Consumer medicine information

Prasugrel SCP

Prasugrel

BRAND INFORMATION

Brand name

Prasugrel Lupin

Active ingredient

Prasugrel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Prasugrel SCP.

SUMMARY CMI

Prasugrel Lupin

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Prasugrel Lupin?

Prasugrel Lupin contains the active ingredient prasugrel. Prasugrel Lupin is used to prevent blood cells from clotting.

For more information, see Section 1. Why am I using Prasugrel Lupin? in the full CMI.

2. What should I know before I use Prasugrel Lupin?

Do not use if you have ever had an allergic reaction to prasugrel or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Prasugrel Lupin? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Prasugrel Lupin and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Prasugrel Lupin?

  • Take Prasugrel Lupin as directed by your doctor or pharmacist. This may differ from the information contained in this leaflet.

More instructions can be found in Section 4. How do I use Prasugrel Lupin? in the full CMI.

5. What should I know while using Prasugrel Lupin?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Prasugrel Lupin.
  • If you or you are going to have surgery, tell the surgeon that you are taking this medicine.
  • If you or you are about to have any blood tests, tell your doctor that you are taking this medicine.
  • If you become pregnant while taking this medicine, tell your doctor immediately.
Things you should not do
  • Do not stop taking Prasugrel Lupin or change the dosage without checking with your doctor.
  • Do not take Prasugrel Lupin to treat any other complaints unless your doctor prescribes.
  • Do not give your medicine to anyone else, even if they have the same condition as you
Driving or using machines
  • Be careful driving or operating machinery until you know how it affects you.
Looking after your medicine
  • Keep your tablets in a cool dry place where the temperature stays below 25°C

For more information, see Section 5. What should I know while using Prasugrel Lupin? in the full CMI.

6. Are there any side effects?

Some common side effects with Prasugrel Lupin includes rash, nose bleeds, cuts taking longer than usual to stop bleeding, bleeding gums. Serious side effects include signs of anemia, uncontrollable bleeding, coughing up blood, pink or brown urine, blood in the eyes, etc.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Prasugrel Lupin

Active ingredient(s): Prasugrel

Consumer Medicine Information (CMI)

This leaflet provides important information about using Prasugrel Lupin. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Prasugrel Lupin.

Where to find information in this leaflet:

1. Why am I using Prasugrel Lupin?
2. What should I know before I use Prasugrel Lupin?
3. What if I am taking other medicines?
4. How do I use Prasugrel Lupin?
5. What should I know while using Prasugrel Lupin?
6. Are there any side effects?
7. Product details

1. Why am I using Prasugrel Lupin?

Prasugrel Lupin contains the active ingredient prasugrel. Prasugrel belongs to the group of medicines called antiplatelet agents.

Prasugrel Lupin is used to prevent blood cells from clotting. 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.

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.

Prasugrel Lupin 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.

2. What should I know before I use Prasugrel Lupin?

Warnings

Do not use Prasugrel Lupin if:

  • you are allergic to prasugrel, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine. 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.
  • 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.
  • 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.

Check with your doctor if you:

  • are not sure if you have an allergy to prasugrel.
  • take any medicines for any other condition.
  • 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.
  • are already taking aspirin.
  • 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.
  • 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 Prasugrel Lupin.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Your doctor will discuss the possible risks and benefits of taking this medicine during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed. Prasugrel Lupin is not recommended while you are breastfeeding. It is not known whether it passes into breast milk.

3. What if I am taking other medicines?

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

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

Some medicines may interfere with Prasugrel Lupin and affect how it works.

These include:

  • 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 (eg. efavirenz);
  • some medicines used to treat cancer (eg. cyclophosphamide);
  • morphine or other opioids, medicines to treat pain.

These medicines may be affected by Prasugrel Lupin 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 Prasugrel Lupin.

These may differ from the information contained in this leaflet.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Prasugrel Lupin.

4. How do I use Prasugrel Lupin?

How much to take

  • Your doctor will tell you how many tablets to take each day.
  • Prasugrel Lupin is available as a 5 mg 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 Prasugrel Lupin

  • Take your Prasugrel Lupin tablets 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.
  • The tablets can be taken before or after meals.
  • Continue taking Prasugrel Lupin for as long as your doctor recommends.

How to take Prasugrel Lupin

  • You should swallow the tablets with a glass of water.
  • Do not break the tablet in half. Talk to your doctor or pharmacist if you have trouble swallowing tablets.

If you forget to use Prasugrel Lupin

Prasugrel Lupin should be used regularly at the same time each day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

If you use too much Prasugrel Lupin

If you think that you have used too much Prasugrel Lupin, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26); or
  • contact your doctor; or
  • go to the Emergency Department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Prasugrel Lupin?

Things you should do

Take Prasugrel Lupin every day exactly as your doctor has prescribed.

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

If you decide to breastfeed your baby, tell your doctor. Your doctor may want to discuss this and change your medicine.

Tell your doctor, dentist or pharmacist that you are taking Prasugrel Lupin 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 Prasugrel Lupin 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 Prasugrel Lupin.

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

Remind any doctor, dentist or pharmacist you visit that you are using Prasugrel Lupin.

Things you should 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.

Driving or using machines

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.

Drinking alcohol

Tell your doctor if you drink alcohol.

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

Looking after your medicine

  • Store Prasugrel Lupin tablets below 25°C.
  • Keep your tablets in the blister pack until it is time to take them.

Follow the instructions on the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink; or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Rash.
  • Nose bleeds.
  • Cuts that take longer than usual to stop bleeding.
  • Bleeding gums.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • 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.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed her may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Prasugrel Lupin contains

Active ingredient
(main ingredient)		Prasugrel
Other ingredients
(inactive ingredients)		Croscarmellose sodium
Microcrystalline cellulose
Lactose monohydrate
Crospovidone
Sucrose stearate
Opadry II 32K220036 Yellow (5 mg)
Opadry II 32K230012 Orange (10 mg)

Do not take this medicine if you are allergic to any of these ingredients.

What Prasugrel Lupin looks like

Prasugrel Lupin 5 mg tablets are yellow, oblong-shaped, biconvex, film-coated tablets debossed on one side with “F1” and plain on the other side. (ARTG 314201)

Prasugrel Lupin 10 mg tablets are orange, oblong-shaped, biconvex, film-coated tablets debossed on one side with “F2” and plain on the other side. (ARTG 314206)

Who distributes Prasugrel Lupin

Generic Health Pty Ltd
Suite 2, Level 2
19-23 Prospect Street
Box Hill, VIC, 3128
Australia

ii1319501  [email protected]

ii1319502  +61 3 9809 7900

ii1319503  www.generichealth.com.au

This leaflet was prepared in May 2024.

Published by MIMS June 2025

BRAND INFORMATION

Brand name

Prasugrel Lupin

Active ingredient

Prasugrel

Schedule

S4

 

Notes

Distributed by Generic Health Pty Ltd

1 Name of Medicine

Prasugrel.

2 Qualitative and Quantitative Composition

Prasugrel Lupin is available in two strengths, with each 10 mg tablet containing 10 mg prasugrel, and each 5 mg tablet containing 5 mg prasugrel.

Excipients with known effect.

Lactose and sugars.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Prasugrel Lupin 5 mg tablets are yellow, oblong-shaped, biconvex, film-coated tablets debossed on one side with "F1" and plain on the other side.
Prasugrel Lupin 10 mg tablets are orange, oblong-shaped, biconvex, film-coated tablets debossed on one side with "F2" and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Prasugrel Lupin, co-administered with aspirin, is indicated for the prevention of atherothrombotic events (myocardial infarction (MI), stroke and cardiovascular (CV) 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).

4.2 Dose and Method of Administration

Use in adults (≥ 18 years).

Prasugrel Lupin 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 LD should generally be given at the time of PCI (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). Patients taking Prasugrel Lupin should also take aspirin (75 mg to 325 mg) daily.
Prasugrel Lupin may be taken with or without food (see Section 5.2 Pharmacokinetic Properties, Absorption).

Use in the elderly (≥ 75 years).

Prasugrel Lupin is generally not recommended in patients ≥ 75 years of age (see Section 4.4 Special Warnings and Precautions for Use). Prasugrel Lupin should be given as a single 60 mg LD and consideration may be given to a 5 mg once daily MD. 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.

Prasugrel Lupin should be given as a single 60 mg LD and then continued at a 5 mg once daily MD. 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 Section 4.4 Special Warnings and Precautions for Use).

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 Section 5.2 Pharmacokinetic Properties, 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 Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, 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 Section 5.2 Pharmacokinetic Properties, Special populations).

4.3 Contraindications

Prasugrel Lupin 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.

4.4 Special Warnings and Precautions for Use

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 Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, 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 MD should be considered for patients ≥ 75 years of age (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of 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 body weight < 60 kg. In these patients, a 5 mg MD is recommended (see Section 4.4 Special Warnings and Precautions for Use, Body weight; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration);
with concomitant administration of medications that may increase the risk of bleeding, including oral anticoagulants, non steroidal 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 (LD) in NSTEMI.

In a clinical trial of NSTEMI patients (the ACCOAST study), patients given a 30 mg LD 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 peri-procedural bleeding and no additional benefit compared to patients receiving a LD of 60 mg at the time of PCI. Therefore in NSTEMI patients the 60 mg LD should generally be given at the time of PCI (see Section 4.2 Dose and Method of Administration).

Body weight.

Of the total number of prasugrel patients in the TRITON study, 4.6% had body weight < 60 kg. Individuals with body weight < 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 Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Bleeding risk; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Analysis of patients by body weight).

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 Coronary Artery Bypass Graft (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 Acute Coronary Syndrome (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 non-clinical studies were negative for carcinogenicity and tumour stimulation (see Section 5.3 Preclinical Safety Data, 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.

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 Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special populations).

Use in renal impairment.

No dosage adjustment is necessary for patients with renal impairment; including patients with end-stage renal disease (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Bleeding risk; Section 5.2 Pharmacokinetic Properties, Special populations).

Use in the 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 Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Bleeding risk; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties, Special populations).

Lactose.

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

Paediatric use.

Safety and effectiveness in paediatric patients has not been established (see Section 5.2 Pharmacokinetic Properties, Special populations).

Morphine and other opioids.

Reduced prasugrel efficacy has been seen in patients co-administered prasugrel and morphine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of 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 co-administered 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 inhibition of platelet aggregation (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 co-administration 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 co-administration of a proton pump inhibitor (PPI) or H2 receptor blocker, and the reduction in the primary endpoint from 0-3 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 co-administered 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.

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 and prasugrel should be co-administered 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.

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.

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 co-administered 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 co-administered 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 co-administered with digoxin, a substrate of P-glycoprotein transporter, the AUC of digoxin was not altered, while Cmax decreased by 17%.

4.6 Fertility, Pregnancy and Lactation

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 1,500 times that anticipated at the recommended human MD.
(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 MD of 10 mg daily (based on AUC) of prasugrel. Only minor decreases in maternal body weight gain (3%) and offspring body weight (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.
 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.

4.7 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.

4.8 Adverse Effects (Undesirable 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 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 non-CABG-related (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 2 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 3.

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 4.
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 Section 5.1 Pharmacodynamic Properties, 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 5.
In TRITON, in patients with or without a history of TIA or stroke, the incidence of stroke is shown in Table 6.
CABG-related bleeding. In TRITON, 437 patients underwent CABG during the course of the study (see Table 7). 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 Section 4.4 Special Warnings and Precautions for Use).
Bleeding reported as adverse events. Table 8 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 LD 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 peri-procedural bleeding compared to patients receiving a prasugrel LD of 60 mg at the time of PCI (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Other adverse events.

In TRITON, common and other important non-haemorrhagic 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 9 shows common non-haemorrhagic adverse events reported by at least 2.5% of patients.
a When 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.
b Newly diagnosed only.

Spontaneous data.

Blood and lymphatic system disorders.

Very rare (< 0.01%): thrombotic thrombocytopenic purpura (TTP) (see Section 4.4 Special Warnings and Precautions for Use).

Immune system disorders.

Rare (> 0.01% and < 0.1%): hypersensitivity including angioedema and anaphylaxis (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

IPA induced by 5 or 20 microM adenosine diphosphate (ADP) 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 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 MD 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.

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 CV events such as MI or stroke.

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 (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 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 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 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 pre-specified secondary outcome events, including stent thrombosis (see Table 10). The superior efficacy was accompanied by an increase in major bleeding (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable 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 CV therapies, including heparin/low molecular weight heparin, bivalirudin, intravenous GPIIb/IIIa inhibitors, lipid-lowering drugs, beta-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, non-study 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 0-3 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 10).
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 Section 4.8 Adverse Effects (Undesirable 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 11). 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 MI, 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-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 pre-specified 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 < 0.001) 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 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 < 0.001) 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 Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable 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 body weight.

In the All ACS population, the event rate with prasugrel compared to clopidogrel for patients with body weight ≥ 60 kg was 8.6% versus 10.7%; (HR=0.80; 95% CI 0.71, 0.90; p < 0.001) while for patients with body weight < 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 body weight (< 60 kg) there was an increased risk of non-CABG related bleeding compared to patients ≥ 60 kg (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable 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 Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)).

Analysis of the UA/NSTEMI and STEMI populations.

As shown in Table 12, 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 Figure 4 and Figure 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.

5.2 Pharmacokinetic Properties

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

Excretion.

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 Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric.

Pharmacokinetics and pharmacodynamics of prasugrel have not been evaluated in a paediatric population (see Section 4.2 Dose and Method of 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 body weight, 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.

Body weight.

The mean exposure (AUC) of the active metabolite is approximately 30 to 40% higher in healthy subjects with a body weight of < 60 kg and patients with a body weight of < 60 kg compared to those weighing ≥ 60 kg (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Smoking.

Pharmacokinetics of prasugrel are similar in smokers and non-smokers.

Renal impairment.

No dosage adjustment is necessary for patients with renal impairment, including patients with 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 Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

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.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Prasugrel Lupin contains the following inactive ingredients: crospovidone, lactose monohydrate, croscarmellose sodium, microcrystalline cellulose, sucrose stearate and Opadry II 32K220036 Yellow (5 mg), Opadry II 32K230012 Orange (10 mg).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in the original package. Do not crush or break the tablet.

6.5 Nature and Contents of Container

Prasugrel Lupin is available in PA/Al/PVC/Al blister packs of 28 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Prasugrel, an ADP receptor antagonist of the thienopyridine class, is a potent inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Prasugrel is white or almost white solid, soluble in methylene chloride; sparingly soluble in acetonitrile, acetic acid and 1M hydrochloric acid; practically insoluble in water, 1M sodium hydroxide, methanol and 2-propanol.

Chemical structure.


Chemical name: 5-[(R/S)-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno [3,2-c]pyridin-2-yl acetate.
Molecular formula: C20H20FNO3S.
Molecular weight: 373.44.

CAS number.

150322-43.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes