Repatha

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to evolocumab injection.

Ask your pharmacist any questions you have about evolocumab injection.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

The following adverse reactions are also discussed in other sections of the label:

• Allergic Reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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

REPATHA is not indicated for use in patients without familial hypercholesterolemia or atherosclerotic CVD [see INDICATIONS AND USAGE].

The data described below reflect exposure to REPATHA in 8 placebo-controlled trials that included 2651 patients treated with REPATHA, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks). The mean age of the population was 57 years, 49% of the population were women, 85% White, 6% Black, 8% Asians, and 2% other races.

In a 52-week, double-blind, randomized, placebo-controlled trial (Study 2), 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies]. The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% women, 80% White, 8% Black, 6% Asian, and 6% Hispanic. Adverse reactions reported in at least 3% of REPATHA-treated patients, and more frequently than in placebo-treated patients in Study 2, are shown in Table 1. Adverse reactions led to discontinuation of treatment in 2.2% of REPATHA-treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to REPATHA treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for REPATHA and placebo, respectively).

Table 1: Adverse Reactions Occurring in Greater than or Equal to 3% of REPATHA-treated Patients and More Frequently than with Placebo in Study 2

In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of REPATHA subcutaneously every 2 weeks and 1059 patients received 420 mg of REPATHA subcutaneously monthly. The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% women, 85% White, 5% Black, 9% Asian, and 5% Hispanic. Adverse reactions reported in at least 1% of REPATHA-treated patients, and more frequently than in placebotreated patients, are shown in Table 2.

Table 2: Advers e Reactions Occurring in Greater than 1% of REPATHA-treated Patients and More Frequently than with Placebo in Pooled 12-Week Studies

The adverse reactions described below are from a pool of the 52-week trial (Study 2) and seven 12- week trials. The mean and median exposure durations of REPATHA in this pool of eight trials were 20 weeks and 12 weeks, respectively.

Injection site reactions occurred in 3.2% and 3.0% of REPATHA-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in REPATHAtreated patients and placebo-treated patients were 0.1% and 0%, respectively.

Allergic reactions occurred in 5.1% and 4.7% of REPATHA-treated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% versus 0.5% for REPATHA and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%).

In placebo-controlled trials, neurocognitive events were reported in less than or equal to 0.2% in REPATHA-treated and placebo-treated patients.

In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1988 patients treated with REPATHA had at least one LDL-C value < 25 mg/dL. Changes to background lipid-altering therapy were not made in response to low LDL-C values, and REPATHA dosing was not modified or interrupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by REPATHA are unknown.

Musculoskeletal adverse reactions were reported in 14.3% of REPATHA-treated patients and 12.8% of placebo-treated patients. The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for REPATHA and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).

In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (Study 4), 33 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies]. The mean age was 31 years (range: 13 to 57 years), 49% were women, 90% White, 4% Asian, and 6% other. The adverse reactions that occurred in at least two (6.1%) REPATHA-treated patients, and more frequently than in placebo-treated patients, included:

• Upper respiratory tract infection (9.1% versus 6.3%)
• Influenza (9.1% versus 0%)
• Gastroenteritis (6.1% versus 0%)
• Nasopharyngitis (6.1% versus 0%)

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of REPATHA has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.

In a pool of placebo- and active-controlled clinical trials, 0.1% of patients treated with at least one dose of REPATHA tested positive for binding antibody development. Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies.

There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of REPATHA, but the long-term consequences of continuing REPATHA treatment in the presence of anti-drug binding antibodies are unknown.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to REPATHA with the incidence of antibodies to other products may be misleading.

No information provided.

Repatha is the brand name of the injectable drug evolocumab, which helps lower cholesterol levels.

This prescription medicine is used along with diet and other cholesterol medicines (statins) in people who have:

• Homozygous or heterozygous familial hypercholesterolemia (forms of inherited high cholesterol)
• Certain types of cardiovascular disease

Repatha is a human monoclonal antibody. It works by reducing the production of low-density lipoprotein (LDL, or "bad" cholesterol) in the body.

According to its manufacturer, in one trial, Repatha lowered LDL cholesterol by an average of 71 percent when it was added to a high-dose statin treatment.

The U.S. Food and Drug Administration (FDA) approved Repatha in 2015. It's marketed by Amgen.

Repatha Warnings

Before taking Repatha, tell your doctor if you have, or have ever had:

• Kidney disease
• Liver disease
• A latex allergy, or allergies to medications

This drug isn't approved to treat anyone under age 13.

Your doctor may recommend a specific diet plan for you to follow while you're taking Repatha. Be sure to follow these instructions carefully.

Repatha helps control high cholesterol, but it won't cure your condition.

Continue to use this medicine even if you feel well. Don't stop taking Repatha without first talking with your doctor.

You may need to have your blood tested often while using Repatha. Keep all appointments with your doctor and laboratory.

Pregnancy and Repatha

It's not known whether Repatha could harm an unborn baby.

Tell your doctor if you're pregnant, or might become pregnant, before starting on this drug.

It's also not known whether Repatha passes into breast milk or could hurt a breastfeeding baby. Talk to your doctor before taking this medicine if you're breastfeeding.

Repatha comes as a prefilled syringe or auto-injector to inject under the skin.

The medicine is usually injected once every two weeks (dose of 140 milligrams) or once every month (dose of 420 milligrams), depending on your condition.

You can inject this drug under the skin of your thigh or stomach area — but not the two-inch area surrounding your belly button.

If someone else is injecting Repatha for you, that person can inject it into your upper arm.

Try to use a different spot on your body each time you receive an injection.

Follow your doctor's instructions carefully when administering a dose of Repatha. Use the medicine exactly as it's prescribed.

You may be instructed to give more than one injection at a time, depending on your dose. Be sure to finish all injections within 30 minutes.

Don't mix Repatha with any other medicine before injecting it.

Each syringe or auto-injector contains enough medicine for just one dose. Discard the device after one use.

Don't inject Repatha in an area that's bruised, red, tender, hard, or scarred.

Look at the solution before injecting it. Make sure it's free of floating particles and hasn't changed color.

Don't shake the prefilled syringe or auto-injector before using it.

Repatha is meant to be stored in the refrigerator, but you can keep it at room temperature in its original box for up to 30 days.

Talk to your doctor if you have any questions about how to administer or store Repatha.

Repatha Overdose

If you suspect an overdose of Repatha, contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Repatha

If you miss a dose of Repatha, inject it as soon as you remember.

But if your next scheduled dose is due in seven days or less, skip the missed dose and continue with your regular injection schedule.

Don't inject two doses of Repatha to make up for a missed dose.

Call your doctor if you have any questions about what to do if you miss a dose.

Before you start using Repatha, tell your healthcare provider about all your medical conditions, including allergies, and if you:

• are allergic to rubber or latex. The needle covers on the single-use prefilled syringes and within the needle caps on the single-use prefilled SureClick autoinjectors contain dry natural rubber.
• are pregnant or plan to become pregnant. It is not known if Repatha will harm your unborn baby. Tell your healthcare provider if you become pregnant while taking Repatha.
• are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take Repatha or breastfeed. You should not do both without talking to your healthcare provider first.

Tell your healthcare provider or pharmacist about any prescription and over-the-counter medicines you are taking or plan to take, including natural or herbal remedies.

If you take too much Repatha, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Antilipemic agent; fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 (PCSK9).1 3 6 7 10 11 12 19 34

Storage

Parenteral

2–8°C.1 Store in original carton to protect from light.1 Do not shake, freeze, or expose to temperatures >25°C or direct sunlight.1 15 16

May store prefilled syringes and auto-injectors at room temperature (i.e., up to 25°C) in original carton, but must use within 30 days if stored under these conditions.1 Discard drug if not used within 30 days.1

This medicine is given as a shot under your skin, usually in the abdomen or stomach, thighs, or upper arms.

If you are using this medicine at home, your doctor will teach you how to prepare and inject the medicine. Be sure that you understand exactly how the medicine is prepared and injected.

This medicine comes in 3 forms: single-dose prefilled pen (autoinjector), single-dose prefilled syringe, and single-use Pushtronex™ system (on-body infusor with prefilled cartridge). Your doctor will prescribe the type and dose that is right for you.

You will be shown the body areas where this shot can be given. Use a different body area each time you give yourself a shot. Keep track of where you give each shot to make sure you rotate body areas. This will help prevent skin problems from the injections.

Do not inject on skin areas that have cuts, scrapes, infection, scars, or stretch marks.

If you are receiving the 420 mg dose of Repatha®, it can be given by: over 9 minutes by using the single-use Pushtronex™ system, or by 3 injections consecutively within 30 minutes using the single use prefilled syringe or autoinjector.

The autoinjector pen or prefilled syringe should be removed from the refrigerator and allowed to reach room temperature for at least 30 minutes prior to injection, or for at least 45 minutes for single-use Pushtronex™ system. Do not shake the medicine.

Use each autoinjector pen or syringe only one time. Do not save an open pen or syringe. If the medicine in the pen or syringe has changed color, or if you see particles in it, do not use it.

In addition to this medicine, your doctor may change your diet to one that is low in fat, sugar, and cholesterol. Carefully follow your doctor's order about any special diet.

This medicine should come with patient instructions. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For injection dosage form:
  • For primary hyperlipidemia:
    • Adults—140 milligrams (mg) injected under your skin every 2 weeks, or 420 mg injected under your skin once a month.
    • Children—Use and dose must be determined by your doctor.
  • For homozygous familial hypercholesterolemia:
    • Adults and children 13 years of age and older—420 milligrams (mg) injected under your skin once a month.
    • Children younger than 13 years of age—Use and dose must be determined by your doctor.

Missed Dose

This medicine needs to be given on a fixed schedule. If you miss a dose or forget to use your medicine, call your doctor or pharmacist for instructions.

If you missed a dose, use this medicine within 7 days from the missed dose. Then, resume your original schedule.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store in the refrigerator. Do not freeze.

You may also keep the medicine in the original carton at room temperature for 30 days. Throw away any unused medicine within 30 days.

Throw away used needles in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.

      Allergic Reactions

Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients treated with Repatha, including some that led to discontinuation of therapy. 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. 

      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. 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. 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.

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.

      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.

      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)]. In this trial, 7 adolescents received Repatha 420 mg subcutaneously once monthly and 3 adolescents received placebo. 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.

The safety and effectiveness of Repatha have not been established in pediatric patients with HoFH who are younger than 13 years old.

The safety and effectiveness of Repatha have not been established in pediatric patients with primary hyperlipidemia or HeFH.

      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.

      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 [see Clinical Pharmacology (12.3)].

      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 [see Clinical Pharmacology (12.3)].