REPATHA

Evolocumab is a monoclonal antibody designed for the treatment of hyperlipidemia by Amgen.

It is a subcutaneous injection approved by the FDA for individuals on maximum statin therapy who still require additional LDL-cholesterol lowering.

It is approved for both homozygous and heterozygous familial cholesterolemia as an adjunct to other first-line therapies.

Evolocumab is a human

IgG2 monoclonal antibody that targets the proprotein convertase subtilisin/kexin type 9 (PCSK9).

PCSK9 is a protein that targets LDL receptors for degradation, therefore reducing the liver's ability to remove LDL-cholesterol (LDL-C), or "bad" cholesterol, from the blood.

Evolocumab is designed to bind to

PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface, resulting in more LDL receptors on the surface of the liver to remove LDL-C from the blood.

Evolocumab is the second

PCSK9 inhibitor on the market, first being alirocumab.

Evolocumab is indicated in adult patients at risk of major adverse cardiovascular events (MACE) to reduce the risk of myocardial infarction, stroke, cardiovascular death, unstable angina requiring hospitalization and coronary revascularization.

It is also indicated as an adjunct to diet, alone or in combination with other hypolipidemic treatments, in adults with primary hyperlipidemia (and in pediatric patients ≥10 years old with heterozygous familial hypercholesterolemia) to reduce LDL-C.

In addition, it is indicated adjunctly to other hypolipidemic treatments in patients ≥10 years old with homozygous familiar hypercholesterolemia to reduce LDL-C.

Mechanism of Action Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin type 9 (PCSK9).

PCSK9 binds to the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver.

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. 12.2 Pharmacodynamics Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours.

PCSK9 concentrations returned toward baseline when evolocumab concentrations decreased below the limit of quantitation.

LDL-C reduction occurred by 2 weeks after a single-dose of 140 mg of evolocumab and by 3 weeks after a single-dose of 420 mg of evolocumab. 12.3 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 C max mean of 18.6 µg/mL and AUC last mean of 188 day∙µg/mL.

Administration of the 420 mg dose in healthy volunteers resulted in a C max mean of 59.0 µg/mL and AUC last mean of 924 day∙µg/mL.

Following a single 420 mg intravenous dose, the mean systemic clearance was estimated to be 12 mL/hr. An approximate 2.

• to 3-fold accumulation was observed in trough serum concentrations (C min 7.21) following 140 mg doses administered subcutaneously every 2 weeks or following 420 mg doses administered subcutaneously monthly (C min 11.2), and serum trough concentrations approached steady-state by 12 weeks of dosing.

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

Following a single 420 mg intravenous dose, the mean steady-state volume of distribution was estimated to be 3.3 L. 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 to 17 days.

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.

Pediatric Patients The pharmacokinetics of

REPATHA were evaluated in 103 pediatric patients aged to 17 years with HeFH (Study 6) .

Following subcutaneous administration of 420 mg REPATHA once monthly, mean trough serum concentrations were 22.4 mcg/mL and 25.8 mcg/mL over the Week and Week 24 time points, respectively.

The pharmacokinetics of

REPATHA were evaluated in 12 pediatric patients aged to 17 years with HoFH (Study 9) .

Following subcutaneous administration of 420 mg REPATHA once monthly, mean serum trough concentrations were 20.3 mcg/mL and 17.6 mcg/mL at Week and Week 80, respectively.

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

In a clinical trial of 18 patients with either normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m 2, n = 6), severe renal impairment (eGFR < 30 mL/min/1.73 m 2, n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6), exposure to evolocumab after a single 140 mg subcutaneous dose was decreased in patients with severe renal impairment or ESRD receiving hemodialysis.

Reductions in

PCSK9 levels in patients with severe renal impairment or ESRD receiving hemodialysis was similar to those with normal renal function.

Following a single 140 mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 20-30% lower mean C max and 40-50% lower mean AUC were observed as compared to healthy patients.

An approximately 20% decrease in the C max and AUC of evolocumab was observed in adult patients co-administered with a high-intensity statin regimen.

This difference is not clinically meaningful.

Total bioavailability from subcutaneous injection was 82% in cynomolgus monkeys.

Evolocumab showed non-linear, dose-dependent clearance in healthy volunteers; clearance decreased with increasing dose.

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is contraindicated in patients with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients in REPATHA.

Serious hypersensitivity reactions including angioedema have occurred in patients treated with REPATHA.

Patients with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients in REPATHA.

In adults at increased risk for CV events or with hypercholesterolemia: The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously.

If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.

In adults and pediatric patients aged 10 years and older with HeFH: The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously.

In adults and pediatric patients aged 10 years and older with HoFH: The initial recommended dosage of REPATHA is 420 mg once monthly administered subcutaneously.

The dosage can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks.

Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule.

REPATHA after the apheresis session is complete.

LDL-C when clinically appropriate.

The LDL-lowering effect of

REPATHA may be measured as early as 4 weeks after initiation.

REPATHA is available as prefilled single-dose

SureClick ® autoinjectors and prefilled single-dose syringes that either contain dry natural rubber (a derivative of latex) in the needle cover or are not made with natural rubber latex.

Consider prescribing a presentation of

REPATHA that does not contain dry natural rubber for individuals that are sensitive to latex.

REPATHA subcutaneously into areas of the abdomen, thigh, or upper arm.

Rotate injection sites for each administration.

Information for important administration instructions. 2.1 Recommended Dosage In adults at increased risk for CV events or with hypercholesterolemia: The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously.

When monitoring LDL-C for patients receiving

REPATHA 420 mg once monthly, note that LDL-C can vary during the dosing interval in some patients; recommend measuring LDL-C just prior to the next scheduled dose. 2.2 Missed Doses If a dose is missed: Within 7 days from the missed dose, instruct the patient to administer REPATHA and resume the patient's original schedule.

More than 7 days after the missed dose: For an every 2-week dose, instruct the patient to wait until the next dose on the original schedule.

For a once-monthly dose, instruct the patient to administer the dose and start a new schedule based on this date. 2.3 Important Administration Instructions REPATHA is available as prefilled single-dose SureClick ® autoinjectors and prefilled single-dose syringes that either contain dry natural rubber (a derivative of latex) in the needle cover or are not made with natural rubber latex.

Train patients and/or caregivers on how to prepare and administer REPATHA, according to the Instructions for Use and instruct them to read and follow the Instructions for Use each time they use REPATHA.

Prior to use, allow REPATHA to warm to room temperature for at least 30 minutes for the prefilled single-dose SureClick ® autoinjector or prefilled single-dose syringe and for at least 45 minutes for the on-body infusor with prefilled cartridge if REPATHA has been refrigerated.

Visually inspect

REPATHA prior to administration.

REPATHA is a clear to opalescent, colorless to pale yellow solution.

Do not use if the solution is cloudy, discolored, or contains particles.

REPATHA subcutaneously into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated.

Avoid injecting into areas with scars or stretch marks.

The 420 mg dose of REPATHA can be administered: over 5 minutes by using the single-dose on-body infusor with prefilled cartridge, or by giving 3 injections consecutively within 30 minutes using the prefilled single-dose SureClick ® autoinjector or prefilled single-dose syringe.

is a clear to opalescent, colorless to pale yellow solution supplied as follows: Not Made with Natural Rubber Latex – 140 mg/mL prefilled single-dose SureClick ® autoinjector 2 pack NDC 72511-393-02 140 mg/mL prefilled single-dose SureClick ® autoinjector 1 pack NDC 72511-393-01 140 mg/mL prefilled single-dose Syringe 1 pack NDC 72511-501-01 420 mg/3.5 mL single-dose Pushtronex ® system (on-body infusor with prefilled cartridge) 1 pack NDC 72511-770-01 Contains Dry Natural Rubber – 140 mg/mL prefilled single-dose SureClick ® autoinjector The needle cover of the glass prefilled single-dose SureClick ® autoinjector and prefilled single-dose syringe contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex. 2 pack NDC 72511-760-02 140 mg/mL prefilled single-dose Syringe 1 pack NDC 72511-750-01 Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Do not shake.

For convenience, REPATHA may be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton for 30 days.

If not used within the 30 days, discard REPATHA.

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Do not shake.

For convenience, REPATHA may be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton for 30 days.

If not used within the 30 days, discard REPATHA.

Available data from clinical trials and postmarketing reports on REPATHA use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

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.

In a similar study with another drug in the PCSK9 inhibitor antibody class, humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses.

The exposures where immune suppression occurred in infant monkeys were greater than those expected clinically.

No assessment for immune suppression was conducted with evolocumab in infant monkeys.

Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier.

Monoclonal antibodies are transported across the placenta in increasing amounts especially near term; therefore, evolocumab has the potential to be transmitted from the mother to the developing fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown.

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.

There is a pregnancy safety study for REPATHA.

If REPATHA is administered during pregnancy, healthcare providers should report REPATHA exposure by contacting Amgen at 1-800-77-AMGEN or Data Animal Data In cynomolgus monkeys, no effects on embryo-fetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed during organogenesis to parturition at 50 mg/kg once every 2 weeks by the subcutaneous route at exposures 30.

• and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.

No test of humoral immunity in infant monkeys was conducted with evolocumab.

The safety and effectiveness of

REPATHA in combination with diet and other LDL-C-lowering therapies for the treatment of HoFH have been established in pediatric patients aged 10 years and older.

Use of

REPATHA for this indication is supported by evidence from an adequate and well-controlled trial in adults and pediatric patients aged 13 years and older with HoFH (including 7 pediatric patients treated with REPATHA) and from open-label studies which included an additional 19 pediatric patients aged 11 years and older with HoFH not previously treated with REPATHA.

The safety and effectiveness of REPATHA as an adjunct to diet and other LDL-C-lowering therapies for the treatment of HeFH have been established in pediatric patients aged 10 years and older.

REPATHA for this indication is based on data from a 24-week, randomized, placebo-controlled, double-blind trial in pediatric patients with HeFH.

In the trial, 104 patients received REPATHA 420 mg subcutaneously once monthly and 53 patients received placebo; 39 patients (25%) were to 11 years of age.

REPATHA have not been established in pediatric patients with HeFH or HoFH who are younger than 10 years old or in pediatric patients with other types of hypercholesterolemia.

In controlled trials, 7656 (41%) patients treated with REPATHA were ≥ 65 years old and 1500 (8%) 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.