prasugrel: prescribing information – dosing, contraindications, interactions, side effects

Efient, 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.

Posology
Adults
Efient 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 Efient 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 Efient, 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 Efient is clinically indicated (see sections 4.4 and 5.1).

Patients ≥ 75 years old
The use of Efient 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
Efient 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). Efient is contraindicated in patients with severe hepatic impairment (Child Pugh class C).

Paediatric population
The safety and efficacy of Efient 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
For oral use. Efient may be administered with or without food. Administration of the 60 mg prasugrel loading dose in the fasted state may provide most rapid onset of action (see section 5.2). Do not crush or break the tablet.

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).

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) 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
< 60 kg (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.

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

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 Efient and ASA showed an increased risk of major and minor bleeding according to the TIMI classification system. Therefore, the use of Efient 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 Efient is required, platelet transfusion may be appropriate.

The use of Efient 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, Efient 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 (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.

Lactose and sodium
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’.

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

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

Non-steroidal anti-inflammatory drugs (NSAIDs):
Concomitant administration with chronic NSAIDs has not been studied. Because of the potential for increased risk of bleeding, chronic NSAIDs (including COX-2 inhibitors) and Efient should be co- administered with caution (see section 4.4).

Efient 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. Efient 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, Efient 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 Efient
Acetylsalicylic acid:
Efient 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 Efient 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, Efient 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 Efient on other medicinal products
Digoxin:
Prasugrel has no clinically significant effect on the pharmacokinetics of digoxin.

Medicinal products metabolised by CYP2C9:
Prasugrel did not inhibit CYP2C9, as it did not affect the pharmacokinetics of S-warfarin. Because of the potential for increased risk of bleeding, warfarin and Efient 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).

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, Efient 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).

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

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

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC22.

Mechanism of action / Pharmacodynamic effects
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. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function can result in the reduction of the rate of cardiovascular events such as death, myocardial infarction, or stroke.

Following a 60 mg loading dose of prasugrel, inhibition of ADP-induced platelet aggregation occurs at 15 minutes with 5 µM ADP and 30 minutes with 20 µM ADP. The maximum inhibition by prasugrel of ADP-induced platelet aggregation is 83% with 5 µM ADP and 79% with 20 µM ADP, in both cases with 89% of healthy subjects and patients with stable atherosclerosis achieving at least 50% inhibition of platelet aggregation by 1 hour. Prasugrel-mediated inhibition of platelet aggregation exhibits low between-subject (9%) and within-subject (12%) variability with both 5 µM and 20 µM ADP.
Mean steady-state inhibition of platelet aggregation was 74% and 69% respectively for 5 µM ADP and 20 µM ADP, and was achieved following 3 to 5 days of administration of the 10 mg prasugrel maintenance dose preceded by a 60 mg loading dose. More than 98% of subjects had ≥ 20% inhibition of platelet aggregation during maintenance dosing.

Platelet aggregation gradually returned to baseline values after treatment in 7 to 9 days after administration of a single 60 mg loading dose of prasugrel and in 5 days following discontinuation of maintenance dosing at steady-state.

Switching data: Following administration of 75 mg clopidogrel once daily for 10 days, 40 healthy subjects were switched to prasugrel 10 mg once daily with or without a loading dose of 60 mg.
Similar or higher inhibition of platelet aggregation was observed with prasugrel. Switching directly to prasugrel 60 mg loading dose resulted in the most rapid onset of higher platelet inhibition.
Following administration of a 900 mg loading dose of clopidogrel (with ASA), 56 subjects with ACS were treated for 14 days with either prasugrel 10 mg once daily or clopidogrel 150 mg once daily, and then switched to either clopidogrel 150 mg or prasugrel 10 mg for another 14 days. Higher inhibition of platelet aggregation was observed in patients switched to prasugrel 10 mg compared with those treated with clopidogrel 150 mg. In a study of 276 ACS patients managed with PCI, switching from an initial loading dose of 600 mg clopidogrel or placebo administered upon presentation to the hospital prior to coronary angiography to a 60 mg loading dose of prasugrel administered at the time of percutaneous coronary intervention, resulted in a similar increased inhibition of platelet aggregation for the 72 hour duration of the study.

Clinical efficacy and safety

Prasugrel is a prodrug and is rapidly metabolised in vivo to an active metabolite and inactive metabolites. The active metabolite’s exposure (AUC) has moderate to low between-subject (27%) and within-subject (19%) variability. Prasugrel’s pharmacokinetics are similar in healthy subjects, patients with stable atherosclerosis, and patients undergoing percutaneous coronary intervention.

Absorption
The absorption and metabolism of prasugrel are rapid, with peak plasma concentration (Cmax) of the active metabolite occurring in approximately 30 minutes. The active metabolite’s exposure (AUC) increases proportionally over the therapeutic dose range. In a study of healthy subjects, AUC of the active metabolite was unaffected by a high fat, high calorie meal, but Cmax was decreased by 49% and the time to reach Cmax (Tmax) was increased from 0.5 to 1.5 hours. Efient was administered without regard to food in TRITON. Therefore, Efient can be administered without regard to food; however, the administration of prasugrel loading dose in the fasted state may provide most rapid onset of action (see section 4.2).

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

Biotransformation
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 Efient, there was no relevant effect of genetic variation in CYP3A5, CYP2B6, CYP2C9, or CYP2C19 on the pharmacokinetics of prasugrel or its inhibition of platelet aggregation.

Elimination