4.1. Therapeutic indications

Prasugrel Mylan, co administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndrome (i.e. unstable angina, non-ST segment elevation myocardial infarction [UA/NSTEMI] or ST segment elevation myocardial infarction [STEMI]) undergoing primary or delayed percutaneous coronary intervention (PCI).

For further information please refer to section 5.1.

4.2. Posology and method of administration

Posology

Adults

Prasugrel Mylan should be initiated with a single 60 mg loading dose and then continued at 10 mg once a day. In UA/NSTEMI patients, where coronary angiography is performed within 48 hours after admission, the loading dose should only be given at the time of PCI (see sections 4.4, 4.8 and 5.1). Patients taking Prasugrel Mylan should also take ASA daily (75 mg to 325 mg).

In patients with acute coronary syndrome (ACS) who are managed with PCI, premature discontinuation of any antiplatelet agent, including Prasugrel Mylan, could result in an increased risk of thrombosis, myocardial infarction or death due to the patient's underlying disease. A treatment of up to 12 months is recommended unless the discontinuation of Prasugrel Mylan is clinically indicated (see sections 4.4 and 5.1).

Patients ≥75 years old

The use of Prasugrel Mylan in patients ≥75 years of age is generally not recommended. If, after a careful individual benefit/risk evaluation by the prescribing physician (see section 4.4), treatment is deemed necessary in the patients age group ≥75 years, then following a 60 mg loading dose a reduced maintenance dose of 5 mg should be prescribed. Patients ≥75 years of age have greater sensitivity to bleeding and higher exposure to the active metabolite of prasugrel (see sections 4.4, 4.8, 5.1 and 5.2).

Patients weighing <60 kg

Prasugrel Mylan should be given as a single 60 mg loading dose and then continued at a 5 mg once daily dose. The 10 mg maintenance dose is not recommended. This is due to an increase in exposure to the active metabolite of prasugrel, and an increased risk of bleeding in patients with body weight <60 kg when given a 10 mg once daily dose compared with patients ≥60 kg (see sections 4.4, 4.8 and 5.2).

Renal impairment

No dose adjustment is necessary for patients with renal impairment, including patients with end stage renal disease (see section 5.2). There is limited therapeutic experience in patients with renal impairment (see section 4.4).

Hepatic impairment

No dose adjustment is necessary in subjects with mild to moderate hepatic impairment (Child Pugh class A and B) (see section 5.2). There is limited therapeutic experience in patients with mild and moderate hepatic dysfunction (see section 4.4). Prasugrel Mylan is contraindicated in patients with severe hepatic impairment (Child Pugh class C).

Paediatric population

The safety and efficacy of Prasugrel Mylan in children below age 18 has not been established. Limited data are available in children with sickle cell anaemia (see section 5.1).

Method of administration

Prasugrel Mylan is for oral use. It may be administered with or without food. Administration of the 60 mg prasugrel loading dose in the fasted state may provide most rapid onset of action (see section 5.2). The tablets should not be crushed or broken.

4.3. Contraindications

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

Active pathological bleeding.

History of stroke or transient ischaemic attack (TIA).

Severe hepatic impairment (Child Pugh class C).

4.4. Special warnings and precautions for use

Bleeding risk

In the phase 3 clinical trial (TRITON) key exclusion criteria included an increased risk of bleeding; anaemia; thrombocytopaenia; a history of pathological intracranial findings. Patients with acute coronary syndromes undergoing PCI treated with prasugrel and ASA showed an increased risk of major and minor bleeding according to the TIMI classification system. Therefore, the 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 bleedings. This concern applies especially to patients:

• ≥75 years of age (see below).

• with a propensity to bleed (e.g. due to recent trauma, recent surgery, recent or recurrent gastrointestinal bleeding, or active peptic ulcer disease)

• with body weight <60 kg (see sections 4.2 and 4.8). In these patients the 10 mg maintenance dose is not recommended. A 5 mg maintenance dose should be used.

• with concomitant administration of medicinal products that may increase the risk of bleeding, including oral anticoagulants, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and fibrinolytics.

For patients with active bleeding for whom reversal of the pharmacological effects of prasugrel is required, platelet transfusion may be appropriate.

The use of Prasugrel Mylan in patients ≥75 years of age is generally not recommended and should only be undertaken with caution after a careful individual benefit/risk evaluation by the prescribing physician indicates that benefits in terms of prevention of ischaemic events outweigh the risk of serious bleedings. In the phase 3 clinical trial these patients were at greater risk of bleeding, including fatal bleeding, compared to patients <75 years of age. If prescribed, a lower maintenance dose of 5 mg should be used; the 10 mg maintenance dose is not recommended (see sections 4.2 and 4.8).

Therapeutic experience with prasugrel is limited in patients with renal impairment (including ESRD) and in patients with moderate hepatic impairment. These patients may have an increased bleeding risk. Therefore, prasugrel should be used with caution in these patients.

Patients should be told that it might take longer than usual to stop bleeding when they take prasugrel (in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician.

Bleeding risk associated with timing of loading dose in NSTEMI

In a clinical trial of NSTEMI patients (the ACCOAST study), where patients were scheduled to undergo coronary angiography within 2 to 48 hours after randomization, a prasugrel loading dose given on average 4 hours prior to coronary angiography increased the risk of major and minor peri-procedural bleeding compared with a prasugrel loading dose at the time of PCI. Therefore, in UA/NSTEMI patients, where coronary angiography is performed within 48 hours after admission, the loading dose should be given at the time of PCI. (see sections 4.2, 4.8 and 5.1).

Surgery

Patients should be advised to inform physicians and dentists that they are taking prasugrel before any surgery is scheduled and before any new medicinal product is taken. If a patient is to undergo elective surgery, and an antiplatelet effect is not desired, Prasugrel Mylan should be discontinued at least 7 days prior to surgery. Increased frequency (3­fold) and severity of bleeding may occur in patients undergoing CABG surgery within 7 days of discontinuation of prasugrel (see section 4.8). The benefits and risks of prasugrel should be carefully considered in patients in whom the coronary anatomy has not been defined and urgent CABG is a possibility.

Hypersensitivity including angioedema

Hypersensitivity reactions including angioedema have been reported in patients receiving prasugrel, including in patients with a history of hypersensitivity reaction to clopidogrel. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised (see section 4.8).

Thrombotic thrombocytopaenic purpura (TTP)

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

Morphine and other opioids

Reduced prasugrel efficacy has been seen in patients co-administered prasugrel and morphine (see section 4.5).

Prasugrel Mylan 5 mg contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Prasugrel Mylan 10 mg contains sunset yellow FCF aluminium lake (E110) and sodium

Sunset yellow FCF aluminium lake is an azo colouring agent, which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Warfarin

Concomitant administration of Prasugrel Mylan with coumarin derivatives other than warfarin has not been studied. Because of the potential for increased risk of bleeding, warfarin (or other coumarin derivatives) and prasugrel should be co-administered with caution (see section 4.4).

Non-steroidal anti-inflammatory drugs (NSAIDs)

Concomitant administration with chronic NSAIDs has not been studied. Because of the potential for increased risk of bleeding, chronic NSAIDs (including COX­2 inhibitors) and Prasugrel Mylan should be co-administered with caution (see section 4.4).

Prasugrel Mylan 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 Mylan 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 has been co-administered in the phase 3 clinical trial with low molecular weight heparin, bivalirudin, and GP IIb/IIIa inhibitors (no information available regarding the type of GP IIb/IIIa inhibitor used) without evidence of clinically significant adverse interactions.

Effects of other medicinal products on Prasugrel Mylan

Acetylsalicylic acid

Prasugrel Mylan is to be administered concomitantly with acetylsalicylic acid (ASA). Although a pharmacodynamic interaction with ASA leading to an increased risk of bleeding is possible, the demonstration of the efficacy and safety of prasugrel comes from patients concomitantly treated with ASA.

Heparin

A single intravenous bolus dose of unfractionated heparin (100 U/kg) did not significantly alter the prasugrel-mediated inhibition of platelet aggregation. Likewise, prasugrel did not significantly alter the effect of heparin on measures of coagulation. Therefore, both medicinal products can be administered concomitantly. An increased risk of bleeding is possible when Prasugrel Mylan is co-administered with heparin.

Statins

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

Medicinal products that elevate gastric pH

Daily co administration of ranitidine (an H2 blocker) or lansoprazole (a proton pump inhibitor) did not change the prasugrel active metabolite's AUC and Tmax, but decreased the Cmax by 14% and 29%, respectively. In the phase 3 clinical trial, prasugrel was administered without regard to co administration of a proton pump inhibitor or H2 blocker. Administration of the 60 mg prasugrel loading dose without concomitant use of proton pump inhibitors may provide most rapid onset of action.

Inhibitors of CYP3A

Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the prasugrel active metabolite's AUC and Tmax, but decreased the Cmax by 34% to 46%. Therefore, CYP3A inhibitors such as azol antifungals, HIV protease inhibitors, clarithromycin, telithromycin, verapamil, diltiazem, indinavir, ciprofloxacin, and grapefruit juice are not anticipated to have a significant effect on the pharmacokinetics of the active metabolite.

Inducers of cytochromes P450

Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6, and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not anticipated to have significant effect on the pharmacokinetics of the active metabolite.

Morphine and other opioids

A delayed and decreased exposure to oral P2Y12 inhibitors, including prasugrel and its active metabolite, has been observed in patients with acute coronary syndrome treated with morphine. This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced prasugrel efficacy in patients co-administered prasugrel and morphine. In patients with acute coronary syndrome, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

Effects of Prasugrel Mylan on other medicinal products

Digoxin

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

Medicinal products metabolised by CYP2C9

Prasugrel did not inhibit CYP2C9, as it did not affect the pharmacokinetics of S­warfarin. Because of the potential for increased risk of bleeding, warfarin and Prasugrel Mylan should be co-administered with caution (see section 4.4).

Medicinal products metabolised by CYP2B6

Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%. This effect is likely to be of clinical concern only when prasugrel is co administered with medicinal products for which CYP2B6 is the only metabolic pathway and have a narrow therapeutic window (e.g. cyclophosphamide, efavirenz).

4.6. Fertility, pregnancy and lactation

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

Pregnancy

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Because animal reproduction studies are not always predictive of a human response, Prasugrel Mylan should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether prasugrel is excreted in human breast milk. Animal studies have shown excretion of prasugrel in breast milk. The use of prasugrel during breastfeeding is not recommended.

Fertility

Prasugrel had no effect on fertility of male and female rats at oral doses up to an exposure 240 times the recommended daily human maintenance dose (based on mg/m²).

4.7. Effects on ability to drive and use machines

Prasugrel has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

Safety in patients with acute coronary syndrome undergoing PCI was evaluated in one clopidogrel controlled study (TRITON) in which 6741 patients were treated with prasugrel (60 mg loading dose and 10 mg once daily maintenance dose) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for more than 1 year). The rate of study drug discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel. Of these, bleeding was the most common adverse reaction for both drugs leading to study drug discontinuation (2.5% for prasugrel and 1.4% for clopidogrel).

Bleeding

Non-Coronary Artery Bypass Graft (CABG) related bleeding

In TRITON, the frequency of patients experiencing a non-CABG related bleeding event is shown in Table 1. The incidence of Non-CABG-related TIMI major bleeding, including life-threatening and fatal, as well as TIMI minor bleeding, was statistically significantly higher in subjects treated with prasugrel compared to clopidogrel in the UA/NSTEMI and All ACS populations. No significant difference was seen in the STEMI population. The most common site of spontaneous bleeding was the gastrointestinal tract (1.7% rate with prasugrel and 1.3% rate with clopidogrel); the most frequent site of provoked bleeding was the arterial puncture site (1.3% rate with prasugrel and 1.2% with clopidogrel).

Table 1: Incidence of Non-CABG related bleedinga (% Patients)

Event

All ACS

UA/NSTEMI

STEMI

Prasugrelb + ASA

(N=6741)

Clopidogrelb + ASA

(N=6716)

Prasugrelb + ASA

(N=5001)

Clopidogrelb + ASA

(N=4980)

Prasugrelb + ASA

(N=1740)

Clopidogrelb + ASA

(N=1736)

TIMI major bleedingc

2.2

1.7

2.2

1.6

2.2

2.0

Life-threateningd

1.3

0.8

1.3

0.8

1.2

1.0

Fatal

0.3

0.1

0.3

0.1

0.4

0.1

Symptomatic ICHe

0.3

0.3

0.3

0.3

0.2

0.2

Requiring inotropes

0.3

0.1

0.3

0.1

0.3

0.2

Requiring surgical intervention

0.3

0.3

0.3

0.3

0.1

0.2

Requiring transfusion (≥4 units)

0.7

0.5

0.6

0.3

0.8

0.8

TIMI minor bleedingf

2.4

1.9

2.3

1.6

2.7

2.6

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

b Other standard therapies were used as appropriate.

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

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

e ICH = intracranial haemorrhage.

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

Patients ≥75 years old

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

Age

Prasugrel 10 mg

Clopidogrel 75 mg

≥75 years (N=1785)*

9.0% (1.0% fatal)

6.9% (0.1% fatal)

<75 years (N=11672)*

3.8% (0.2% fatal)

2.9% (0.1% fatal)

<75 years (N=7180)**

2.0% (0.1% fatal)a

1.3% (0.1% fatal)

Prasugrel 5 mg

Clopidogrel 75 mg

≥75 years (N=2060)**

2.6% (0.3% fatal)

3.0% (0.5% fatal)

* TRITON study in ACS patients undergoing PCI

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

a 10 mg prasugrel; 5 mg prasugrel if <60 kg

Patients <60 kg

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

Weight

Prasugrel 10 mg

Clopidogrel 75 mg

<60 kg (N=664)*

10.1% (0% fatal)

6.5% (0.3% fatal)

≥60 kg (N=12672)*

4.2% (0.3% fatal)

3.3% (0.1% fatal)

≥60 kg (N=7845)**

2.2% (0.2% fatal)a

1.6% (0.2% fatal)

Prasugrel 5 mg

Clopidogrel 75 mg

<60kg (N=1391)**

1.4% (0.1% fatal)

2.2% (0.3% fatal)

* TRITON study in ACS patients undergoing PCI

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

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

Patients ≥60 kg and age <75 years

In patients ≥60 kg and age <75 years, non-CABG-related TIMI major or minor bleeding rates were 3.6% for prasugrel and 2.8% for clopidogrel; rates for fatal bleeding were 0.2% for prasugrel and 0.1% for clopidogrel.

CABG-related bleeding

In the phase 3 clinical trial, 437 patients underwent CABG during the course of the study. Of those patients, the rate of CABG-related TIMI major or minor bleeding was 14.1% for the prasugrel group and 4.5% in the clopidogrel group. The higher risk for bleeding events in subjects treated with prasugrel persisted up to 7 days from the most recent dose of study drug. For patients who received their thienopyridine within 3 days prior to CABG, the frequencies of TIMI major or minor bleeding were 26.7% (12 of 45 patients) in the prasugrel group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group. Beyond 7 days after drug discontinuation, the observed rates of CABG-related bleeding were similar between treatment groups (see section 4.4).

Bleeding risk associated with timing of loading dose in NSTEMI

In a clinical study of NSTEMI patients (the ACCOAST study), where patients were scheduled to undergo coronary angiography within 2 to 48 hours after randomization, patients given a 30 mg loading dose on average 4 hours prior to coronary angiography followed by a 30 mg loading dose at the time of PCI had an increased risk of non-CABG peri-procedural bleeding and no additional benefit compared to patients receiving a 60 mg loading dose at the time of PCI (see sections 4.2 and 4.4). Non-CABG- related TIMI bleeding rates through 7 days for patients were as follows:

Adverse reaction

Prasugrel prior to coronary angiographya (N=2037) %

Prasugrel at time of PCIa (N=1996) %

TIMI Major bleedingb

1.3

0.5

Life-threateningc

0.8

0.2

Fatal

0.1

0.0

Symptomatic ICHd

0.0

0.0

Requiring inotropes

0.3

0.2

Requiring surgical intervention

0.4

0.1

Requiring transfusion (≥4 units)

0.3

0.1

TIMI Minor bleedinge

1.7

0.6

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

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

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

d ICH = intracranial haemorrhage.

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

Tabulated list of adverse reactions

Table 2 summarises haemorrhagic and non-haemorrhagic adverse reactions in TRITON, or that were spontaneously reported, classified by frequency and system organ class. Frequencies are defined as follows:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 2: Haemorrhagic and non-haemorrhagic adverse reactions

System Organ Class

Common

Uncommon

Rare

Not known

Blood and Lymphatic System disorders

Anaemia

Thrombocytopaenia

Thrombotic thrombocytopaenic purpura (TTP) –see section 4.4

Immune system disorders

Hypersensitivity including angioedema

Eye disorders

Eye haemorrhage

Vascular Disorders

Haematoma

Respiratory, thoracic and mediastinal disorders

Epistaxis

Haemoptysis

Gastrointestinal disorders

Gastrointestinal haemorrhage

Retroperitoneal haemorrhage

Rectal haemorrhage

Haematochezia

Gingival bleeding

Skin and subcutaneous tissue disorders

Rash

Ecchymosis

Renal and urinary disorders

Haematuria

General disorders and administration site conditions

Vessel puncture site haematoma

Puncture site haemorrhage

Injury, poisoning and procedural complications

Contusion

Post-procedural haemorrhage

Subcutaneous haematoma

In patients with or without a history of TIA or stroke, the incidence of stroke in the phase 3 clinical trial was as follows (see section 4.4):

History of TIA or stroke

Prasugrel

Clopidogrel

Yes (N=518)

6.5% (2.3% ICH*)

1.2% (0% ICH*)

No (N=13090)

0.9% (0.2% ICH*)

1.0% (0.3% ICH*)

* ICH = intracranial haemorrhage.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9. Overdose

Overdose of Prasugrel Mylan may lead to prolonged bleeding time and subsequent bleeding complications. No data are available on the reversal of the pharmacological effect of prasugrel; however, if prompt correction of prolonged bleeding time is required, platelet transfusion and/or other blood products may be considered.