Evolocumab is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor indicated as an add-on treatment to reduce low density lipoprotein cholesterol (LDL-C) in adult patients with primary hyperlipidemia and adult and pediatric patients 10 years and older with heterozygous or homozygous familial hypercholesterolemia (HeFH, HoFH). Evolocumab also is indicated to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease. During various clinical trials, evolocumab produced negative mean differences from placebo from baseline in LDL-C ranging from 31% to 71%. Evolocumab is recommended as second-line therapy in addition to maximally tolerated statin therapy in patients with clinical atherosclerotic cardiovascular disease (ASCVD) and comorbidities that still require 25% or greater LDL-C reduction. Factors to consider include cost, benefit of ASCVD risk reduction, dosing frequency requirements, and administration by subcutaneous injection.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific 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.
-Missed dose: 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 at least 30 minutes for the single-use prefilled syringe or autoinjector and at least 45 minutes for the single-use on-body infusor with prefilled cartridge to reach room temperature prior to administration. 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, indurated, thick, or scaly. Avoid areas with scars or stretch marks.
-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 5 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.
Naso-pharyngitis (4% to 12%), upper respiratory tract infection (2% to 9%), influenza (1% to 9%), cough (1% to 5%), urinary tract infection (1% to 5%), and sinusitis (4%) were reported in evolocumab-treated patients during clinical trials. Influenza-like illness has been reported with postmarketing use of evolocumab.
Hypersensitivity reactions were reported in 5% of patients receiving evolocumab during clinical trials. The most common reactions included rash (1%), eczema (0.4%), erythema (0.4%), and urticaria (0.4%). Angioedema has been reported with postmarketing use. If signs or symptoms of serious hypersensitivity reactions, anaphylaxis, or anaphylactoid reactions occur, discontinue evolocumab treatment, treat with standard of care, and monitor until symptoms resolve.
Diarrhea (3%), gastroenteritis (3% to 6%), and nausea (2%) were reported in evolocumab-treated patients during clinical trials. Oropharyngeal pain was reported in 7% of pediatric patients.
Back pain (2% to 6%), arthralgia (2%), myalgia (4%), muscle cramps/spasms (1%), musculoskeletal pain (3%), fatigue (2%), and contusion (1%) were reported in evolocumab-treated patients during clinical trials.
Injection site reaction, including erythema, pain, and bruising, was reported in 3% to 6% of evolocumab-treated patients during clinical trials.
Hypertension (3%), headache (4%), and dizziness (4%) were reported in evolocumab-treated patients during clinical trials. Headache was reported in 11% of pediatric patients.
Antibody formation may occur with evolocumab. In a pool of placebo- and active-controlled clinical trials, 0.3% of adult patients treated with at least 1 dose of evolocumab tested positive for binding antibody development. Patients who tested positive for binding antibodies were tested for neutralizing antibodies, and none of the patients were positive for neutralizing antibodies. The development of anti-evolocumab antibodies was not detected in pediatric clinical trials. There is no evidence that the presence of anti-drug antibodies impacts the pharmacokinetics, clinical response, or safety of evolocumab.
Hyperglycemia (reported as diabetes mellitus) was reported in 9% of adult patients receiving evolocumab and 8% of those receiving placebo during the cardiovascular outcomes trial. The incidence of new-onset diabetes mellitus during the trial was approximately 8% in both groups.
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.
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.
Do not expose the Pushtronex system, a single-use on-body infuser for evolocumab, to a magnetic resonance environment, such as magnetic resonance imaging (MRI).
There are no data on the presence of evolocumab in human milk, the effects on the breast-fed child, or the effects on milk production. 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 developmental and health benefits of breast-feeding along with the mother's clinical need for evolocumab and any potential adverse effects on the breast-fed child from evolocumab or from the underlying maternal condition.
General Dosing Information
-Assess LDL-C when clinically appropriate. The LDL-C lowering effect of evolocumab may be measured as soon as 4 weeks after treatment initiation.
-Measure LDL-C just prior to the next scheduled dose. LDL-C can vary during the dosing interval in some patients, particularly those receiving once monthly dosing.
For the treatment of primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH):
-for the treatment of primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), in adult patients as an adjunct to diet, alone or in combination with other LDL-C lowering therapies:
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 the treatment of heterozygous familial hypercholesterolemia (HeFH) in pediatric patients as an adjunct to diet and other LDL-C lowering therapies:
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 the treatment of homozygous familial hypercholesterolemia (HoFH) as an adjunct to other LDL-C lowering therapies:
-for the treatment of homozygous familial hypercholesterolemia (HoFH) in persons NOT on lipid apheresis:
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.
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.
-for the treatment of homozygous familial hypercholesterolemia (HoFH) in persons on lipid apheresis:
Subcutaneous dosage:
Adults: 420 mg subcutaneously once monthly or every 2 weeks to correspond with apheresis schedule (administer after apheresis session is complete). For those initiated on monthly dosing, increase to 420 mg subcutaneously every 2 weeks if a clinically meaningful response is not attained in 12 weeks.
Children and Adolescents 10 to 17 years: 420 mg subcutaneously once monthly or every 2 weeks to correspond with apheresis schedule (administer after apheresis session is complete). For those initiated on monthly dosing, increase to 420 mg subcutaneously every 2 weeks if a clinically meaningful response is not attained in 12 weeks.
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 Limits:
-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.
Patients with Hepatic Impairment Dosing
Mild to moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment is needed.
Severe hepatic impairment: Specific guidelines for dosage adjustments are not available.
Patients with Renal Impairment Dosing
No dosage adjustment is needed.
*non-FDA-approved indication
There are no drug interactions associated with Evolocumab products.
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.
Evolocumab is administered subcutaneously. The Vd following a single subcutaneous dose of 420 mg was 3.3 L. 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
-Route-Specific Pharmacokinetics
Subcutaneous Route
The absolute bioavailability after subcutaneous administration is 72%. The median Tmax after administration of single doses of 140 mg or 420 mg to adult patients 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. Following administration of a subcutaneous dose of 140 mg and 420 mg to healthy adults, the mean Cmax was 18.6 mcg/mL and 59 mcg/mL, respectively. An approximate 2- to 3-fold accumulation is observed in trough serum concentrations after 140 mg doses administered every 2 weeks (Cmin 7.21) or 420 mg doses administered monthly (Cmin 11.2). Steady state is reached within 12 weeks of dosing.
-Special Populations
Hepatic Impairment
The mean Cmax and AUC are lower (20% to 30% and 40% to 50%, respectively) in patients with mild and moderate hepatic impairment. Evolocumab has not been studied in patients with severe hepatic impairment.
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. In a clinical trial of 18 adult patients with either normal renal function (eGFR 90 mL/minute/1.73 m2 or more; n = 6), severe renal impairment (eGFR less than 30 mL/minute/1.73 m2; 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 concentrations in patients with severe renal impairment or ESRD receiving hemodialysis were similar to those with normal renal function.
Pediatrics
Children and Adolescents 10 to 17 years
Mean trough serum concentrations of evolocumab were 22.4 mcg/mL and 25.8 mcg/mL over Week 12 and Week 24 time points, respectively, during clinical trials in 103 pediatric patients with heterozygous familial hypercholesteremia (HeFH). Mean trough serum concentrations of evolocumab were 20.3 mcg/mL and 17.6 mcg/mL over Week 12 and Week 80 time points, respectively, during clinical trials in 12 pediatric patients with homozygous familial hypercholesteremia (HoFH).
Geriatric
Age was not shown to have an effect on the pharmacokinetics of evolocumab.
Gender Differences
Gender was not shown to have an effect on the pharmacokinetics of evolocumab.
Ethnic Differences
Race was not shown to have an effect on the pharmacokinetics of evolocumab.
Obesity
Evolocumab exposure has been found to decrease with increasing body weight; however, these differences are not clinically meaningful.