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  • CLASSES

    Antilipemic Monoclonal Antibodies Targeting PCSK9

    DEA CLASS

    Rx

    DESCRIPTION

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor
    Used for add-on treatment to reduce LDL-C in primary hyperlipidemia or heterozygous or homozygous familial hypercholesterolemia
    Also used for risk reduction in adults with established cardiovascular disease

    COMMON BRAND NAMES

    Repatha, Repatha SureClick

    HOW SUPPLIED

    Repatha Subcutaneous Inj Sol: 1mL, 3.5mL, 140mg, 420mg

    DOSAGE & INDICATIONS

    For use adjunct to diet and/or other LDL-C lowering therapies in patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), who require further reduction of LDL-C.
    For use adjunct to diet and/or other LDL-C lowering therapies in adult patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH).
    Subcutaneous dosage
    Adults

    140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the previous regimen.

    For use adjunct to diet and other LDL-C lowering therapies in pediatric patients with heterozygous familial hypercholesterolemia (HeFH).
    Subcutaneous dosage
    Children and Adolescents 10 to 17 years

    140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the previous regimen.

    For use adjunct to other LDL-C lowering therapies in patients with homozygous familial hypercholesterolemia (HoFH) who require further reduction of LDL-C.
    Subcutaneous dosage
    Adults

    420 mg subcutaneously once monthly. Increase to 420 mg subcutaneously every 2 weeks if a clinically meaningful response is not attained in 12 weeks. Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule; administer after the apheresis session is complete.

    Children and Adolescents 10 to 17 years

    420 mg subcutaneously once monthly. Increase to 420 mg subcutaneously every 2 weeks if a clinically meaningful response is not attained in 12 weeks. Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule; administer after the apheresis session is complete.

    For myocardial infarction prophylaxis, stroke prophylaxis, and to reduce the risk of coronary revascularization in patients with established cardiovascular disease.
    Subcutaneous dosage
    Adults

    140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the previous regimen.

    MAXIMUM DOSAGE

    Adults

    420 mg/dose subcutaneously once monthly for most indications or every 2 weeks for homozygous familial hypercholesterolemia (HoFH).

    Geriatric

    420 mg/dose subcutaneously once monthly for most indications or every 2 weeks for homozygous familial hypercholesterolemia (HoFH).

    Adolescents

    420 mg/dose subcutaneously once monthly for heterozygous familial hypercholesterolemia (HeFH) or every 2 weeks for homozygous familial hypercholesterolemia (HoFH).

    Children

    10 to 12 years: 420 mg/dose subcutaneously once monthly for heterozygous familial hypercholesterolemia (HeFH) or every 2 weeks for homozygous familial hypercholesterolemia (HoFH).
    1 to 9 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is needed for mild to moderate hepatic impairment (Child-Pugh A or B). Specific guidelines for dosage adjustments in severe hepatic impairment are not available.

    Renal Impairment

    No dosage adjustment is needed for mild to moderate renal impairment. Specific guidelines for dosage adjustments in severe renal impairment are not available.

    ADMINISTRATION

    Injectable Administration

    Visually inspect for particulate matter and discoloration prior to administration. Solution is clear to opalescent, colorless to pale yellow. Do not use if the solution is cloudy or discolored or contains particles.
    If a dose is missed, and it is within 7 days from the missed dose, administer evolocumab and resume the original dosing schedule. If it has been more than 7 days from the missed dose, for every 2 week dosing, wait until the next dose on the original schedule and, for once monthly dosing, administer the dose and start a new schedule based on this date.

    Subcutaneous Administration

    If stored in the refrigerator, allow it to warm to room temperature for at least 30 minutes for the single-use prefilled syringe or autoinjector or 45 minutes for the single-use on-body infusor with prefilled cartridge before use. Do not warm by using a heat source or leave in direct sunlight. If the solution has not reached room temperature, it may cause discomfort and may take longer to inject the full dose.
    Do not shake.
    Administer into areas of the abdomen (except for a 2-inch area around the umbilicus), thigh, or upper arm that are not tender, bruised, red, or indurated.
    Rotate the site with each injection.
    Do not administer with other injectable drugs at the same injection site.
    The 420 mg dose can be administered as 3 injections, consecutively within 30 minutes, utilizing the single-use prefilled syringe or autoinjector or as a single injection over 9 minutes using the single-use on-body infusor with the prefilled cartridge.
     
    Single-use prefilled syringe administration
    Carefully remove the syringe from the tray.
    Do not pick up or pull the prefilled syringe by the plunger rod or gray needle cap. Always hold the syringe by the barrel.
    Pull the gray needle cap straight off. It is normal to see a drop of solution at the end of the needle. Do not try to remove any air bubbles in the syringe.
    Pinch the skin injection site to create a firm surface approximately 2 inches wide. Hold the pinch, and insert the needle into the skin using a 45 to 90-degree angle.
    Using slow and constant pressure, push the plunger rod all the way down until the syringe is empty.
    When done, release the plunger, and gently lift the syringe off the skin.
    Storage: Store in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F) in the original carton to protect from light. Do not freeze. If needed, may keep at room temperature at 20 to 25 degrees C (68 to 77 degrees F) in the original carton for 30 days. If not used within 30 days, discard evolocumab.
     
    Single-use SureClick autoinjector administration
    Do not use it if it has been dropped on a hard surface, even if you cannot see a break in the autoinjector.
    Do not remove the orange cap until you are ready to inject. Do not leave the orange cap off for more than 5 minutes; this can dry out the medication.
    When ready for injection, pull the orange cap straight off. Do not twist, bend, or wiggle the orange cap. Do not put fingers into or on the yellow safety guard.
    Stretch (thigh) or pinch (stomach or upper arm) the cleansed injection site skin to create a firm surface approximately 2 inches wide. Hold the stretch or pinch, and place the yellow end of the autoinjector on the skin at 90 degrees.
    Firmly push the autoinjector down onto the skin until it stops moving. When ready to inject, press the gray button. A click should be heard. Keep pushing on the skin and then lift the thumb. The injection could take about 15 seconds. The window on the autoinjector will turn from clear to yellow when the injection is complete. A second click may be heard.
    Remove the autoinjector from the skin; the needle will be automatically covered.
    After removing the autoinjector from the skin, if the window has not turned yellow or if it looks like the medicine is still injecting, this means you have not received a full dose. Do not try to reuse the autoinjector. Call the health care provider immediately. For more information, call 1-844-REPATHA.
    Dispose of the used autoinjector in an appropriate sharps container.
    Storage: Store in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F) in the original carton to protect from light. Do not freeze. If needed, may keep at room temperature at 20 to 25 degrees C (68 to 77 degrees F) in the original carton for 30 days. If not used within 30 days, discard evolocumab.
     
    Single-use on-body infusor with prefilled cartridge (Pushtronex system) administration
    Pediatric patients 10 to 17 years of age should only use the on-body infusor and prefilled cartridge under adult supervision.
    Do not expose the on-body infuser to Magnetic Resonance (MR) Environment (e.g., MRI).
    Open the carton and peel away the white paper cover. Remove the plastic cover from the clear tray.
    Do not use if the white paper cover is missing or damaged or if the cartridge looks cracked, broken, or pieces are missing or not securely attached.
    Open the on-body infusor by swinging the cartridge door to the right and leave the door open. Do not close the cartridge door before the cartridge is loaded. If the cartridge door accidentally closes, press the left side of the door to release the door latch.
    Load the cleaned cartridge straight into the on-body infusor and firmly press the top until it is securely in place.
    Do not touch the start button until the on-body infusor is on the skin and ready for injection.
    Swing the door to the left, and squeeze firmly until it snaps shut. Make sure the cartridge fits securely in the on-body infusor before closing the door.
    Peel away both green pull tabs to show the adhesive. Do not pull the skin adhesive backing off of the on-body infusor. Do not touch the skin adhesive. Do not touch the needle cover area. Do not place on the body if the red status light flashes continuously.
    Choose the injection site. Use a firm and flat skin surface. Avoid injecting into areas with wrinkles, skin folds, scars, stretch marks, moles, and excessive hair. Adjust body posture to avoid skin folds and bulges.
    The on-body infusor is ready when the blue light flashes. If using the stomach, keep the skin stretched. Hold the loaded on-body infusor with the blue light visible and place it on the skin. The beeping may be heard. The loaded on-body infusor will lay flat on the body. Make sure all of the adhesive is attached to the skin. Run a finger around the adhesive edges to secure it. Ensure clothing does not get in the way of the infusor. The blue light should be visible at all times.
    Do not move the infusor once it is attached to the skin.
    Firmly press and release the start button. A flashing green light and a click signals the injection has started.
    An audible pumping sound may be heard, and a pinch may be felt.
    The injection takes about 5 minutes. The status light turns solid green and the device beeps when finished.
    When the injection is finished, grab the skin adhesive to carefully peel the on-body infusor from the skin. After removal, check the medicine window. The green light should be off. The infusor will beep when removed from the skin. A few drops of fluid on the skin after removal of the infusor are normal.
    Storage: Store in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F) in the original carton to protect from light. Do not freeze. If needed, may keep at room temperature at 20 to 25 degrees C (68 to 77 degrees F) in the original carton for 30 days. If not used within 30 days, discard evolocumab.

    STORAGE

    Repatha:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use
    Repatha SureClick :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Evolocumab is contraindicated in patients with a history of a serious evolocumab hypersensitivity reaction. Hypersensitivity reactions, including angioedema, rash, and urticaria, have been reported during treatment with evolocumab. Some hypersensitivity reactions resulted in discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue evolocumab, provide appropriate care, and monitor until signs and symptoms resolve.[60127]

    Latex hypersensitivity

    The needle cover of the glass prefilled syringe and the autoinjector contain dry natural rubber (a derivative of latex), which may cause an allergic reaction in individuals with latex hypersensitivity.

    Pregnancy

    Available data from clinical trials and postmarketing reports on the use of evolocumab in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No effects on pregnancy or neonatal or infant development were observed when monkeys were given evolocumab from organogenesis through parturition at dose exposures up to 12 times the maximum recommended human dose. Measurable evolocumab serum concentrations were observed in infant monkeys at birth at comparable concentrations in 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, there is a potential for evolocumab to be transmitted from mother to the developing fetus. Before administering evolocumab to a pregnant woman, consider the benefits and risks of treatment to the mother and the possible risks to the fetus. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to evolocumab; information about the registry can be obtained at mothertobaby.org-ongoinf-study/repatha or by calling 1-800-772-6436.

    Breast-feeding

    According to the manufacturer, there is no information on evolocumab presence in human milk, effects on milk production, or effects on the breastfed infant. Human IgG is present in human milk, but data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    Magnetic resonance imaging (MRI)

    The Pushtronex system, a single-use on-body infuser for evolocumab should not be exposed to a Magnetic Resonance environment, such as magnetic resonance imaging (MRI).

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / Incidence not known

    Moderate

    hyperglycemia / Delayed / 8.8-8.8
    hypertension / Early / 3.2-3.2
    erythema / Early / 0.4-0.4
    antibody formation / Delayed / 0.3-0.3

    Mild

    pharyngitis / Delayed / 4.0-12.0
    headache / Early / 4.0-11.0
    infection / Delayed / 1.3-9.3
    influenza / Delayed / 1.2-9.1
    back pain / Delayed / 2.3-6.2
    cough / Delayed / 1.2-4.5
    sinusitis / Delayed / 4.2-4.2
    myalgia / Early / 4.0-4.0
    dizziness / Early / 3.7-3.7
    musculoskeletal pain / Early / 3.3-3.3
    injection site reaction / Rapid / 3.2-3.2
    diarrhea / Early / 3.0-3.0
    nausea / Early / 1.8-1.8
    arthralgia / Delayed / 1.8-1.8
    fatigue / Early / 1.6-1.6
    rash / Early / 1.0-1.0
    urticaria / Rapid / 0.4-0.4

    DRUG INTERACTIONS

    There are no drug interactions associated with Evolocumab products.

    PREGNANCY AND LACTATION

    Pregnancy

    Available data from clinical trials and postmarketing reports on the use of evolocumab in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No effects on pregnancy or neonatal or infant development were observed when monkeys were given evolocumab from organogenesis through parturition at dose exposures up to 12 times the maximum recommended human dose. Measurable evolocumab serum concentrations were observed in infant monkeys at birth at comparable concentrations in 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, there is a potential for evolocumab to be transmitted from mother to the developing fetus. Before administering evolocumab to a pregnant woman, consider the benefits and risks of treatment to the mother and the possible risks to the fetus. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to evolocumab; information about the registry can be obtained at mothertobaby.org-ongoinf-study/repatha or by calling 1-800-772-6436.

    According to the manufacturer, there is no information on evolocumab presence in human milk, effects on milk production, or effects on the breastfed infant. Human IgG is present in human milk, but data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Evolocumab is a human monoclonal IgG2 antibody that binds to and inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) binding to low-density lipoprotein receptors (LDLR). PCSK9 binds to LDLR on the hepatocyte surface to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL; with evolocumab inhibiting the binding of PCSK9 to LDLR, the number of LDLRs available to clear LDL increases, thereby lowering LDL-C concentrations.

    PHARMACOKINETICS

    Evolocumab is administered subcutaneously. At low concentrations, evolocumab is eliminated primarily via saturable binding to proprotein convertase subtilisin/kexin type 9 (PCSK9). At higher concentrations, evolocumab is eliminated mainly through a non-saturable proteolytic pathway. The estimated effective half-life of evolocumab is 11 to 17 days. Maximum LDL-C reduction occurred 2 weeks after a single dose of 140 mg and 3 weeks after a single dose of 420 mg.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Subcutaneous Route

    The median time to maximum serum evolocumab concentration (Tmax) after administration of single doses of 140 mg or 420 mg is 3 to 4 days. Maximum suppression of free circulating PCSK9 occurs within 4 hours after a single subcutaneous dose of evolocumab 140 mg or 420 mg and returns to baseline once evolocumab concentrations are undetectable. Evolocumab exhibits non-linear pharmacokinetics. An approximate 2- to 3-fold accumulation is observed in trough serum concentrations after 140 mg doses administered every 2 weeks or 420 mg doses administered monthly. Steady state is reached within 12 weeks of dosing. The absolute bioavailability after subcutaneous administration is 72%.