Novel Drug Approvals for 2015

1.Name       -  REPATHA

2. Active Ingredient-     Evolocumab

3. Indication-      To treat certain patients with high cholesterol

Date of Approval     August 2015

 HIGHLIGHTS OF PRESCRIBING INFORMATION -

These highlights do not include all the information needed to use                               REPATHA™ safely and effectively.

See full prescribing information for REPATHA. REPATHA (evolocumab) injection, for subcutaneous use

Initial U.S. Approval: 2015-

INDICATIONS AND USAGE-

­ REPATHA is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody indicated as an adjunct to diet and:

• Maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).

 • Other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. 

Limitations of Use

• The effect of REPATHA on cardiovascular morbidity and mortality has not been determined.

ADVERSE REACTIONS-

­ Common adverse reactions in clinical trials (>5% of patients treated with REPATHA and occurring more frequently than placebo): nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions.

CONTRAINDICATIONS-

­ Patients with a history of a serious hypersensitivity reaction to REPATHA.

WARNINGS AND PRECAUTIONS-

­ Allergic Reactions: Rash and urticaria have occurred. If signs or symptoms of serious allergic reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve.

DOSAGE AND ADMINISTRATION--

­ • Administer by subcutaneous injection

 • Primary hyperlipidemia with established clinical atherosclerotic CVD or HeFH: 140 mg every 2 weeks or 420 mg once monthly in abdomen, thigh, or upper arm. (2.1) • HoFH: 420 mg once monthly.

 • To administer 420 mg, give 3 REPATHA injections consecutively within 30 minutes.

 • See Dosage and Administration for important administration instructions. 

DOSAGE FORMS AND STRENGTHS-

­ • Injection: 140 mg/mL in a single-use prefilled syringe

 • Injection: 140 mg/mL in a single-use prefilled SureClick® autoinjector 

PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the FDA-approved patient labeling [Patient Information and Instructions for Use (IFU)] before the patient starts using REPATHA, and each time the patient gets a refill as there may be new information they need to know.

Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the pre-filled autoinjector or pre-filled syringe correctly (see Instructions for Use leaflet).

Inform patients that it may take up to 15 seconds to inject REPATHA.

Advise latex-sensitive patients that the following components contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex: the needle cover of the glass prefilled syringe and the autoinjector.

For more information about REPATHA, go to www.REPATHA.com or call 1-844-REPATHA (1-844­ 737-2842). REPATHA™ (evolocumab)

Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 U.S. License Number 1080 Patent: http://pat.amgen.com/repatha/ © 2015 Amgen Inc. All rights reserved

CLINICAL PHARMACOLOGY

1. Mechanism of Action Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface.

By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.

2. Pharmacodynamics- Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours. Unbound PCSK9 concentrations returned toward baseline when evolocumab concentrations decreased below the limit of quantitation.

3. Pharmacokinetics- Evolocumab exhibits non-linear kinetics as a result of binding to PCSK9. Administration of the 140 mg dose in healthy volunteers resulted in a Cmax mean (standard deviation [SD]) of 18.6 (7.3) µg/mL and AUClast mean (SD) of 188 (98.6) day•µg/mL.

Absorption-                                                                                                              Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days, and estimated absolute bioavailability was 72%.

Distribution-                                                                                                           Following a single 420 mg intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L.

Metabolism and Elimination-                                                                                       Two elimination phases were observed for REPATHA. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of REPATHA is largely through a non-saturable proteolytic pathway. REPATHA was estimated to have an effective half-life of 11 to 17 days.

Specific Populations-                                                                                                     The pharmacokinetics of evolocumab were not affected by age, gender, race, or creatinine clearance, across all approved populations

The exposure of evolocumab decreased with increasing body weight. These differences are not clinically meaningful.

Renal Impairment-                                                                                                           Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of evolocumab.

Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2 ) have not been studied.

Hepatic Impairment-                                                                                               Following a single 140 mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 20-30% lower mean Cmax and 40-50% lower mean AUC were observed as compared to healthy patients; however, no dose adjustment is necessary in these patients.

Pregnancy-                                                                                                                     The effect of pregnancy on evolocumab pharmacokinetics has not been studied

Drug Interaction Studies-                                                                                                    An approximately 20% decrease in the Cmax and AUC of evolocumab was observed in patients coadministered with a high-intensity statin regimen. This difference is not clinically meaningful and does not impact dosing recommendations. 

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary -                                                                                        There are no data available on use of REPATHA in pregnant women to inform a drug-associated risk.

FDA’s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester.

Consider the benefits and risks of REPATHA and possible risks to the fetus before prescribing REPATHA to pregnant women.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

2. Lactation Risk Summary-                                                                                      There is no information regarding the presence of evolocumab in human milk, the effects on the breastfed infant, or the effects on milk production.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for REPATHA and any potential adverse effects on the breastfed infant from REPATHA or from the underlying maternal condition.

Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.

3. Pediatric Use -                                                                                                           The safety and effectiveness of REPATHA in combination with diet and other LDL-C-lowering therapies in adolescents with HoFH who require additional lowering of LDL-C were established based on data from a 12-week, placebo-controlled trial that included 10 adolescents ages 13 to 17 years old with HoFH [see Clinical Studies (14.3)].

The effect of REPATHA on LDL-C was generally similar to that observed among adult patients with HoFH. Including experience from open-label, uncontrolled studies, a total of 14 adolescents with HoFH have been treated with REPATHA, with a median exposure duration of 9 months.

The safety profile of REPATHA in these adolescents was similar to that described for adult patients with HoFH.

4.Geriatric Use-                                                                                                                 In controlled studies, 1420 patients treated with REPATHA were = 65 years old and 171 were = 75 years old.

No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out

5. Renal Impairment -                                                                                                        No dose adjustment is needed in patients with mild to moderate renal impairment. No data are available in patients with severe renal impairment

6. Hepatic Impairment-                                                                                                       No dose adjustment is needed in patients with mild to moderate hepatic impairment (Child-Pugh A or B). No data are available in patients with severe hepatic impairment