Effient

Generic Name: prasugrel hydrochloride

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

WARNING: BLEEDING RISK

Effient can cause significant, sometimes fatal, bleeding [see Warnings and Precautions (5.1 and 5.2) and Adverse Reactions (6.1)].

Do not use Effient in patients with active pathological bleeding or a history of transient ischemic attack or stroke [see Contraindications (4.1 and 4.2)].

In patients ≥ 75 years of age, Effient is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI) where its effect appears to be greater and its use may be considered [see Use in Specific Populations (8.5)].

Do not start Effient in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Effient at least 7 days prior to any surgery.

Additional risk factors for bleeding include:

• body weight < 60 kg


• propensity to bleed


• concomitant use of medications that increase the risk of bleeding (e.g., warfarin, heparin, fibrinolytic therapy, chronic use of non-steroidal anti-inflammatory drugs [NSAIDS])

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of Effient.

If possible, manage bleeding without discontinuing Effient. Discontinuing Effient, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.3)].

Indications and Usage for Effient

Acute Coronary Syndrome

Effient™ is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows:

• Patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI).


• Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.

Effient has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke compared to clopidogrel. The difference between treatments was driven predominantly by MI, with no difference on strokes and little difference on CV death [see Clinical Studies (14)].

It is generally recommended that antiplatelet therapy be administered promptly in the management of ACS because many cardiovascular events occur within hours of initial presentation. In the clinical trial that established the efficacy of Effient, Effient and the control drug were not administered to UA/NSTEMI patients until coronary anatomy was established. For the small fraction of patients that required urgent CABG after treatment with Effient, the risk of significant bleeding was substantial [see Warnings and Precautions (5.2)]. Because the large majority of patients are managed without CABG, however, treatment can be considered before determining coronary anatomy if need for CABG is considered unlikely. The advantages of earlier treatment with Effient must then be balanced against the increased rate of bleeding in patients who do need to undergo urgent CABG.

Effient Dosage and Administration

Initiate Effient treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily. Patients taking Effient should also take aspirin (75 mg to 325 mg) daily [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Effient may be administered with or without food [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

Dosing in Low Weight Patients

Compared to patients weighing ≥ 60 kg, patients weighing < 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. 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.

Dosage Forms and Strengths

Effient 5 mg is a yellow, elongated hexagonal, film-coated, non-scored tablet debossed with “5 MG” on one side and “4760” on the other side.

Effient 10 mg is a beige, elongated hexagonal, film-coated, non-scored tablet debossed with “10 MG” on one side and with “4759” on the other side.

Contraindications

Active Bleeding

Effient is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Prior Transient Ischemic Attack or Stroke

Effient is contraindicated in patients with a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel), patients with a history of TIA or ischemic stroke (> 3 months prior to enrollment) had a higher rate of stroke on Effient (6.5%; of which 4.2% were thrombotic stroke and 2.3% were intracranial hemorrhage [ICH]) than on clopidogrel (1.2%; all thrombotic). In patients without such a history, the incidence of stroke was 0.9% (0.2% ICH) and 1.0% (0.3% ICH) with Effient and clopidogrel, respectively. Patients with a history of ischemic stroke within 3 months of screening and patients with a history of hemorrhagic stroke at any time were excluded from TRITON-TIMI 38. Patients who experience a stroke or TIA while on Effient generally should have therapy discontinued [see Adverse Reactions (6.1) and Clinical Studies (14)].

Hypersensitivity

 Effient is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions (6.2)].

Warnings and Precautions

General Risk of Bleeding

Thienopyridines, including Effient, increase the risk of bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in Myocardial Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin ≥ 5 g/dL, or intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall in hemoglobin of ≥ 3 g/dL but < 5 g/dL) bleeding events were more common on Effient than on clopidogrel [see Adverse Reactions (6.1)]. The bleeding risk is highest initially, as shown in Figure 1 (events through 450 days; inset shows events through 7 days).

Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures even if the patient does not have overt signs of bleeding.

Do not use Effient in patients with active bleeding, prior TIA or stroke [see Contraindications (4.1 and 4.2)].

Other risk factors for bleeding are:

• Age ≥ 75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain effectiveness in patients ≥ 75 years of age, use of Effient is generally not recommended in these patients, except in high-risk situations (patients with diabetes or history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Adverse Reactions (6.1), Use in Specific Populations (8.5), Clinical Pharmacology (12.3), and Clinical Trials (14)].


• CABG or other surgical procedure [see Warnings and Precautions (5.2)].


• Body weight < 60 kg. Consider a lower (5 mg) maintenance dose [see Dosage and Administration (2), Adverse Reactions (6.1), Use in Specific Populations (8.6)].


• Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, or severe hepatic impairment) [see Adverse Reactions (6.1) and Use in Specific Populations (8.8)].


• Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of non-steroidal anti-inflammatory drugs [NSAIDs], and fibrinolytic agents). Aspirin and heparin were commonly used in TRITON-TIMI 38 [see Drug Interactions (7), Clinical Studies (14)].

Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of prasugrel's active metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

Coronary Artery Bypass Graft Surgery-Related Bleeding

The risk of bleeding is increased in patients receiving Effient who undergo CABG. If possible, Effient should be discontinued at least 7 days prior to CABG.

Of the 437 patients who underwent CABG during TRITON-TIMI 38, the rates of CABG-related TIMI Major or Minor bleeding were 14.1% in the Effient group and 4.5% in the clopidogrel group [see Adverse Reactions (6.1)]. The higher risk for bleeding events in patients treated with Effient persisted up to 7 days from the most recent dose of study drug. For patients receiving a thienopyridine within 3 days prior to CABG, the frequencies of TIMI Major or Minor bleeding were 26.7% (12 of 45 patients) in the Effient 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.

Do not start Effient in patients likely to undergo urgent CABG. CABG-related bleeding may be treated with transfusion of blood products, including packed red blood cells and platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

Discontinuation of Effient

Discontinue thienopyridines, including Effient, for active bleeding, elective surgery, stroke, or TIA. The optimal duration of thienopyridine therapy is unknown. In patients who are managed with PCI and stent placement, premature discontinuation of any antiplatelet medication, including thienopyridines, conveys an increased risk of stent thrombosis, myocardial infarction, and death. Patients who require premature discontinuation of a thienopyridine will be at increased risk for cardiac events. Lapses in therapy should be avoided, and if thienopyridines must be temporarily discontinued because of an adverse event(s), they should be restarted as soon as possible [see Contraindications (4.1 and 4.2) and Warnings and Precautions (5.1)].

Thrombotic Thrombocytopenic Purpura

 Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of Effient. TTP can occur after a brief exposure (< 2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment, including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral smear), neurological findings, renal dysfunction, and fever [see Adverse Reactions (6.2)].

Hypersensitivity Including Angioedema

 Hypersensitivity including angioedema has been reported in patients receiving Effient, including patients with a history of hypersensitivity reaction to other thienopyridines [see Contraindications (4.3), Adverse Reactions (6.2)].

Adverse Reactions

Clinical Trials Experience

The following serious adverse reactions are also discussed elsewhere in the labeling:

• Bleeding [see Boxed Warning and Warnings and Precautions (5.1, 5.2)]


• Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.4)]

Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with Effient (60 mg loading dose and 10 mg once daily) 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 population treated with Effient was 27 to 96 years of age, 25% female, and 92% Caucasian. All patients in the TRITON-TIMI 38 study were to receive aspirin. The dose of clopidogrel in this study was a 300 mg loading dose and 75 mg once daily.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials cannot be directly compared with the rates observed in other clinical trials of another drug and may not reflect the rates observed in practice.

Drug Discontinuation

The rate of study drug discontinuation because of adverse reactions was 7.2% for Effient and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for Effient and 1.4% for clopidogrel).

Bleeding

Bleeding Unrelated to CABG Surgery - In TRITON-TIMI 38, overall rates of TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG) were significantly higher on Effient than on clopidogrel, as shown in Table 1.

Table 1: Non-CABG-Related Bleedinga (TRITON-TIMI 38)

	Effient (%) (N=6741)	Clopidogrel (%) (N=6716)	p-value
a Patients may be counted in more than one row.
b See 5.1 for definition.
TIMI Major or Minor bleeding	4.5	3.4	p=0.002
TIMI Major bleedingb	2.2	1.7	p=0.029
Life-threatening	1.3	0.8	p=0.015
Fatal	0.3	0.1
Symptomatic intracranial hemorrhage (ICH)	0.3	0.3
Requiring inotropes	0.3	0.1
Requiring surgical intervention	0.3	0.3
Requiring transfusion (≥4 units)	0.7	0.5
TIMI Minor bleedingb	2.4	1.9	p=0.022

Figure 1 demonstrates non-CABG related TIMI Major or Minor bleeding. The bleeding rate is highest initially, as shown in Figure 1 (inset: Days 0 to 7) [see Warnings and Precautions (5.1)].

Bleeding rates in patients with the risk factors of age ≥ 75 years and weight < 60 kg are shown in Table 2.

Table 2: Bleeding Rates for Non-CABG-Related Bleeding by Weight and Age (TRITON-TIMI 38)

	Major/Minor		Fatal
	Effient (%)	Clopidogrel (%)	Effient (%)	Clopidogrel (%)
Weight < 60 kg (N=308 Effient, N=356 clopidogrel)	10.1	6.5	0.0	0.3
Weight ≥ 60 kg (N=6373 Effient, N=6299 clopidogrel)	4.2	3.3	0.3	0.1
Age < 75 years (N=5850 Effient, N=5822 clopidogrel)	3.8	2.9	0.2	0.1
Age ≥ 75 years (N=891 Effient, N=894 clopidogrel)	9.0	6.9	1.0	0.1

Bleeding Related to CABG - In TRITON-TIMI 38, 437 patients who received a thienopyridine underwent CABG during the course of the study. The rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the Effient group and 4.5% in the clopidogrel group (Table 3). The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug.

Table 3: CABG-Related Bleedinga (TRITON-TIMI 38)

	Effient (%) (N=213)	Clopidogrel (%) (N=224)
a Patients may be counted in more than one row.
TIMI Major or Minor bleeding	14.1	4.5
TIMI Major bleeding	11.3	3.6
Fatal	0.9	0
Reoperation	3.8	0.5
Transfusion of ≥5 units	6.6	2.2
Intracranial hemorrhage	0	0
TIMI Minor bleeding	2.8	0.9

Bleeding Reported as Adverse Reactions - Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for Effient and clopidogrel, respectively: epistaxis (6.2%, 3.3%), gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%, 0.5%), subcutaneous hematoma (0.5%, 0.2%), post-procedural hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%, 0.2%), pericardial effusion/hemorrhage/tamponade (0.3%, 0.2%), and retinal hemorrhage (0.0%, 0.1%).

Malignancies

During TRITON-TIMI 38, newly diagnosed malignancies were reported in 1.6% and 1.2% of patients treated with prasugrel and clopidogrel, respectively. The sites contributing to the differences were primarily colon and lung. It is unclear if these observations are causally-related or are random occurrences.

Other Adverse Events

In TRITON-TIMI 38, common and other important non-hemorrhagic adverse events were, for Effient and clopidogrel, respectively: severe thrombocytopenia (0.06%, 0.04%), anemia (2.2%, 2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions (0.36%, 0.36%), and angioedema (0.06%, 0.04%). Table 4 summarizes the adverse events reported by at least 2.5% of patients.

Table 4: Non-Hemorrhagic Treatment Emergent Adverse Events Reported by at Least 2.5% of Patients in Either Group

	Effient (%) (N=6741)	Clopidogrel (%) (N=6716)
Hypertension	7.5	7.1
Hypercholesterolemia/Hyperlipidemia	7.0	7.4
Headache	5.5	5.3
Back pain	5.0	4.5
Dyspnea	4.9	4.5
Nausea	4.6	4.3
Dizziness	4.1	4.6
Cough	3.9	4.1
Hypotension	3.9	3.8
Fatigue	3.7	4.8
Non-cardiac chest pain	3.1	3.5
Atrial fibrillation	2.9	3.1
Bradycardia	2.9	2.4
Leukopenia (< 4 x 109 WBC/L)	2.8	3.5
Rash	2.8	2.4
Pyrexia	2.7	2.2
Peripheral edema	2.7	3.0
Pain in extremity	2.6	2.6
Diarrhea	2.3	2.6

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)]

Drug Interactions

Warfarin

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

Non-Steroidal Anti-Inflammatory Drugs

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

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)].

USE IN SPECIFIC POPULATIONS

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)].

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.

Pediatric Use

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

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)].

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.

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)].

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)].

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.

Overdosage

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.

Recommendations about Specific Treatment

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

Effient 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 C20H20FNO3S•HCl representing a molecular weight of 409.90. The chemical structure of prasugrel hydrochloride is:

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).

Effient - Clinical Pharmacology

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.

Pharmacodynamics

Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60-mg loading dose of Effient, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% (Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60-mg loading dose of Effient.

Figure 2: Inhibition (Mean±SD) of 20 μM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Prasugrel 60 mg

Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that typically produced by a 10 mg maintenance dose of prasugrel alone. The relationship between inhibition of platelet aggregation and clinical activity has not been established.

Pharmacokinetics

Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.

Absorption and Binding - 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 slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose, the AUC of the active metabolite was unaffected by a high fat, high calorie meal, but Cmax was decreased by 49% and Tmax was increased from 0.5 to 1.5 hours. Effient can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.

Metabolism and Elimination - Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel's active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.

Specific Populations

Pediatric - Pharmacokinetics and pharmacodynamics of prasugrel have not been evaluated in a pediatric population [see Use in Specific Populations (8.4)].

Geriatric - In a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation. In TRITON-TIMI 38, the mean exposure (AUC) of the active metabolite was 19% higher in patients ≥75 years of age than in patients <75 years of age [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Use in Specific Populations (8.5)].

Body Weight - The mean exposure (AUC) to the active metabolite is approximately 30 to 40% higher in subjects with a body weight of <60 kg than in those weighing ≥60 kg [see Dosage and Administration (2), Warnings and Precautions (5.1), Adverse Reactions (6.1), and Use in Specific Populations (8.6)].

Gender - Pharmacokinetics of prasugrel's active metabolite are similar in men and women.

Ethnicity - Exposure in subjects of African and Hispanic descent is similar to that in Caucasians. 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 than in Caucasian subjects.

Smoking - Pharmacokinetics of prasugrel's active metabolite are similar in smokers and nonsmokers.

Renal Impairment - Pharmacokinetics of prasugrel's active metabolite and its inhibition of platelet aggregation are similar in patients with moderate renal impairment (CrCL=30 to 50 mL/min) and healthy subjects. In patients with end stage renal disease, exposure to the active metabolite (both Cmax and AUC(0-tlast)) was about half that in healthy controls and patients with moderate renal impairment [see Use in Specific Populations (8.7)].

Hepatic Impairment - Pharmacokinetics of prasugrel's active metabolite and inhibition of platelet aggregation were similar in patients with mild to moderate hepatic impairment compared to healthy subjects. The pharmacokinetics and pharmacodynamics of prasugrel's active metabolite in patients with severe hepatic disease have not been studied [see Warnings and Precautions (5.1) and Use in Specific Populations (8.8)].

Drug 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 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 expected to have a significant effect on the pharmacokinetics of the active metabolite of prasugrel [see Drug Interactions (7.3)].

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's active metabolite or its inhibition of platelet aggregation. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have significant effect on the pharmacokinetics of the active metabolite of prasugrel [see Drug Interactions (7.3)].

Drugs that Elevate Gastric pH - Daily coadministration of ranitidine (an H2 blocker) or lansoprazole (a proton pump inhibitor) decreased the Cmax of the prasugrel active metabolite by 14% and 29%, respectively, but did not change the active metabolite's AUC and Tmax. In TRITON-TIMI 38, Effient was administered without regard to coadministration of a proton pump inhibitor or H2 blocker [see Drug Interactions (7.3)].

Statins - Atorvastatin (80 mg daily), a drug metabolized by CYP450 3A4, did not alter the pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation [see Drug Interactions (7.3)].

Heparin - A single intravenous dose of unfractionated heparin (100 U/kg) did not significantly alter coagulation or the prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone [see Drug Interactions (7.3)].

Aspirin - Aspirin 150 mg daily did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone [see Drug Interactions (7.3)].

Warfarin - A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15 mg of warfarin [see Drug Interactions (7.1)].

Potential for Prasugrel to Affect Other Drugs

In vitro metabolism studies demonstrate that prasugrel's main circulating metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A.

Drugs Metabolized 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%, an amount not considered clinically significant. Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as

Elaprase

idursulfase

Dosage Form: injection, solution, concentrate
Elaprase ® (idursulfase)

Solution for intravenous infusion

WARNING

Risk of anaphylaxis.

Life-threatening anaphylactic reactions have been observed in some patients during Elaprase infusions. Therefore, appropriate medical support should be readily available when Elaprase is administered. Biphasic anaphylactic reactions have also been observed after Elaprase administration and patients who have experienced anaphylactic reactions may require prolonged observation. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.

Elaprase Description

Elaprase is a formulation of idursulfase, a purified form of human iduronate-2-sulfatase, a lysosomal enzyme. Idursulfase is produced by recombinant DNA technology in a human cell line. Idursulfase is an enzyme that hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes of various cell types.

Idursulfase is a 525-amino acid glycoprotein with a molecular weight of approximately 76 kilodaltons. The enzyme contains eight asparagine-linked glycosylation sites occupied by complex oligosaccharide structures. The enzyme activity of idursulfase is dependent on the post-translational modification of a specific cysteine to formylglycine. Idursulfase has a specific activity ranging from 46 to 74 U/mg of protein (one unit is defined as the amount of enzyme required to hydrolyze 1 µmole of heparin disaccharide substrate per hour under the specified assay conditions).

Elaprase is intended for intravenous infusion and is supplied as a sterile, nonpyrogenic clear to slightly opalescent, colorless solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP. Each vial contains an extractable volume of 3.0 mL with an idursulfase concentration of 2.0 mg/mL at a pH of approximately 6, providing 6.0 mg idursulfase, 24.0 mg sodium chloride, 6.75 mg sodium phosphate monobasic monohydrate, 2.97 mg sodium phosphate dibasic heptahydrate, and 0.66 mg polysorbate 20. Elaprase does not contain preservatives; vials are for single use only.

Elaprase - Clinical Pharmacology

Mechanism of Action

Hunter syndrome (Mucopolysaccharidosis II, MPS II) is an X-linked recessive disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. This enzyme cleaves the terminal 2-O-sulfate moieties from the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, GAG progressively accumulate in the lysosomes of a variety of cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.

Treatment of Hunter syndrome patients with Elaprase provides exogenous enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow specific binding of the enzyme to the M6P receptors on the cell surface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of accumulated GAG.

Pharmacokinetics

The pharmacokinetic characteristics of idursulfase were evaluated in several studies in patients with Hunter syndrome. The serum concentration of idursulfase was quantified using an antigen-specific ELISA assay. The area under the concentration-time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 0.15 mg/kg to 1.5 mg/kg following a single 1-hour infusion of Elaprase. The pharmacokinetic parameters at the recommended dose regimen (0.5 mg/kg Elaprase administered weekly as a 3-hour infusion) were determined at Week 1 and Week 27 in 10 patients ages 7.7 to 27 years (Table 1). There were no apparent differences in PK parameter values between Week 1 and Week 27.

Table 1 Pharmacokinetic Parameters (Mean, Standard Deviation)

Pharmacokinetic Parameter	Week 1	Week 27
Cmax (µg/mL)	1.5 (0.6)	1.1 (0.3)
AUC (min*µg/mL)	206 (87)	169 (55)
t1/2 (min)	44 (19)	48 (21)
Cl (mL/min/kg)	3.0 (1.2)	3.4 (1.0)
Vss (% BW)	21 (8)	25 (9)

Clinical Studies

The safety and efficacy of Elaprase were evaluated in a randomized, double-blind, placebo-controlled clinical study of 96 patients with Hunter syndrome. The study included patients with a documented deficiency in iduronate-2-sulfatase enzyme activity who had a percent predicted forced vital capacity (%-predicted FVC) less than 80%. The patients' ages ranged from 5 to 31 years. Patients who were unable to perform the appropriate pulmonary function testing, or those who could not follow protocol instructions were excluded from the study. Patients received Elaprase 0.5 mg/kg every week (n=32), Elaprase 0.5 mg/kg every other week (n=32), or placebo (n=32). The study duration was 53 weeks.

The primary efficacy outcome assessment was a two-component composite score based on the sum of the ranks of the change from baseline to Week 53 in distance walked during a six-minute walk test (6-MWT) and the ranks of the change in %-predicted FVC. This two-component composite primary endpoint differed statistically significantly between the three groups, and the difference was greatest between the placebo group and the weekly treatment group (weekly Elaprase vs. placebo, p=0.0049).

Examination of the individual components of the composite score showed that, in the adjusted analysis, the weekly Elaprase-treated group experienced a 35 meter greater mean increase in the distance walked in six minutes compared to placebo. The changes in %-predicted FVC were not statistically significant (Table 2).

Table 2 Clinical Study Results

	Elaprase Weekly n=32*			Placebo n=32*			Elaprase Weekly – Placebo
	Baseline	Week 53	Change†	Baseline	Week 53	Change†	Difference in Change
* One patient in the placebo group and one patient in the Elaprase group died before Week 53; imputation was by last observation carried forward in the intent-to-treat analysis † Change, calculated as Week 53 minus Baseline ‡ Observed mean ± SE § ANCOVA model based mean ± SE, adjusted for baseline disease severity, region, and age.
Results from the 6-Minute Walk Test (Meters)
Mean ± SD	392 ± 108	436 ± 138	44 ± 70	393 ± 106	400 ± 106	7 ± 54	37 ± 16‡ 35 ± 14§ (p=0.01)
Median	397	429	31	403	412	-4
Percentiles (25th, 75th)	316, 488	365, 536	0, 94	341, 469	361, 460	-30, 31
Results from the Forced Vital Capacity Test (% of Predicted)
Mean ± SD	55.3 ± 15.9	58.7 ± 19.3	3.4 ± 10.0	55.6 ± 12.3	56.3 ± 15.7	0.8 ± 9.6	2.7 ± 2.5‡ 4.3 ± 2.3§ (p=0.07)
Median	54.9	59.2	2.1	57.4	54.6	-2.5
Percentiles (25th, 75th)	43.6, 69.3	44.4, 70.7	-0.8, 9.5	46.9, 64.4	43.8, 67.5	-5.4, 5.0

Measures of bioactivity were urinary GAG levels and changes in liver and spleen size. Urinary GAG levels were elevated in all patients at baseline. Following 53 weeks of treatment, mean urinary GAG levels were markedly reduced in the Elaprase weekly group, although GAG levels still remained above the upper limit of normal in half of the Elaprase-treated patients. Urinary GAG levels remained elevated and essentially unchanged in the placebo group. Sustained reductions in both liver and spleen volumes were observed in the Elaprase weekly group through Week 53 compared to placebo. There were essentially no changes in liver and spleen volumes in the placebo group.

Indications and Usage for Elaprase

Elaprase is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). Elaprase has been shown to improve walking capacity in these patients.

Contraindications

None.

Warnings

Anaphylaxis and Allergic Reactions

(see BOXED WARNING)

Life-threatening anaphylactic reactions have been observed in some patients during Elaprase infusions. Reactions have included respiratory distress, hypoxia, hypotension, seizure, loss of consciousness, urticaria and/or angioedema of the throat or tongue. Biphasic anaphylactic reactions have also been reported to occur after administration of Elaprase approximately 24 hours after treatment and recovery from an initial anaphylactic reaction that occurred during Elaprase infusion. Interventions for biphasic reactions have included hospitalization, and treatment with epinephrine, inhaled beta-adrenergic agonists, and corticosteroids.

In clinical trials with Elaprase, 16/108 patients (15%) experienced infusion reactions during 26 of 8,274 infusions (0.3%) that involved adverse events in at least two of the following three body systems: cutaneous, respiratory, or cardiovascular. Of these 16 patients, 11 experienced significant allergic reactions during 19 of 8,274 infusions (0.2%). One of these episodes occurred in a patient with a tracheostomy and severe airway disease, who received an Elaprase infusion while he had a pre-existing febrile illness, and then experienced respiratory distress, hypoxia, cyanosis, and seizure with loss of consciousness.

Because of the potential for severe infusion reactions, appropriate medical support should be readily available when Elaprase is administered. Because of the potential for biphasic anaphylactic reactions after Elaprase administration, patients who experience initial severe or refractory reactions may require prolonged observation.

When severe infusion reactions occurred during clinical studies, subsequent infusions were managed by use of antihistamines and/or corticosteroids prior to or during infusions, a slower rate of Elaprase administration, and/or early discontinuation of the Elaprase infusion if serious symptoms developed. With these measures, no patient discontinued treatment permanently due to an allergic reaction.

Patients with compromised respiratory function or acute respiratory disease may be at higher risk of life-threatening complications from infusion reactions. Consider delaying the Elaprase infusion in patients with concomitant acute respiratory and/or febrile illness.

If a severe reaction occurs, immediately suspend the infusion of Elaprase and initiate appropriate treatment, depending on the severity of the symptoms. Consider resuming the infusion at a slower rate, or, if the reaction is serious enough to warrant it, discontinue the Elaprase infusion for that visit.

Precautions

Information for Patients

A Hunter Outcome Survey has been established in order to understand better the variability and progression of Hunter syndrome (MPS II) in the population as a whole, and to monitor and evaluate long-term treatment effects of Elaprase. Patients and their physicians are encouraged to participate in this program. For more information, visit www.Elaprase.com or call OnePathSM at 1-866-888-0660.

Drug Interactions

No formal drug interaction studies have been conducted with Elaprase.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Elaprase.

Elaprase at intravenous doses up to 5 mg/kg, administered twice weekly (about 1.6 times the recommended human weekly dose based on body surface area) had no effect on fertility and reproductive performance in male rats.

Pregnancy

Teratogenic Effects

Category C

Animal reproduction studies have not been conducted with Elaprase. It is also not known whether Elaprase can cause fetal harm when administered to pregnant women or can affect reproduction capacity in women. Elaprase should be given to pregnant women only if clearly needed.

Nursing Mothers

Elaprase was excreted in breast milk of lactating rats at a concentration higher (4 to 5-fold) than that of the plasma. It is not known whether Elaprase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Elaprase is administered to a nursing woman.

Pediatric Use

Patients in the clinical studies were age five and older (see CLINICAL STUDIES). Children, adolescents, and adults responded similarly to treatment with Elaprase. Safety and efficacy have not been established in pediatric patients less than five years of age.

Geriatric Use

Clinical studies of Elaprase did not include patients aged 65 or over. It is not known whether geriatric patients respond differently from younger patients.

Adverse Reactions

The most serious infusion-related adverse reactions reported with Elaprase were anaphylactic and allergic reactions (see BOXED WARNING and WARNINGS).

In clinical studies, the most frequent serious adverse events related to the use of Elaprase were hypoxic episodes. Other notable serious adverse reactions that occurred in the Elaprase treated patients but not in the placebo patients included one case each of: cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory failure, infection, and arthralgia.

Adverse reactions were commonly reported in association with infusions. The most common infusion-related reactions were headache, fever, cutaneous reactions (rash, pruritus, erythema, and urticaria), and hypertension. The frequency of infusion-related reactions decreased over time with continued Elaprase treatment.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in practice.

Table 3 enumerates those adverse reactions that were reported during the 53-week, placebo-controlled study that occurred in at least 10% of patients treated with Elaprase weekly administration, and that occurred more frequently than in the placebo patients. The most common (>30%) adverse reactions were pyrexia, headache, and arthralgia.

Table 3 Summary of Adverse Reactions Occurring in at Least 10% of Patients Treated with Elaprase Weekly in the 53-week Controlled Trial and Occurring More Frequently than in the Placebo Group

Adverse Event	Elaprase 0.5 mg/kg Weekly (n=32)		Placebo (n=32)
Pyrexia	20	(63%)	19	(59%)
Headache	19	(59%)	14	(44%)
Arthralgia	10	(31%)	9	(28%)
Limb pain	9	(28%)	8	(25%)
Pruritus	9	(28%)	5	(16%)
Hypertension	8	(25%)	7	(22%)
Malaise	7	(22%)	6	(19%)
Visual disturbance	7	(22%)	2	(6%)
Wheezing	6	(19%)	5	(16%)
Abscess	5	(16%)	0	(0%)
Musculoskeletal dysfunction NOS	5	(16%)	3	(9%)
Chest wall musculoskeletal pain	5	(16%)	0	(0%)
Urticaria	5	(16%)	0	(0%)
Superficial injury	4	(13%)	3	(9%)
Anxiety, irritability	4	(13%)	1	(3%)
Atrial abnormality	4	(13%)	3	(9%)
Adverse events resulting from injury	4	(13%)	2	(6%)
Dyspepsia	4	(13%)	0	(0%)
Infusion site edema	4	(13%)	3	(9%)
Skin disorder NOS	4	(13%)	1	(3%)
Pruritic rash	4	(13%)	0	(0%)

Immunogenicity

Fifty-one percent (32 of 63) of patients in the weekly Elaprase treatment arm in the clinical study (53-week placebo-controlled study with an open-label extension) developed anti-idursulfase IgG antibodies as assessed by ELISA or conformation specific antibody assay and confirmed by radioimmunoprecipitation assay (RIP). Sera from 4 out of 32 RIP confirmed anti-idursulfase antibody positive patients were found to neutralize idursulfase activity in vitro. The incidence of antibodies that inhibit cellular uptake of idursulfase into cells is currently unknown, and the incidence of IgE antibodies to idursulfase is not known. Patients who developed IgG antibodies at any time had an increased incidence of infusion reactions, including allergic reactions. The reduction of urinary GAG excretion was less in patients in whom circulating anti-idursulfase antibodies were detected. The relationship between the presence of anti-idursulfase antibodies and clinical efficacy outcomes is unknown.

The data reflect the percentage of patients whose test results were positive for antibodies to idursulfase in specific assays, and are highly dependent on the sensitivity and specificity of these assays. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to idursulfase with the incidence of antibodies to other products may be misleading.

Overdosage

There is no experience with overdosage of Elaprase in humans. Single intravenous doses of idursulfase up to 20 mg/kg were not lethal in male rats and cynomolgus monkeys (approximately 6.5 and 13 times, respectively, of the recommended human dose based on body surface area) and there were no clinical signs of toxicity.

Elaprase Dosage and Administration

The recommended dosage regimen of Elaprase is 0.5 mg/kg of body weight administered every week as an intravenous infusion.

Elaprase is a concentrated solution for intravenous infusion and must be diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. Each vial of Elaprase contains a 2.0 mg/mL solution of idursulfase protein (6.0 mg) in an extractable volume of 3.0 mL, and is for single use only. Use of an infusion set equipped with a 0.2 micrometer (µm) filter is recommended.

The total volume of infusion may be administered over a period of 1 to 3 hours. Patients may require longer infusion times due to infusion reactions; however, infusion times should not exceed 8 hours (see STORAGE). The initial infusion rate should be 8 mL/hr for the first 15 minutes. If the infusion is well tolerated, the rate may be increased by 8 mL/hr increments at 15 minute intervals in order to administer the full volume within the desired period of time. However, at no time should the infusion rate exceed 100 mL/hr. The infusion rate may be slowed and/or temporarily stopped, or discontinued for that visit, based on clinical judgment, if infusion reactions were to occur (see WARNINGS). Elaprase should not be infused with other products in the infusion tubing.

Preparation and Administration Instructions: Use Aseptic Techniques

Elaprase should be prepared and administered by a health care professional.

1. Determine the total volume of Elaprase to be administered and the number of vials needed based on the patient's weight and the recommended dose of 0.5 mg/kg.
   
   
   

   Patient's weight (kg) × 0.5 mg per kg of Elaprase ÷ 2 mg per mL = Total # mL of Elaprase

   Total # mL of Elaprase ÷ 3 mL per vial = Total # of vials

   
   Round up to determine the number of whole vials needed from which to withdraw the calculated volume of Elaprase to be administered.


2. Perform a visual inspection of each vial. Elaprase is a clear to slightly opalescent, colorless solution. Do not use if the solution in the vials is discolored or particulate matter is present. Elaprase should not be shaken.


3. Withdraw the calculated volume of Elaprase from the appropriate number of vials.


4. Dilute the total calculated volume of Elaprase in 100 mL of 0.9% Sodium Chloride Injection, USP. Once diluted into normal saline, the solution in the infusion bag should be mixed gently, but not shaken. Diluted solution may be stored refrigerated for up to 24 hours.


5. Elaprase is supplied in single-use vials. Remaining Elaprase left in a vial after withdrawing the patient's calculated dose should be disposed of in accordance with local requirements.

STORAGE

Store Elaprase vials under refrigeration at 2°C to 8°C (36°F to 46°F), and protect from light. Do not freeze or shake. Do not use Elaprase after the expiration date on the vial.

This product contains no preservatives. The diluted solution should be used immediately. If immediate use is not possible, the diluted solution can be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours.

How is Elaprase Supplied

Elaprase is a sterile, aqueous, clear to slightly opalescent, colorless solution supplied in a 5 mL Type I glass vial. The vials are closed with a butyl rubber stopper with fluororesin coating and an aluminum overseal with a blue flip-off plastic cap.

NDC 54092-700-01

Rx Only

Elaprase is manufactured for:

Shire Human Genetic Therapies, Inc.

700 Main Street

Cambridge, MA 02139

US License Number 1593

OnePathSM phone # 1-866-888-0660

Elaprase is a registered trademark of Shire Human Genetic Therapies, Inc.

REV 5 Last revised (Jan 2011)

PRINCIPAL DISPLAY PANEL - 6 mg/3 mL Vial Carton

Elaprase™

(idursulfase)

6 mg/3 mL

(2 mg/mL)

Single Use Vial

Must be diluted prior to

intravenous administration

Shire

Human Genetic Therapies

Rx Only

Elaprase  idursulfase  solution, concentrate

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 54092-700 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength idursulfase (idursulfase) idursulfase 6 mg  in 3 mL

Inactive Ingredients Ingredient Name Strength sodium chloride 24 mg  in 3 mL sodium phosphate, monobasic, monohydrate 6.75 mg  in 3 mL sodium phosphate, dibasic, heptahydrate 2.97 mg  in 3 mL polysorbate 20 0.66 mg  in 3 mL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 54092-700-01 1 VIAL In 1 BOX contains a VIAL, GLASS 1 3 mL In 1 VIAL, GLASS This package is contained within the BOX (54092-700-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA125151	07/24/2006

Labeler - Shire US Manufacturing Inc. (964907406)

Revised: 03/2011Shire US Manufacturing Inc.

More Elaprase resources

• Elaprase Side Effects (in more detail)
• Elaprase Use in Pregnancy & Breastfeeding
• Elaprase Support Group
• 0 Reviews for Elaprase - Add your own review/rating

• Elaprase Monograph (AHFS DI)


• Elaprase Consumer Overview


• Elaprase Advanced Consumer (Micromedex) - Includes Dosage Information


• Elaprase MedFacts Consumer Leaflet (Wolters Kluwer)


• Idursulfase Professional Patient Advice (Wolters Kluwer)

Compare Elaprase with other medications

• Mucopolysaccharidosis Type II

efavirenz

Generic Name: efavirenz (e FAV ir enz)

Brand Names: Sustiva

What is efavirenz?

Efavirenz is an antiviral medication that prevents human immunodeficiency virus (HIV) cells from multiplying in your body.

Efavirenz is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). Efavirenz is not a cure for HIV or AIDS.

Efavirenz may also be used for purposes not listed in this medication guide.

What is the most important information I should know about efavirenz?

Do not use efavirenz if you are pregnant. It could harm the unborn baby. Use two forms of birth control, including a barrier form (such as a condom or diaphragm with spermicide gel) while you are taking efavirenz, and for at least 12 weeks after your treatment ends. Tell your doctor if you become pregnant during treatment.

Efavirenz may cause serious psychiatric symptoms including confusion, severe depression, suicidal thoughts, aggression, extreme fear, hallucinations, or unusual behavior. Contact your doctor at once if you have any of these side effects, even if you have had them before.

Do not take efavirenz with cisapride (Propulsid), pimozide (Orap), midazolam (Versed), triazolam (Halcion), or ergot medicines such as dihydroergotamine (D.H.E. 45), ergonovine (Ergotrate), ergotamine (Ergomar, Cafergot, Wigraine), or methylergonovine (Methergine). These drugs can cause life-threatening side effects if you use them while you are taking efavirenz.

There are many other medicines that can interact with efavirenz, or make it less effective. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Taking this medication will not prevent you from passing HIV to other people. Talk with your doctor about safe methods of preventing HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

What should I discuss with my healthcare provider before taking efavirenz?

You should not use this medication if you are allergic to efavirenz, if you have moderate to severe liver problems, or if you are using any of the following drugs:

• 
  

  cisapride (Propulsid);

  
  


• 
  

  midazolam (Versed) or triazolam (Halcion);

  
  


• 
  

  pimozide (Orap); or

  
  


• 
  

  ergot medicine such as ergotamine (Ergomar, Ergostat, Cafergot, Ercaf, Wigraine), dihydroergotamine (D.H.E. 45, Migranal Nasal Spray), ergonovine (Ergotrate), or methylergonovine (Methergine).

  
  

Using any of these medicines while you are taking efavirenz can cause serious medical problems or death.

To make sure you can safely take efavirenz, tell your doctor if you have any of these other conditions:

• liver disease (including hepatitis B or C);


• 
  

  high cholesterol or triglycerides; or

  
  


• 
  

  if you have ever taken delavirdine (Rescriptor) or nevirapine (Viramune) and they were not effective in treating your condition.

  
  

FDA pregnancy category D. Do not use efavirenz if you are pregnant. It could harm the unborn baby. Use two forms of birth control, including a barrier form (such as a condom or diaphragm with spermicide gel) while you are taking efavirenz, and for at least 12 weeks after your treatment ends. Tell your doctor if you become pregnant during treatment. HIV can be passed to the baby if the mother is not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection while you are pregnant.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of efavirenz on the baby.

Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

How should I take efavirenz?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take efavirenz on an empty stomach at bedtime, unless your doctor tells you otherwise.

Efavirenz can cause side effects such as mood or behavior changes. These symptoms may improve the longer you take the medication. Taking efavirenz at bedtime may also lessen these effects. Contact your doctor if you have more serious symptoms such as severe depression or thoughts of hurting yourself.

Take efavirenz regularly to get the most benefit. Get your prescriptions refilled before you run out of medicine completely.

Do not take efavirenz as your only HIV medication. HIV/AIDS is usually treated with a combination of different drugs. Your disease may become resistant to efavirenz if you do not take it in combination with other HIV medicines your doctor has prescribed. Use all of your medications as directed by your doctor. Do not change your doses or medication schedule without advice from your doctor. Every person with HIV or AIDS should remain under the care of a doctor.

To be sure efavirenz is helping your condition and not causing harmful effects, your blood and liver function may need to be tested often. Visit your doctor regularly.

This medication can cause you to have a false positive drug-screening test. If you provide a urine sample for drug-screening, tell the laboratory staff that you are taking efavirenz.

Store at room temperature away from moisture and heat.

See also: Efavirenz dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose can cause confusion, lack of balance or coordination, severe mood or behavior changes, or thoughts of suicide.

What should I avoid while taking efavirenz?

Efavirenz may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Drinking alcohol can increase certain side effects of efavirenz. Taking this medication will not prevent you from passing HIV to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Efavirenz side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Efavirenz may cause serious psychiatric symptoms including confusion, severe depression, suicidal thoughts, aggression, extreme fear, hallucinations, or unusual behavior. Contact your doctor at once if you have any of these side effects, even if you have had them before.

Call your doctor at once if you have a serious side effect such as:

• 
  

  fever, sore throat, and headache with a severe blistering, peeling, and red skin rash;

  
  


• 
  

  nausea, stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

  
  


• 
  

  fever, chills, body aches, flu symptoms; or

  
  


• 
  

  any other signs of new infection.

  
  

Less serious side effects may include:

• 
  

  mild nausea, vomiting, or stomach pain, diarrhea or constipation;

  
  


• 
  

  cough;

  
  


• 
  

  blurred vision;

  
  


• 
  

  headache, tired feeling, dizziness, spinning sensation;

  
  


• 
  

  trouble concentrating, problems with balance or coordination;

  
  


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  muscle or joint pain;

  
  


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  sleep problems (insomnia), unusual dreams; or

  
  


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  changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist).

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Efavirenz Dosing Information

Usual Adult Dose for HIV Infection:

600 mg orally once a day

Usual Adult Dose for Nonoccupational Exposure:

(Not approved by FDA)

Centers for Disease Control and Prevention (CDC) recommendations: 600 mg orally once a day, in combination with (lamivudine or emtricitabine) plus (zidovudine or tenofovir)

Duration: 28 days

Prophylaxis should be initiated as soon as possible, within 72 hours of exposure.

Usual Adult Dose for Occupational Exposure:

(Not approved by FDA)

CDC recommendations:
Alternate expanded regimen for HIV postexposure prophylaxis: 600 mg orally once a day, in combination with (lamivudine plus zidovudine) or (emtricitabine plus zidovudine) or (lamivudine plus tenofovir) or (emtricitabine plus tenofovir)

Duration: Generally 28 days; however, the exact duration of therapy may differ based on the institution's protocol.

Prophylaxis should be initiated immediately, preferably within hours after exposure.

Usual Pediatric Dose for HIV Infection:

3 years or older:
10 to less than 15 kg: 200 mg orally once a day
15 to less than 20 kg: 250 mg orally once a day
20 to less than 25 kg: 300 mg orally once a day
25 to less than 32.5 kg: 350 mg orally once a day
32.5 to less than 40 kg: 400 mg orally once a day
40 kg or more: 600 mg orally once a day

What other drugs will affect efavirenz?

Cold or allergy medicine, sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by efavirenz. Tell your doctor if you regularly use any of these medicines.

There are many other medicines that can interact with efavirenz, or make it less effective. Before taking efavirenz, tell your doctor if you are using any of the following drugs:

• 
  

  bupropion (Aplenzin, Budeprion, Wellbutrin, Zyban);

  
  


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  cyclosporine (Gengraf, Neoral, Sandimmune);

  
  


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  itraconazole (Sporanox), posaconazole (Noxafil);

  
  


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  maraviroc (Selzentry);

  
  


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  sirolimus (Rapamune), tacrolimus (Prograf);

  
  


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  St. John's wort;

  
  


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  voriconazole (Vfend);

  
  


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  a blood thinner such as warfarin (Coumadin, Jantoven);

  
  


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  a cholesterol medication such as Lipitor or Zocor;

  
  


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  an antibiotic such as clarithromycin (Biaxin), rifabutin (Mycobutin), or rifampin (Rifadin, Rifater, Rifamate, Rimactane);

  
  


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  heart or blood pressure medications such as amlodipine (Norvasc), diltiazem (Tiazac, Cartia, Cardizem), felodipine (Plendil), nicardipine (Cardene), nifedipine (Procardia, Adalat), or verapamil (Calan, Covera, Isoptin, Verelan);

  
  


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  other HIV medicines such as atazanavir (Reyataz), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nevirapine (Viramune), ritonavir (Norvir), or saquinavir (Invirase); or

  
  


• 
  

  seizure medications such as phenytoin (Dilantin) or carbamazepine (Tegretol).

  
  

This list is not complete and there are many other drugs that can interact with efavirenz. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

More efavirenz resources

• Efavirenz Side Effects (in more detail)
• Efavirenz Dosage
• Efavirenz Use in Pregnancy & Breastfeeding
• Efavirenz Drug Interactions
• Efavirenz Support Group
• 2 Reviews for Efavirenz - Add your own review/rating

• efavirenz Advanced Consumer (Micromedex) - Includes Dosage Information


• Efavirenz Professional Patient Advice (Wolters Kluwer)


• Efavirenz MedFacts Consumer Leaflet (Wolters Kluwer)


• Efavirenz Monograph (AHFS DI)


• Sustiva Prescribing Information (FDA)


• Sustiva Consumer Overview

Compare efavirenz with other medications

• HIV Infection
• Nonoccupational Exposure
• Occupational Exposure

Where can I get more information?

• Your pharmacist can provide more information about efavirenz.

See also: efavirenz side effects (in more detail)