Consumer medicine information

Effient Tablets

Prasugrel

BRAND INFORMATION

Brand name

Effient Tablets

Active ingredient

Prasugrel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Effient Tablets.

What is in this leaflet

This leaflet answers some common questions about Effient.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date shown on the final page. More recent information on this medicine may be available. Make sure you speak to your pharmacist, nurse or doctor to obtain the most up to date information on this medicine. You can also download the most up to date leaflet from www.lilly.com.au. The updated leaflet may contain important information about this medicine and its use that you should be aware of.

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

Always follow the instructions that your doctor or pharmacist give you about Effient.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Effient is used for

Effient is used to prevent blood cells from clotting.

It contains the active ingredient, prasugrel.

It is used by people who have had a PCI (percutaneous coronary intervention) because of unstable angina or a heart attack.

PCI is a procedure where a balloon-tipped tube is used to open a blocked artery, with or without a stent being placed in the artery.

Effient belongs to the group of medicines called antiplatelet agents.

It works by reducing the ability of blood cells to clot. By preventing blood cells from clumping, it reduces the chances of blood clots forming (a process called thrombosis), thereby decreasing or even stopping blood supply to the heart muscle.

Effient is always taken with aspirin.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed this medicine for another use. If you want more information, ask your doctor.

This medicine is available only with a doctor's prescription.

Before you take Effient

When you must not take it

Do not take Effient if you have an allergy to Effient or any of the ingredients listed at the end of this leaflet:

Symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash
  • itching.

If you are not sure if you have an allergy to Effient, check with your doctor.

Do not take Effient if you have had any of the following medical conditions:

  • bleeding caused by a stomach ulcer
  • bleeding inside your head
  • stroke
  • transient ischaemic attack (TIA) which resulted in a temporary paralysis, numbness, speech difficulty or other symptoms affecting your nervous system which happened suddenly and disappeared within 24 hours
  • severe liver disease

Do not take Effient if:

  • the packaging is torn or shows signs of tampering (or the tablets do not look quite right)
  • the expiry date on the pack has passed.

If you take this medicine after the expiry date has passed, it may not work as well.

Do not give this medicine to children.

There is no experience with the use of this medicine in children.

Before you start to take it

Tell your doctor if:

  • you have any allergies to any other medicines including those you have previously taken to prevent your blood from clotting, or any other substances such as foods, preservatives or dyes
  • you are already taking aspirin
  • you are pregnant or plan to become pregnant
    Your doctor will discuss the possible risks and benefits of taking this medicine during pregnancy.
  • you are breast-feeding or plan to breast-feed
    Effient is not recommended while you are breast-feeding. It is not known whether it passes into breast-milk.
  • you have or have had any of the following medical conditions:
    - bleeding disorders or blood clotting problems
    - a tendency to bleed as a result of a recent trauma, recent surgery (including dental surgery), recent or recurrent gastrointestinal bleeding, active peptic ulcer disease
    - a history of kidney or liver problems
    - a history of stroke or TIA
    - weigh less than 60 kg
    - are more than 75 years old
    - a history of tumours or cancer
  • you are planning to have surgery (including dental procedures).

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Effient.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

You will be prescribed aspirin at a low dose with Effient. Aspirin works together with Effient.

Some medicines and Effient may interfere with each other. These are:

  • medicines that "thin the blood" such as warfarin and heparin.

There are others so please check with your doctor or pharmacist

  • non steroidal anti-inflammatory drugs (NSAIDs) - medicines used to treat arthritis, period pain, aches and pain
  • fibrinolytics - a group of medicines used to dissolve a blood clot that has formed in an artery or a vein
  • some medicines used to treat HIV (e.g. efavirenz).
  • some medicines used to treat cancer (e.g. cyclophosphamide).

These medicines may be affected by Effient or may affect how well it works. You may need different amounts of your medicine or you may need to take different medicines.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines. They also have a more complete list of medicines to be careful with or avoid while taking Effient.

Ask your doctor or pharmacist if you are not sure if you are taking any of these medicines.

How to take Effient

Take this medicine only as prescribed by your doctor and follow his/her directions carefully.

These may differ from the information contained in this leaflet.

How much to take

Your doctor will tell you how many tablets to take each day.

Effient is available as a 5 and 10 mg tablet. It is usual for your doctor to start you on a single dose of six 10 mg tablets and then continue with a 10 mg or 5 mg once daily dose. Your doctor will also prescribe a daily dose of aspirin to take with this medicine.

When to take it

You should swallow the tablets with a glass of water.

The tablets can be taken before or after meals.

Do not break the tablet in half. Talk to your doctor or pharmacist if you have trouble swallowing tablets.

Take it at the same time each day.

Taking your tablets at the same time will have the best effect. It will also help you to remember when to take it.

How long to take it

Continue taking Effient for as long as your doctor recommends.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you have missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor, or Poisons Information Centre (telephone in Australia: 13 11 26; in New Zealand: 0800 POISON or 0800 764 766) for advice if you think that you or anyone else may have taken too much Effient. Do this even if there are no signs of discomfort or poisoning.

You may need urgent attention.

While you are taking Effient

Things you must do

Take it every day exactly as your doctor has prescribed.

If you become pregnant while you are taking it, tell your doctor.

If you decide to breast-feed your baby, tell your doctor.

Your doctor may want to discuss this and change your medicine.

If you are about to start taking any new medicines, tell your doctor and pharmacist that you are taking Effient.

Tell all doctors, dentists and pharmacists who are treating you that you are taking Effient.

Tell your doctor, dentist or pharmacist that you are taking Effient before you have any surgery.

It may increase the risk of bleeding during an operation or some dental work. Therefore, treatment may need to be stopped before surgery.

Your doctor will decide whether to stop Effient and if so, for how long.

Ask your doctor whether there are any activities you should avoid while taking this medicine, for example, certain sports.

Sometimes after an injury, bleeding may occur inside your body without you knowing about it.

Tell your doctor immediately if you are injured while taking this medicine.

It may take longer than usual to stop bleeding while you are taking Effient.

Tell your doctor immediately if you notice the return of any of the symptoms you had before starting Effient.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not stop taking this medicine without informing your doctor as it may increase the chance of a heart attack or stroke or a blood clot forming.

Things to be careful of

Be careful driving or operating machinery until you know how it affects you.

Make sure you know how you react to it before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or light-headed. If this does occur, do not drive.

If you drink alcohol, faintness or dizziness may be worse.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Effient.

It helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following:

  • rash
  • nose bleeds
  • cuts that take longer than usual to stop bleeding
  • bleeding gums.

Tell your doctor immediately, or go to Accident and Emergency if you notice any of the following:

  • signs of anaemia (being tired and looking pale)
  • severe or uncontrollable bleeding, including after surgery
  • coughing up blood (a sign of bleeding from the stomach)
  • pink or brown urine
  • red or black stools
  • diarrhoea with blood, mucus, stomach pain and fever (a sign of bleeding from the intestine)
  • unusual bruising (bruises that develop without known cause or grow in size)
  • red or purple spots visible through your skin
  • unusually heavy bleeding or bruising from cuts or wounds
  • blood in the eyes
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing .

The above list includes serious side effects. You may need urgent medical attention.

Tell your doctor if you notice any other effects.

Other side effects not listed above may also occur in some people.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

After using Effient

Storage

Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out of the blister pack, they may not keep well.

Keep them in a cool, dry place where it stays below 30°C. Do not store them, or any other medicine, in a bathroom or near a sink. Do not leave them in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep them where children cannot reach them.

A locked cupboard at least one and a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets left over.

Product description

What it looks like

  • The 5 mg tablets are yellow, double-arrow shaped, film-coated, unscored, debossed with "5 MG" on one side and "4760" on the other side.
  • The 10 mg tablets are beige, double-arrow shaped, film-coated, unscored, debossed with "10 MG" on one side and with "4759" on the other side.

A box contains 6 or 28 tablets.

Ingredients

Effient contains either 5 mg or 10 mg of prasugrel (as hydrochloride) as the active ingredient.

It also contains:

  • Mannitol
  • Hypromellose
  • Croscarmellose sodium
  • Cellulose - microcrystalline
  • Magnesium stearate
  • Lactose
  • Titanium dioxide
  • Glycerol acetate
  • Iron oxide yellow CI77492
  • Iron oxide red CI77491.

Supplier

Supplied in Australia by:
Eli Lilly Australia Pty Limited
112 Wharf Road
WEST RYDE NSW 2114

Supplied in New Zealand by:
Eli Lilly and Company (NZ) Limited
Level 1
123 Ormiston Road
Botany South
Auckland 2016
NEW ZEALAND

AUST R Numbers

  • Effient 5 mg - AUST R 150809
  • Effient 10 mg - AUST R 150810

®= Registered Trademark

This leaflet was prepared in May 2013

BRAND INFORMATION

Brand name

Effient Tablets

Active ingredient

Prasugrel

Schedule

S4

 

Name of the medicine

Prasugrel hydrochloride.

Excipients.

Mannitol, hypromellose, croscarmellose sodium, microcrystalline cellulose and vegetable magnesium stearate. The colour coatings contain lactose, hypromellose, titanium dioxide, glycerol triacetate, iron oxide yellow CI77492 and iron oxide red CI77491.

Description

Chemical name: (±)-2-[2-acetyloxy-6, 7-dihydrothieno[3,2-c] pyridin-5(4H)-yl]-1- cyclopropyl-2-(2-fluorophenyl) ethanone hydrochloride. Molecular formula: C20H20FNO3S.HCl. MW: 409.90. CAS: 389574-19-0. Prasurgel hydrochloride is a white to light brown solid. It is soluble at pH 2, slightly soluble at pH 3 to 4, and practically insoluble at pH 6 to 7.5. It also dissolves freely in methanol and is slightly soluble in 1 and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate.
Prasugrel, an adenosine diphosphate (ADP) receptor antagonist of the thienopyridine class, is a potent inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor.
Prasugrel is available for oral administration as a 5 mg or 10 mg double arrow shaped, film coated, not scored tablet, debossed on each side. Each beige 10 mg tablet is manufactured with 10.98 mg prasugrel hydrochloride, equivalent to 10 mg of prasugrel and each yellow 5 mg tablet with 5.49 mg prasugrel hydrochloride, equivalent to 5 mg of prasugrel.

Pharmacology

Mechanism of action.

Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established atherosclerotic disease. 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 death and the rate of ischaemic cardiovascular events such as myocardial infarction or stroke.

Pharmacodynamics.

Inhibition of platelet aggregation (IPA) induced by 5 or 20 microM ADP (termed ‘platelet inhibition’ in the remainder of this document) measured by light transmission aggregometry has been assessed in clinical pharmacology studies in healthy subjects and patients with stable atherosclerosis for both prasugrel and clopidogrel with or without aspirin. Following a 60 mg loading dose (LD) of prasugrel, IPA occurs at 15 minutes for 5 microM ADP and 30 minutes for 20 microM ADP (see Figure 1). This rapid onset of action is a result of the rapid biotransformation of prasugrel to its active metabolite which is responsible for the IPA.
The mean maximum IPA after a 60 mg LD of prasugrel was 79% and 83%, respectively for 20 microM and 5 microM ADP, with at least 89% of all healthy subjects and patients with stable atherosclerosis achieving at least 50% IPA by 1 hour for both ADP concentrations. Prasugrel mediated IPA exhibits low between subject (9%) and within subject (12%) variability with both 5 microM and 20 microM ADP.
Mean steady-state IPA was 69% and 74%, respectively for 20 microM and 5 microM ADP, and was achieved following 3 to 5 days of 10 mg maintenance dosing with a preceding LD of prasugrel. Greater than 98% of subjects had ≥ 20% IPA during maintenance dosing. The extent of IPA is dependent on the dose of prasugrel and exposure to the active metabolite.
Platelet aggregation gradually returned to baseline values after treatment in 7 to 9 days following a single 60 mg LD of prasugrel and in 5 days following discontinuation of maintenance dosing at steady state.

Pharmacokinetics.

Prasugrel is a prodrug and is rapidly metabolised to a pharmacologically 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 (PCI).

Absorption.

Following oral administration, ≥ 79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. 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 Cmax was decreased by 49% and the time to reach Cmax (Tmax) was increased from 0.5 to 1.5 hours. Prasugrel was administered without regard to food in the large phase 3 clinical trial. Therefore, Effient can be administered without regard to food.

Distribution.

In a sodium phosphate buffer (pH 7.4), active metabolite binding to 4% human serum albumin was 98%. Prasugrel metabolites have limited penetration into red blood cells.

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 acute coronary syndromes (ACS) receiving Effient, there was no relevant effect of genetic variation in CYP3A, CYP2B6, CYP2C9, or CYP2C19 on the pharmacokinetics of prasugrel or its IPA.

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).
In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP3A5, CYP2B6, CYP2C9, or CYP2C19 on the pharmacokinetics of prasugrel or its IPA.

Special populations.

Elderly.

In a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel or its IPA. 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 patients < 75 years of age (see Dosage and Administration, Precautions and Adverse Effects).

Paediatric.

Pharmacokinetics and pharmacodynamics of prasugrel have not been evaluated in a paediatric population (see Dosage and Administration).

Gender and ethnicity.

In healthy subjects and patients, the pharmacokinetics of prasugrel are similar in men and women.
In clinical pharmacology studies, after adjusting for bodyweight, the AUC of the active metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects compared to Caucasian subjects. 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.

Bodyweight.

The mean exposure (AUC) of the active metabolite is approximately 30 to 40% higher in healthy subjects with a bodyweight of < 60 kg (132 pounds) and patients with a bodyweight of < 60 kg compared to those weighing ≥ 60 kg (see Dosage and Administration, Precautions and Adverse Effects).

Smoking.

Pharmacokinetics of prasugrel are similar in smokers and nonsmokers.

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 IPA are similar in patients with moderate renal impairment (CrCL = 30 to 50 mL/min) and healthy subjects. Prasugrel mediated IPA was also similar in patients with ESRD who required haemodialysis compared to healthy subjects, although Cmax and AUC of the active metabolite decreased 51% and 42%, respectively, in ESRD patients.

Hepatic impairment.

Pharmacokinetics of prasugrel and its IPA were similar in patients with mild to moderate hepatic impairment (Child-Pugh class A and B) compared to healthy subjects. No dose adjustment is thus necessary for these patients.
Pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied. Prasugrel should not be used in patients with severe hepatic disease due to the potential risk of bleeding in this population (see Contraindications and Precautions).

Clinical Trials

TRITON study.

The clinical evidence for the efficacy of prasugrel is derived from a large phase 3 clinical trial (the TRITON study), comparing prasugrel to clopidogrel, with both given in combination with aspirin and other standard therapy.
The TRITON study was a 13,608 patient, multicentre, international, randomised, double blind, double dummy and parallel group study. The patients randomised had acute coronary syndrome (ACS) with moderate to high risk unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI), or ST segment elevation myocardial infarction (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 coronary angiography. Patients with STEMI within 12 hours of symptoms and planned for primary PCI could be randomised prior to coronary angiography. For all patients, the loading dose (LD) could be administered anytime between randomisation and 1 hour after the patient left the catheterisation lab. If patients with STEMI were treated with thrombolytic therapy, randomisation could not occur until after 24 hours for fibrin specific lytic therapy or 48 hours for nonfibrin specific lytic therapy.
Patients were randomised to receive prasugrel (60 mg LD followed by 10 mg once daily) or clopidogrel (300 mg LD followed by 75 mg once daily) and were to be followed for a maximum of 15 months and a minimum of 6 months (actual median 14.5 months). Patients also received aspirin (75 mg to 325 mg once daily). 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 GPIIb/IIIa inhibitor used) and 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 was the composite of cardiovascular (CV) death, nonfatal MI, or nonfatal stroke. Analysis of the composite endpoint in the all ACS population (combined UA/NSTEMI and STEMI cohorts) was contingent upon showing statistical superiority of prasugrel versus clopidogrel in the UA/NSTEMI cohort (p < 0.05).

Analysis of the all ACS population.

In TRITON, prasugrel showed superior efficacy compared to clopidogrel in reducing the primary composite outcome events and the prespecified secondary outcome events, including stent thrombosis (see Table 1). The superior efficacy was accompanied by an increase in major bleeding (see Precautions and Adverse Effects).
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 drugs, β-blockers, and angiotensin converting enzyme inhibitors. The efficacy of prasugrel was independent of aspirin dose (75 mg to 325 mg once daily). The use of oral anticoagulants, nonstudy antiplatelet drugs, and chronic NSAIDs was not allowed in TRITON.
The Kaplan Meier curve shows the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke over time in the all ACS population (see Figure 2). The all ACS event curves separated as early as 3 days and continued to diverge over the 15 month follow-up period. Prasugrel demonstrated a relative risk reduction of 18% and an absolute risk reduction of 0.9% in the primary composite endpoint from 0 to 3 days (4.7% in the prasugrel group and 5.6% in the clopidogrel group; HR 0.825; 95% CI, 0.711, 0.957; p = 0.011). Prasugrel demonstrated a relative risk reduction of 20% and an absolute risk reduction of 1.2% in the primary composite endpoint from 3 days to the end of the study (5.2% in the prasugrel group and 6.4% in the clopidogrel group; HR 0.805; 95% CI, 0.698, 0.927; p = 0.003). Primary individual outcome events showed an absolute risk reduction of 2.1% and relative risk reduction of 24.3% in nonfatal MI with prasugrel compared to clopidogrel. A 0.2% absolute risk reduction and 11.4% relative risk reduction in CV death was seen in the prasugrel group compared to clopidogrel while for nonfatal stroke, there was no difference between the prasugrel and clopidogrel treated groups (see Table 1).
The incidence of non-CABG related major bleeding, including life threatening and fatal, as well as TIMI minor bleeding was higher in prasugrel treated patients compared to clopidogrel treated patients (4.5% for prasugrel and 3.4% for clopidogrel; HR 1.314; 95% CI, 1.107, 1.559; p = 0.002). In the prasugrel group, the incidence of fatal bleeding was 0.3% compared to 0.1% in clopidogrel treated patients (HR 4.664; 95% CI, 1.341, 16.230; p = 0.008). Study drug discontinuation due to bleeding events was 2.5% in the prasugrel arm and 1.4% for clopidogrel (OR 1.872; 95% CI, 1.448, 2.421; p < 0.001) (see Adverse Effects).
Prasugrel demonstrated a relative risk reduction of 50.2% and an absolute risk reduction of 0.9% in stent thrombosis through the 15 month follow-up period (see Table 2). The reduction in stent thrombosis with prasugrel was observed both early and beyond 30 days for both bare metal and drug eluting stents.
For patients who survived an on study stroke or myocardial infarction, prasugrel treated patients demonstrated a relative risk reduction of 33% and an absolute risk reduction of 4.1% in the incidence of subsequent primary endpoint events compared to clopidogrel treated patients (7.8% for prasugrel and 11.9% for clopidogrel, HR 0.67; 95% CI, 0.45, 0.98, p = 0.037).
An analysis of the composite endpoint of death from any cause, nonfatal MI, nonfatal stroke, or non-coronary artery bypass graft (CABG) related TIMI major haemorrhage favoured prasugrel compared to clopidogrel (11.5% in the prasugrel group and 13.1% in the clopidogrel group; HR, 0.87; 95% CI, 0.79 to 0.95; p = 0.004). In TRITON, for every 1000 patients treated with prasugrel, there were 22 fewer patients with MI, and 5 more with non-CABG related TIMI major haemorrhages, compared with patients treated with clopidogrel.
Analyses were performed to assess the effect of demographics, baseline characteristics, and medical history on the incidence of the primary endpoint of CV death, nonfatal MI, or nonfatal stroke by patients randomised to prasugrel or clopidogrel. The treatment benefit associated with prasugrel was preserved across the major prespecified subgroups in all 3 populations (UA/NSTEMI, STEMI and all ACS) as shown in Figure 3.

Analysis of patients with diabetes.

Patients with diabetes treated with prasugrel had a greater treatment benefit with respect to the primary composite efficacy endpoint when compared to those with diabetes treated with clopidogrel. In the all ACS population, the relative risk reduction with prasugrel compared to clopidogrel in 3146 patients with diabetes was 11.42% versus 15.80%; (HR = 0.705; 95% CI 0.582, 0.854; p < .001) while for patients without diabetes (N = 10,462) it was 8.84% versus 10.20%; (HR = 0.861; 95% CI 0.761, 0.976; p = .019). A similar pattern was seen for the UA/NSTEMI and STEMI populations. There were also reductions in urgent target vessel revascularistion (UTVR) and stent thrombosis in patients with diabetes treated with prasugrel.
The incidence of TIMI major or minor bleeding was similar in patients with and without diabetes. TIMI major or minor bleeding in patients with diabetes treated with prasugrel was 4.9% compared to 3.8% with clopidogrel (HR 1.297; 95% CI, 0.923, 1.822; p = 0.133) and for patients without diabetes, TIMI major or minor bleeding was 4.4% for prasugrel and 3.3% with clopidogrel (HR 1.320; 95% CI, 1.083, 1.609; p = 0.006).

Analysis of patients according to age.

In the all ACS population, the event rate with prasugrel compared to clopidogrel for patients aged < 75 years was 8.44% versus 10.65%; (HR = 0.784; 95% CI 0.687, 0.881; p < .001) while for patients aged ≥ 75 years it was 15.98% versus 16.96%; (HR = 0.940; 95% CI 0.749, 1.181; p = .596). Similar results were seen in the UA/NSTEMI and STEMI populations.
In the elderly (≥ 75 years of age) there was an increased risk of non-CABG related bleeding compared to patients < 75 years of age, including an increased risk of both life threatening and fatal bleeding. Life threatening bleeding in patients < 75 years treated with prasugrel was 1.06% (0.2% fatal) compared to 0.72% (0.1% fatal) with clopidogrel (HR = 1.475; 95% CI 0.997, 2.182; p = 0.051) and for patients ≥ 75 years of age it was 2.58% (1.0% fatal) with prasugrel versus 1.57% (0.1% fatal) with clopidogrel (HR = 1.694; 95% CI 0.870, 3.298); p = 0.117) (see Precautions and Adverse Effects). Patients ≥ 75 years of age also had a higher rate of stroke with prasugrel compared to clopidogrel (2.89% versus 1.43%; HR 2.117; 95% CI 1.087, 4.125; p = 0.024) while for patients aged < 75 years the rate of stroke was 0.83% with prasugrel and 0.99% with clopidogrel (HR 0.841; 95% CI 0.575, 1.230; p = 0.371).

Analysis of patients by bodyweight.

In the all ACS population, the event rate with prasugrel compared to clopidogrel for patients with bodyweight ≥ 60 kg was 8.6% versus 10.7%; (HR = 0.80; 95% CI 0.71, 0.90; p < 0.001) while for patients with bodyweight < 60 kg it was 14.4% versus 16.4%; (HR = 0.860; 95% CI 0.66, 1.121; p = 0.255). In patients with low bodyweight (< 60 kg) there was an increased risk of non-CABG related bleeding compared to patients ≥ 60 kg (see Precautions and Adverse Effects).

Analysis of patients with prior TIA/ stroke.

In the all ACS population, there was an increase in the incidence of the primary composite endpoint with prasugrel compared to clopidogrel in patients with prior TIA or stroke (17.94% versus 13.67%; HR = 1.375; p = .153). This was primarily due to an increase in all stroke in patients with prior TIA or stroke randomised to prasugrel compared to clopidogrel (6.49% versus 1.17%; HR = 5.643; p = .002). There was also an increased risk of non-CABG related bleeding in patients with a history of prior TIA or stroke compared to those not in this population (see Contraindications and Adverse Effects).

Analysis of the UA/NSTEMI and STEMI populations.

As shown in Table 3, prasugrel reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI populations.
The secondary endpoint data for the UA/NSTEMI and STEMI populations are similar to those for the all ACS population.
The Kaplan Meier curves show the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke over time (see Figures 4 and 5) in the UA/NSTEMI population and the STEMI population. The UA/NSTEMI event curve (see Figure 4) separated as early as 3 days and continued to diverge over the 15 month follow-up period. The STEMI event curve (see Figure 5) separated as early as 3 days and remained separate over the 15 month follow-up period.

Indications

Effient, coadministered with aspirin, is indicated for the prevention of atherothrombotic events (myocardial infarction, stroke and cardiovascular death) in patients with acute coronary syndromes (moderate to high risk unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI)) who are to undergo percutaneous coronary intervention (PCI).

Contraindications

Effient is contraindicated in patients with: active pathological bleeding; a known history of transient ischaemic attack (TIA) or stroke; severe hepatic impairment (Child-Pugh class C); a known hypersensitivity or allergy to any ingredient of the product.

Precautions

Prior TIA or stroke.

In the phase 3 clinical trial, prasugrel treated patients with a history of TIA or a history of ischaemic stroke more than 3 months prior to drug therapy had a higher rate of the primary composite endpoint, including ischaemic or haemorrhagic stroke compared to clopidogrel. The rate of TIMI major or minor bleeding was also increased in these patients compared to patients without a history of TIA or stroke. Patients with a history of ischaemic stroke within 3 months of drug therapy or haemorrhagic stroke were excluded from the phase 3 clinical trial (see Adverse Effects and Clinical Trials).
Prasugrel has not been studied without aspirin in patients with prior history of TIA or stroke.

Bleeding risk.

In the phase 3 clinical trial 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 prasugrel showed an increased risk of major and minor bleeding according to the TIMI classification system. Therefore use of prasugrel 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 bleeding. In particular, caution is necessary in patients:
≥ 75 years of age. In the phase 3 clinical trial patients ≥ 75 years of age taking prasugrel were at a greater risk of bleeding, including fatal bleeding, compared to patients < 75 years of age. A 5 mg maintenance dose (MD) should be considered for patients ≥ 75 years of age (see Use in elderly, Adverse Effects and Dosage and Administration);
with a propensity to bleed (e.g. due to recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, severe hepatic impairment or moderate to severe renal impairment);
with bodyweight < 60 kg. In these patients, a 5 mg MD is recommended (see Bodyweight, Adverse Effects and Dosage and Administration);
with concomitant administration of medications that may increase the risk of bleeding, including oral anticoagulants, nonsteroidal anti-inflammatory drugs (NSAIDs), and fibrinolytics.
Patients should be told that it may take longer than usual for bleeding to stop when they take prasugrel, and that they should report any unusual bleeding (site or duration) to their physician.
For patients with active bleeding for whom reversal of the pharmacological effects of prasugrel is required, platelet transfusion may be appropriate.

Bleeding risk associated with timing of loading dose in NSTEMI

In a clinical trial of NSTEMI patients (the ACCOAST study), patients given a 30 mg loading dose of prasugrel a median of approximately 4 hours prior to coronary angiography followed by 30 mg at the time of PCI had an increased risk of major and minor periprocedural bleeding and no additional benefit compared to patients receiving a loading dose of 60 mg at the time of PCI. Therefore in NSTEMI patients the 60 mg loading dose should generally be given at the time of PCI (see Dosage and Administration).

Use in elderly.

Of the total number of prasugrel treated patients in TRITON, 38.5% were ≥ 65 years of age and 13.2% were ≥ 75 years of age. The event rate of the primary composite endpoint with prasugrel compared to clopidogrel for patients aged ≥ 75 years was 15.98% versus 16.96%; (HR = 0.940; 95% CI 0.749, 1.181; p = .596). Individuals ≥ 75 years of age had an increased risk of TIMI major or minor bleeding (including life threatening and fatal bleeding) due to greater sensitivity to bleeding and higher exposure to the active metabolite of prasugrel in patients ≥ 75 years of age compared to patients < 75 years of age. There was also an increase in the incidence of stroke in patients ≥ 75 years compared to those < 75 years of age. The use of prasugrel in patients ≥ 75 years of age is generally not recommended and should be used with caution only 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 bleeding. Consideration should be given to a 5 mg once daily MD, the 10 mg MD is not recommended for these patients (see Dosage and Administration, Bleeding risk, Adverse Effects and Pharmacology).

Bodyweight.

Of the total number of prasugrel patients in the TRITON study, 4.6% had bodyweight < 60 kg. Individuals with bodyweight < 60 kg had an increased risk of TIMI major or minor bleeding and an increased exposure to the active metabolite of prasugrel. Prasugrel should be used 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 bleeding. For patients < 60 kg, a 5 mg once daily MD should be used, the 10 mg MD is not recommended for these patients (see Bleeding risk, Dosage and Administration, Adverse Effects and Pharmacology).

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, prasugrel should be discontinued at least 7 days prior to surgery. Increased frequency (3-fold) and severity of bleeding may occur in patients undergoing CABG surgery within 7 days of discontinuation of prasugrel. 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.

Discontinuation of prasugrel.

In patients with ACS who are managed with PCI, premature discontinuation of any antiplatelet medication, including prasugrel, could result in an increased risk of thrombosis, MI, or death. Patients who require premature discontinuation of prasugrel (e.g. secondary to active bleeding) should be monitored for cardiac events. Once the patient is stabilised, at the discretion of the patient's treating physician, restarting antiplatelet treatment may be considered.

Neoplasms.

In TRITON, the incidence of newly diagnosed neoplasms was higher for prasugrel treated patients compared to clopidogrel treated patients (1.4% (94/6741) to 1.2% (80/6716) respectively, p = 0.30). The higher incidence appeared to be related to a higher incidence of colorectal neoplasms (19 prasugrel vs 10 clopidogrel). This imbalance may have resulted from the more potent antiplatelet effect of prasugrel bringing more events to medical attention. The nonclinical studies were negative for carcinogenicity and tumour stimulation (see Precautions, Carcinogenicity). Bleeding in patients taking antiplatelet therapy warrants diagnostic investigation since it may unmask a previously unsuspected lesion (e.g. tumour, ulcer).

Thrombotic thrombocytopenic purpura (TTP).

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

Hypersensitivity.

Hypersensitivity reactions including angioedema and anaphylaxis 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.

Effects on fertility.

Animal studies did not indicate direct harmful effects with respect to fertility. Prasugrel had no effect on fertility of male or female rats at oral doses up to 300 mg/kg per day, corresponding to an active metabolite exposure (based on AUC) of approximately 1500 times that anticipated at the recommended human maintenance dose.

Use in pregnancy.

(Category B1)
There are no adequate and well controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of a human response, prasugrel should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.
Embryo foetal developmental toxicology studies in rats and rabbits showed no evidence of malformations at doses corresponding to more than 100 times the active metabolite exposure anticipated in humans at the maintenance dose of 10 mg daily (based on AUC) of prasugrel. Only minor decreases in maternal bodyweight gain (3%) and offspring bodyweight (3 to 5%) were observed relative to controls. In prenatal and postnatal rat studies, a similar dose exposure had no effect on the behavioural or reproductive development of offspring.

Use in lactation.

There are no clinical studies in lactating women.
A study in rats has shown that prasugrel metabolites are excreted in the animals' milk. It is not known whether prasugrel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the nursing woman.

Carcinogenicity.

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. Therefore, the increase in liver tumours with prasugrel administration in mice is not considered a relevant human risk.

Genotoxicity.

Assays for gene mutations (Ames test) and chromosomal damage (Chinese hamster ovary cells in vitro, mouse micronucleus in vivo test) did not provide any evidence of a genotoxic potential for prasugrel.

Paediatric use.

Safety and effectiveness in paediatric patients has not been established (see Pharmacology).

Renal impairment.

No dosage adjustment is necessary for patients with renal impairment; including patients with end stage renal disease (see Bleeding risk, Dosage and Administration and Pharmacology).

Use in hepatic impairment.

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied. Prasugrel should not be used in patients with severe hepatic disease due to the potential risk of bleeding in this population (see Precautions and Pharmacology).

Effects on ability to drive and use machines.

No studies on effects on ability to drive and use machines have been performed. Prasugrel is expected to have no or negligible influence on the ability to drive and use machines.

Lactose.

Patient with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/ galactose malabsorption should not take Effient.

Interactions

Prasugrel 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. Prasugrel can also be concomitantly administered with ASA, heparin, digoxin, and medicinal products that elevate gastric pH, including proton pump inhibitors and H2 blockers. Although not studied in specific interaction studies, prasugrel was coadministered in the phase 3 clinical trial with low molecular weight heparin, bivalirudin, and GPIIb/IIIa inhibitors (no information is available regarding the type of GPIIb/IIIa inhibitor used) without evidence of clinically significant adverse interactions.

Potential for other drugs to affect prasugrel.

Inhibitors of CYP3A.

Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel mediated IPA or the active metabolite's AUC and Tmax, but decreased the Cmax by 34% to 46%. Therefore, CYP3A inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, 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 and its IPA. 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.

Drugs that elevate gastric pH.

Daily coadministration of ranitidine (an H2 receptor blocker) or lansoprazole (a proton pump inhibitor) did not change the metabolite's AUC and Tmax, but decreased the Cmax by 14% and 29%, respectively. In the pivotal phase 3 trial, prasugrel was administered without regard to coadministration of a proton pump inhibitor (PPI) or H2 receptor blocker, and the reduction in the primary endpoint from 0 to 3 days was consistent for patients taking prasugrel with and without concomitant use of a PPI or H2 receptor blocker.

Statins.

Atorvastatin (80 mg daily) did not alter the pharmacokinetics of prasugrel or its IPA. Therefore, statins that are substrates of CYP3A are not anticipated to have an effect on the pharmacokinetics of prasugrel or its IPA.

Heparin.

A single intravenous dose of unfractionated heparin (100 U/kg) did not significantly alter the prasugrel mediated IPA. Likewise, prasugrel did not significantly alter the effect of heparin on measures of coagulation. An increased risk of bleeding is possible when prasugrel is coadministered with heparin.

Aspirin.

Aspirin (150 mg daily with an additional single 900 mg) did not alter prasugrel mediated IPA. Although a pharmacodynamic interaction with aspirin leading to an increased risk of bleeding is possible, the demonstration of the efficacy and safety of prasugrel comes from patients concomitantly treated with aspirin.

Nonsteroidal anti-inflammatory drugs.

Concomitant administration with chronic NSAIDs has not been studied. Because of the potential for increased risk of bleeding, chronic NSAIDs and prasugrel should be coadministered with caution.

Clopidogrel.

Following administration of 75 mg clopidogrel daily for 10 days, healthy subjects were switched to 10 mg of prasugrel once daily, with or without a 60 mg LD. Throughout the study, all subjects were concurrently taking 81 mg of aspirin once daily. Higher IPA was observed with prasugrel compared to clopidogrel.

Potential for prasugrel to affect other drugs.

Drugs metabolised by CYP2C9 and 2C19.

Prasugrel did not inhibit CYP2C9 or CYP2C19, as it did not affect the pharmacokinetics of S-warfarin or R-warfarin. Because of the potential for increased risk of bleeding, warfarin and prasugrel should be coadministered with caution.

Drugs 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%, which is not considered to be clinically significant. This effect is likely to be of clinical concern only when prasugrel is coadministered with medicinal products for which CYP2B6 is the only metabolic pathway and have a narrow therapeutic window (e.g. cyclophosphamide, efavirenz).

Effect on digoxin.

Prasugrel has no clinically significant effect on the pharmacokinetics of digoxin. When prasugrel was coadministered with digoxin, a substrate of P-glycoprotein transporter, the AUC of digoxin was not altered, while Cmax decreased by 17%.

Adverse Effects

During clinical development, 7681 patients with atherosclerosis with or without ACS who did or did not undergo PCI were exposed to prasugrel in 5 studies using clopidogrel as the comparator.
Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel controlled study, TRITON, in which 6741 patients were treated with prasugrel (60 mg LD and 10 mg once daily MD) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for more than 1 year).

Drug discontinuation.

The rate of study drug discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel (OR 1.150; 95% CI, 1.005, 1.317; p = 0.042). 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; OR 1.872; 95% CI, 1.448, 2.421; p < 0.001).

Bleeding.

Non-CABG related bleeding.

In TRITON, the frequency of patients experiencing a non-CABG related bleeding event is shown in Table 4. 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 non-CABG related thrombolysis in myocardial infarction (TIMI) major or minor bleeding was the GI 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 5 shows the incidence of non-CABG related bleeding by UA/NSTEMI and STEMI subgroups.

Patients < 60 kg.

In TRITON, among prasugrel treated patients, non-CABG related TIMI major or minor bleeding for patients in two weight groups are shown in Table 6.

Very elderly patients (≥ 75 years).

In TRITON, among prasugrel treated patients, non-CABG related TIMI major or minor bleeding for patients in two age groups are shown in Table 7.
Patients ≥ 75 years of age also had a higher risk of stroke compared to those < 75 years. The incidence of stroke in patients ≥ 75 years of age treated with prasugrel was 2.89% compared to 1.43% with clopidogrel while for patients < 75 years the rate of stroke was 0.83% with prasugrel and 0.99% with clopidogrel (see Clinical Trials).

Prior TIA or stroke.

In TRITON, among prasugrel treated patients, non-CABG related TIMI major or minor bleeding for patients with and without a history of TIA or stroke are shown in Table 8.
In TRITON, in patients with or without a history of TIA or stroke, the incidence of stroke is shown in Table 9.

CABG related bleeding.

In TRITON, 437 patients underwent CABG during the course of the study (see Table 10). 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 (OR 3.587; 95% CI, 1.702, 7.557; p < 0.001). The higher risk for bleeding events in patients 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% (3 of 90 patients) in the clopidogrel group. Beyond 7 days after drug discontinuation, the observed rates of CABG related bleeding were similar between treatment groups (see Precautions).

Bleeding reported as adverse events.

Table 11 shows the incidence of common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 to < 1/100) haemorrhagic adverse events in TRITON.

Other clinical studies

In a clinical study of NSTEMI (the ACCOAST study) patients given a 30 mg loading dose of prasugrel a median of approximately 4 hours prior to coronary angiography followed by 30 mg of prasugrel at the time of PCI had an increased risk of non-CABG periprocedural bleeding compared to patients receiving a prasugrel loading dose of 60 mg at the time of PCI (see Precautions and Dosage and Administration).

Other adverse events.

In TRITON, common and other important nonhaemorrhagic adverse events for prasugrel and clopidogrel, respectively, were: severe thrombocytopenia (0.06%, 0.04%), anaemia (2.2%, 2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions (0.36%, 0.36%), angioedema (0.06%, 0.04%) and neoplasm (1.4%, 1.2%)a,b. Table 12 shows common nonhaemorrhagic adverse events reported by at least 2.5% of patients.
aWhen colorectal neoplasms are excluded, reporting rates are 1.1 and 1.0% for prasugrel and clopidogrel respectively. In each treatment group, the evaluation of GI bleeding or anemia led to the diagnosis in 80% of colorectal cancers. The diagnosis of colorectal cancers is related to GI bleeding in TRITON-TIMI 38.
bNewly diagnosed only.

Spontaneous data.

Blood and lymphatic system disorders.

Very rare (< 0.01%): thrombotic thrombocytopenic purpura (TTP) (see Precautions).

Immune system disorders.

Rare (> 0.01% and < 0.1%): hypersensitivity including angioedema and anaphylaxis (see Precautions).

Dosage and Administration

General.

Use in adults (≥ 18 years).

Effient should be initiated with a single 60 mg loading dose (LD) and then continued at a 10 mg once daily dose maintenance dose (MD). In NSTEMI patients, the loading dose should generally be given at the time of PCI (see Precautions and Adverse Effects). Patients taking prasugrel should also take aspirin (75 mg to 325 mg) daily.
Effient may be taken with or without food (see Pharmacology).

Use in elderly (≥ 75 years).

Effient is generally not recommended in patients ≥ 75 years of age (see Precautions). Effient should be given as a single 60 mg LD and consideration may be given to a 5 mg once daily maintenance dose. The 10 mg MD is not recommended. The evidence for the 5 mg dose is based on pharmacodynamic/ pharmacokinetic analyses only and no clinical data currently exist on the safety and efficacy of this dose.

Patients weighing < 60 kg.

Effient should be given as a single 60 mg LD and then continued at a 5 mg once daily maintenance dose. The 10 mg MD is not recommended. The evidence for the 5 mg dose is based on pharmacodynamic/ pharmacokinetic analyses only and no clinical data currently exist on the safety and efficacy of this dose (see Precautions).

Use in children and adolescents.

The safety and efficacy of prasugrel has not been established in paediatric patients.

Use in renal impairment.

No dosage adjustment is necessary for patients with renal impairment; including patients with end stage renal disease (ESRD). As ESRD significantly impacts both the AUC and Cmax of the active metabolite of prasugrel, the use of prasugrel needs to be closely monitored in this class of patient (see Pharmacology, Pharmacokinetics, Special populations).

Use in hepatic impairment.

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease (Child-Pugh class C) have not been studied (see Contraindications, Precautions and Pharmacology, Pharmacokinetics, Special populations).

Use in Asian populations.

No dosage adjustment is necessary based on ethnicity alone. In clinical pharmacology studies the AUC of the active metabolite of prasugrel was higher in Chinese, Japanese, and Korean subjects compared to Caucasian subjects. Therapeutic experience with prasugrel is limited in Asian patients; therefore the use of prasugrel needs to be closely monitored in these patients (see Pharmacology, Pharmacokinetics, Special populations).

Overdosage

Overdose following prasugrel administration may lead to prolonged bleeding time and subsequent bleeding complications. In rats, lethality was observed only after administration of the very high dose of 2000 mg/kg. Symptoms of acute toxicity in dogs included emesis, increased serum alkaline phosphatase, and hepatocellular atrophy. Symptoms of acute toxicity in rats included mydriasis, irregular respiration, decreased locomotor activity, ptosis, staggering gait, and lacrimation. Consistent with known pharmacologic activity, platelet aggregation was inhibited in dogs.
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 at the discretion of the treating physician.
In case of overdose, immediately contact the Poisons Information Centre (in Australia, call 131 126) for advice.

Presentation

Tablets (film coated, double arrow shaped, not scored), 5 mg (prasugrel hydrochloride 5.49 mg; yellow, marked 5 MG on one side, 4760 on reverse), 10 mg (prasugrel hydrochloride 10.98 mg; beige, marked 10 MG on one side, 4759 on reverse): 6's*, 28's (blister pack).
*Not currently marketed in Australia.

Storage

Store below 30°C. Store in the original package. Do not crush or break the tablet.

Poison Schedule

S4.