weak or tired

you have unusual (not normal) muscle pain

you have trouble breathing

you feel sleepy or drowsy

you have stomach pains, nausea or vomiting

Most people who have had lactic acidosis with metformin have other things that, combined with the metformin,

led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance

for getting lactic acidosis with JANUET if you:

have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable

have liver problems

drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking

get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever,

vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and

do not drink enough fluids

have surgery

have a heart attack, severe infection, or stroke

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you

have any of the problems in the list above. Your doctor may decide to stop your JANUET for a while if you

have any of these things.

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

Certain medical problems make you more likely to get pancreatitis.

Stop taking JANUET 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.

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

Before you start takeing JANUET, 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, ankles or legs

an unusually fast increase in weight

unusual tiredness

these may be symptoms of heart failure.

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

Signs and symptoms of low blood sugar may include: headache, drowsiness, weakness, dizziness,

confusion, irritability, hunger, fast heart beat, sweating, feeling jittery.

4.5 Serious allergic reactions (frequency not known) can happen with JANUET or sitagliptin, one of the

medicines in JANUET. Symptoms of a serious allergic reaction to JANUET 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. If you have any symptoms of a serious allergic reaction, stop taking JANUET 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.

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

4.7 Joint pain (frequency not known), Some people who take medicines called DPP-4 inhibitors, one of the

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

pain.

4.8 Skin reaction (frequency not known), Some people who take medicines called DPP-4 inhibitors, one of

the medicines in JANUET, 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 JANUET.

The most common side effects (may affect more than 1 in 10 people) of JANUET include:

stuffy or runny nose and sore throat

upper respiratory infection

diarrhea

nausea and vomiting

gas, upset stomach, indigestion

weakness

headache

blood

sugar

(hypoglycemia)

when

used

combination

with

certain

medications, such

sulfonylurea or insulin

Taking JANUET with meals can help lessen the common stomach side effects of metformin that usually

happen at the beginning of treatment. If you have unusual or sudden stomach problems, talk with your doctor.

Stomach problems that start later during treatment may be a sign of something more serious.

JANUET may have other side effects including:

Swelling of the hands or legs. Swelling of the hands and legs can happen if you take JANUET in

combination with rosiglitazone (Avandia

Rosiglitazone is another type of diabetes medicine.

Joint pain

Muscle aches

Arm or leg pain

Back pain

Itching

Blisters

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

Tell your doctor if you have any side effect that bothers you, is unusual, or does not go away.

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

this leaflet, consult your doctor.

Reporting side effects:

Side effects can be reported to the Ministry of Health by using the online form for reporting side effects in

the homepage of the ministry of health website www.health.gov.il or by entering the following link:

https://sideeffects.health.gov.il

5. HOW TO STORE JANUET?

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 JANUET after the expiry date (exp. date) which is stated on pack. The expiry date refers to the

last day of the indicated month.

Store JANUET below 30°C.

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 JANUET contains?

Active ingredients: sitagliptin and metformin.

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

Microcrystalline

cellulose,

polyvinylpyrrolidone

(povidone),

sodium

lauryl

sulfate,

sodium

stearyl

fumarate.

The tablet film coating contains the following inactive ingredients:

Polyvinyl alcohol, macrogol/

polyethylene glycol, talc, titanium dioxide, iron oxide red, and iron oxide black.

6.2 What JANUET looks like and contents of the pack

JANUET tablets are available in three strengths:

JANUET 50 mg/500 mg are light pink, film-coated tablets, debossed ‘575’ on one side and blank on the other.

JANUET 50 mg/850 mg are pink, film-coated tablets, debossed ‘515’ on one side and blank on the other.

JANUET 50 mg/1000 mg are red, film-coated tablets, debossed ‘577’ on one side and blank on the other.

Pack sizes:

JANUET 50 mg/500 mg: pack sizes of 56 tablets.

JANUET 50 mg/850 mg: pack sizes of 14, 56 tablets.

JANUET 50 mg/1000 mg: pack sizes of 14, 56 tablets.

Not all pack sizes may be marketed.

Manufacturer:

Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey, USA

Marketing authorization holder: Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O. Box 7121

Petah-Tikva 49170

Revised on July 2020

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

JANUET 50 mg/500 mg: 139.89.31706

JANUET 50 mg/850 mg: 139.90.31902

JANUET 50 mg/1000 mg: 139.88.31705

JANUET

®

(sitagliptin/metformin HCl) tablets

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death,

hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated

lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise,

myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic

acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis

(without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and

metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment,

concomitant use of certain drugs (e.g., carbonic anhydrae inhibitors such as topiramate), age

65 years old or greater, having a radiological study with contrast, surgery and other

procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and

hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high

risk groups are provided in the full prescribing information [see Dosage and Administration

(2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in

Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue JANUET and

institute

general

supportive

measures

in

a

hospital

setting.

Prompt

hemodialysis

is

recommended [see Warnings and Precautions (5.1)].

1

INDICATIONS AND USAGE

JANUET is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients

with type 2 diabetes mellitus

Important Limitations of Use

JANUET 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.

JANUET 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 JANUET.

[See Warnings and Precautions (5.2).]

2

DOSAGE AND ADMINISTRATION

2.1

Adults with normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90

mL/min/173 m

2

)

The dosage of JANUET should be individualized on the basis of the patient’s current regimen,

effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg

sitagliptin and 2000 mg metformin hydrochloride (HCl). Initial combination therapy or maintenance of

combination therapy should be individualized and left to the discretion of the health care provider.

JANUET should generally be given twice daily with meals, with gradual dose escalation, to reduce the

gastrointestinal (GI) side effects due to metformin.

JANUET must not be split or divided before swallowing.

The starting dose of JANUET should be based on the patient’s current regimen. JANUET should be

given twice daily with meals. The following doses are available:

50 mg sitagliptin/500 mg metformin HCl

50 mg sitagliptin/850 mg metformin HCl50 mg sitagliptin/1000 mg metformin HCl

recommended

starting

dose

patients

currently

treated

with

metformin

50 mg

sitagliptin/500 mg metformin HCl twice daily, with gradual dose escalation recommended to reduce

gastrointestinal side effects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg

twice daily (100 mg total daily dose) and the dose of metformin already being taken.

Patients treated with an insulin secretagogue or insulin

Coadministration of JANUET 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

No studies have been performed specifically examining the safety and efficacy of JANUET in patients

previously treated with other oral antihyperglycemic agents and switched to JANUET. Any change in

therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in

glycemic control can occur.

2.2 Recommendations for Use in Renal Impairment

An eGFR should be assessed before initiation of treatment with metformin containing products and

at least annually thereafter. In patients at an increased risk of further progression of renal impairment and

in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that

may increase the risk of lactic acidosis [see Warnings and Precautions (5.1)] should be reviewed before

considering initiation of metformin in patients with eGFR<60 mL/min/1.73 m

If no adequate strength of JANUET is available, individual monocomponents should be used instead

of the fixed dose combination.

eGFR mL/min/1.73 m

2

Metformin

Sitagliptin

60-89

Maximum daily dose is 2550 mg.

Dose reduction may be considered

in relation to declining renal function.

Maximum daily dose is 100 mg.

45-59

Maximum daily dose is 2000 mg.

The starting dose is at most half of

the maximum dose.

Maximum daily dose is 100 mg.

30-44

Maximum daily dose is 1000 mg.

The starting dose is at most half of

the maximum dose.

Maximum daily dose is 50 mg.

< 30

Metformin is contraindicated.

Maximum daily dose is 25 mg.

3

DOSAGE FORMS AND STRENGTHS

Tablets:

50 mg/500 mg tablets are light pink, capsule-shaped, film-coated tablets with “575” debossed on

one side.

50 mg/850 mg tablets are pink, capsule-shaped, film-coated tablets with “515” debossed on one

side.

50 mg/1000 mg tablets are red, capsule-shaped, film-coated tablets with “577” debossed on one

side.

4

CONTRAINDICATIONS

JANUET is contraindicated in patients with:

Severe renal impairment (eGFR below 30 mL/min/1. 73 m

) [see Warnings and Precautions (5.1)].

Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should

be treated with insulin.

History of a serious hypersensitivity reaction to JANUET, sitagliptin, or metformin, such as

anaphylaxis or angioedema. [See Warnings and Precautions (5.9); Adverse Reactions (6.2).]

5

WARNINGS AND PRECAUTIONS

5.1

Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.

These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise,

myalgias,

abdominal

pain,

respiratory

distress,

increased

somnolence;

however,

hypothermia,

hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated

lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap

acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin

plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate

blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted

promptly in a hospital setting, along with immediate discontinuation of JANUET. In JANUET - treated

patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to

correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of

up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of

symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur

instruct them to discontinue JANUET and report these symptoms to their healthcare provider.

each

known

possible

risk

factors

metformin-associated

lactic

acidosis,

recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided

below:

Renal Impairment

The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with

significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis

increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

Clinical recommendations based upon the patient’s renal function include [see Dosage and

Administration (2.2), Clinical Pharmacology (12.3)]:

Before initiating JANUET, obtain an estimated glomerular filtration rate (eGFR).

JANUET is contraindicated in patients with an eGFR below 30 mL/min/1.73 m

[see

Contraindications (4)].

JANUET is not recommended in patients with an eGFR between 30 and less than 45

mL/min/1.73 m

because these patients require a lower dosage of sitagliptin than what is

available in the fixed combination JANUET product.

Obtain an eGFR at least annually in all patients taking JANUET. In patients at increased risk for

the development of renal impairment (e.g., the elderly), renal function should be assessed more

frequently.

Drug Interactions

The concomitant use of JANUET with specific drugs may increase the risk of metformin-associated lactic

acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-

base balance or increase metformin accumulation [see Drug Interactions (7)]. Therefore, consider more

frequent monitoring of patients.

Age 65 or Greater

The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly

patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients.

Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].

Radiological Studies with Contrast

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an

acute decrease in renal function and the occurrence of lactic acidosis. Stop JANUET at the time of, or

prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60

mL/min/1.73 m

; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in

patients

who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging

procedure, and restart JANUET if renal function is stable.

Surgery and Other Procedures

Withholding of food and fluids during surgical or other procedures may increase the risk for volume

depletion, hypotension and renal impairment. JANUET should be temporarily discontinued while patients

have restricted food and fluid intake.

Hypoxic States

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of

acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).

Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with

hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such

events occur, discontinue JANUET.

Excessive Alcohol Intake

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of

metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving

JANUET.

Hepatic Impairment

Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis.

This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use

of JANUET in patients with clinical or laboratory evidence of hepatic disease.

5.2

Pancreatitis

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

or necrotizing pancreatitis, in patients taking JANUET. After initiation of JANUET, patients should be

observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUET 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 JANUET.

5.3 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 JANUET 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 JANUET.

5.4

Assessment of Renal Function

Metformin and sitagliptin are known to be substantially excreted by the kidney.

Metformin HCl

JANUET is contraindicated in patients with severe renal impairment [see Contraindications (4) and

Warnings and Precautions (5.1)].

Sitagliptin

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

sometimes requiring dialysis. Before initiation of therapy with JANUET and at least annually thereafter,

renal function should be assessed. In patients in whom development of renal dysfunction is anticipated,

particularly

elderly

patients,

renal

function

should

assessed

more

frequently

JANUET

discontinued if evidence of renal impairment is present.

5.5

Vitamin B

12

Deficiency

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of

previously normal serum vitamin B

levelswas observed in approximately 7% of patients. Such decrease,

possibly due to interference with B

absorption from the B

-intrinsic factor complex, may be associated

with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B

supplementation. Certain individuals (those with inadequate vitamin B

or calcium intake or absorption)

appear to be predisposed to developing subnormal vitamin B

levels. Measure hematologic parameters on

an annual basis and vitamin B

measurements at 2- to 3-year intervalsin patients on JANUET and manage

any abnormalities [seeAdverse Reactions (6.1)].

5.6

Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes

A patient with type 2 diabetes previously well controlled on JANUET who develops laboratory

abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly

for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones,

blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form

occurs, JANUET must be stopped immediately and other appropriate corrective measures initiated.

5.7

Use with Medications Known to Cause Hypoglycemia

Sitagliptin

When sitagliptin 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)]. Therefore, patients also receiving an insulin

secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin

to reduce the risk of hypoglycemia [see Drug Interactions (7.4)].

Metformin HCl

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use,

but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric

supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and

insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary

insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may

be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.

5.8

Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection,

or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold

JANUET and temporarily administer insulin. JANUET may be reinstituted after the acute episode is

resolved.

5.9

Hypersensitivity Reactions

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

sitagliptin, one of the components of JANUET. These reactions include anaphylaxis, angioedema, and

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

the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose.

If a hypersensitivity reaction is suspected, discontinue JANUET, 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 JANUET.

5.10 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.

5.11 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 of blisters or

erosions while receiving JANUET. If bullous pemphigoid is suspected, JANUET should be discontinued

and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

5.12

Macrovascular Outcomes

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

with JANUET.

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.

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

Diet and Exercise

Table 1 summarizes the most common (

5% of patients) adverse reactions reported (regardless of

investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and

metformin were coadministered to patients with type 2 diabetes inadequately controlled on diet and

exercise.

Table 1: Sitagliptin and Metformin Coadministered to Patients with Type 2 Diabetes Inadequately Controlled

on Diet and Exercise:

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

5% of

Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo)*

Number of Patients (%)

Placebo

Sitagliptin

100 mg once

daily

Metformin 500 mg/

Metformin 1000 mg

twice daily

Sitagliptin

50 mg twice daily +

Metformin 500 mg/

Metformin 1000 mg twice

daily

N = 176

N = 179

N = 364

N = 372

Diarrhea

7 (4.0)

5 (2.8)

28 (7.7)

28 (7.5)

Upper Respiratory

Tract 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.

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

In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily

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

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

due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin,

1.9%; placebo and metformin, 2.5%).

Gastrointestinal Adverse Reactions

The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin

and metformin were similar to those reported for patients treated with metformin alone. See Table 2.

Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of

Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin

Number of Patients (%)

Study of Sitagliptin and Metformin in Patients Inadequately Controlled

on Diet and Exercise

Study of Sitagliptin Add-on in

Patients Inadequately Controlled

on Metformin Alone

Placebo

Sitagliptin

100 mg

once daily

Metformin 500 mg/

Metformin 1000 mg

twice daily*

Sitagliptin 50 mg twice

daily +

Metformin 500 mg/

Metformin 1000 mg

twice daily*

Placebo and

Metformin

1500 mg

daily

Sitagliptin 100 mg

once daily and

Metformin

1500 mg daily

N = 176

N = 179

N = 364

N = 372

N = 237

N = 464

Diarrhea

7 (4.0)

5 (2.8)

28 (7.7)

28 (7.5)

6 (2.5)

11 (2.4)

Nausea

2 (1.1)

2 (1.1)

20 (5.5)

18 (4.8)

2 (0.8)

6 (1.3)

Vomiting

1 (0.6)

0 (0.0)

2 (0.5)

8 (2.2)

2 (0.8)

5 (1.1)

Abdominal

Pain

4 (2.3)

6 (3.4)

14 (3.8)

11 (3.0)

9 (3.8)

10 (2.2)

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

Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.

Sitagliptin in Combination with Metformin and Glimepiride

In a 24-week placebo-controlled study of sitagliptin 100

mg as add-on therapy in patients with type 2

diabetes inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), the

adverse reactions reported regardless of investigator assessment of causality in

5% of patients treated

with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3) and

headache (6.9%, 2.7%).

Sitagliptin in Combination with Metformin and Rosiglitazone

In a placebo-controlled study of sitagliptin 100

mg as add-on therapy in patients with type 2 diabetes

inadequately controlled on metformin and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse

reactions reported regardless of investigator assessment of causality through Week 18 in

5% of patients

treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory

tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the

adverse reactions reported regardless of investigator assessment of causality in

5% of patients treated

with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract

infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%,

5.2%), and headache (5.5%, 4.1%).

Sitagliptin in Combination with Metformin and Insulin

In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2

diabetes inadequately controlled on metformin and insulin (sitagliptin, N=229; placebo, N=233), the only

adverse reaction reported regardless of investigator assessment of causality in

5% of patients treated with

sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).

Hypoglycemia

In the abovestudies(N=5), adverse reactions of hypoglycemia were based on all reports of symptomatic

hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of

hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of

sitagliptin and metformin was coadministered with a sulfonylurea or with insulin, the percentage of patients

reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and

metformin coadministered with a sulfonylurea or with insulin (Table 3).

Table 3:

Incidence and Rate of Hypoglycemia

*

(Regardless of Investigator Assessment of Causality) in

Placebo-

Controlled Clinical Studies of Sitagliptin in Combination with Metformin Coadministered with

Glimepiride or Insulin

Add-On to Glimepiride +

Metformin (24 weeks)

Sitagliptin 100 mg

+ Metformin

+ Glimepiride

Placebo

+ Metformin

+ Glimepiride

N = 116

N = 113

Overall (%)

19 (16.4)

1 (0.9)

Rate (episodes/patient-year)

0.82

0.02

Severe (%)

0 (0.0)

0 (0.0)

Add-On to Insulin

+ Metformin (24 weeks)

Sitagliptin 100 mg

+ Metformin

+ Insulin

Placebo

+ Metformin

+ Insulin

N = 229

N = 233

Overall (%)

35 (15.3)

19 (8.2)

Rate (episodes/patient-year)

0.98

0.61

Severe (%)

1 (0.4)

1 (0.4)

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.

The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes

inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given

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

combination with metformin. In patients with type 2 diabetes inadequately controlled on metformin alone,

the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin

and 2.1% in patients given add-on placebo.

In the study of sitagliptin and add-on combination therapy with metformin and rosiglitazone, the overall

incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin 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 sitagliptin and 1.0% in patients given add-on placebo.

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.

Vital Signs and Electrocardiograms

With the combination of sitagliptin and metformin, no clinically meaningful changes in vital signs or in

ECG (including in QTc interval) were observed.

Pancreatitis

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 (5.2).]

Sitagliptin

The most common adverse experience in sitagliptin monotherapy reported regardless of investigator

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

nasopharyngitis.

Metformin HCl

The most common (>5%) established adverse reactions due to initiation of metformin therapy are

diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

Laboratory Tests

Sitagliptin

The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and

metformin (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all

studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs

placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in

neutrophils. This change in laboratory parameters is not considered to be clinically relevant.

Metformin HCl

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of

previously normal serum vitamin B

levels, without clinical manifestations, was observed in approximately

7% of patients. Such decrease, possibly due to interference with B

absorption from the B

-intrinsic factor

complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with

discontinuation of metformin or vitamin B

supplementation. [See Warnings and Precautions (5.5).]

6.2

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of JANUET, sitagliptin, or

metformin. 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

(5.9 )]; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and

non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1); Warnings and

Precautions (5.2)]; worsening renal function, including acute renal failure (sometimes requiring dialysis)

[see Warnings and Precautions (5.4)]; severe and disabling arthralgia [see Warnings and Precautions

(5.10)]; bullous pemphigoid [see Warnings and Precautions (5.11)]; constipation; vomiting; headache;

myalgia; pain in extremity; back pain; pruritus; mouth ulceration; stomatitis; cholestatic, hepatocellular,

and mixed hepatocellular liver injury; rhabdomyolysis.

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.

7

DRUG INTERACTIONS

7.1

Carbonic Anhydrase Inhibitors

Topiramate

other

carbonic

anhydrase

inhibitors

(e.g.,

zonisamide,

acetazolamide

dichlorphenamide) frequently cause a

decrease in serum

bicarbonate

induce non-anion gap,

hyperchloremic metabolic acidosis. Concomitant use of these drugs with JANUET may increase the risk of

lactic acidosis. Consider more frequent monitoring of these patients.

7.2

Drugs that Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the

renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion

[MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic

exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)].

Consider the benefits and risks of concomitant use.

7.3 Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against

excessive alcohol intake while receiving JANUET.

7.4 Insulin Secretagogues or Insulin

Co-administration of JANUET 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 (5.7).]

7.5 Use of Metformin with Other Drugs

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs

include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral

contraceptives,

phenytoin,

nicotinic

acid,

sympathomimetics,

calcium

channel

blocking

drugs,

isoniazid. When such drugs are administered to a patient receiving JANUET the patient should be closely

observed to maintain adequate glycemic control.

7.6 Digoxin

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

max,

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 JANUET is recommended.

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary

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

risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have

not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. 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. No adverse developmental effects were observed when metformin

was administered to pregnant Sprague Dawley rats and rabbits during organogenesis at doses up to 2- and

6-times, respectively, a 2000 mg clinical dose, based on body surface area [see Data].

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

with a 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

Human Data

Published data from post-marketing studies do not report a clear association with metformin and major

birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy.

However, these studies cannot definitely establish the absence of any risk because of methodological

limitations, including small sample size and inconsistent comparator groups.

Animal Data

Sitagliptin and Metformin

No animal reproduction studies were conducted with the coadministration of sitagliptin and metformin.

Sitagliptin

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 doses) 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

Metformin HCl

Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague

Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an

exposure of about 2- and 6- times a 2000 mg clinical dose based on body surface area (mg/m

) for rats and

rabbits, respectively.

8.2 Lactation

Risk Summary

JANUET

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

infant, or the effects on milk production. Limited published studies report that metformin is present in human

milk [see Data]. There are no reports of adverse effects on breastfed infants exposed to metformin. There

is no information on the effects of metformin 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 JANUET and any potential

adverse effects on the breastfed infant from JANUET or from the underlying maternal condition.

Data

Sitagliptin

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

Metformin HCl

Published clinical lactation studies report that metformin is present in human milk, which resulted in

infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio

ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use

of metformin during lactation because of small sample size and limited adverse event data collected in

infants.

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin

may result in ovulation in some anovulatory women.

8.4

Pediatric Use

Safety and effectiveness of JANUET in pediatric patients under 18 years have not been established.

8.5

Geriatric Use

JANUET

Because sitagliptin and metformin are 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 (5.1, 5.4); Clinical Pharmacology (12.3).]

Sitagliptin

Of the total number of subjects (N=3884) in Phase II and III clinical studies of sitagliptin, 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.

Metformin HCl

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine

whether they respond differently from younger patients, although other reported clinical experience has not

identified differences in responses between the elderly and young patients. In general, dose selection for

an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the

greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other

drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients.

[See Contraindications (4); Warnings and Precautions (5.1); Clinical Pharmacology (12.3).]

8.6 Renal Impairment

JANUET

JANUET is not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m

because these patients require a lower dosage of sitagliptin than what is available in the fixed dose

combination JANUET product. JANUET is contraindicated in severe renal impairment, patients with an

eGFR below 30 mL/min/1.73 m². [See Dosage and Administration (2.2), Contraindications (4), Warnings

and Precautions (5.1) and Clinical Pharmacology (12.3).]

Sitagliptin

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).

Metformin

HCl

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic

acidosis increases with the degree of renal impairment.

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic

acidosis. JANUET is not recommended in patients with hepatic impairment. [See Warnings and Precautions

(5.1)]

10

OVERDOSAGE

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

material

from

gastrointestinal

tract,

employ

clinical

monitoring

(including

obtaining

electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over

a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It

is not known if sitagliptin is dialyzable by peritoneal dialysis.

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams.

Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl

has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose

cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min

under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated

drug from patients in whom metformin overdosage is suspected.

11

DESCRIPTION

JANUET (sitagliptin and metformin HCl) tablets contain two oral antihyperglycemic drugs: sitagliptin and

metformin HCl.

Sitagliptin

Sitagliptin is an

orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin is present

in JANUET tablets in the form of sitagliptin phosphate monohydrate. Sitagliptin phosphate monohydrate is

described

chemically

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 with an empirical formula of

OH

H

O and a molecular weight of 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.

Metformin HCl

Metformin

(N,N-dimethylimidodicarbonimidic

diamide

hydrochloride)

chemically

pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin HCl is a white

to off-white crystalline compound with a molecular formula of C

HCl and a molecular weight of

165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and

chloroform. The pK

of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The

structural formula is as shown:

JANUET

JANUET is available as film-coated tablets containing:

64.25 mg

sitagliptin

monohydrate

equivalent

50 mg

sitagliptin

500 mg

metformin

hydrochloride (JANUET 50 mg/500 mg).

64.25 mg

sitagliptin

monohydrate

equivalent

50 mg

sitagliptin

metformin

hydrochloride (JANUET 50 mg/850 mg).

64.25 mg

sitagliptin

monohydrate

equivalent

50 mg

sitagliptin

1000 mg

metformin

hydrochloride (JANUET 50 mg/1000 mg).

Each film-coated tablet of JANUET contains the following inactive ingredients: microcrystalline cellulose,

polyvinylpyrrolidone (Povidone), sodium lauryl sulfate, and sodium stearyl fumarate. In addition, the film

coating contains the following inactive ingredients: polyvinyl alcohol, macrogol/polyethylene glycol, talc,

titanium dioxide, iron oxide red, and iron oxide black.

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

JANUET

JANUET combines two antihyperglycemic agents with complementary mechanisms of action to improve

glycemic control in patients with type 2 diabetes mellitus: sitagliptin, a dipeptidyl peptidase-4 (DPP-4)

inhibitor, and metformin HCl, a member of the biguanide class.

Sitagliptin

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

increases 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.

Metformin HCl

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2

diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic

glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by

increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains

unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

12.2

Pharmacodynamics

Sitagliptin

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

insulin

release

glucose,

resulting

higher

C-peptide

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 HCl 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 of

sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not

metformin, increased active GIP concentrations. It is unclear what these findings mean for 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 at 3 hours postdose 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

Sitagliptin

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

M*hr, 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

Sitagliptin

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

Coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin.

Metformin HCl

The absolute bioavailability of a metformin HCl 500-mg tablet given under fasting conditions is

approximately 50-60%. Studies using single oral doses of metformin HCl tablets 500 mg to 1,500 mg, and

850 mg to 2,550 mg (approximately 1.3 times the maximum recommended daily dosage), indicate that

there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather

than an alteration in elimination.

Effect of Food

Food

decreases

extent

slightly

delays

absorption

metformin,

shown

approximately a 40% lower mean peak plasma concentration (C

), a 25% lower area under the plasma

concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration

) following administration of a single 850-mg tablet of metformin with food, compared to the same

tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

Sitagliptin

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%).

Metformin HCl

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl

tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to

sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely

as a function of time. At usual clinical doses and dosing schedules of metformin HCl tablets, steady-state

plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL.

Elimination

Sitagliptin

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 was

approximately 12.4 hours and renal clearances was approximately 350 mL/min.

Metformin HCl

Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route

within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the

elimination half-life is approximately 17.6

hours, suggesting that the erythrocyte mass

may be

compartment of distribution.

Metabolism

Sitagliptin

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.

Metformin HCl

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged

in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor

biliary excretion.

Excretion

Sitagliptin

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.

Metformin HCl

Elimination of metformin occurs primarily via renal excretion. Renal clearance is approximately 3.5 times

greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin

elimination.

Specific Populations

Patients with Renal Impairment

JANUET

Studies characterizing the pharmacokinetics of sitagliptin and metformin after administration of

JANUET in renally impaired patients have not been performed [see Dosage and Administration (2.2)].

Sitagliptin

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 m

, and an approximately 4-fold

increase was observed in patients with severe renal impairment including patients with end-stage renal

disease (ESRD) on hemodialysis, as compared to normal healthy control subjects. [see Dosage and

Administration (2.2).]

Metformin HCl

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and

the renal clearance is decreased [see Contraindications (4); Warnings and Precautions (5.1)].

Patients with Hepatic Impairment

JANUET

Studies characterizing the pharmacokinetics of sitagliptin and metformin after administration of JANUET

in patients with hepatic impairment have not been performed.

Sitagliptin

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) [see Use in Specific Populations (8.7)].

Metformin HCl

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

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

Sitagliptin

Based on a population pharmacokinetic analysis or a composite analysis of 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.

Metformin HCl

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest

that total plasma clearance of metformin is decreased, the half-life is prolonged, and C

is increased,

compared to healthy young subjects. From these data, it appears that

the change

metformin

pharmacokinetics with aging is primarily accounted for by a change in renal function.

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients

with type 2 diabetes mellitus when analyzed according to gender. Similarly, in controlled clinical studies in

patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males

and females.

No studies of metformin pharmacokinetic parameters according to race have been performed. In

controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect

was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).

Pediatric Patients

Sitagliptin

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

Drug Interaction Studies

JANUET

Coadministration of multiple doses of sitagliptin (50 mg) and metformin (1000 mg) given twice daily did

not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes.

Pharmacokinetic drug interaction studies with JANUET have not been performed; however, such

studies have been conducted with the individual components of JANUET (sitagliptin and metformin HCl).

Sitagliptin

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 contraception (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 Coadministered 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).

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

Metformin HCl

Table 6: Effect of Metformin on Systemic Exposure of Coadministered Drugs

Coadministered Drug

Dose of

Coadministered

Drug*

Dose of Metformin*

Geometric Mean Ratio

(ratio with/without metformin)

No Effect = 1.00

Cimetidine

400 mg

850 mg

Cimetidine

0.95

1.01

Glyburide

5 mg

500 mg

Glyburide

0.78

0.63

Furosemide

40 mg

850 mg

Furosemide

0.87

0.69

Nifedipine

10 mg

850 mg

Nifedipine

1.10

1.08

Propranolol

40 mg

850 mg

Propranolol

1.01

0.94

Ibuprofen

400 mg

850 mg

Ibuprofen

0.97

1.01

*

All doses administered as single dose unless otherwise specified.

AUC is reported as AUC

0-∞

unless otherwise specified.

0-24hr

Ratio of arithmetic means, p value of difference <0.05.

GLUMETZA (metformin

extended-release tablets) 500 mg.

Ratio of arithmetic means.

Table 7: Effect of Coadministered Drugs on Systemic Exposure of Metformin

Coadministered

Drug

Dose of

Coadministered

Drug*

Dose of

Metformin*

Geometric Mean Ratio

(ratio with/without coadministered drug)

No Effect = 1.00

Glyburide

5 mg

500 mg

Metformin

0.98

0.99

Furosemide

40 mg

850 mg

Metformin

1.09

1.22

Nifedipine

10 mg

850 mg

Metformin

1.16

1.21

Propranolol

40 mg

850 mg

Metformin

0.90

0.94

Ibuprofen

400 mg

850 mg

Metformin

1.05

1.07

Drugs that are eliminated by renal tubular secretion may increase the accumulation of

metformin. [See Warnings and Precautions (5.1) and Drug Interactions (7.2).]

Cimetidine

400 mg

850 mg

Metformin

1.40

1.61

Carbonic anhydrase inhibitors may cause metabolic acidosis. [See Warnings and Precautions (5.1) and Drug

Interactions (7.1).]

Topiramate

100 mg

500 mg

Metformin

1.25

1.17

*

All doses administered as single dose unless otherwise specified.

AUC is reported as AUC

0-∞

unless otherwise specified.

GLUMETZA (metformin HCl extended-release tablets) 500 mg.

Ratio of arithmetic means.

Steady state 100 mg Topiramate every 12 hr + metformin 500 mg every 12 hr AUC = AUC

0-12hr

13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

JANUET

No animal studies

have

been conducted with the combined

products

JANUET to evaluate

carcinogenesis, mutagenesis or impairment of fertility. The following data are based on the findings in

studies with sitagliptin and metformin individually.

Sitagliptin

A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin

of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma

in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures

approximately 60 times the human exposure at the maximum recommended daily adult human dose

(MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg,

approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted

in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no

increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure

at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames

bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro

cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo

micronucleus assay.

In rat fertility studies with oral gavage doses of 125, 250, and 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).

Metformin HCl

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice

(dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day,

respectively. These doses are both approximately four times the maximum recommended human daily

dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin

was found in either male or female mice. Similarly, there was no tumorigenic potential observed with

metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in

female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test

(S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human

lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female

rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is

approximately three times the maximum recommended human daily dose based on body surface area

comparisons.

14

CLINICAL STUDIES

The coadministration of sitagliptin and metformin has been studied in patients with type 2 diabetes

inadequately controlled on diet and exercise and in combination with other antihyperglycemic agents.

None

clinical

efficacy

studies

described

below

conducted

with

JANUET;

however,

bioequivalence of JANUET with coadministered sitagliptin and metformin HCl tablets was demonstrated.

Sitagliptin and Metformin Coadministration in Patients with Type 2 Diabetes Inadequately

Controlled on Diet and Exercise

A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise

participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess

the efficacy of sitagliptin and metformin coadministration. Patients on an antihyperglycemic agent (N=541)

underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period,

patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week

single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with

inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in

period and then were randomized. Approximately equal numbers of patients were randomized to receive

placebo, 100 mg of sitagliptin once daily, 500 mg or 1000 mg of metformin twice daily, or 50 mg of sitagliptin

twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet

specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Sitagliptin and metformin coadministration provided significant improvements in A1C, FPG, and 2-hour

PPG compared to placebo, to metformin alone, and to sitagliptin alone (Table 8, Figure 1). Mean reductions

from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not

on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: sitagliptin 100

mg once daily, -1.1%; metformin 500 mg bid, -1.1%; metformin 1000 mg bid, -1.2%; sitagliptin 50 mg bid

with metformin 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin 1000 mg bid, -1.9%; and for patients

receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups

given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or

placebo.

Table 8: Glycemic Parameters at Final Visit (24-Week Study)

for Sitagliptin and Metformin, Alone and in Combination in Patients with Type 2 Diabetes Inadequately Controlled

on Diet and Exercise

*

Placebo

Sitagliptin

100 mg

once daily

Metformin

500 mg

twice daily

Metformin

1000 mg

twice daily

Sitagliptin

50 mg twice

daily +

Metformin

500 mg

twice daily

Sitagliptin

50 mg

twice

daily +

Metformin

1000 mg

twice daily

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 in Patients with Type 2 Diabetes Inadequately Controlled with Diet and

Exercise

*

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

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

to the discretion of the health care provider.

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

Alone

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-

controlled study designed to assess the efficacy of sitagliptin in combination with metformin. Patients

already on metformin (N=431) at a dose of at least 1500 mg per day were randomized after completing a

2-week, single-blind placebo run-in period. Patients on metformin and another antihyperglycemic agent

(N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were

randomized after a run-in period of approximately 10 weeks on metformin (at a dose of at least 1500 mg

per day) in monotherapy. Patients were randomized to the addition of either 100 mg of sitagliptin or placebo,

administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated

with pioglitazone rescue.

In combination with metformin, sitagliptin provided significant improvements in A1C, FPG, and 2-hour

PPG compared to placebo with metformin (Table 9). Rescue glycemic therapy was used in 5% of patients

treated with sitagliptin 100 mg and 14% of patients treated with placebo. A similar decrease in body weight

was observed for both treatment groups.

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 at Final Visit (24-Week Study) of Sitagliptin as Add-on Combination

Therapy with Metformin

*

Sitagliptin 100 mg once

daily + 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.

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

Combination of Metformin and Glimepiride

A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind,

placebo-controlled study designed to assess the efficacy of sitagliptin in combination with glimepiride, with

or without metformin. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or

glimepiride in combination with metformin (≥1500 mg per day). After a dose-titration and dose-stable run-

in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control

(A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of sitagliptin or placebo,

administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated

with pioglitazone rescue.

Patients receiving sitagliptin with metformin and glimepiride had significant improvements in A1C and

FPG compared to patients receiving placebo with metformin and glimepiride (Table 10), with mean

reductions from baseline relative to placebo in A1C of -0.9% and in FPG of -21 mg/dL. Rescue therapy was

used in 8% of patients treated with add-on sitagliptin 100 mg and 29% of patients treated with add-on

placebo. The patients treated with add-on sitagliptin had a mean increase in body weight of 1.1 kg vs. add-

on placebo (+0.4 kg vs. -0.7 kg). In addition, add-on sitagliptin resulted in an increased rate of hypoglycemia

compared to add-on placebo. [See Warnings and Precautions (5.7 ); Adverse Reactions (6.1).]

Table 10: Glycemic Parameters at Final Visit (24-Week Study)

for Sitagliptin in Combination with Metformin and Glimepiride

*

Sitagliptin 100 mg

+ Metformin

and Glimepiride

Placebo

+ Metformin

and Glimepiride

A1C (%)

N = 115

N = 105

Baseline (mean)

Change from baseline (adjusted

mean

-0.6

Difference from placebo (adjusted

mean

) (95% CI)

-0.9

(-1.1, -0.7)

Patients (%) achieving A1C <7%

26 (23%)

1 (1%)

FPG (mg/dL)

N = 115

N = 109

Baseline (mean)

Change from baseline (adjusted

mean

Difference from placebo (adjusted

mean

) (95% CI)

(-32, -10)

*

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.

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

Combination of Metformin and Rosiglitazone

A total of 278 patients with type 2 diabetes participated in a 54-week, randomized, double-blind,

placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin and

rosiglitazone. Patients on dual therapy with metformin

1500 mg/day and rosiglitazone

4 mg/day or with

metformin

1500 mg/day and pioglitazone

30 mg/day (switched to rosiglitazone

4 mg/day) entered a

dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin

1500 mg/day and rosiglitazone

4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks

in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were

randomized 2:1 to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients

who failed to meet specific glycemic goals during the studies were treated with glipizide (or other

sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.

In combination with metformin and rosiglitazone, sitagliptin provided significant improvements in A1C,

FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 11) at Week 18. At

Week 54, mean reduction in A1C was -1.0% for patients treated with sitagliptin and -0.3% for patients

treated with placebo in an analysis based on the intent to treat population. Rescue therapy was used in

18% of patients treated with sitagliptin 100 mg and 40% of patients treated with placebo. There was no

significant difference between sitagliptin and placebo in body weight change.

Table 11: Glycemic Parameters at Week 18 for Sitagliptin in Add-on

Combination Therapy with Metformin and Rosiglitazone

*

Week 18

Sitagliptin

100 mg +

Metformin +

Rosiglitazone

Placebo +

Metformin +

Rosiglitazone

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.

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

Combination of Metformin and Insulin

A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind,

placebo-controlled study designed to assess the efficacy of sitagliptin as add-on to insulin therapy.

Approximately 75% of patients were also taking metformin. Patients entered a 2-week, single-blind run-in

treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin

(≥1500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was

administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic

control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of sitagliptin (N=229) or

placebo (N=233), administered once daily. Patients were on a stable dose of insulin prior to enrollment with

no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic

goals during the double-blind treatment period were to have uptitration of the background insulin dose as

rescue therapy.

Among patients also receiving metformin, the median daily insulin (pre-mixed, intermediate or long

acting) dose at baseline was 40 units in the sitagliptin-treated patients and 42 units in the placebo-treated

patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of

the study. Patients receiving sitagliptin with metformin and insulin had significant improvements in A1C,

FPG and 2-hour PPG compared to patients receiving placebo with metformin and insulin (Table 12). The

adjusted mean change from baseline in body weight was -0.3 kg in patients receiving sitagliptin with

metformin and insulin and -0.2 kg in patients receiving placebo with metformin and insulin. There was an

increased rate of hypoglycemia in patients treated with sitagliptin. [See Warnings and Precautions (5.7);

Adverse Reactions (6.1).]

Table 12: Glycemic Parameters at Final Visit (24-Week Study)

for Sitagliptin as Add-on Combination Therapy with Metformin and Insulin

*

Sitagliptin 100 mg

+ Metformin

+ Insulin

Placebo

+ Metformin

+ Insulin

A1C (%)

N = 223

N = 229

Baseline (mean)

Change from baseline (adjusted mean

†,‡

-0.7

-0.1

Difference from placebo (adjusted mean

) (95% CI)

-0.5

(-0.7, -0.4)

Patients (%) achieving A1C <7%

32 (14%)

12 (5%)

FPG (mg/dL)

N = 225

N = 229

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo (adjusted mean

) (95% CI)

(-28, -8.4)

2-hour PPG (mg/dL)

N = 182

N = 189

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo (adjusted mean

) (95% CI)

(-53, -28)

*

Intent to-treat population using last observation on study prior to rescue therapy.

Least squares means adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed

vs. non pre-mixed [intermediate- or long-acting]), and baseline value.

Treatment by insulin stratum interaction was not significant (p >0.10).

p<0.001 compared to placebo.

Maintenance of Sitagliptin 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 sitagliptin 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 sitagliptin (100 mg/day) directly entered the double-blind treatment period; those on

another DPP-4 inhibitor and/or on a sulfonylurea entered a 4-8 week run-in period in which they were

maintained on metformin and switched to sitagliptin (100 mg); other DPP-4 inhibitors and sulfonylureas

were discontinued. At randomization patients were randomized either to continue sitagliptin or to

discontinue sitagliptin and switch to a matching placebo. On the day of randomization, insulin glargine

was initiated at a dose of 10 units subcutaneously in the evening. Patients were instructed to 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 13). 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 13: Change from Baseline in A1C and FPG at Week 30 in the Maintenance of Sitagliptin During

Initiation and Titration of Insulin Glargine Study

Sitagliptin 100 mg

+ Metformin

+ Insulin Glargine

Placebo

+ Metformin

+ Insulin Glargine

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.

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

Inadequately Controlled on Metformin

The efficacy of sitagliptin was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority

trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered

a run-in treatment period of up to 12 weeks duration with metformin monotherapy (dose of ≥1500 mg per

day) which included washout of medications other than metformin, if applicable. After the run-in period,

those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of sitagliptin

100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of

5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed

to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration

to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.

After 52 weeks, sitagliptin and glipizide had similar mean reductions from baseline in A1C in the intent-

to-treat analysis (Table 14). These results were consistent with the per protocol analysis (Figure 2). A

conclusion in favor of the non-inferiority of sitagliptin to glipizide may be limited to patients with baseline

A1C comparable to those included in the study (over 70% of patients had baseline A1C less than 8% and

over 90% had A1C less than 9%).

Table 14: Glycemic Parameters in a 52-Week Study Comparing

Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately

Controlled on Metformin (Intent-to-Treat Population)

*

Sitagliptin 100 mg

+ Metformin

Glipizide

+ Metformin

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 Sitagliptin to

Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Per Protocol Population)

*

The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had

observations at baseline and at Week 52.

The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly (p<0.001) lower than

that in the glipizide group (32.0%). Patients treated with sitagliptin exhibited a significant mean decrease

from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg

vs. +1.1 kg).

16

HOW SUPPLIED/STORAGE AND HANDLING

Tablets

JANUET,

50 mg/500 mg,

light

pink,

capsule-shaped,

film-coated

tablets

with

“575”

debossed on one side. They are supplied as follows: pack sizes of 56 tablets.

Tablets JANUET, 50 mg/850 mg, are pink, capsule-shaped, film-coated tablets with “515” debossed on

one side. They are supplied as follows: pack sizes of 14, 56 tablets. Not all pack sizes may be marketed.

Tablets JANUET, 50 mg/1000 mg, are red, capsule-shaped, film-coated tablets with “577” debossed on

one side. They are supplied as follows: pack sizes of 14, 56 tablets. Not all pack sizes may be marketed.

Store below 30°C.

Manufacturer: Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey, USA

License Holder: 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:

Januet 50/850 mg: 139.90.31902

Januet 50/1000 mg: 139.88.31705

Januet 50/500 mg: 139.89.31706

Revised on July 2020

לע העדוה ( הרמחה

עדימ ל ןולעב )תוחיטב אפור

ןכדועמ(

.102.50

___ ךיראת

.2015

__

תילגנאב רישכת םש

Januet 50mg/500 mg, 50 mg/850 mg, 50 mg/1000 mg Tablets

םושירה רפסמ

31706, 31902, 31705

םושירה לעב םש

.

1996) Company Ltd

Merck Sharp & Dohme (Israel

ה טורפל דעוימ הז ספו דבלב תורמחה

תושקובמה תורמחהה

ןולעב קרפ

טסקט

יחכונ

שדח טסקט

5

WARNINGS

AND

PRECAUTIONS

5.15 Severe and Disabling Arthralgia

There have been postmarketing reports of severe and

disabling arthralgia in patients taking D

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

restarting the

experienced a recurrence of symptoms when

4 inhibitor.

same drug or a different DPP

Consider DPP-4 inhibitors as a possible cause for severe joint

pain and discontinue drug if appropriate.

6

ADVERSE

REACTIONS

6.2

Postmarketing

Experience

arthralgia

[see Warnings and Precautions

arthralgi

severe and disabling

(5.15)];

17

PATIENT

COUNSELING

INFORMATION

17.1 Instructions

Inform patients that severe and disabling joint pain may

occur with this class of drugs. The time to onset of symptoms

Instruct patients to seek

can range from one day to years.

[see Warnings and

medical advice if severe joint pain occurs

Precautions (5.15)]

ןכרצל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה

ןכדועמ(

.102.50

___ ךיראת

.2015

__

תילגנאב רישכת םש

Januet 50mg/500 mg, 50 mg/850 mg, 50 mg/1000 mg Tablets

םושירה רפסמ

31706, 31902, 31705

םושירה לעב םש

.

1996) Company Ltd

Merck Sharp & Dohme (Israel

וט ! דבלב תורמחהה טורפל דעוימ הז ספ

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

4

יאוול תועפות

.

תוירשפא

םיקרפמ באכ םימייוסמ םישנא 0 תוארקנה תופורת םילטונה יבכעמ

תופורתהמ תחא ,

טאונ'ג

חתפל םילולע ,הליכמ רשא םיקרפמ באכ

לוכי תויהל רוצ 0רומח ךלש אפורה םע רשק םיקרפמ באכמ לבוס ךנה םא 0רומח

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