Effient (Page 3 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Effient. 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 (17.3)]

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

7 DRUG INTERACTIONS

7.1 Warfarin

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

7.3 Other Concomitant Medications

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

Effient 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 H2 blockers [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B — There are no adequate and well-controlled studies of Effient use in pregnant women. Reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite) revealed no evidence of fetal harm; however, animal studies are not always predictive of a human response. Effient should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

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 pup 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 [see Nonclinical Toxicology (13.1)].

8.3 Nursing Mothers

It is not known whether Effient is excreted in human milk; however, metabolites of Effient were found in rat milk. Because many drugs are excreted in human milk, prasugrel should be used during nursing only if the potential benefit to the mother justifies the potential risk to the nursing infant.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established [see Clinical Pharmacology (12.3)].

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 (Effient compared with clopidogrel) was similar across age groups.

Patients ≥ 75 years of age who received Effient 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 Effient 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 Effient 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 Effient 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.

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 [see 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)].

8.9 Metabolic Status

In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.

10 OVERDOSAGE

10.1 Signs and Symptoms

Platelet inhibition by prasugrel is rapid and irreversible, lasting for the life of the platelet, and is unlikely to be increased in the event of an overdose. In rats, lethality was observed after administration 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.

10.2 Recommendations about Specific Treatment

Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis.

11 DESCRIPTION

Effient contains prasugrel, a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Effient is formulated as the hydrochloride salt, a racemate, which is chemically designated as 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride. Prasugrel hydrochloride has the empirical formula C20 H20 FNO3 S•HCl representing a molecular weight of 409.90. The chemical structure of prasugrel hydrochloride is:


						Chemical Structure

Prasugrel hydrochloride is a white to practically white solid. It is soluble at pH 2, slightly soluble at pH 3 to 4, and practically insoluble at pH 6 to 7.5. It also dissolves freely in methanol and is slightly soluble in 1- and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate.

Effient is available for oral administration as 5 mg or 10 mg elongated hexagonal, film-coated, non-scored tablets, debossed on each side. Each yellow 5 mg tablet is manufactured with 5.49 mg prasugrel hydrochloride, equivalent to 5 mg prasugrel and each beige 10 mg tablet with 10.98 mg prasugrel hydrochloride, equivalent to 10 mg of prasugrel. During manufacture and storage, partial conversion from prasugrel hydrochloride to prasugrel free base may occur. Other ingredients include mannitol, hypromellose, croscarmellose sodium, microcrystalline cellulose, and vegetable magnesium stearate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10 mg tablet).

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