EFFIENT 10 MG

Israel - English - Ministry of Health

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Active ingredient:
PRASUGREL AS HYDROCHLORIDE
Available from:
ELI LILLY ISRAEL LTD
ATC code:
B01AC
Pharmaceutical form:
FILM COATED TABLETS
Composition:
PRASUGREL AS HYDROCHLORIDE 10 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
LILLY S.A., SPAIN
Therapeutic group:
PLATELET AGGREGATION INHIBITORS, EXCL. HEPARIN
Therapeutic indications:
Effient, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in patients with acute coronary syndrome ( i.e. unstable angina, non-ST segment elevation myocardial infarction [UA/NSTEMI] or ST segment elevation myocardial infarction [STEMI] undergoing primary or delayed percutaneous coronary intervention (PCI). The increased efficacy should be balanced with the increased risk in patients with bleeding tendencyin those who had TIA/CVA in the past and in those above the age of 75 or weight below 60 kg.
Authorization number:
142 56 32011 00
Authorization date:
2015-01-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

19-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

28-03-2019

Page 1 of 6

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS’

REGULATIONS (PREPARATIONS) – 1986

The medicine is dispensed with a doctor’s prescription only

Effient 10 mg

Coated tablets

Each tablet contains:

Prasugrel (as Hydrochloride) 10 mg

Effient 5 mg

Coated tablets

Composition:

Each tablet contains:

Prasugrel (as Hydrochloride) 5 mg

For the list of inactive ingredients and allergens, please see section “Additional information about

the ingredients of this medicine” and section 6 “Additional information”.

The medication contains lactose and may cause an allergy in people who are sensitive to

lactose.

Read this leaflet carefully in its entirety before using this medicine. This leaflet contains

concise information about the medicine. If you have any further questions, please contact your

doctor or pharmacist.

This medicine has been prescribed for the treatment of your illness. Do not pass it on to others.

It may harm them, even if it seems to you that their medical condition is similar.

Effient is not intended for children and adolescents below 18 years of age, since there is no

information about the efficacy and safety of this medicine in this age group.

1. WHAT IS THIS MEDICINE INTENDED FOR?

Effient, co-administered with acetylsalicylic acid, is indicated for the prevention of

atherothrombotic events in patients with acute coronary syndrome (unstable angina, acute

myocardial infarction) who are undergoing initial or elective catheterization, with or without stent

implantation.

Therapeutic group:

Platelet aggregation inhibitors.

2. BEFORE USING THIS MEDICINE

Do not use this medicine if:

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

contained in this medicine (see section 6). An allergic reaction may appear as a rash,

itching, swelling of the face and lips or shortness of breath.

You suffer from active bleeding (such as bleeding from a peptic ulcer)

You have ever had a stroke or a transient ischemic attack (TIA).

You have severe liver disease.

Page 2 of 6

Special warnings regarding the use of this medicine

During the course of treatment with this medicine, you must be under medical supervision.

Before starting treatment with Effient, tell your doctor if:

You are over the age of 75 or weigh less than 60 kg. The risk of bleeding is higher for those

patients. Therefore, should the doctor decide to treat such patients, a lower dose will be

administered.

You have suffered from a recent serious injury.

You have undergone recent surgery (including some dental procedures).

You have planned surgery (including some dental procedures), you must inform your doctor,

as there may be a need to temporarily discontinue treatment due to an increased risk of

bleeding.

You have recent or recurrent bleeding from the stomach or intestines (including a stomach

ulcer or colon polyps).

You suffer from a renal (kidney) disease or moderate liver problems.

You are taking additional medications (see the section "Drug Interactions”).

You have had an allergic reaction (hypersensitivity) to clopidogrel or any other anti-platelet

agent. If you have taken Effient and experienced an allergic reaction that included rash,

itching, a swollen face and tongue or shortness of breath - contact your doctor immediately.

You experience a side effect called Thrombotic Thrombocytopaenic Purpura (TTP), which

includes fever and bruising under the skin that may appear as red pinpoint dots, with or

without unexplained extreme tiredness, confusion, yellowing of the skin or eyes (jaundice) –

contact the doctor immediately! (see section 4 – “Side effects”).

Drug interactions:

If you are taking, or have taken recently, other medications including over-the-counter

medicines and nutritional supplements, tell your doctor or pharmacist, especially inform

your doctor or pharmacist if you are taking:

Medications that may increase the risk of bleeding when given concomitantly with Effient:

Anti-platelet agents, such as clopidogrel

Anti-coagulants, such as

eparin

and h

warfarin

Non-steroidal anti-inflammatory drugs (NSAIDs, including COX-2 inhibitors), such as

ibuprofen, naproxen, etoricoxib.

Medications whose concentration in the blood is affected when used concomitantly with

Effient:

Cyclophosphamide

Efavirenz

A reduced efficacy in Effient treatment was observed in patients taking Effient and

morphine concomitantly. Tell your doctor if you are taking morphine or other opioids (used to

treat severe pain).

Taking Effient with food and drink:

Effient may be taken with or without food.

Page 3 of 6

Pregnancy and breastfeeding:

If you are breastfeeding, pregnant or planning a pregnancy, you must consult your doctor

regarding the possible risks to the fetus versus the benefit of taking this medication.

If you are breastfeeding, consult your doctor.

Driving and using machines:

Effient is unlikely to affect your ability to drive or use machines.

Important information about some of the ingredients of the medicine:

Effient contains lactose. If you have an intolerance to some sugars, contact your doctor before

taking Effient.

3. HOW SHOULD YOU USE THIS MEDICINE?

Always use this medicine as instructed by your doctor. You should check with your doctor or

pharmacist if you are not sure about the dosage and manner of treatment with this medicine.

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

Do not exceed the recommended dose.

Take the tablet at around the same time every day.

The tablet is coated. Do not chew, break or crush the tablet!

You must be under medical supervision during treatment with this medication.

If you have accidentally taken a higher dose or if a child has accidentally swallowed the

medicine, proceed immediately to your doctor or hospital Emergency Room and bring the

package of the medicine with you because you or your child are at an increased risk of

bleeding.

Do not induce vomiting without explicit instructions from the doctor!

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

remember. If you forgot to take the medicine for a whole day, take the next dose at the usual

time the following day, but never take two doses on the same day!

Treatment should be continued as recommended by the doctor.

Even if there is an improvement in your health, do not stop taking this medicine without

consulting your doctor or pharmacist. If you stop taking the medicine too soon, your risk of a

heart attack may be higher.

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 about the use of this medicine, consult your doctor

or pharmacist.

4. SIDE EFFECTS

As with any medicine, the use of Effient may cause side effects in some users. Do not be

alarmed by reading the list of side effects. You may not suffer from any of them.

Contact a doctor as soon as possible if:

You suffer from the following symptoms which may indicate a stroke:

You are suffering from sudden numbness or weakness of the arm, leg or face, especially if it

happens only on one side of the body.

Page 4 of 6

You experience sudden confusion, difficulty speaking or understanding others.

You experience a sudden difficulty in walking or loss of balance or coordination.

You experience a sudden dizziness or a sudden severe headache with no known cause.

If you have never had a stroke or transient ischemic attack (TIA), the probability of having a

stroke as a side effect is low.

You notice fever and bruising under the skin that may appear as red pinpoint dots - these

symptoms may indicate Thrombotic Thrombocytopaenic Purpura (TTP).

This may be accompanied by unexplained extreme tiredness, confusion, and yellowing of

the skin or eyes (jaundice) (see Section 2 - "Before using this medicine").

You notice rash, itching, a swollen face and tongue or shortness of breath. These symptoms

may be signs of a severe allergic reaction.

You experience any of the following symptoms, which indicate bleeding:

You notice blood in your urine.

You are bleeding from the rectum, notice blood in your stools or your stool is black.

You experience uncontrollable bleeding, for example: bleeding from a cut or a wound.

Bleeding is the most common side effect with Effient. Although uncommon, severe

bleeding can be life-threatening.

Common side effects:

Bleeding in the stomach or bowels.

Bleeding from a needle puncture site.

Nose bleeds.

Skin rash.

Bruising, particularly small red bruises on the skin (ecchymoses).

Blood in urine.

Hematoma (bleeding under the skin at the site of an injection, or into a muscle, causing

swelling).

Low hemoglobin or red blood cell count (anemia).

Uncommon side effects:

An allergic reaction including angioedema (rash, itching, swollen lips/tongue, or shortness of

breath).

Spontaneous bleeding from the eye, rectum, gums or in the abdomen (around the internal

organs).

Bleeding after surgery.

Coughing up blood.

Blood in stools.

Rare side effects:

Low blood platelet count

Subcutaneous hematoma

If a side effects occurs, if one of the side effects gets worse, or if you suffer from a side

effect not mentioned in this leaflet, you must consult a doctor.

Page 5 of 6

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

Effects due to Drug Treatment" that can be found on the Home Page of the Ministry of Health’s

website (www.health.gov.il), which refers to the online form for reporting side effects, or via the

following link:

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

moh.gov.il

5. HOW TO STORE THIS MEDICINE?

Avoid poisoning! This medicine and any other medicine must be kept in a closed place out

of the reach and sight of children and/or infants to avoid poisoning. Do not induce vomiting

without an explicit instruction from the doctor.

Do not use this medicine after the expiry date (exp. date) which is stated on the package.

The expiry date refers to the last day of that month.

Do not store at a temperature above 30

Store in the original package in order to protect from air and moisture.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist

how to throw away medicines you no longer use. These measures will help to protect the

environment.

6. ADDITIONAL INFORMATION

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

Microcrystalline cellulose, Mannitol, Croscarmellose sodium, Hypromellose, Magnesium

stearate, Lactose monohydrate, Titanium dioxide, Triacetin, Iron oxide yellow, Iron oxide red

(only in the 10 mg tablet), Talc.

Each tablet contains no more than 0.68 mg sodium and 2.7 mg lactose.

What the medicine looks like and contents of the pack:

Effient 5 mg is a yellow and double-arrow-shaped tablet, with “5 MG” debossed on one

side and “4760” on the other.

Effient 10 mg is a beige and double-arrow shaped tablet, with “10 MG” debossed on

one side and “4759” on the other.

The product comes in aluminium foil blisters containing 28 tablets.

Drug registration numbers:

Effient 5 mg: 142-55-32010-00

Effient 10 mg: 142-56-32011-00

Manufacturer: Lilly S.A., Alcobendas (Madrid), Spain

License holder: Eli Lilly Israel Ltd., P.O.Box 2160, Herzeliya Pituach 46120.

Page 6 of 6

This leaflet has been reviewed and approved by the Ministry of Health in February 2014, and

was updated according to the Ministry of Health guidelines in January 2019.

I EFFITB A 04

X EFFITB A 05

This leaflet format was set by MOH and its content has been reviewed and approved on

March 2016 and updated according to the guidelines of the Ministry of Health on January 2019.

EFFIENT

1.

NAME OF THE MEDICINAL PRODUCT

Effient 5 mg film-coated tablets.

Effient 10 mg film-coated tablets.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 mg tablet contains: 5 mg prasugrel (as hydrochloride).

Excipient with known effect: Each tablet contains 2.7 mg lactose.

Each 10 mg tablet contains: 10 mg prasugrel (as hydrochloride).

Excipient with known effect: Each tablet contains 2.1 mg lactose.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

The 5 mg tablets are: Yellow and double-arrow-shaped tablets, debossed with “5 MG” on one side

and “4760” on the other.

The 10 mg tablets are: Beige and double-arrow shaped tablets, debossed with “10 MG”on one side

and “4759” on the other.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Effient, co-administered with acetylsalicylic acid (ASA), is indicated for

the prevention of

atherothrombotic events in patients with acute coronary syndrome (i.e. unstable angina, non-ST

segment elevation myocardial infarction [UA/NSTEMI] or ST segment elevation myocardial infarction

[STEMI]) undergoing primary or delayed percutaneous coronary intervention (PCI).

The increased efficacy should be balanced with the increased risk in patients with bleeding tendency

in those who had TIA/CVA in the past and in those above the age of 75 or weight below 60 kg.

For further information please refer to section 5.1.

4.2

Posology and method of administration

Page 2 of 16

Posology

Adults

Effient should be initiated with a single 60 mg loading dose and then continued at 10 mg once a day.

In UA/NSTEMI patients, where coronary angiography is performed within 48 hours after admission,

the loading dose should only be given at the time of PCI (see sections 4.4, 4.8 and 5.1). Patients

taking Effient should also take ASA daily (75 mg to 325 mg).

In patients with acute coronary syndrome (ACS) who are managed with PCI, premature

discontinuation of any antiplatelet agent, including Effient, could result in an increased risk of

thrombosis, myocardial infarction or death due to the patient’s underlying disease. A treatment of up

to 12 months is recommended unless the discontinuation of Effient is clinically indicated (see sections

4.4 and 5.1).

Patients 75 years old

The use of Effient in patients ≥ 75 years of age is generally not recommended. If, after a careful

individual benefit/risk evaluation by the prescribing physician (see section 4.4), treatment is deemed

necessary in the patients age group ≥ 75 years, then following a 60 mg loading dose a reduced

maintenance dose of 5 mg should be prescribed. Patients ≥ 75 years of age have greater sensitivity

to bleeding and higher exposure to the active metabolite of prasugrel (see sections 4.4, 4.8, 5.1 and

5.2).

Patients weighing <60 kg

Effient should be given as a single 60 mg loading dose and then continued at a 5 mg once daily dose.

The 10 mg maintenance dose is not recommended. This is due to an increase in exposure to the

active metabolite of prasugrel, and an increased risk of bleeding in patients with body weight <60 kg

when given a 10 mg once daily dose compared with patients ≥60 kg (see sections 4.4, 4.8 and 5.2).

Renal impairment

No dose adjustment is necessary for patients with renal impairment, including patients with end stage

renal disease (see section 5.2). There is limited therapeutic experience in patients with renal

impairment (see section 4.4).

Hepatic impairment

No dose adjustment is necessary in subjects with mild to moderate hepatic impairment (Child Pugh

class A and B) (see section 5.2). There is limited therapeutic experience in patients with mild and

moderate hepatic dysfunction (see section 4.4). Effient is contraindicated in patients with severe

hepatic impairment (Child Pugh class C).

Paediatric population

Effient is not recommended for use in children below age 18 due to a lack of data on safety and

efficacy.

Method of administration

For oral use. Effient may be administered with or without food. Administration of the 60 mg prasugrel

loading dose in the fasted state may provide most rapid onset of action (see section 5.2). Do not

crush or break the tablet.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active pathological bleeding.

Page 3 of 16

History of stroke or transient ischaemic attack (TIA).

Severe hepatic impairment (Child Pugh class C).

4.4

Special warnings and precautions for use

Bleeding risk

In the phase 3 clinical trial (TRITON) key exclusion criteria included an increased risk of bleeding;

anaemia; thrombocytopaenia; a history of pathological intracranial findings. Patients with acute

coronary syndromes undergoing PCI treated with Effient and ASA showed an increased risk of major

and minor bleeding according to the TIMI classification system. Therefore, the use of Effient in

patients at increased risk of bleeding should only be considered when the benefits in terms of

prevention of ischaemic events are deemed to outweigh the risk of serious bleedings. This concern

applies especially to patients:

≥75 years of age (see below).

with a propensity to bleed (e.g. due to recent trauma, recent surgery, recent or recurrent

gastrointestinal bleeding, or active peptic ulcer disease)

with body weight <60 kg (see sections 4.2 and 4.8). In these patients the 10 mg maintenance dose

is not recommended. A 5 mg maintenance dose should be used.

with concomitant administration of medicinal products that may increase the risk of bleeding,

including oral anticoagulants, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and

fibrinolytics.

For patients with active bleeding for whom reversal of the pharmacological effects of Effient is

required, platelet transfusion may be appropriate.

The use of Effient in patients ≥75 years of age is generally not recommended and should only be

undertaken with caution after a careful individual benefit/risk evaluation by the prescribing physician

indicates that benefits in terms of prevention of ischaemic events outweigh the risk of serious

bleedings. In the phase 3 clinical trial these patients were at greater risk of bleeding, including fatal

bleeding, compared to patients <75 years of age. If prescribed, a lower maintenance dose of 5 mg

should be used; the 10 mg maintenance dose is not recommended (see sections 4.2 and 4.8).

Therapeutic experience with prasugrel is limited in patients with renal impairment (including ESRD)

and in patients with moderate hepatic impairment. These patients may have an increased bleeding

risk. Therefore, prasugrel should be used with caution in these patients.

Patients should be told that it might take longer than usual to stop bleeding when they take prasugrel

(in combination with ASA), and that they should report any unusual bleeding (site or duration) to their

physician.

Bleeding Risk Associated with Timing of Loading Dose in NSTEMI

In a clinical trial of NSTEMI patients (the ACCOAST study), where patients were scheduled to

undergo coronary angiography within 2 to 48 hours after randomization, a prasugrel loading dose

given on average 4 hours prior to coronary angiography increased the risk of major

and minor peri-procedural bleeding compared with a prasugrel loading dose at the time of

PCI. Therefore, in UA/NSTEMI patients, where coronary angiography is performed within 48 hours

after admission, the loading dose should be given at the time of PCI. (see sections 4.2, 4.8 and 5.1).

Surgery

Patients should be advised to inform physicians and dentists that they are taking prasugrel before any

surgery is scheduled and before any new medicinal product is taken. If a patient is to undergo elective

surgery, and an antiplatelet effect is not desired, Effient should be discontinued at least 7 days prior to

surgery.

Increased frequency (3-fold) and severity of bleeding may occur in patients undergoing

Page 4 of 16

CABG surgery within 7 days of discontinuation of prasugrel (see 4.8). The benefits and risks of

prasugrel should be carefully considered in patients in whom the coronary anatomy has not been

defined and urgent CABG is a possibility.

Hypersensitivity including angioedema

Hypersensitivity reactions including angioedema have been reported in patients receiving

prasugrel, including in patients with a history of hypersensitivity reaction to clopidogrel.

Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is

advised (see section 4.8).

Thrombotic Thrombocytopaenic Purpura (TTP)

TTP has been reported with the use of prasugrel. TTP is a serious condition and requires prompt

treatment.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or

glucose-galactose malabsorption should not take Effient.

Morphine and other opioids

Reduced prasugrel efficacy has been seen in patients co-administered prasugrel and morphine (see

section 4.5).

4.5

Interaction with other medicinal products and other forms of interaction

Warfarin: Concomitant administration of Effient with coumarin derivatives other than warfarin has not

been studied. Because of the potential for increased risk of bleeding, warfarin (or other coumarin

derivatives) and prasugrel should be co-administered with caution (see section 4.4).

Non-steroidal anti-inflammatory drugs (NSAIDs): Concomitant administration with chronic NSAIDs has

not been studied. Because of the potential for increased risk of bleeding, chronic NSAIDs (including

COX-2 inhibitors) and Effient should be co-administered with caution (see section 4.4).

Effient can be concomitantly administered with medicinal products metabolised by cytochrome P450

enzymes (including statins), or medicinal products that are inducers or inhibitors of cytochrome P450

enzymes. Effient can also be concomitantly administered with ASA, heparin, digoxin, and medicinal

products that elevate gastric pH, including proton pump inhibitors and H

blockers. Although not

studied in specific interaction studies, Effient has been co-administered in the phase 3 clinical trial

with low molecular weight heparin, bivalirudin, and GP IIb/IIIa inhibitors (no information available

regarding the type of GP IIb/IIIa inhibitor used) without evidence of clinically significant adverse

interactions.

Effects of other medicinal products on Effient

Acetylsalicylic acid: Effient is to be administered concomitantly with acetylsalicylic acid (ASA).

Although a pharmacodynamic interaction with ASA leading to an increased risk of bleeding is

possible, the demonstration of the efficacy and safety of prasugrel comes from patients concomitantly

treated with ASA.

Heparin: A single intravenous bolus dose of unfractionated heparin (100 U/kg) did not significantly

alter the prasugrel-mediated inhibition of platelet aggregation. Likewise, prasugrel did not significantly

alter the effect of heparin on measures of coagulation. Therefore, both medicinal products can be

administered concomitantly.

An increased risk of bleeding is possible when Effient is co-administered

Page 5 of 16

with heparin

Statins: Atorvastatin (80 mg daily) did not alter the pharmacokinetics of prasugrel and its inhibition of

platelet aggregation. Therefore, statins that are substrates of CYP3A are not anticipated to have an

effect on the pharmacokinetics of prasugrel or its inhibition of platelet aggregation.

Medicinal products that elevate gastric pH: Daily co-administration of ranitidine (an H

blocker) or

lansoprazole (a proton pump inhibitor) did not change the prasugrel active metabolite’s AUC and T

but decreased the C

by 14% and 29%, respectively.

In the phase 3 clinical trial, Effient was

administered without regard to co-administration of a proton pump inhibitor or H

blocker.

Administration of the 60 mg prasugrel loading dose without concomitant use of proton pump inhibitors

may provide most rapid onset of action.

Inhibitors of CYP3A: Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and

CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the prasugrel active

metabolite’s AUC and T

, but decreased the C

by 34% to 46%. Therefore, CYP3A inhibitors such

as azol antifungals, HIV protease inhibitors, clarithromycin, telithromycin, verapamil, diltiazem,

indinavir, ciprofloxacin, and grapefruit juice are not anticipated to have a significant effect on the

pharmacokinetics of the active metabolite.

Inducers of cytochromes P450: Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6,

and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the

pharmacokinetics of prasugrel. Therefore, known CYP3A inducers such as rifampicin,

carbamazepine, and other inducers of cytochromes P450 are not anticipated to have significant effect

on the pharmacokinetics of the active metabolite.

Morphine and other opioids

:

A delayed and decreased exposure to oral P2Y12 inhibitors, including prasugrel and its active

metabolite, has been observed in patients with acute coronary syndrome treated with morphine. This

interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical

relevance is unknown, but data indicate the potential for reduced prasugrel efficacy in patients co-

administered prasugrel and morphine. In patients with acute coronary syndrome, in whom morphine

cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12

inhibitor may be considered.

Effects of Effient on other medicinal products

Digoxin: Prasugrel has no clinically significant effect on the pharmacokinetics of digoxin.

Medicinal products metabolised by CYP2C9

Prasugrel did not inhibit CYP2C9, as it did not affect the

pharmacokinetics of S-warfarin. Because of the potential for increased risk of bleeding, warfarin and

Effient should be co-administered with caution (see section 4.4).

Medicinal products metabolised by CYP2B6: Prasugrel is a weak inhibitor of CYP2B6. In healthy

subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of

bupropion, by 23%. This effect is likely to be of clinical concern only when prasugrel is co-

administered with medicinal products for which CYP2B6 is the only metabolic pathway and have a

narrow therapeutic window (e.g. cyclophosphamide, efavirenz).

4.6

Fertility, pregnancy and lactation

No clinical study has been conducted in pregnant or breast-feeding women.

Page 6 of 16

Pregnancy

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal

development, parturition or postnatal development (see section 5.3). Because animal reproduction

studies are not always predictive of a human response, Effient should be used during pregnancy only

if the potential benefit to the mother justifies the potential risk to the foetus.

Breast-feeding

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

excretion of prasugrel in breast milk. The use of prasugrel during breastfeeding is not recommended.

Fertility

Prasugrel had no effect on fertility of male and female rats at oral doses up to an exposure 240 times

the recommended daily human maintenance dose (based on mg/m

4.7

Effects on ability to drive and use machines

Prasugrel is expected to have no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

Safety in patients with acute coronary syndrome undergoing PCI was evaluated in one clopidogrel-

controlled study (TRITON) in which 6741 patients were treated with prasugrel (60 mg loading dose

and 10 mg once daily maintenance dose) for a median of 14.5 months (5802 patients were treated for

over 6 months, 4136 patients were treated for more than 1 year). The rate of study drug

discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel. Of these,

bleeding was the most common adverse reaction for both drugs leading to study drug discontinuation

(2.5% for prasugrel and 1.4% for clopidogrel).

Bleeding

Non-Coronary Artery Bypass Graft (CABG) related bleeding

In TRITON, the frequency of patients experiencing a non-CABG related bleeding event is shown in

Table 1. The incidence of Non-CABG-related TIMI major bleeding, including life-threatening and fatal,

as well as TIMI minor bleeding, was statistically significantly higher in subjects treated with prasugrel

compared to clopidogrel in the UA/NSTEMI and All ACS populations. No significant difference was

seen in the STEMI population. The most common site of spontaneous bleeding was the

gastrointestinal tract (1.7% rate with prasugrel and 1.3% rate with clopidogrel); the most frequent site

of provoked bleeding was the arterial puncture site (1.3% rate with prasugrel and 1.2% with

clopidogrel).

Table 1: Incidence of Non-CABG related bleeding

a

(% Patients)

Page 7 of 16

a Centrally adjudicated events defined by the Thrombolysis in Myocardial Infarction (TIMI) Study Group criteria.

b Other standard therapies were used as appropriate.

c Any intracranial haemorrhage or any clinically overt bleeding associated with a fall in haemoglobin ≥5 g/dL.

d Life-threatening bleeding is a subset of TIMI major bleeding and includes the types indented below. Patients may be

counted in more than one row.

e ICH=intracranial haemorrhage.

f Clinically overt bleeding associated with a fall in haemoglobin of ≥3 g/dL but <5 g/dL.

Patients 75 years old

Non-CABG-related TIMI major or minor bleeding rates:

Prasugrel 10 mg

Clopidogrel 75 mg

75 years (N=1785)

9.0% (1.0% fatal)

6.9% (0.1% fatal)

<75 years (N=11672)

3.8% (0.2% fatal)

2.9% (0.1% fatal)

<75 years (N=7180)**

2.0% (0.1% fatal)

1.3% (0.1% fatal)

Prasugrel

5 mg

Clopidogrel 75 mg

≥75 years (N=2060) **

2.6% (0.3% fatal)

3.0% (0.5% fatal)

*TRITON study in ACS patients undergoing PCI

**TRILOGY-ACS study in patients not undergoing PCI (see 5.1):

10 mg prasugrel; 5 mg prasugrel if <60 kg

Patients < 60 kg

Non-CABG-related TIMI major or minor bleeding rates:

Weight

Prasugrel 10 mg

Clopidogrel 75 mg

<60 kg (N=664)*

10.1% (0% fatal)

6.5% (0.3% fatal)

60 kg (N=12672)*

4.2% (0.3% fatal)

3.3% (0.1% fatal)

≥60 kg (N=7845)**

2.2% (0.2% fatal)

1.6% (0.2% fatal)

Prasugrel

5 mg

Clopidogrel 75 mg

<60kg (N=1391)**

1.4% (0.1% fatal)

2.2% (0.3% fatal)

*TRITON study in ACS patients undergoing PCI

**TRILOGY-ACS study in patients not undergoing PCI (see 5.1):

Event

All ACS

UA/NSTEMI

STEMI

Prasugrel

b

+ASA

(N=6741)

Clopidogrel

b

+ASA

(N=6716)

Prasugrel

b

+ASA

(N=5001)

Clopidogrel

b

+ASA

(N=4980)

Prasugrel

b

+ASA

(N=1740)

Clopidogrel

b

+ASA

(N=1736)

TIMI major

bleeding

Life-threatening

Fatal

Symptomatic

Requiring

inotropes

Requiring

surgical intervention

Requiring

transfusion (

units)

TIMI minor bleeding

Page 8 of 16

10 mg prasugrel; 5 mg prasugrel if ≥75 years of age

Patients ≥60 kg and age <75 years

In patients ≥60 kg and age <75 years, non-CABG-related TIMI major or minor bleeding rates were

3.6% for prasugrel and 2.8% for clopidogrel; rates for fatal bleeding were 0.2% for prasugrel and

0.1% for clopidogrel.

CABG-related bleeding

In the phase 3 clinical trial, 437 patients underwent CABG during the course of the study. Of those

patients, the rate of CABG-related TIMI major or minor bleeding was 14.1% for the prasugrel group

and 4.5% in the clopidogrel group. The higher risk for bleeding events in subjects treated with

prasugrel persisted up to 7 days from the most recent dose of study drug.

For patients who received

their thienopyridine within 3 days prior to CABG, the frequencies of TIMI major or minor bleeding were

26.7% (12 of 45 patients) in the prasugrel group, compared with 5.0% (3 of 60 patients) in the

clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior

to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.

% (3

9 patients) in the clopidogrel group. Beyond 7 days after drug discontinuation, the observed rates

of CABG-related bleeding were similar between treatment groups

(see section 4.4).

Bleeding Risk Associated with Timing of Loading Dose in NSTEMI

In a clinical study of NSTEMI patients (the ACCOAST study), where patients were scheduled to

undergo coronary angiography within 2 to 48 hours after randomization, patients given a 30 mg

loading dose on average 4 hours prior to coronary angiography followed by a 30 mg loading dose at

the time of PCI had an increased risk of non-CABG peri-procedural bleeding and no additional benefit

compared to patients receiving a 60 mg loading dose at the time of PCI (see sections 4.2 and 4.4).

Non-CABG- related TIMI bleeding rates through 7 days for patients were as follows:

Adverse Reaction

Prasugrel Prior to

Coronary

Angiography

a

(N=2037)

%

Prasugrel At

time of PCI

a

(N=1996)

%

TIMI Major bleeding

Life-threatening

Fatal

Symptomatic ICH

Requiring inotropes

Requiring surgical intervention

Requiring transfusion (

4 units)

TIMI Minor bleeding

a

Other standard therapies were used as appropriate. The clinical study protocol provided for all patients to receive aspirin and a

daily maintenance dose of prasugrel.

b

Any intracranial haemorrhage or any clinically overt bleeding associated with a fall in haemoglobin

5 g/dL.

c

Life-threatening is a subset of TIMI Major bleeding and includes the types indented below. Patients may be counted in more than

one row.

d

ICH=intracranial haemorrhage.

e

Clinically overt bleeding associated with a fall in haemoglobin of ≥3 g/dL but <5 g/dL.

Tabulated summary of adverse reactions

Page 9 of 16

Table 2 summarises haemorrhagic and non-haemorrhagic adverse reactions in TRITON, or that were

spontaneously reported, classified by frequency and system organ class. Frequencies are defined as

follows:

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100);

rare (≥ 1/10,000 to <1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the

available data).

Table 2: Haemorrhagic and Non-haemorrhagic adverse reactions

System Organ

Class

Common

Uncommon

Rare

Not Known

Blood and

Lymphatic System

disorders

Anaemia

Thrombocytopaenia

Thrombotic

thrombocytopaenic

purpura (TTP)

-see

section 4.4

Immune system

disorders

Hypersensitivity

including angioedema

Eye disorders

Eye haemorrhage

Vascular

Disorders

Haematoma

Respiratory,

thoracic and

mediastinal

disorders

Epistaxis

Haemoptysis

Gastrointestinal

disorders

Gastrointestinal

haemorrhage

Retroperitoneal

haemorrhage

Rectal haemorrhage

Haematochezia

Gingival bleeding

Skin and

subcutaneous

tissue disorders

Rash

Ecchymosis

Renal and urinary

disorders

Haematuria

General disorders

and administration

site conditions

Vessel puncture site

haematoma

Puncture site

haemorrhage

Injury, poisoning

and procedural

complications

Contusion

Post-procedural

haemorrhage

Subcutaneous

haematoma

In patients with or without a history of TIA or stroke, the incidence of stroke in the phase 3 clinical trial

was as follows (see section 4.4):

History of TIA or

stroke

Prasugrel

Clopidogrel

Yes (N=518)

6.5% (2.3% ICH*)

1.2% (0% ICH*)

No (N=13090)

0.9% ( 0.2% ICH*)

1.0% (0.3% ICH*)

* ICH=intracranial haemorrhage

.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

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

Page 10 of 16

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

Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.go

v.il

4.9

Overdose

Overdose of Effient may lead to prolonged bleeding time and subsequent bleeding complications. No

data are available on the reversal of the pharmacological effect of prasugrel; however, if prompt

correction of prolonged bleeding time is required, platelet transfusion and/or other blood products may

be considered.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin

, ATC code: B01AC22

Pharmacodynamics

Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its

active metabolite to the P2Y

class of ADP receptors on platelets. Since platelets participate in the

initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet

function can result in the reduction of the rate of cardiovascular events such as death, myocardial

infarction, or stroke.

Following a 60 mg loading dose of prasugrel, inhibition of ADP-induced platelet aggregation occurs at

15 minutes with 5 µM ADP and 30 minutes with 20 µM ADP. The maximum inhibition by prasugrel of

ADP-induced platelet aggregation is 83% with 5 µM ADP and 79% with 20 µM ADP, in both cases

with 89% of healthy subjects and patients with stable atherosclerosis achieving at least 50% inhibition

of platelet aggregation by 1 hour. Prasugrel-mediated inhibition of platelet aggregation exhibits low

between-subject (9%) and within-subject (12%) variability with both 5 µM and 20 µM ADP. Mean

steady-state inhibition of platelet aggregation was 74% and 69% respectively for 5 µM ADP and 20

µM ADP, and was achieved following 3 to 5 days of administration of the 10 mg prasugrel

maintenance dose preceded by a 60 mg loading dose. More than 98% of subjects had ≥20%

inhibition of platelet aggregation during maintenance dosing.

Platelet aggregation gradually returned to baseline values after treatment in 7 to 9 days after

administration of a single 60 mg loading dose of prasugrel and in 5 days following discontinuation of

maintenance dosing at steady-state.

Switching data: Following administration of 75 mg clopidogrel once daily for 10 days, 40 healthy

subjects were switched to prasugrel 10 mg once daily with or without a loading dose of 60 mg.

Similar or higher inhibition of platelet aggregation was observed with prasugrel. Switching directly to

prasugrel 60 mg loading dose resulted in the most rapid onset of higher platelet inhibition. Following

administration of a 900 mg loading dose of clopidogrel (with ASA), 56 subjects with ACS were treated

for 14 days with either prasugrel 10 mg once daily or clopidogrel 150 mg once daily, and then

switched to either clopidogrel 150 mg or prasugrel 10 mg for another 14 days. Higher inhibition of

platelet aggregation was observed in patients switched to prasugrel 10 mg compared with those

treated with clopidogrel 150 mg. In a study of 276 ACS patients managed with PCI, switching from an

initial loading dose of 600 mg clopidogrel or placebo administered upon presentation to the hospital

prior to coronary angiography to a 60 mg loading dose of prasugrel administered at the time of

Page 11 of 16

percutaneous coronary intervention, resulted in a similar increased inhibition of platelet aggregation

for the 72 hour duration of the study.

Efficacy and Safety in Acute Coronary Syndrome (ACS)

The phase 3 TRITON study compared Effient (prasugrel) with clopidogrel, both co-administered with

ASA and other standard therapy. TRITON was a 13,608 patient, multicentre international,

randomised, double blind, parallel group study. Patients had ACS with moderate to high risk UA,

NSTEMI, or STEMI and were managed with PCI.

Patients with UA/NSTEMI within 72 hours of symptoms or STEMI between 12 hours to 14 days of

symptoms were randomised after knowledge of coronary anatomy. Patients with STEMI within 12

hours of symptoms and planned for primary PCI could be randomised without knowledge of coronary

anatomy. For all patients, the loading dose could be administered anytime between randomisation

and 1 hour after the patient left the catheterisation lab.

Patients randomised to receive prasugrel (60 mg loading dose followed by 10 mg once daily) or

clopidogrel (300 mg loading dose followed by 75 mg once daily) were treated for a median of 14.5

months (maximum of 15 months with a minimum of 6 months follow-up). Patients also received ASA

(75 mg to 325 mg once daily). Use of any thienopyridine within 5 days before enrolment was an

exclusion criterion. Other therapies, such as heparin and GPIIb/IIIa inhibitors, were administered at

the discretion of the physician. Approximately 40% of patients (in each of the treatment groups)

received GPIIb/IIIa inhibitors in support of PCI (no information available regarding the type of GP

IIb/IIIa inhibitor used). Approximately 98% of patients (in each of the treatment groups) received

antithrombins (heparin, low molecular weight heparin, bivalirudin, or other agent) directly in support of

PCI.

The trial’s primary outcome measure was the time to first occurrence of cardiovascular (CV) death,

non-fatal myocardial infarction (MI), or non-fatal stroke. Analysis of the composite endpoint in the All

ACS population (combined UA/NSTEMI and STEMI cohorts) was contingent on showing statistical

superiority of prasugrel versus clopidogrel in the UA/NSTEMI cohort (p<0.05).

All ACS population: Effient showed superior efficacy compared to clopidogrel in reducing the primary

composite outcome events as well as the pre-specified secondary outcome events, including stent

thrombosis (see Table 3).

The benefit of prasugrel was apparent within the first 3 days and it

persisted to the end of study. The superior efficacy was accompanied by an increase in major

bleeding (see sections 4.4 and 4.8). The patient population was 92% Caucasian, 26% female, and

39% ≥65 years of age. The benefits associated with prasugrel were independent of the use of other

acute and long-term cardiovascular therapies, including heparin/low molecular weight heparin,

bivalirudin, intravenous GPIIb/IIIa inhibitors, lipid-lowering medicinal products, beta-blockers, and

angiotensin converting enzyme inhibitors. The efficacy of prasugrel was independent

of the ASA dose

(75 mg to 325 mg once daily).

The use of oral anticoagulants, non-study antiplatelet medicinal

products and chronic NSAIDs was not allowed in TRITON. In the All ACS population, prasugrel was

associated with a lower incidence of CV death, non-fatal MI, or non-fatal stroke compared to

clopidogrel, regardless of baseline characteristics such as age, sex, body weight, geographical

region, use of GPIIb/IIIa inhibitors, and stent type. The benefit was primarily due to a significant

decrease in non-fatal MI (see Table 3). Subjects with diabetes had significant reductions in the

primary and all secondary composite endpoints.

The observed benefit of prasugrel in patients ≥ 75 years was less than that observed in patients <75

years. Patients ≥ 75 years were at increased risk of bleeding, including fatal (see sections 4.2, 4.4,

and 4.8). Patients ≥ 75 years in whom the benefit with prasugrel was more evident included those

with diabetes, STEMI, higher risk of stent thrombosis, or recurrent events.

Page 12 of 16

Patients with a history of TIA or a history of ischaemic stroke more than 3 months prior to prasugrel

therapy had no reduction in the primary composite endpoint.

Table 3: Patients with Outcome Events in TRITON Primary Analysis

Outcome Events

Prasugrel

+ ASA

Clopidogre

l

+ASA

Hazard Ratio (HR)

(95% CI)

p-

value

All ACS

(N=6813)

%

(N=6795)

%

0.812 (0.732,

0.902)

<0.00

Primary Composite Outcome Events

Cardiovascular (CV) death, non fatal MI, or

non fatal stroke

11.5

Primary Individual Outcome Events

CV death

0.886 (0.701,

1.118)

0.307

Nonfatal MI

0.757 (0.672,

0.853)

<0.00

Nonfatal stroke

1.016 (0.712,

1.451)

0.930

UA/NSTEMI

Primary Composite Outcome Events

(N= 5044)

%

(N=5030)

%

CV death, nonfatal MI, or nonfatal stroke

11.2

0.820 (0.726,

0.927)

0.002

CV death

0.979 (0.732,1.309)

0.885

Nonfatal MI

0.761 (0.663,0.873)

<0.00

Nonfatal stroke

0.979 (0.633,1.513)

0.922

STEMI

Primary Composite Outcome Events

(N= 1769)

%

(N=1765)

%

CV death, nonfatal MI, or nonfatal stroke

12.2

0.793 (0.649,

0.968)

0.019

CV death

0.738 (0.497,1.094)

0.129

Nonfatal MI

0.746 (0.588,0.948)

0.016

Nonfatal stroke

1.097 (0.590,2.040)

0.770

In the All ACS population, analysis of each of the secondary endpoints showed a significant benefit

(p<0.001) for prasugrel versus clopidogrel. These included definite or probable stent thrombosis at

study end (0.9% vs. 1.8%; HR 0.498; CI 0.364, 0.683); CV death, nonfatal MI, or urgent target vessel

revascularisation through 30 days (5.9% vs. 7.4%; HR 0.784; CI 0.688,0.894); all cause death,

nonfatal MI, or nonfatal stroke through study end (10.2% vs. 12.1%; HR 0.831; CI 0.751, 0.919); CV

death, nonfatal MI, nonfatal stroke or rehospitalisation for cardiac ischaemic event through study end

(11.7% vs. 13.8%; HR 0.838; CI 0.762, 0.921). Analysis of all cause death did not show any

significant difference between prasugrel and clopidogrel in the All ACS population (2.76% vs. 2.90%),

in the UA/NSTEMI population (2.58% vs. 2.41%), and in the STEMI population (3.28% vs. 4.31%).

Prasugrel was associated with a 50% reduction in stent thrombosis through the 15 month follow-up

period. The reduction in stent thrombosis with Effient was observed both early and beyond 30 days

for both bare metal and drug eluting stents.

In an analysis of patients who survived an ischaemic event, prasugrel was associated with a reduction

in the incidence of subsequent primary endpoint events (7.8% for prasugrel vs 11.9% for clopidogrel).

Page 13 of 16

Although bleeding was increased with prasugrel, an analysis of the composite endpoint of death from

any cause, nonfatal myocardial infarction, nonfatal stroke, and non-CABG-related TIMI major

haemorrhage favoured Effient compared to clopidogrel (Hazard ratio, 0.87; 95% CI, 0.79 to 0.95;

p=0.004). In TRITON, for every 1000 patients treated with Effient, there were 22 fewer patients with

myocardial infarction, and 5 more with non–CABG-related TIMI major haemorrhages, compared with

patients treated with clopidogrel.

Results of a pharmacodynamic/pharmacogenomic study in 720 Asian ACS PCI patients demonstrated

that higher levels of platelet inhibition are achieved with prasugrel compared to clopidogrel, and that

prasugrel 60-mg loading dose/10-mg maintenance dose is an appropriate dose regimen in Asian

subjects who weigh at least 60 kg and are less than 75 years of age (see section 4.2).

In a 30 month study (TRILOGY–ACS) in 9326 patients with UA/NSTEMI ACS medically managed

without revascularisation (non-licensed indication), prasugrel did not significantly reduce the

frequency of the composite endpoint of CV death, MI or stroke compared to clopidogrel. Rates of

TIMI major bleeding (including life threatening, fatal and ICH) were similar in prasugrel and

clopidogrel treated patients. Patients ≥75 years old or those below 60 kg (N=3022) were randomized

to 5 mg prasugrel. As in the < 75 years old and ≥60 kg patients treated with 10 mg prasugrel, there

was no difference between 5 mg prasugrel and 75 mg clopidogrel in CV outcomes. Rates of major

bleeding were similar in patients treated with 5 mg prasugrel and those treated with 75 mg

clopidogrel. Prasugrel 5 mg provided greater antiplatelet effect than clopidogrel 75 mg. Prasugrel

should be used with caution in patients ≥ 75 years old and in patients weighing <60 kg (see sections

4.2, 4.4 and 4.8).

In a 30-day study (ACCOAST) in 4033 patients with NSTEMI with elevated troponin who were

scheduled for coronary angiography followed by PCI within 2 to 48 hours after randomization,

subjects who received prasugrel 30 mg loading dose on average 4 hours prior to coronary

angiography followed by a 30 mg loading dose at the time of PCI (n=2037) had an increased risk of

non-CABG peri-procedural bleeding and no additional benefit compared to patients receiving a 60 mg

loading dose at the time of PCI (n=1996). Specifically, prasugrel did not significantly reduce the

frequency of the composite endpoint of cardiovascular (CV) death, myocardial infarction (MI), stroke,

urgent revascularization (UR), or glycoprotein (GP) IIb/IIIa inhibitor bailout through 7 days from

randomization in subjects receiving prasugrel prior to coronary angiography compared to patients

receiving the full loading dose of prasugrel at the time of PCI, and the rate of the key safety objective

for all TIMI major bleeding (CABG and non-CABG events) through 7 days from randomization in all

treated subjects was significantly higher in subjects receiving prasugrel prior to coronary angiography

versus patients receiving the full loading dose of prasugrel at the time of PCI. Therefore, in

UA/NSTEMI patients, where coronary angiography is performed within 48 hours after admission, the

loading dose should be given at the time of PCI. (See sections 4.2, 4.4, and 4.8).

5.2

Pharmacokinetic properties

Prasugrel is a prodrug and is rapidly metabolised in vivo to an active metabolite and inactive

metabolites. The active metabolite’s exposure (AUC) has moderate to low between-subject (27%) and

within-subject (19%) variability. Prasugrel’s pharmacokinetics are similar in healthy subjects, patients

with stable atherosclerosis, and patients undergoing percutaneous coronary intervention.

Absorption

The absorption and metabolism of prasugrel are rapid, with peak plasma concentration (C

) of the

active metabolite occurring in approximately 30 minutes. The active metabolite’s exposure (AUC)

increases proportionally over the therapeutic dose range. In a study of healthy subjects, AUC of the

active metabolite was unaffected by a high fat, high calorie meal, but C

was decreased by 49% and

the time to reach C

) was increased from 0.5 to 1.5 hours. Effient was administered without

Page 14 of 16

regard to food in TRITON. Therefore, Effient can be administered without regard to food; however,

the administration of prasugrel loading dose in the fasted state may provide most rapid onset of action

(see section 4.2).

Distribution

Active metabolite binding to human serum albumin (4% buffered solution) was 98%.

Metabolism

Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolysed in the

intestine to a thiolactone, which is then converted to the active metabolite by a single step of

cytochrome P450 metabolism, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9

and CYP2C19. The active metabolite is further metabolised to two inactive compounds by S-

methylation or conjugation with cysteine.

In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving Effient, there

was no relevant effect of genetic variation in CYP3A5, CYP2B6, CYP2C9, or CYP2C19 on the

pharmacokinetics of prasugrel or its inhibition of platelet aggregation.

Elimination

Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the faeces, as inactive

metabolites. The active metabolite has an elimination half-life of about 7.4 hours (range 2 to 15

hours).

Special Populations

Elderly: In a study of healthy subjects between the ages of 20 and 80 years, age had no significant

effect on pharmacokinetics of prasugrel or its inhibition of platelet aggregation. In the large phase 3

clinical trial, the mean estimated exposure (AUC) of the active metabolite was 19% higher in very

elderly patients (≥75 years of age) compared to subjects <75 years of age. Prasugrel should be used

with caution in patients ≥ 75 years of age due to the potential risk of bleeding in this population (see

sections 4.2 and 4.4). In a study in subjects with stable atherosclerosis, the mean AUC of the active

metabolite in patients ≥75 years old taking 5 mg prasugrel was approximately half that in patients <

65 years old taking 10 mg prasugrel, and the antiplatelet effect of 5 mg was reduced but was non-

inferior compared to 10 mg.

Hepatic impairment: No dose adjustment is necessary for patients with mild to moderate impaired

hepatic function (Child Pugh Class A and B). Pharmacokinetics of prasugrel and its inhibition of

platelet aggregation were similar in subjects with mild to moderate hepatic impairment compared to

healthy subjects. Pharmacokinetics and pharmacodynamics of prasugrel in patients with severe

hepatic impairment have not been studied. Prasugrel must not be used in patients with severe hepatic

impairment (see section 4. 3).

Renal impairment: No dosage adjustment is necessary for patients with renal impairment, including

patients with end stage renal disease (ESRD). Pharmacokinetics of prasugrel and its inhibition of

platelet aggregation are similar in patients with moderate renal impairment (GFR 30<50

ml/min/1.73m

) and healthy subjects. Prasugrel-mediated inhibition of platelet aggregation was also

similar in patients with ESRD who required haemodialysis compared to healthy subjects, although

and AUC of the active metabolite decreased 51% and 42%, respectively, in ESRD patients.

Body weight: The mean exposure (AUC) of the active metabolite of prasugrel is approximately 30 to

40% higher in healthy subjects and patients with a body weight of <60 kg compared to those weighing

≥60 kg. Prasugrel should be used with caution in patients with a body weight of <60 kg due to the

potential risk of bleeding in this population (see section 4.4). In a study in subjects with stable

atherosclerosis, the mean AUC of the active metabolite in patients <60 kg taking 5 mg prasugrel was

Page 15 of 16

38% lower than in patients ≥60 kg taking 10 mg prasugrel, and the antiplatelet effect of 5 mg was

similar to 10 mg.

Ethnicity: In clinical pharmacology studies, after adjusting for body weight, the AUC of the active

metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects compared to

that of Caucasians,

predominantly related to higher exposure in Asian subjects <60 kg. There is no

difference in exposure among Chinese, Japanese, and Korean subjects. Exposure in subjects of

African and Hispanic descent is comparable to that of Caucasians. No dose adjustment is

recommended based on ethnicity alone.

Gender: In healthy subjects and patients, the pharmacokinetics of prasugrel are similar in men and

women.

Paediatric population: Pharmacokinetics and pharmacodynamics of prasugrel have not been

evaluated in a paediatric population (see section 4.2).

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, or toxicity to reproduction.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the

maximum human exposure indicating little relevance to clinical use.

Embryo-foetal developmental toxicology studies in rats and rabbits showed no evidence of

malformations due to prasugrel. At a very high dose (>240 times the recommended daily human

maintenance dose on a mg/m

basis) that caused effects on maternal body weight and/or food

consumption, there was a slight decrease in offspring body weight (relative to controls). In pre- and

post-natal rat studies, maternal treatment had no effect on the behavioural or reproductive

development of the offspring at doses up to an exposure 240 times the recommended daily human

maintenance dose (based on mg/m

No compound-related tumours were observed in a 2-year rat study with prasugrel exposures ranging

to greater than 75 times the recommended therapeutic exposures in humans (based on plasma

exposures to the active and major circulating human metabolites). There was an increased incidence

of tumours (hepatocellular adenomas) in mice exposed for 2 years to high doses (>75 times human

exposure), but this was considered secondary to prasugrel-induced enzyme-induction. The rodent-

specific association of liver tumours and drug-induced enzyme induction is well documented in the

literature. The increase in liver tumours with prasugrel administration in mice is not considered a

relevant human risk.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet Core:

Microcrystalline cellulose

Mannitol

Croscarmellose sodium

Hypromellose

Magnesium stearate

Page 16 of 16

Film-Coat:

Lactose monohydrate

Hypromellose

Titanium dioxide

Triacetin

Iron oxide yellow

Iron oxide red (only in 10 mg)

Talc

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years.

6.4

Special precautions for storage

Store below 30°C. Store in the original package to protect from air and moisture.

6.5

Nature and contents of container

Aluminium foil blisters in cartons of 6, 14, 28, 30, 56 tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7. Manufacturer

Lilly S.A. Alcobendas (Madrid) – Spain.

8.

Licence Holder

Eli Lilly Israel Ltd

POB 2160 Herzliya Pituach 46120 Israel

X EFFITB A 05

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ךיראת

09

-

Jan-2014

םש

רישכת

תילגנאב

רפסמו

םושירה

Effient 5 mg, 10 mg

142-55-32010-00

,

142-56-32011-00

םש

לעב

םושירה

Eli Lilly Israel Ltd

.

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Posology, dosage &

administration

4.2 Posology and method

of administration

Posology

Adults

Effient should be initiated

with a single 60 mg loading

dose and then continued at

10 mg once a day. Patients

taking Effient should also

take ASA daily (75 mg to 325

mg).

4.2 Posology and method of administration

Posology

Adults

Effient should be initiated with a single 60 mg

loading dose and then continued at 10 mg once

a day. In UA/NSTEMI patients, where coronary

angiography is performed within 48 hours after

admission, the loading dose should only be

given at the time of PCI (see sections 4.4, 4.8

and 5.1). Patients taking Effient should also take

ASA daily (75 mg to 325 mg).

Special Warnings and

Special Precautions for

Use

תפסות

4.4 Special warnings and precautions for use

Bleeding risk

[…]

Bleeding Risk Associated with Timing of

Loading Dose in NSTEMI

In a clinical trial of NSTEMI patients (the

ACCOAST study), where patients were

scheduled to undergo coronary angiography

within 2 to 48 hours after randomization, a

prasugrel loading dose given on average 4

hours prior to coronary angiography increased

the risk of major

and minor peri-procedural bleeding compared

with a prasugrel loading dose at the time of

PCI. Therefore, in UA/NSTEMI patients, where

coronary angiography is performed within 48

hours after admission, the loading dose should

be given at the time of PCI. (see sections 4.2,

4.8 and 5.1).

Pharmacological

properties

תפסות

5. PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

In a 30-day study (ACCOAST) in 4033 patients

with NSTEMI with elevated troponin who were

scheduled for coronary angiography followed by

PCI within 2 to 48 hours after randomization,

subjects who received prasugrel 30 mg loading

dose on average 4 hours prior to coronary

angiography followed by a 30 mg loading dose

at the time of PCI (n=2037) had an increased

risk of non-CABG peri-procedural bleeding and

no additional benefit compared to patients

receiving a 60 mg loading dose at the time of

PCI (n=1996). Specifically, prasugrel did not

significantly reduce the frequency of the

composite endpoint of cardiovascular (CV)

death, myocardial infarction (MI), stroke, urgent

revascularization (UR), or glycoprotein (GP)

IIb/IIIa inhibitor bailout through 7 days from

randomization in subjects receiving prasugrel

prior to coronary angiography compared to

patients receiving the full loading dose of

prasugrel at the time of PCI, and the rate of the

key safety objective for all TIMI major bleeding

(CABG and non-CABG events) through 7 days

from randomization in all treated subjects was

significantly higher in subjects receiving

prasugrel prior to coronary angiography versus

patients receiving the full loading dose of

prasugrel at the time of PCI. Therefore, in

UA/NSTEMI patients, where coronary

angiography is performed within 48 hours after

admission, the loading dose should be given at

the time of PCI. (See sections 4.2, 4.4, and 4.8)

Adverse events

תפסות

4.8 Undesirable effects

Bleeding Risk Associated with Timing of

Loading Dose in NSTEMI

In a clinical study of NSTEMI patients (the

ACCOAST study), where patients were

scheduled to undergo coronary angiography

within 2 to 48 hours after randomization,

patients given a 30 mg loading dose on average

4 hours prior to coronary angiography followed

by a 30 mg loading dose at the time of PCI had

an increased risk of non-CABG peri-procedural

bleeding and no additional benefit compared to

patients receiving a 60 mg loading dose at the

time of PCI (see sections 4.2 and 4.4). Non-

CABG- related TIMI bleeding rates through 7

days for patients were as follows:

a

Other standard th erap ies were used as

approp riate. Th e clinical study protocol

prov id ed fo r all patients to receive aspirin and

a daily ma intenance dose of prasugrel.

b

Any in tracran ial haemo rrhag e or any clin ically

overt bleeding asso ciated with a fall in

haemoglobin

5 g/dL.

c

Life-threatenin g is a subset of TIMI Major

bleeding and in clud es th e types indented

belo w. Patients may b e co un ted in mo re th an

on e row.

d

ICH=intracranial haemo rrhage.

e

Clin ically overt bleeding asso ciated with a fall in

haemoglob in of ≥3 g/dL but <5 g/dL

ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

שקובמה תו

לע

עקר

בוהצ

.

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