Prasugrel (Page 3 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of prasugrel tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders — Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions ( 5.4) and Patient Counseling Information ( 17)]

Immune system disorders — Hypersensitivity reactions including anaphylaxis [see Contraindications ( 4.3)]

7 DRUG INTERACTIONS

7.1 Warfarin

Coadministration of prasugrel and warfarin increases the risk of bleeding [see Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3)] .

7.2 Non-Steroidal Anti-Inflammatory Drugs

Coadministration of prasugrel and NSAIDs (used chronically) may increase the risk of bleeding [see Warnings and Precautions ( 5.1)] .

7.3 Opioids

As with other oral P2Y 12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of prasugrel’s active metabolite presumably because of slowed gastric emptying [see Clinical Pharmacology ( 12.3)] .

Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

7.4 Other Concomitant Medications

Prasugrel tablets can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [see Clinical Pharmacology ( 12.3)] .

Prasugrel tablets can be administered with aspirin (75-mg to 325-mg per day), heparin, GPIIb/IIIa inhibitors, statins, digoxin, and drugs that elevate gastric pH, including proton pump inhibitors and H 2 blockers [see Clinical Pharmacology ( 12.3)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
There are no data with prasugrel use in pregnant women to inform a drug-associated risk. No structural malformations were observed in animal reproductive and developmental toxicology studies when rats and rabbits were administered prasugrel during organogenesis at doses of up to 30 times the recommended therapeutic exposures in humans [see Data] . Due to the mechanism of action of prasugrel, and the associated identified risk of bleeding, consider the benefits and risks of prasugrel and possible risks to the fetus when prescribing prasugrel tablets to a pregnant woman [see Boxed Warning, and Warnings and Precautions (5.1, 5.3)] .
The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data
Animal Data
In embryo fetal developmental toxicology studies, pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure. A slight decrease in fetal body weight was observed; but, there were no structural malformations in either species. In prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure.

8.2 Lactation

Risk Summary
There is no information regarding the presence of prasugrel in human milk, the effects on the breastfed infant, or the effects on milk production. Metabolites of prasugrel were found in rat milk [see Data] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for prasugrel tablets and any potential adverse effects on the breastfed child from prasugrel or from the underlying maternal condition.

Data
Animal Data Following a 5-mg/kg oral dose of [ 14 C]-prasugrel to lactating rats, metabolites of prasugrel were detected in the maternal milk and blood.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Information describing a pediatric clinical study in another indication in which efficacy was not demonstrated in patients is approved for Eli Lilly and Company’s Effient ® (prasugrel) tablets. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

In TRITON-TIMI 38, 38.5% of patients were ≥65 years of age and 13.2% were ≥75 years of age. The risk of bleeding increased with advancing age in both treatment groups, although the relative risk of bleeding (prasugrel compared with clopidogrel) was similar across age groups.

Patients ≥75 years of age who received prasugrel 10-mg had an increased risk of fatal bleeding events (1.0%) compared to patients who received clopidogrel (0.1%). In patients ≥75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received prasugrel and in 3 patients (0.3%) who received clopidogrel. Because of the risk of bleeding, and because effectiveness is uncertain in patients ≥75 years of age [see Clinical Studies ( 14)] , use of prasugrel is generally not recommended in these patients, except in high-risk situations (diabetes and past history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Warnings and Precautions ( 5.1), Clinical Pharmacology ( 12.3), and Clinical Studies ( 14)] .

8.6 Low Body Weight

In TRITON-TIMI 38, 4.6% of patients treated with prasugrel tablets had body weight <60 kg. Individuals with body weight <60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel [see Dosage and Administration ( 2), Warnings and Precautions ( 5.1), and Clinical Pharmacology ( 12.3)] . Consider lowering the maintenance dose to 5-mg in patients <60 kg. The effectiveness and safety of the 5-mg dose have not been prospectively studied [see Dosage and Administration ( 2) and Clinical Pharmacology ( 12.3)] .

8.7 Renal Impairment

No dosage adjustment is necessary for patients with renal impairment. There is limited experience in patients with end-stage renal disease, but such patients are generally at higher risk of bleeding [see Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3)] .

8.8 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, but such patients are generally at higher risk of bleeding [see Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3)] .

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