Indication:
REPATHA (evolocumab) injection, for subcutaneous use
Initial U.S. Approval: 2015
NEW MOLECULAR ENTITY AND NEW THERAPEUTIC BIOLOGICAL
PRODUCTS APPROVED FOR 2015
Certain drugs are classified as New molecular Emtities- NME- for FDA review
Many of these products contain active moieties that have not been approved
by FDA previously, either as a single ingredient or as part of a combination
products; these products frequently provide important new therapies for the
patients.
Some drugs are characterized as NMEs for administrative purposes ,but
nonetheless contain certain active moieties in products that have been
previously approved by FDA. For example, CDER classifies biological
products submitted in an application under section 351(a) of the Public
Service Act as NME for purposes of FDA review, regardless of whether
the agency previously approved a related active moiety in a different
product.
FDAs classification of a drug as an -NME- for review purposes is distinct
from FDAs determination of whether a drug is a - New Chemical Entity or - NCE-
within the meaning of the Federal Food,Drug, and Cosmetic Act
No.22
Drug Name - Evolucumab
Active Ingredient- Repatha
Date of approval - 8/27/2015
FDA-approved use - To treat certain patients with high cholesterol
Approved by US FDA on 8/27/2015- (Ref- FDA approved List- 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 Reaction:
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 reaction
Contra-Indications:
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.
Dosages/ Overdosage Etc:
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.
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.
HoFH: 420 mg once monthly.
To administer 420 mg, give 3 REPATHA injections consecutively within
30 minutes.
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 Information:
PATIENT COUNSELING INFORMATION
1.Advise the patient and/or caregiver to read the FDA-approved patient labeling
before the patient starts using REPATHA, and each time the patient gets a refill
as there may be new information they need to know.
2. 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).
3. Inform patients that it may take up to 15 seconds to inject REPATHA.
4. 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.
Pharmacology/ Pharmacokinetics:
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. 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) ìg/mL and AUClast mean (SD) of 188 (98.6)
day•ìg/mL. Administration of the 420 mg dose in healthy volunteers resulted in
a Cmax mean (SD) of 59.0 (17.2) ìg/mL and AUClast mean (SD) of 924 (346) day•ìg/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%.
Pregnancy and lactation:
1. Pregnancy
Risk Summary
There are no data available on use of REPATHA in pregnant women
to inform a drug-associated risk.
In animal reproduction studies, there were no effects on pregnancy or neonatal/infant
development when monkeys were subcutaneously administered evolocumab from
organogenesis through parturition at dose exposures up to 12 times the exposure
at the maximum recommended human dose of 420 mg every month.
FDAs 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.
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 motherfs
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.
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.
