ONGLYZA 5 MG

Israel - English - Ministry of Health

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Active ingredient:
SAXAGLIPTIN AS HYDROCHLORIDE
Available from:
ASTRA ZENECA (ISRAEL) LTD
ATC code:
A10BH03
Pharmaceutical form:
FILM COATED TABLETS
Composition:
SAXAGLIPTIN AS HYDROCHLORIDE 5 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
ASTRA ZENECA PHARMACEUTICALS LP, USA
Therapeutic group:
SAXAGLIPTIN
Therapeutic area:
SAXAGLIPTIN
Therapeutic indications:
Monotherapy: Onglyza is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.Onglyza should not be used in patients with ESRDCombination therapy: Add-on combination: Onglyza is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin, a thiazolidinedione (TZD), or a sulfonylurea (SU), when the single agent alone, with diet and exercise, does not provide adequate glycemic control.Initial combination: Onglyza is indicated for use as initial combination therapy with metformin, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus when dual saxagliptin and metformin therapy is appropriate.Onglyza should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. In combination with insulin (with or without metformin), when this regimen alone, with diet and exercise, does not provide adequate glycaemic control.
Authorization number:
144 74 33080 00
Authorization date:
2015-10-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

24-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

03-01-2019

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor's prescription only

Onglyza

TM

2.5 mg

Onglyza

TM

5 mg

Film-coated tablets

Film-coated tablets

Composition:

Each tablet contains:

saxagliptin (as HCl) 2.5 mg

saxagliptin (as HCl) 5 mg

For inactive ingredients, please see section 6 – Further Information.

Read this leaflet carefully in its entirety before using the medicine.

Keep this leaflet; you may need it again.

This leaflet contains concise information about the medicine. If you have

further questions, refer to the doctor or pharmacist.

This medicine has been prescribed to treat your ailment. Do not pass it on to

others. It may harm them even if it seems to you that their ailment is similar.

This medicine is not intended for children and adolescents under the

age of 18 years.

1.

WHAT IS THE MEDICINE INTENDED FOR?

Onglyza is intended to balance blood sugar levels in adult patients (from the

age of 18 and above) with type 2 diabetes:

in combination with diet and exercise.

in combination with insulin or other oral anti-diabetic medicine, in cases in

which the diabetes is inadequately controlled when using one anti-diabetic

medicine.

as an initial treatment in combination with metformin, diet and exercise.

Do not use in patients with end-stage renal disease (ESRD)

Therapeutic group:

Dipeptidyl peptidase (DPP 4) inhibitor

2.

BEFORE USING THE MEDICINE

X Do not use the medicine if:

you are sensitive (allergic) to the active ingredient or to any of the other

ingredients contained in the medicine.

you have had a severe allergic reaction (hypersensitivity) to Onglyza or to

any other similar medicine intended to balance blood sugar levels. See

section 4 – Side Effects.

you are pregnant.

you are breastfeeding.

you have type 1 diabetes.

you are suffering from ketoacidosis (a complication of diabetes manifested

by high levels of certain acids – ketones in the blood or urine, rapid

weight loss, nausea or vomiting).

Onglyza is not intended for the treatment of patients with end-stage renal

disease (ESRD).

!

Special warnings regarding use of Onglyza

If you have symptoms of severe pancreatitis, such as severe and

prolonged abdominal pain (sometimes radiating toward the back), with or

without vomiting, stop the treatment and consult the doctor immediately.

Pancreatitis can be serious and even life-threatening.

Certain medical conditions increase the likelihood of pancreatitis; before

you begin treatment with Onglyza, tell the doctor if you have suffered from:

Severe pancreatitis.

Gallstones.

Addiction to alcohol.

High blood triglyceride levels.

It is unknown whether these problems can increase the risk of pancreatitis

during treatment with Onglyza.

Skin lesions are common complications among diabetes patients. Rash is

an effect observed following treatment with Onglyza and other

anti-diabetic

medicines. Follow the doctor's instructions regarding treatment of the skin

and legs.

If you are suffering from an intolerance to galactose, a Lapp lactase

deficiency or impaired glucose-galactose absorption.

! Before treatment with Onglyza, tell the doctor if:

you are taking insulin. Do not use Onglyza as an insulin substitute.

you have type 1 diabetes (your body does not produce any insulin) or

diabetic ketoacidosis (a complication of diabetes with high blood pressure,

drastic weight loss, nausea and vomiting). Onglyza should not be used for

these conditions.

you have, or have ever had, a pancreatic disease.

you are taking insulin or another

anti-diabetic medicine of the

sulphonylurea

group together with Onglyza; the doctor may lower the dosage of insulin

and/or sulphonylurea to prevent low blood sugar levels.

you suffered in the past from hypersensitivity to any other

anti-diabetic

medicine.

you have a disease that reduces the activity of the immune system, such

as the immune deficiency syndrome AIDS, or if you are taking medicines

that cause a reduction in immune system activity, for example, medicines

taken after organ transplantation.

you suffer from heart failure.

you have ever had heart failure, or if you have risk factors for heart failure,

such as problems with your kidneys. Your doctor will explain the signs of

heart failure to you. Immediately refer to a doctor, pharmacist or nurse if

you experience any of these signs. The signs can include (but are not

limited to) – escalating shortness of breath, rapid weight gain and swelling

of the feet (edema in the feet and ankles).

you have moderate or severe kidney function impairment; you may need to

take a lower dosage of Onglyza. If you are undergoing hemodialysis – do

not use Onglyza.

you have moderate or severe liver function impairment. If you have severe

liver function impairment, use of Onglyza is not recommended.

If you are sensitive to any food or medicine, inform the doctor before taking

the medicine.

! If you are taking other medicines

If you are taking any other medicine, including non-prescription medicines and

nutritional

supplements,

tell

doctor

pharmacist.

particularly

important to inform the doctor or pharmacist if you are taking medicines from

the following groups:

Carbamazepine, phenobarbital or phenytoin (for seizures or long lasting

pain that does not pass),

Dexamethasone (a steroid for treatment of inflammations),

Rifampicin (to treat infections such as tuberculosis),

Ketoconazole (for fungal infections),

Diltiazem (to lower blood pressure).

Use of Onglyza and food

Onglyza can be taken with or without food.

Pregnancy and breastfeeding

Do not use this medicine if you are pregnant, planning to become pregnant or

are breastfeeding.

Driving and using machines

Use of this medicine may cause dizziness. If you feel dizzy when taking

Onglyza, do not drive a car, operate dangerous machinery or engage in any

activity that requires alertness. Hypoglycemia may affect your ability to drive

and to operate dangerous machinery. There is risk of hypoglycemia when

taking Onglyza with preparations known to cause hypoglycemia, such as

insulin and sulphonylurea.

Important information regarding some of the ingredients of the medicine

The tablets contain lactose (milk sugar). If you have been told by the doctor

that you have an intolerance to certain sugars, consult the doctor before

taking this medicine.

Onglyza 2.5 mg and Onglyza 5 mg tablets: each tablet contains 99 mg lactose

monohydrate.

3.

HOW SHOULD YOU USE THE MEDICINE?

Always use in accordance with the doctor's instructions. Check with the

doctor or pharmacist if you are uncertain.

The dosage and treatment regimen will be determined by the doctor only.

Do not exceed the recommended dose.

Onglyza will be given to you in combination with another anti-diabetic

medicine. Take Onglyza and the other medicine precisely as instructed by

your doctor.

If you have kidney function impairment, the doctor may prescribe a lower

dosage of Onglyza; this dosage is 2.5 mg Onglyza, once a day.

When your body is in a state of stress, such as fever, trauma (e.g., car

accident), infection or surgery, you may need to change the dosage of the

medicine. Inform the doctor if any of these conditions apply to you.

Instructions for use:

Do not halve or cut the tablets. There is no data regarding crushing the

tablets. Swallow the tablets with water.

Onglyza can be taken with or without food.

Onglyza can be taken at any time during the day, but try to take the tablets

at the same time every day.

If you accidentally take too high a dosage or if a child has accidentally

swallowed the medicine, immediately refer to the doctor or proceed to the

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

If you forgot to take this medicine at the scheduled time, take a dose as

soon as you remember; but if you remembered close to the time for the next

dose, do not take the previous dose that you missed. Never take two doses

together.

Adhere to the treatment regimen as recommended by the doctor.

How can you contribute to the success of the treatment?

Complete the treatment regimen as recommended by the doctor.

Even if there is an improvement in your health, do not stop treatment with the

medicine without consulting the doctor.

Do not take medicines in the dark! Check the label and the dose each

time you take medicine. Wear glasses if you need them.

If you have further questions regarding use of the medicine, consult the doctor

or pharmacist.

4.

SIDE EFFECTS

As with any medicine, use of Onglyza may cause side effects in some users.

Do not be alarmed when reading the list of side effects. You may not suffer

from any of them.

Stop treatment with Onglyza and immediately refer to a doctor if you

experience the following effects that are due to low blood sugar levels

Very common effects (affect more than 1 in 10 patients):

trembling,

sweating,

anxiety,

blurred vision,

rapid heartbeat,

tingling lips,

paleness,

mood change,

vagueness or confusion (hypoglycemia),

headache,

hunger.

Symptoms of a severe allergic reaction (seen rarely, at a frequency of 1-10 in

10,000 users) can include:

rash

red patches (lumps) on the skin (hives)

swelling of the face, lips, tongue, and throat that can cause breathing or

swallowing difficulties.

If you have these signs, stop taking Onglyza and immediately refer to the

attending doctor or nurse. The doctor may prescribe a medicine for you to

treat the allergic reaction and a different medicine for your diabetes.

Severe and persistent abdominal pain that can radiate to the back, as well

as nausea and vomiting; this can be a sign of pancreatitis.

Possible side effects when taking Onglyza with metformin:

Common side effects (affect 1-10 in 100 patients):

upper respiratory tract infection,

urinary tract infection,

inflammation of the stomach or intestines usually caused by an infection

(gastroenteritis),

sinusitis,

inflamed nose or throat (a cold or sore throat),

headache,

muscle pain,

vomiting,

inflammation of the stomach (gastritis),

stomachache and indigestion.

Uncommon side effects:

joint pain,

difficulty in getting or maintaining an erection.

Possible side effects while taking Onglyza with a sulphonylurea:

Very common side effects (affect more than 1 in 10 patients):

low blood sugar level (hypoglycemia).

Common side effects (affect 1-10 in 100 patients):

upper respiratory tract infection,

urinary tract infection,

inflammation of the stomach or intestines usually caused by an infection

(gastroenteritis),

sinusitis,

headache,

stomachache and vomiting.

Uncommon side effects (affect 1-10 in 1,000 patients):

tiredness,

abnormal blood fat (lipid) levels (dyslipidemia, hypertriglyceridemia).

Possible side effects while taking Onglyza with a thiazolidinedione:

Common side effects (affect 1-10 in 100 patients):

upper respiratory tract infection,

urinary tract infection,

inflammation of the stomach or intestines usually caused by an infection

(gastroenteritis),

sinusitis,

headache,

vomiting,

stomachache,

swelling of the hands, ankles or legs (edema).

Other possible side effects while taking Onglyza alone:

Common side effects (affect 1-10 in 100 patients):

dizziness

diarrhea

stomachache

Some patients reported constipation. The frequency of the effect is unknown

(the frequency of this effect cannot be determined from the currently available

data) when using Onglyza alone or in combination with another medicine.

In some patients, a small reduction in the number of white blood cells,

lymphocytes, has been shown in blood tests. Observed in blood tests when

using Onglyza alone or in combination with another medicine.

If one of the side effects worsens, or if you are suffering from a side effect not

mentioned in the leaflet, consult the doctor.

Report side effects

Side effects can be reported to the Ministry of Health by clicking on the link "Report

Side Effects of Drug Treatment" found on the Ministry of Health homepage

(www.health.gov.il)

that

directs

the online form for

reporting side

fects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffe

ctMedic@moh.gov.il

5.

HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine, and any other medicine, must be kept 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

the doctor.

Do not use the medicine after the expiry date (exp. date) that appears on

the package/bottle/carton/label. The expiry date refers to the last day of

that month.

Even

when

stored

packaging/storage

recommendations,

medicines may be kept for a limited period only. Do not store different

medicines in the same package.

Store below 30

6.

FURTHER INFORMATION

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

Contents of the Onglyza 2.5 mg and Onglyza 5 mg tablet:

Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium

stearate.

Onglyza 2.5 mg tablet coating:

Polyvinyl

alcohol,

macrogol/3350,

titanium

dioxide

(E171),

talc

(E553b),

shellac, indigo carmine aluminium lake (E132), iron oxide yellow (E172).

Onglyza 5 mg tablet coating:

Polyvinyl

alcohol,

macrogol/3350,

titanium

dioxide

(E171),

talc

(E553b),

shellac, indigo carmine aluminium lake (E132), iron oxide red (E172).

What the medicine looks like:

Onglyza 5 mg tablets are film-coated, round, biconvex, and pink, with "5"

imprinted on one side and "4215" imprinted on the other side, in blue ink.

Onglyza 2.5 mg tablets are film-coated, round, biconvex, and yellow to light

yellow, with "2.5" imprinted on one side and "4214" imprinted on the other

side, in blue ink.

License holder and importer: AstraZeneca (Israel) Ltd., P.O. Box 1455, Hod

Hasharon 4524075.

Manufacturer: AstraZeneca Pharmaceuticals LP, Mount Vernon, Indiana,

USA.

The format of this leaflet was determined and approved by the Ministry

of Health in June 2015.

Registration number of the medicine in the National Drug Registry of the

Ministry of Health:

Onglyza 2.5 mg: 146 47 33404 00

Onglyza 5 mg: 144 74 33080 00

רשואו קדבנ ונכותו תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ

ינויב

2015

The format of this leaflet was determined by the Ministry of Health and its content was checked and approved

in June 2015

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Onglyza 5 mg film-coated tablets

Onglyza 2.5 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5mg or 5 mg saxagliptin (as hydrochloride).

Excipients:

Each tablet contains 99 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Onglyza 5 mg tablets are pink, biconvex, round, film-coated tablet, with “5” printed on one side and “4215”

printed on the other side, in blue ink.

Onglyza 2.5 mg tablets are pale yellow to light yellow, biconvex, round, film-coated tablets, with “2.5” printed

on one side and “4214” printed on the other side, in blue ink.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Monotherapy:

Onglyza is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2

diabetes mellitus.

Onglyza should not be used in patients with ESRD

Combination therapy:

Add-on combination:

Onglyza is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with

metformin, a thiazolidinedione (TZD), or a sulfonylurea (SU), when the single agent alone, with diet and

exercise, does not provide adequate glycemic control.

Initial combination:

Onglyza is indicated for use as initial combination therapy with metformin, as an adjunct to diet and exercise,

to improve glycemic control in patients with type 2 diabetes mellitus when dual saxagliptin and metformin

therapy is appropriate.

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

In combination with insulin (with or without metformin), when this regimen alone, with diet and exercise, does

not provide adequate glycaemic control.

4.2 Posology and method of administration

The recommended dose of ONGLYZA is 2.5 mg or 5 mg once daily taken regardless of meals.

Onglyza tablets must not be split or cut.

Posology

Monotherapy and Add-On Combination Therapy

The recommended dose of Onglyza is 5 mg once daily as monotherapy or as add-on combination therapy

with metformin ,a thiazolidinedione (TZD), insulin , or a sulfonylurea. Onglyza can be taken with or without

food .

When Onglyza is used in combination with insulin or a sulphonylurea, a lower dose of the insulin or

sulphonylurea may be required to reduce the risk of hypoglycaemia (see section 4.4).

Initial Combination Therapy

The recommended starting doses of Onglyza and metformin when used as initial combination therapy is 5 mg

Onglyza plus 500 mg metformin once daily. Patients with inadequate glycemic control on this starting dose

should further have their metformin dose increased according to approved local label guidelines.

The safety and efficacy of saxagliptin as triple oral therapy in combination with metformin and a

thiazolidinedione, or with metformin and a sulphonylurea, has not been established.

Special populations

Renal impairment

No dosage adjustment for ONGLYZA is recommended for patients with mild renal impairment (creatinine

clearance [CrCl] >50 mL/min).

The dose of ONGLYZA is 2.5 mg once daily for patients with moderate or severe renal impairment.

Because the dose of ONGLYZA should be limited to 2.5 mg based upon renal function, assessment of renal

function is recommended prior to initiation of ONGLYZA and periodically thereafter. Renal function can be

estimated from serum creatinine using the Cockcroft-Gault formula or Modification of Diet in Renal Disease

formula. (see sections 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild or moderate hepatic impairment (see section

5.2). Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is not

recommended for use in patients with severe hepatic impairment (see section 4.4).

Elderly (≥65 years)

No dose adjustment is recommended based solely on age. Because elderly patients are more likely to have

decreased renal function, care should be taken in dose selection in the elderly based on renal function (see

also sections 4.4, 5.1 and 5.2).

Paediatric population

The safety and efficacy of Onglyza in children aged birth to < 18 years have not yet been established: No

data are available.

Method of administration

Onglyza can be taken with or without a meal at any time of the day. If a dose is missed, it should be

taken as soon as the patient remembers. A double dose should not be taken on the same day.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients or history of serious hypersensitivity

reaction, including anaphylactic reaction, anaphylactic shock, and angioedemaangioedema or exfoliative skin

conditions, to any dipeptidyl peptidase 4 DPP4 inhibitor (see sections 4.4 and 4.8).

Do not take Onglyza if you are pregnant or breastfeeding.

4.4 Special warnings and precautions for use

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

ketoacidosis. Onglyza is not a substitute for insulin in insulin-requiring patients.

Acute Pancreatitis

Use of DPP4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be

informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominal pain. If

pancreatitis is suspected, Onglyza should be discontinued; if acute pancreatitis is confirmed, Onglyza should

not be restarted. Caution should be exercised in patients with a history of pancreatitis.

In post-marketing experience of saxagliptin, there have been spontaneously reported adverse reactions of

acute pancreatitis.

In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes

Mellitus-Thrombolysis in Myocardial Infarction (SAVOR) Trial, the incidence of adjudicated

pancreatitis events was 0.3% in both ONGLYZA-treated patients and placebo-treated patients in the intent-to-

treat population. (See 4.8 Clinical experience.)

Renal impairment.

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

Impairment. Saxagliptin is contraindicated for use in patients with end-stage renal disease (ESRD) requiring

haemodialysis.

Assessment of renal function is recommended prior to initiation of Onglyza and in keeping with routine care,

renal assessment should be done periodically thereafter (see sections 4.2

and 5.2).

Hepatic impairment Saxagliptin should be used with caution in patients with moderate hepatic impairment,

and is not recommended for use in patients with severe hepatic impairment (see section 4.2).

Use with medicinal products known to cause hypoglycaemia

Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, a lower dose of sulphonylurea or

insulin may be required to reduce the risk of hypoglycaemia when used in combination with Onglyza.

Hypersensitivity reactions Onglyza should not be used in patients who have had any serious hypersensitivity

reaction to a dipeptidyl peptidase 4 (DPP4) inhibitor.

During postmarketing experience, the following adverse reactions have been reported with use of saxagliptin:

serious hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, angioedema and

exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of

treatment with ONGLYZA, with some reports occurring after the first dose.

If a serious hypersensitivity reaction to saxagliptin is suspected, discontinue Onglyza, assess for other

potential causes for the event, and institute alternative treatment for diabetes (see sections 4.3 and 4.8).

Elderly patients

Of the 16,492 patients randomized in the SAVOR trial, 8561 (51.9%) patients were 65 years and

over and 2330 (14.1%) were 75 years and over. The number of subjects treated with

ONGLYZA in the SAVOR study that were 65 years and over was 4290 and the number of

subjects that were 75 years and over was 1169.

Of the total number of subjects (N=4148) in six, double-blind, controlled clinical safety and

efficacy studies of ONGLYZA, 634 (15.3%) patients were 65 years and over, of which 59

(1.4%) patients were 75 years and over.[

No overall differences in safety or effectiveness were observed between subjects 65 years and

over, 75 years and over, and younger subjects.

While this clinical experience has not identified differences in responses between the elderly and younger

patients, greater sensitivity of some older individuals cannot be ruled out.

Saxagliptin and its active metabolite are eliminated in part by the kidney. Because elderly

patients are more likely to have decreased renal function, care should be taken in dose selection

in the elderly based on renal function

Skin disorders Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-

clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increased

incidence in clinical trials, there is limited experience in patients with diabetic skin complications.

Postmarketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an

adverse event (AE) for Onglyza (section 4.8). Therefore, in keeping with routine care of the diabetic patient,

monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.

Cardiac failure

In the SAVOR trial an increase in the rate of hospitalization for heart failure was observed in the saxagliptin

treated patients compared to placebo, although a causal relationship has not been established. Caution is

warranted if Onglyza is used in patients who have known risk factors for hospitalization for heart failure, such

as a history of heart failure or moderate to severe renal impairment. Patients should be advised of the

characteristic symptoms of heart failure, and to immediately report such symptoms.

Immunocompromised patients Immunocompromised patients, such as patients who have undergone organ

transplantation or patients diagnosed with human immunodeficiency syndrome, have not been studied in the

Onglyza clinical program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not

been established.

Use with potent CYP 3A4 inducers Using CYP3A4 inducers like carbamazepine, dexamethasone,

phenobarbital, phenytoin, and rifampicin may reduce the glycaemic lowering effect of Onglyza (see section

4.5).

Lactose The tablet contain lactose monohydrate. Patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal

product.

4.5 Interaction with other medicinal products and other forms of interaction

Clinical data described below suggest that the risk for clinically meaningful interactions with co-

administered medicinal products is low.

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). In in vitro

studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or

3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. In studies conducted in healthy subjects, neither the

pharmacokinetics of saxagliptin and its major metabolite, were meaningfully altered by metformin,

glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or famotidine. In addition, saxagliptin

did not meaningfully alter the pharmacokinetics of metformin, glibenclamide, pioglitazone, digoxin,

simvastatin, diltiazem or ketoconazole or an estrogen/progestin combined oral contraceptive

Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, increased the

Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding values for the

active metabolite were decreased by 44 and 34%, respectively.

Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, increased the

Cmax and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding values for the

active metabolite were decreased by 95% and 88%, respectively.

Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin, reduced Cmax and

AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the plasma

DPP4 activity inhibition over a dose interval were not influenced by rifampicin (see section 4.4).

The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as carbamazepine,

dexamethasone, phenobarbital and phenytoin) have not been studied and may result in decreased plasma

concentration of saxagliptin and increased concentration of its major metabolite. Glycaemic control should be

carefully assessed when saxagliptin is used concomitantly with a potent CYP3A4 inducer.

The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of saxagliptin have

not been specifically studied.

4.6 Fertility, Pregnancy and lactation

Pregnancy

There are no data from the use of saxagliptin in pregnant women. Studies in animals have shown

reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown.

Onglyza should not be used during pregnancy unless clearly necessary.

Lactation It is unknown whether saxagliptin is excreted in human breast milk. Animal studies have shown

excretion of saxagliptin and/or metabolite in milk. A risk to the suckling child cannot be excluded. A decision

must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit

of breast-feeding for the child and the benefit of therapy to the woman.

Fertility

The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observed in male

and female rats at high doses producing overt signs of toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines

Onglyza may have a negligible influence on the ability to drive and use machines.

No studies on the effects on the ability to drive and use machines have been performed. However, when

driving or using machines, it should be taken into account that dizziness has been reported with saxagliptin. In

addition, patients should be alerted to the risk of hypoglycaemia when Onglyza is used in combination with

other antidiabetic medicinal products known to cause hypoglycaemia (e.g. insulin, sulphonylureas).

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in placebo-controlled trials reported in ≥ 5% of patients

treated with Onglyza 5 mg and more commonly than in patients treated with placebo are upper respiratory

tract infection (7.7%), urinary tract infection (6.8%) and headache (6.5%).

There were 4,148 patients with type 2 diabetes, including 3,021 patients treated with Onglyza, randomised

in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of

saxagliptin on glycaemic control.

In randomised, controlled, double-blind clinical trials (including developmental and postmarketing experience),

over 17,000 patients with type 2 diabetes have been treated with Onglyza.

. In a pooled analysis of 1,681 patients with type 2 diabetes including 882 patients treated with Onglyza 5 mg,

randomised in five double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate

the effects of saxagliptin on glycaemic control, the overall incidence of adverse events in patients treated with

saxagliptin 5 mg was similar to placebo.

Discontinuation of therapy due to adverse events was higher in patients who received saxagliptin 5 mg as

compared to placebo (3.3% as compared to 1.8%).

Tabulated list of adverse reactions

Adverse reactions reported (in ≥5% of patients treated with saxagliptin 5 mg and more commonly than in

patients treated with placebo or that were reported in ≥2% of patients treated with saxagliptin 5 mg and

≥1% more frequently compared to placebo from the pooled analysis of five studies of glycaemic control,

plus an additional active-controlled study of initial combination with metformin are shown in Table 1.

The adverse reactions are listed by system organ class and absolute frequency. Frequencies are defined as

Very common (≥ 1/10), Common (≥ 1/100 to <1/10), Uncommon (≥ 1/1,000 to 1/100), Rare (≥ 1/10,000 to

1/1,000), or Very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1 Frequency of adverse reactions by system organ class from clinical trials and postmarketing

experience

System organ

class Adverse

Reaction

Frequency of adverse reactions by treatment regimen

Saxagliptin

monotherapy

Saxagliptin

with

metformin

1

Saxagliptin with

a sulphonylurea

(glibenclamide)

Saxagliptin with a

thiazolidinedione

Infections and

infestations

Upper respiratory

Common

Common

Common

Common

infection

Urinary tract

Common

Common

Common

Common

infection

Gastroenteritis

Common

Common

Common

Common

Sinusitis

Common

Common

Common

Common

Nasopharyngitis

Common

Immune system

disorders

Hypersensitivity

reactions

†‡

Uncommon

Uncommon

Uncommon

Uncommon

Anaphylactic

reactions including

anaphylactic shock

†‡

Rare

Rare

Rare

Rare

Metabolism and

nutrition disorders

Hypoglycaemia

Very common

Dyslipidemia

Uncommon

Hypertri-

Glyceridemia

Uncommon

Nervous system

disorders

Dizziness

Common

Headache

Common

Common

Common

Common

Gastrointestinal

disorders

Abdominal pain†

Common

Common

Common

Common

Diarrhoea

Common

Common

Common

Common

Dyspepsia

Common

Gastritis

Common

Nausea†

Common

Common

Common

Common

Vomiting

Common

Common

Common

Common

Pancreatitis†

Constipation†

Uncommon

Not Known

Uncommon

Not Known

Uncommon

Not Known

Uncommon

Not Known

Skin and

subcutaneous

tissue disorders

Rash

Common

Common

Common

Dermatitis†

Uncommon

Uncommon

Uncommon

Uncommon

Pruritus†

Uncommon

Uncommon

Uncommon

Uncommon

Urticaria†

Uncommon

Uncommon

Uncommon

Uncommon

Angioedema

†‡

Rare

Rare

Rare

Rare

Musculo-skeletal

and connective

tissue disorders

Arthralgia

Uncommon

Myalgia

Common

Reproductive

system and breast

disorders

Erectile dysfunction

Uncommon

General disorders

and administration

site conditions

Fatigue

Common

Uncommon

Oedema peripheral

Common

Includes saxagliptin in add-on to metformin and initial combination with metformin.

Only in the initial combination therapy.

There was no statistically significant difference compared to placebo. The incidence of confirmed

hypoglycaemia was

uncommon for Onglyza 5 mg (0.8%) and placebo (0.7%).

The incidence of diarrhoea was 4.1% (36/882) in the saxagliptin 5 mg group and 6.1% (49/799) in the

placebo group.

As initial combination with metformin, myalgia is reported as uncommon

Adverse reactions were identified through postmarketing surveillance

See sections 4.3 and 4.4

SAVOR trial results

The SAVOR trial included 8240 patients treated with Onglyza 5 mg or 2.5 mg once daily and 8173 patients on

placebo. The overall incidence of adverse events in patients treated with Onglyza in this trial was similar to

placebo (72.5% versus 72.2%, respectively).

The incidence of adjudicated pancreatitis events was 0.3% in both Onglyza-treated patients and placebo-

treated patients in the intent-to-treat population.

The incidence of hypersensitivity reactions was 1.1% in both Onglyza-treated patients and placebo-treated

patients.

The overall incidence of reported hypoglycaemia (recorded in daily patient diaries) was 17.1% in subjects

treated with Onglyza and 14.8% among patients treated with placebo. The percent of subjects with reported

on-treatment events of major hypoglycemia (defined as an event that required assistance of another person)

was higher in the saxagliptin group than in the placebo group (2.1% and 1.6%, respectively) The increased

risk of overall hypoglycemia and major hypoglycemia observed in the saxagliptin-treated group occurred

primarily in subjects treated with SU at baseline and not in subjects on insulin or metformin monotherapy at

baseline. The increased risk of overall and major hypoglycemia was primarily observed in subjects with A1C <

7% at baseline.

Decreased lymphocyte counts were reported in 0.5% of Onglyza treated patients and 0.4% of placebo-treated

patients.

Hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with the

placebo group (2.8%), with nominal statistical significance favouring placebo [HR = 1.27; 95% CI 1.07, 1.51);

P = 0.007]. See also section 5.1.

Description of selected adverse reactions

Hypoglycaemia

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

measurement was not required.

When used as add-on combination therapy with metformin plus sulphonylurea, the overall incidence of

reported hypoglycemia was 10.1 % for Onglyza 5 mg and 6.3% for placebo.

When used as add-on to insulin (with or without metformin), the overall incidence of reported hypoglycaemia

was 18.4% for Onglyza 5 mg and 19.9% for placebo.

Investigations tests

Across clinical studies, the incidence of laboratory adverse events was similar in patients treated with

saxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte count

was observed. From a baseline mean absolute lymphocyte count of approximately 2,200 cells/μl, a mean

decrease of approximately 100 cells/μl relative to placebo was observed in the placebo-controlled-pooled

analysis. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration.

The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The clinical

significance of this decrease in lymphocyte count relative to placebo is not known.

4.9 Overdose

Onglyza has been shown to be safe and well-tolerated with no clinically meaningful effect on QTc interval or

heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose). In the event of an

overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status.

Saxagliptin and its major metabolite can be removed by haemodialysis (23% of dose over 4 hours).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group; Drugs used in diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code:

A10BH03

Mechanism of action Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP-4

inhibitor. In patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP-4 enzyme activity

for a 24-hour period. After an oral glucose load, this DPP-4 inhibition resulted in a 2-to 3-fold increase in

circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent

insulinotropic polypeptide (GIP), decreased glucagon concentrations and increased glucose-dependent beta-

cell responsiveness, which resulted in higher insulin and C-peptide concentrations. The rise in insulin from

pancreatic beta-cells and the decrease in glucagon from pancreatic alpha-cells were associated with lower

fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Saxagliptin improves glycaemic control by reducing fasting and postprandial glucose concentrations in patients

with type 2 diabetes.

Clinical safety and efficacy A total of 4,148 patients with type 2 diabetes, including 3,021 patients treated with,

saxagliptin were randomised in 6 double-blind, controlled clinical safety and efficacy studies conducted to

evaluate the effects of saxagliptin on glycaemic control. In these studies 634 patients were 65 years and older,

while 59 patients were 75 years and older. Treatment with saxagliptin 5 mg once daily produced clinically

relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG)

and postprandial glucose (PPG) compared to placebo in monotherapy, in combination with metformin (initial or

add-on therapy), in combination with a sulphonylurea, and in combination with a thiazolidinedione (see Table 2).

There was also no apparent change in body weight associated with saxagliptin. Reductions in HbA1c were

seen across subgroups including gender, age, race, and baseline body mass index (BMI) and higher baseline

HbA1c was associated with a greater adjusted mean change from baseline with saxagliptin.

Saxagliptin as monotherapy

Two double-blind, placebo-controlled studies of 24-week duration were conducted to evaluate the efficacy

and safety of saxagliptin monotherapy in patients with type 2 diabetes. In both studies, once-daily

treatment with saxagliptin provided significant improvements in HbA1c.

The findings of these studies were confirmed with two subsequent 24-week regional (Asian) monotherapy

studies comparing saxagliptin 5 mg with placebo.

Saxagliptin add-on to metformin therapy

An add-on to metformin placebo-controlled study of 24-week duration was conducted to evaluate the efficacy

and safety of saxagliptin in combination with metformin in patients with inadequate glycaemic control (HbA1c 7-

10%) on metformin alone. Saxagliptin (n=186) provided significant improvements in HbA1c, FPG and PPG

compared to placebo (n=175). Improvements in HbA1c, PPG, and FPG following treatment with saxagliptin

5 mg plus metformin were sustained up to Week 102. The HbA1c change for saxagliptin 5 mg plus metformin

(n=31) compared to placebo plus metformin (n=15) was -0.8% at Week 102.

Saxagliptin add-on to metformin compared with SU add-on to metformin

A 52-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with

metformin (428 patients) compared with sulphonylurea (glipizide, 5 mg titrated as needed to 20 mg, mean dose

of 15 mg) in combination with metformin (430 patients) in 858 patients with inadequate glycaemic control

(HbA1c 6.5%-10%) on metformin alone. The mean metformin dose was approximately 1900 mg in each

treatment group. After 52 weeks, the saxagliptin and glipizide groups had similar mean reductions from baseline

in HbA1c in the per-protocol analysis (-0.7% vs. –0.8%, respectively, mean baseline HbA1c of 7.5% for both

groups). The intent-to-treat analysis showed consistent results. The reduction in FPG was slightly less in the

saxagliptin-group and there were more discontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG

criteria during the first 24 weeks of the study. Saxagliptin also resulted in a significantly lower proportion of

patients with hypoglycaemia, 3% (19 events in 13 subjects) vs. 36.3% (750 events in 156 patients) for glipizide.

Patients treated with saxagliptin exhibited a significant decrease from baseline in body weight compared to a

weight gain in patients administered glipizide (-1.1 vs. +1.1 kg).

Saxagliptin add-on to metformin compared with sitagliptin add-on to metformin

An 18-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with

metformin (403 patients), compared with sitagliptin 100 mg in combination with metformin (398 patients) in

801 patients with inadequate glycaemic control on metformin alone. After 18 weeks, saxagliptin was non-inferior

to sitagliptin in mean reduction from baseline in HbA1c in both the per-protocol and the full analysis sets . The

reductions from baseline in HbA1c respectively for saxagliptin and sitagliptin in the primary per-protocol analysis

were -0.5% (mean and median) and -0.6% (mean and median). In the confirmatory full analysis set, mean

reductions were -0.4% and -0.6% respectively for saxagliptin and sitagliptin, with median reductions of -0.5% for

both groups.

Controlled long-term study extension

Patients who completed all visits during the initial 24-week study period without need for hyperglycaemia rescue

therapy were eligible to enter a controlled long-term study extension. Patients who received saxagliptin plus

metformin in the initial 24-week study period maintained the same dose of saxagliptin in the long-term

extension. Treatment with saxagliptin 5 mg plus metformin was associated with a greater reduction in HbA1c

than in the placebo plus metformin group, and this effect was sustained up to Week 102. The HbA1c change for

saxagliptin 5 mg plus metformin compared to placebo plus metformin was − 0.7% at Week 102.

Saxagliptin in combination with metformin as initial therapy

A 24-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with

metformin as initial combination therapy in treatment-naive patients with inadequate glycaemic control (HbA1c

8-12%). Initial therapy with the combination of saxagliptin 5 mg plus metformin (n=306) provided significant

improvements in HbA1c, FPG and PPG compared to with either saxagliptin (n=317) or metformin (n=313) as

initial therapy. Reductions in HbA1c from baseline to Week 24 were observed in all evaluated subgroups

defined by baseline HbA1c, with greater reductions observed in patients with a baseline HbA1c ≥10% (see

Table 2). Improvements in HbA1c, PPG and FPG following initial therapy with saxagliptin 5 mg plus metformin

were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg plus metformin (n=177) compared to

metformin plus placebo (n=147) was -0.5% at Week 76.

Saxagliptin add-on to glibenclamide therapy

An add-on placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of

saxagliptin in combination with glibenclamide in patients with inadequate glycaemic control at enrolment (HbA1c

7.5-10%) on a sub-maximal dose of glibenclamide alone. Saxagliptin in combination with a fixed, intermediate

dose of a sulphonylurea (glibenclamide 7.5 mg) was compared to titration to a higher dose of glibenclamide

(approximately 92% of patients in the placebo plus glibenclamide group were up-titrated to a final total daily

dose of 15 mg). Saxagliptin (n=250) provided significant improvements in HbA1c, FPG and PPG compared to

titration to a higher dose of glibenclamide (n=264). Improvements in HbA1c and PPG following treatment with

saxagliptin 5 mg were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=56) compared to

uptitrated glibenclamide plus placebo (n=27) was -0.7% at Week 76.

Saxagliptin add-on combination therapy with insulin (with or without metformin)

A total of 455 patients with type 2 diabetes participated in a 24-week randomised, double-blind, placebo-

controlled study to evaluate the efficacy and safety of saxagliptin in combination with a stable dose of insulin

(baseline mean: 54.2 Units) in patients with inadequate glycaemic control (HbA1c

7.5% and

11%) on insulin

alone (n=141) or on insulin in combination with a stable dose of metformin (n=314). Saxagliptin 5 mg add-on to

insulin with or without metformin provided significant improvements after 24 weeks in HbA1c and PPG

compared with placebo add-on to insulin with or without metformin. Similar HbA1c reductions versus placebo

were achieved for patients receiving saxagliptin 5 mg add-on to insulin regardless of metformin use (−0.4% for

both subgroups). Improvements from baseline HbA1c were sustained in the saxagliptin add-on to insulin group

compared to the placebo add-on to insulin group with or without metformin at Week 52. The HbA1c change for

the saxagliptin group (n=244) compared to placebo (n=124) was -0.4% at Week 52.

Saxagliptin add-on to thiazolidinedione therapy

A placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin

in combination with a thiazolidinedione (TZD) in patients with inadequate glycaemic control (HbA1c 7-10.5%) on

TZD alone. Saxagliptin (n=183) provided significant improvements in HbA1c, FPG and PPG compared to

placebo (n=180). Improvements in HbA1c, PPG and FPG following treatment with saxagliptin 5 mg were

sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=82) compared to TZD plus placebo (n=53)

was -0.9% at Week 76.

Patients with renal impairment

A 12-week, multi-centre, randomised, double-blind, placebo-controlled study was conducted to

evaluate the treatment effect of saxagliptin 2.5 mg once daily compared with placebo in 170 patients

(85 patients on saxagliptin and 85 on placebo) with type 2 diabetes (HbA1c 7.0-11%) and renal

impairment (moderate [N=90]; severe [N=41]; or ESRD [N=39]). In this study, 98.2% of the patients

were treated with other antihyperglycaemic medication (75.3% on insulin and 31.2% on oral

antihyperglycaemic drugs; some received both). Saxagliptin significantly decreased HbA1c compared

with placebo; the HbA1c change for saxagliptin was -0.9% at Week 12 (HbA1c change of -0.4% for

placebo). Improvements in HbA1c following treatment with saxagliptin 2.5 mg were sustained up to

Week 52, however the number of patients who completed 52 weeks without modification of other

antihyperglycaemic medications was low (26 subjects in the saxagliptin group versus 34 subjects in

the placebo group). The incidence of confirmed hypoglycaemic events was somewhat higher in the

saxagliptin group (9.4%) versus placebo group (4.7%) although the number of subjects with any

hypoglycaemic event did not differ between the treatment groups. There was no adverse effect on

renal function as determined by estimated glomerular filtration rate or CrCL at Week 12 and Week 52.

Table 2.

Key efficacy results of Onglyza 5 mg per day in placebo-controlled monotherapy

trials and in add-on combination therapy trials

Mean

baseline

HbA1c

(%)

Mean change2

from baseline

HbA1c (%) at

Week 24

Placebo-corrected

mean change in

HbA1c (%) at Week

24 (95% CI)

MONOTHERAPY STUDIES

Study CV181011 (n=103)

-0.5

-0.6 (-0.9, -0.4)

Study CV181038 (n=69)

-0.7 (morning)

-0.4 (-0.7, -0.1)

(n=70)

-0.6 (evening)

-0.4 (-0.6, -0.1)

ADD-ON/COMBINATION STUDIES

Study CV181014: add-on to metformin

(n=186)

-0.7

-0.8 (-1.0, -0.6)

Study CV181040: add-on to SU

(n=250)

Study CV181013: add-on to TZD (n=183)

-0.6

-0.9

-0.7 (-0.9, -0.6)

-0.6 (-0.8, -0.4)

Study CV181039: initial combination with

Metformin

Overall population (n=306)

-2.5

-0.5 (-0.7, -0.4)

Baseline HbA1c ≥10% strata (n=107)

Study CV181057: Add-on to insulin

(+/- metformin)Overall population (n=300)

10.8

-3.3

-0.7

-0.6 (-0.9, -0.3)

n=Randomized patients (primary efficacy-intention-to-treat analysis).

Placebo group had uptitration of glibenclamidefrom 7.5 to 15 mg total daily dose.

Adjusted mean change from baseline adjusted for baseline value (ANCOVA).

p<0.0001 compared to placebo.

p=0.0059 compared to placebo.

p=0.0157 compared to placebo.

Metformin was uptitrated from 500 to 2000 mg per day as tolerated.

Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups

(p<0.0001).

Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups.

Cardiovascular safety

In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes

Mellitus-Thrombolysis in Myocardial Infarction (SAVOR) Trial, the effect of ONGLYZA

(saxagliptin) on the occurrence of major cardiovascular disease (CVD) events was assessed in

16,492 adult patients with type 2 diabetes who had either established CVD or multiple risk

factors for vascular disease, including patients with moderate or severe renal impairment.

Patients ≥40 years of age, diagnosed with type 2 diabetes and with A1C ≥6.5%, and with either

established CVD or multiple CV risk factors were enrolled.

Patients were randomly assigned to placebo (n=8212) or saxagliptin (5 mg or 2.5 mg for patients

with moderate or severe renal insufficiency) once daily (n=8280). Randomization to the

saxagliptin and placebo groups was stratified by CV risk with 3533 patients (21.4%) with CV

risk factors only and 12,959 patients (78.6%) with established CVD and by renal impairment

including 13,916 subjects (84.4%) with normal renal function to mild impairment, 2240 subjects

(13.6%) with moderate impairment, and 336 subjects (2.0%) with severe renal impairment.

Patients with established CVD were defined by a history of ischemic heart disease, peripheral

vascular disease, or ischemic stroke. Patients with CV risk factors only had age as a CV risk

factor (men ≥55 years and women ≥60 years) plus at least one additional risk factor of

dyslipidemia, hypertension, or current cigarette smoking.

The demographics and baseline characteristics of subjects were balanced between the saxagliptin

and placebo groups. The study population was 67% male and 33% female with a mean age at

randomization of 65 years. Of the 16,492 patients randomized, 8561 (52%) patients were 65

years and over and 2330 (14%) were 75 years and over.

All study subjects had a mean duration of T2DM of 12 years (median = 10.3) and a mean A1C

level of 8.0% (median = 7.6%). Overall, 25% of subjects had baseline A1C levels <7%. Subjects

were followed for a mean duration of 2 (median = 2.0) years.

Concomitant medication use was similar for the two treatment groups. Overall, the use of

diabetes medications was consistent with local treatment practice and the saxagliptin clinical

program (metformin 69%, insulin 41%, sulfonylureas 40%, and TZDs 6%). The use of CVD

medications was also consistent with local treatment practice (ACE inhibitors or ARBs 79%,

statins 78%, aspirin 75%, beta blockers 62%, and nonaspirin antiplatelet medications 24%).

Approximately 6% of subjects were treated with diet and exercise only at baseline. Concomitant

medications were managed throughout the trial to local guideline targets for glycemic control

and CV risk reduction in order to minimize differences between the two treatment groups,

particularly for glycemic control.

The primary safety and efficacy endpoint was a composite endpoint consisting of the time-tofirst

occurrence of any of the following major adverse CV events (MACE): CV death, nonfatal

myocardial infarction, or nonfatal ischemic stroke.

The primary safety objective of this trial was to establish that the upper bound of the 2-sided

95% CI for the estimated risk ratio comparing the incidence of the composite endpoint of CV

death, non-fatal MI or non-fatal ischemic stroke observed with saxagliptin to that observed in the

placebo group was <1.3.

The primary efficacy objective was to determine, as a superiority assessment, whether treatment

with saxagliptin, compared with placebo when added to current background therapy, resulted in

a significant reduction in the primary MACE endpoint.

The first secondary efficacy endpoint was a composite endpoint consisting of the time-to-first

occurrence of MACE plus hospitalization for heart failure, hospitalization for unstable angina

pectoris, or hospitalization for coronary revascularization (MACE plus). The next secondary

efficacy endpoint was to determine whether treatment with saxagliptin compared with placebo

when added to current background therapy in subjects with T2DM would result in a reduction of

all-cause mortality.

The cardiovascular safety of saxagliptin was evaluated in the SAVOR trial which established

that saxagliptin did not increase the CV risk (CV death, nonfatal myocardial infarction, or

nonfatal ischemic stroke) in patients with T2DM compared to placebo when added to current

background therapy (HR 1.00; 95% CI: 0.89, 1.12; P<0.001 for noninferiority).

The primary efficacy endpoint did not demonstrate a statistically significant difference in major

adverse coronary events for saxagliptin compared to placebo when added to current background

therapy in patients with T2DM.

Table 3: Primary and Secondary Clinical Endpoints by Treatment Group in the SAVOR Study *

Figure 1 : Cumulative percent of time to first CV event for primary composite endpoint *

Events accumulated consistently over time, and the event rates for ONGLYZA and placebo

did not diverge notably over time.

One component of the secondary composite endpoint, hospitalization for heart failure, occurred

at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with

nominal statistical significance (ie, without adjustment for testing of multiple endpoints) favoring

placebo [HR = 1.27; (95% CI 1.07, 1.51); P = 0.007]. Clinically relevant factors predictive of

increased relative risk with saxagliptin treatment could not be definitively identified. Subjects at

higher risk for hospitalization for heart failure, irrespective of treatment assignment, could be

identified by known risk factors for heart failure such as baseline history of heart failure or

impaired renal function. However, subjects on saxagliptin with a history of heart failure or

impaired renal function at baseline were not at an increased risk relative to placebo for the

primary or secondary composite endpoints or all-cause mortality.

No increased risk for the primary endpoint was observed between saxagliptin and placebo in any

of the following subgroups: CVD, multiple risk factors for CVD, mild, moderate, or severe renal

impairment, age, gender, race, region, duration of type 2 diabetes, history of heart failure,

baseline A1C, albumin/creatinine ratio, baseline antidiabetic medication, or baseline use of

statins, aspirin, ACE inhibitors, ARBs, beta-blockers, or antiplatelet medications.

Despite active management of concomitant antidiabetic therapy in both study arms, mean A1C

levels were lower in the saxagliptin group compared to the placebo group at Year 1 (7.6% versus

7.9%, difference of -0.35% [95% CI: -0.38, -0.31]) and at Year 2 (7.6% versus 7.9%,

difference of -0.30% [95% CI: -0.34, -0.26]). The proportions of subjects with A1C <7% in the

saxagliptin group compared to the placebo group were 38% versus 27% at Year 1 and 38%

versus 29% at Year 2.

Compared to placebo, saxagliptin resulted in less need for the initiation of new or increases in

current oral diabetes medications or insulin. The improvements in A1C and the proportion of

subjects reaching A1C targets among saxagliptin-treated subjects were observed despite lower

rates of upward adjustments in diabetes medications or initiation of new diabetes medications or

insulin compared with placebo.

5.2 Pharmacokinetic properties

The pharmacokinetics of saxagliptin and its major metabolite were similar in healthy subjects and in patients

with type 2 diabetes.

Absorption Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma

concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax),

respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased proportionally with

the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg.

Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for

saxagliptin and its major metabolite were 78 ng·h/ml and 214 ng·h/ml, respectively. The corresponding plasma

Cmax values were 24 ng/ml and 47 ng/ml, respectively. The intra-subject coefficients of variation for saxagliptin

Cmax and AUC were less than 12%.

The inhibition of plasma DPP-4 activity by saxagliptin for at least 24 hours after oral administration of saxagliptin

is due to high potency, high affinity, and extended binding to the active site.

Interaction with food

Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects. Administration

with food (a high-fat meal) resulted in no change in saxagliptin Cmax and a 27% increase in AUC compared

with the fasted state. The time for saxagliptin to reach Cmax (Tmax) was increased by approximately 0.5

hours with food compared with the fasted state. These changes were not considered to be clinically

meaningful.

Distribution

The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible.

Thus, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are

not expected to alter the disposition of saxagliptin.

Biotransformation

The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).

The major metabolite of saxagliptin is also a selective, reversible, competitive DPP-4 inhibitor, half as

potent as saxagliptin.

Elimination The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5

hours and 3.1 hours respectively, and the mean t1/2 value for plasma DPP-4 inhibition was 26.9 hours.

Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of

C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major metabolite,

and total radioactivity respectively. The average renal clearance of saxagliptin (

230 ml/min) was greater than

the average estimated glomerular filtration rate (

120 ml/min), suggesting some active renal excretion. For the

major metabolite, renal clearance values were comparable to estimated glomerular filtration rate. A total of 22%

of the administered radioactivity was recovered in faeces representing the fraction of the saxagliptin dose

excreted in bile and/or unabsorbed medicinal product from the gastrointestinal tract.

Linearity The Cmax and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin

dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with repeated

once-daily dosing at any dose level. No dose-and time-dependence was observed in the clearance of

saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5

mg to 400 mg.

Special populations

Renal impairment

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral dose of

saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal

function. The study included patients with renal impairment classified on the basis of creatinine clearance

(based on the Cockcroft-Gault formula) a mild (>50 to ≤80 ml/min), moderate (≥30 to ≤50 ml/min), or severe (

≤30 ml/min) as well as patients with ESRD on haemodialysis

The degree of renal impairment did not affect the C

of saxagliptin or its major metabolite. In subjects with

mild renal impairment, the mean AUC values of saxagliptin and its major metabolite were 1.2- and 1.7- fold

higher, respectively, than mean AUC values in subjects with normal renal function. Because increases of this

magnitude are not clinically relevant, dose adjustment in patients with mild renal impairment is not

recommended. In subjects with moderate or severe renal impairment or in subjects with ESRD on

haemodialysis, the AUC values of saxagliptin and its major metabolite were up to 2.1- and 4.5-fold higher,

respectively, than AUC values in subjects with normal renal function. The dose of Onglyza should be reduced to

2.5 mg once daily in patients with moderate or severe renal impairment (see sections 4.2 and 4.4).

Hepatic impairment

In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C)

hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher, respectively, and the

exposures to BMS-510849 were 22%, 7%, and 33% lower, respectively, than those observed in healthy

subjects.

Elderly patients (≥65 years)

Elderly (65-80 years) had about 60% higher saxagliptin AUC than young patients (18-40 years). This is not

considered clinically meaningful, therefore, no dose adjustment for Onglyza is recommended on the basis of

age alone.

5.3 Preclinical safety data

In cynomolgus monkeys saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in

extremities (tail, digits, scrotum and/or nose) at doses ≥3 mg/kg/day. The no effect level (NOEL) for the lesions

is 1 and 2 times the human exposure of saxagliptin and the major metabolite respectively, at the recommended

human dose of 5 mg/day (RHD).

The clinical relevance of the skin lesions is not known, however clinical correlates to skin lesions in monkeys

have not been observed in human clinical trials of saxagliptin.

Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes and bone

marrow with no adverse sequelae have been reported in all species tested at exposures starting from 7

times the RHD.

Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and enteropathy at

higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the major metabolite,

respectively, at RHD.

Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies in vitro and in vivo. No

carcinogenic potential was observed in two-year carcinogenicity assays with mice and rats.

Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity.

Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats, saxagliptin

caused reduced ossification (a developmental delay) of the foetal pelvis and decreased foetal body weight (in

the presence of maternal toxicity), with a NOEL 303 and 30 times the human exposure for saxagliptin and the

major metabolite, respectively, at RHD. In rabbits, the effects of saxagliptin were limited to minor skeletal

variations observed only at maternally toxic doses (NOEL 158 and 224 times the human exposure for

saxagliptin and the major metabolite, respectively at RHD). In a pre- and postnatal developmental study in rats,

saxagliptin caused decreased pup weight at maternally toxic doses, with NOEL 488 and 45 times the human

exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights

were noted until postnatal day 92 and 120 in females and males, respectively.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate

Cellulose microcrystalline

Croscarmellose sodium

Magnesium stearate

Film coating:

Polyvinyl alcohol

Macrogol/3350

Titanium dioxide (E171)

Talc (E553b)

Iron oxide red (E172) 5 mg Tablets only

Iron oxide yellow (E172) 2.5 mg Tablets only

Printing ink:

Shellac

Indigo carmine aluminium lake (E132)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 30°C

6.5 Nature and contents of container

Alu/Alu blister.

Pack sizes of 14, 28, 56 and 98 film-coated tablets in non-perforated blisters.

Pack sizes of 14, 28, 56 and 98 film-coated tablets in non-perforated calendar blisters.

Pack sizes of 10 and 30x1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Manufacturer: Bristol-Mayers Squibb Company, USA (for AstraZeneca)

License Holder and importer: Astra Zeneca Israel Ltd POB 4070, Raanana

4366241

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

__

_

15/06/14

__

ןוכדע

ףסונ

1-6-15

___________

םש

רישכת

תילגנאב

רפסמו

םושירה

ONGLYZA 5MG(144-74-33080-

00) ,ONGLYZA 2.5 MG(146-4733404-00)

םש

לעב

םושירה

ASTRA ZENECA ISRAEL LTD

.

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ

Indication

Onglyza shold not be used in patients with

ESRD

contraindications

Hypersensitivity to the active substance or to

any of the excipients. or history of serious

hypersensitivity reaction, such as anaphylaxis

to any dipeptidyl peptidase 4

(see sections 4.4 and

Posology, dosage &

administration

sulphonylurea, a lower dose of the insulin

care should be taken in dose selection in

Special Warnings and

Special Precautions

for Use

Use of DPP4 inhibitors has been associated

with a risk of developing acute pancreatitis.

characteristic symptoms of acute pancreatitis;

pancreatitis is suspected, Onglyza should be

confirmed, Onglyza should not be restarted.

Caution should be exercised in patients with

In post-marketing experience of saxagliptin,

there have been spontaneously reported

anaphylactic reaction, anaphylactic shock,

Onset of these reactions occurred

In the SAVOR trial an increase in the rate of

hospitalization for heart failure was observed

in the saxagliptin treated patients compared

to placebo, although a causal relationship

warranted if Onglyza is used in patients who

have known risk factors for hospitalization for

heart failure, such as a history of heart failure

or moderate to severe renal impairment.

characteristic symptoms of heart failure, and

use machines

to the risk of hypoglycaemia when

Onglyza is used in combination with

other

antidiabetic

medicinal

products

known to cause hypoglycaemia (e.g.

insulin, sulphonylureas)

Interaction with

Other Medicaments

and Other Forms of

Interaction

Fertility, pregnancy

and Lactation

Undesirable effects

Diarrhoea

(Frequency- Common)

Abdominal pain (Frequency- Unknown

In the SAVOR trial decreased

lymphocyte counts were reported in

0.5% of ONGLYZA treated patients

and 0.4% of placebo-treated patients

ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

שקובמה תו

לע

עקר

בוהצ

.

םייוניש

םניאש

רדגב

תורמחה

ונמוס

)ןולעב( עבצב

שי .הנוש

ןמסל

קר

ןכות

יתוהמ

אלו

םייוניש םוקימב

.טסקטה רבעוה

ראודב

ינורטקלא

........ךיראתב

15/06/14

......

ךיראתבו

1.6.2015

..

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ןכרצל ןכרצל

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

________

15/06/14

__

ןוכדיעו

1-6-15

___

םש

רישכת

תילגנאב

רפסמו

םושירה

_________________________

ONGLYZA 5MG(144-74-33080-00) ,ONGLYZA 2.5 MG(146-4733404-00)

םש

לעב

םושירה

_

___

ASTRA ZENECA ISRAEL LTD

.

_

דבלב תורמחהה טורפל דעוימ הז ספוט

תורמחהה

תושקובמה

קרפ

ןולעב טסקט

יחכונ טסקט

שדח

1

.

שומיש ינפל הפורתב שמתשהל ןיא

:םא הפורת

לופיטל תדעוימ הניא הזיילגנוא... תלחמ םע םילוחב יתילכ

בלשב

יפוסה ןוירהב ךניה

!

תורהזא תודחוימ תועגונה שומישב הזיילגנואב

תקלד לש םינימסת ךל שי םא ןוגכ ,)סיטיטאירקנפ( הפירח בלבל ךשמתמ השק ןטב באכ םימעפל( ,)בגל ןירקמ תואקה ילב וא םע

ץעייתהו לופיטה תא קספה םע אפורה דיימ

הלוכי בלבלב תקלד .םייח תנכסמ ףאו הרומח תויהל םילעמ םימייוסמ םייאופר םיבצמ לופיטה ינפל רפס הזיילגנואב םא אפורל

תקלדב תוקלל תוריבסה תא לופיט ליחתמ התאש ינפל ,בלבלה תלבס םא אפורל רפס הזיילגנואב

הפירח בלבל תקלד )סיטיטאירקנפ(

.הרמה סיכב םינבאמ

תורכמתה

לוהוכלאל

תומר

תוהובג

לש םידירצילגירט .םדב אל תולוכי ולא תויעב םא עודי תעב בלבלב תקלדל יוכיסה תא תולעהל

הזיילגנואב לופיט

רפס הזיילגנואב לופיטה ינפל םא אפורל

ךניה

לטונ

ןיא .ןילוסניא

שמתשהל הזיילגנואב

ףילחתכ

.ןילוסניאל

שי

ךל

וא

היה

ךל

רבעב

הלחמ

לש בלבלה

..

שי

ךל

תרכוס

גוס

ףוגה(

ךלש וניא

רציימ

וא

)ןילוסניא סיזודיצאוטק

יתרכוס

ךוביס(

לש תרכוס

םע

ץחל

םד

הדירי ,ההובג הדח

תוליחב ,לקשמב

ןיא )תואקהו שמתשהל

הזיילגנואב

םיבצמל

ולא

תקיפס יא םעפ יא רבעב ךל היה ןוכיס ימרוג ךל שי וא בל בל תקיפס יא לש תוחתפתהל אפורה .ךלש הילכב תויעב ומכ לש םינמיסה לע ךל ריבסי ךלש תונפל ךילע .בל תקיפס יא תוחא וא חקור ,אפורל תידיימ םינמיסמ דחאב שיגרמ ךנה םא םג לולכל םילוכי םינמיסה .ולא ,רבגתמ המישנ רצוק – )קר אל( תוחיפנו לקשמב הריהמ הילע תופכ תקצב( םיילגר תופכ רוזאב . )לוסרקו םיילגר

…………

יוקילמ לבוס ךניה רומח וא ןותמ ךרטצתש ןכתיי הילכה דוקפתב לש רתוי

ךומנ ןונימ לוטיל הזיילגנוא

רבוע ךנה םא

הזילאידומה

הניא הזיילגנוא .........שומישל תרשואמ

שומישו הגיהנ תונוכמב םורגל לולע וז הפורתב שומישה שח ךניה םא .תרוחרחסל תליטנ

תעב

תרוחרחסב

הזיילגנוא ןיא ,בכרב גוהנל ןיא , וא תונכוסמ תונוכמ ליעפהל עצבל תונריע תבייחמה תוליעפ לכ

לע עיפשהל לולע הימקילגופיה ליעפהלו

גוהנל ךלש תלוכיה ןוכיס םייק . תונכוסמ תונוכמ םילטונשכ

הימקילגופיהל הזיילגנוא םיעודיה םירישכת םע ומכ

הימקילגופיהל

םימרוגכ .האירואלינופלוסו ןילוסניא

:

הקנהו ןוירה

םא אפורל יחווד הזיילגנוא תחיקל ינפל . ןוירהב תויהל תננכתמ וא ןוירהב ךניה ךניה םא הזיילגנואב שמתשהל ןיא ןוירהב

אפורל יחווד תננכתמ וא תנינועמ תא םא .קינהל רבעומ הזיילגנוא םא עודי אל לוטיל ןיא .הקנה תעב םא בלחל תננכתמ וא הקינמ ךניה םא הזיילגנוא קינהל

שמתשת דציכ

:

הפורתב ,םוח ןוגכ ,ץחל יבצמב אצמנ ךפוג רשאכ וא םוהיז ,)םיכרד תנואת ןוגכ( המוארט חותינ

ןונימ יונישב ךרוצ היהיש ןכתי דחא םא אפורה תא ןכדעל שי .הפורתה .ךילע לח םיבצמה

:

יאוול תועפות

ב שומישה תא קיספהל שי הזיילגנוא ךניה םא אפורל תידיימ תונפלו תועבונש תואבה תועפותה תא שיגרמ םדב הכומנ רכוס תמרמ

.....

באכ שאר

....

...ןטב יבאכ באכ

ןטב

רומח

ךשמתמו לוכיש

ןירקהל

ומכ ,בגל

םג

תוליחב הז ,תואקהו

לוכי

תויהל

ןמיס

לש תקלד

בלבלב

(סיטיטארקנפ)

תליטנב תוירשפא יאוול תועפות

הזיילגנוא

ןימרופטמ םע

תוחיכש יאוול תועפות

......

תקלד

הביקב )סיטירטסג( ןטב יבאכ

תליטנב תוירשפא יאוול תועפות

הזיילגנוא

האירואלינופלוס םע

.....

תוחיכש יאוול תועפות

......

ןטב יבאכ

תליטנב תוירשפא יאוול תועפות

הזיילגנוא

ןוידנידילוזאית םע דחי

.....

תוחיכש יאוול תועפות

......

ןטב יבאכ

יאוול תועפות תופסונ הזיילגנוא תליטנב תוירשפא דבלב

:תוחיכש יאוול תועפות

תרוחרחס

לושלש

ןטב באכ

תוריצע לע וחוויד םימיוסמ םילוח ןתינ אל( העודי אל העפותה תוחיכש וז העפות תעפוה תוכיחש תא עובקל שומיש תעב )תעכ שיש עדימהמ הפורת םע בולישב וא דבל הזיילגנואב .תפסונ ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

תושקובמה

לע

עקר

בוהצ

םייוניש

םניאש

רדגב

תורמחה

ונמוס

ןולעב עבצב )

שי .הנוש

ןמסל

קר

ןכות

יתוהמ

אלו

םייוניש םוקימב

.טסקטה רבעוה

ראודב

ינורטקלא

ךיראתב

15.06.14

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