Alirocumab is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for adjunct treatment to diet, alone or in combination with other lipid-lowering therapies in adult and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH) or as an adjunct to other lipid-lowering therapies in adults with homozygous familial hypercholesterolemia (HoFH) who require lowering of low-density lipoprotein cholesterol (LDL-C). Alirocumab is also indicated for reducing the risk of myocardial infarction, stroke prophylaxis, and hospitalization for unstable angina in adults with cardiovascular disease. During various clinical trials, alirocumab produced negative mean differences from placebo from baseline in LDL-C ranging from approximately 31% to 58%. In the Odyssey Outcomes study, alirocumab therapy was associated with a significant reduction in the primary composite outcome, which was defined as time to first occurrence of non-fatal myocardial infarction, fatal stroke, non-fatal stroke, coronary heart disease death, ischemic stroke, or unstable angina requiring hospitalization (p = 0.0003). Serious hypersensitivity reactions including hypersensitivity vasculitis have occurred with use.
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, colorless to pale yellow. Do not use if discolored or if flakes or particulate matter is present.
-If a dose is missed, administer the injection within 7 days from the missed dose and then resume original schedule.
-If more than 7 days after missed dose:
--For every 2 week dosage regimen, instruct the patient to wait until the next dose on the original schedule.
-For every 4 week dosage regimen, instruct patient to administer dose and start a new schedule based on this date.
Subcutaneous Administration
-If stored in the refrigerator, remove prefilled pen from the refrigerator and allow it to warm to room temperature for 30 to 40 minutes prior to use. Do not warm by using a heat source or leave in direct sunlight; allow it to warm to room temperature on its own. Do not place back in the refrigerator after removal.
-Do not shake.
-Review the label on the alirocumab injection pen to ensure the correct product and dose.
-Do not administer with other injectables at the same injection site.
-To administer the 300 mg dose, give two 150-mg injections consecutively at 2 different injection sites.
Administration:
-Clean the skin in the injection site with an alcohol wipe. Injection sites include the thighs, abdomen (except for the 2-inch area around the belly button) or upper arms. Rotate injection site with each injection.
-Air bubbles may be present; this is normal. Do not use if the window appears solid yellow. Do not use if the blue cap is missing or not securely attached.
-Do not inject into areas of the skin that are tender, bruised, hard or red. Do not inject into areas with visible veins, scars, or stretch marks.
-For administration to pediatric patients,
--Children and Adolescents 12 to 17 years: administer by an adult or under direct adult supervision.
-Children 8 to 11 years: administer by a caregiver.
-Do not remove the blue cap until you are ready to inject alirocumab. Once blue cap removed, do not put blue cap back on.
-When ready for the injection, remove the blue cap from the alirocumab injection pen.
-Hold the pen with the yellow safety cover pointing down. Do not touch the yellow safety cover; ensure the window is visible.
-Firmly press the yellow safety cover onto the skin at approximately a 90-degree angle and until the yellow safety cover is no longer visible. The alirocumab injection pen will not work if the yellow safety cover is not fully depressed.
--Children younger than 12 years: pinch the skin before and during the injection.
-Adults, Adolescents, Children 12 years and older: pinching of the skin may be required to make the injection site firm.
-Push and immediately release the green (75 mg prefilled pen) or gray (150 mg prefilled pen) button with the thumb. You will hear a click and see that the window starts to turn yellow, indicating that the injection has started.
-Continue to hold the alirocumab injection pen against the skin after releasing the button. The injection may take up to 20 seconds.
-The window of the pen will turn completely yellow when the injection is complete. A second click may be heard at the end of the injection. Do not remove the pen until the entire window is yellow.
-If the window does not turn completely yellow, call 1-844-772-5836 for assistance. Do not administer a second dose without speaking to your care team.
-Pull the alirocumab injection pen away from the skin; do not rub the skin after the injection.
-Dispose of the alirocumab injection pen and cap into an appropriate sharps container.
-The alirocumab injection pen is provided as a single use system; discard after use.
-Storage: Store in 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 up to 25 degrees C (77 degrees F) for a maximum of 30 days in the original carton to protect from light. After removal from the refrigerator, use within 30 days or discard. Do not store above 77 degrees F.
Serious hypersensitivity reactions including hypersensitivity vasculitis, angioedema, nummular eczema, and other reactions requiring hospitalization have occurred with alirocumab use. Allergic reactions were reported in 8.6% of adult patients treated with alirocumab compared to 7.8% of those who received placebo during clinical trials. Pruritis was the most common hypersensitivity symptom, which occurred in 1.1% of alirocumab patients and 0.4% of placebo patients. Allergic reaction-related angioedema has been reported with postmarketing use of alirocumab.
During clinical trials, 1.7% of alirocumab-treated patients experienced elevated hepatic enzymes more than 3 times the upper limit of normal (ULN) compared to 1.4% of placebo-treated patients. Overall, liver related disorders (mostly related to abnormal hepatic enzymes) were reported in 2.5% alirocumab-treated patients compared to 1.8% of placebo-treated patients.
An injection site reaction could occur with the use of alirocumab. Injection site reactions including erythema, pruritus, edema (swelling), and pain/tenderness, occurred in 3.8% to 16.6% of patients who received alirocumab vs. 2.1% to 7.9% of those who received placebo in clinical trials. Treatment discontinuation due to injection site reactions associated with alirocumab use was reported in 0.2% to 0.7% of patients. Alirocumab-treated patients had more injection site reactions, more associated symptoms, and longer average duration of injection site reactions compared to those who received placebo. In a pediatric alirocumab clinical trial, injection site reactions occurred in 5% of alirocumab-treated patients compared to 0% of placebo-treated patients. Other dermatologic reactions reported with alirocumab use in adults include ecchymosis/contusion (2%).
Antibody formation may occur with alirocumab use. In clinical trials, anti-alirocumab antibody formation was reported in 4.8% to 5.5% of alirocumab-treated adult patients and neutralizing antibodies were reported in 0.5% to 1.2%. Some patients with persistent or neutralizing antibodies experienced an attenuation of LDL-C lowering effects in alirocumab clinical trials. Adult patients who developed anti-alirocumab antibodies had a higher incidence of injection site reactions compared to patients without anti-alirocumab antibodies (7.5% vs. 3.6%, respectively). The incidence of ADA in pediatric patients aged 8 to 17 years with heterozygous familial hypercholesterolemia treated with alirocumab during clinical trials was 3%; no patients tested positive for neutralizing antibodies. Due to the small number of pediatric patients enrolled in the clinical trial and low occurrence of ADA, the effect of anti-alirocumab antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of alirocumab in pediatric patients is unknown.
Influenza was reported in 6% of alirocumab-treated patients compared to 5% of placebo-treated patients in clinical trials. Influenza-like illness has been reported with postmarketing use of alirocumab.
Myalgia (4% to 6%, alirocumab vs. 3% to 5%, placebo) and muscle spasms (3% vs. 2%) were reported in placebo-controlled, clinical trials with alirocumab.
In clinical trials with alirocumab, diarrhea was reported in 5% of alirocumab-treated patients vs. 4% of placebo-treated patients.
There are no available human data examining drug-associated risks with alirocumab use during pregnancy. Animal data indicate that alirocumab crosses the placental barrier. Like other IgG antibodies, it is unlikely that alirocumab crosses the placenta in the first trimester, but it is likely that alirocumab crosses the placenta in the second and third trimester. In animal reproduction studies, there were no embryo-fetal adverse effects with dose exposures up to 12 times the exposure at the maximum recommended human dose (MRHD) of 150 mg every 2 weeks. In monkeys, suppression of the humoral immune response occurred in infant monkeys when alirocumab was dosed during organogenesis to birth at dose exposures 13-fold the exposure at the MRHD. No additional effects on pregnancy or neonatal/infant development were ob served at dose exposures up to 81-fold the MRHD. Consider the benefits and risks of alirocumab prior to exposure during pregnancy. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to alirocumab; information about the registry can be obtained by calling 1-877-311-8972.
There is no information regarding the presence of alirocumab in human milk, the effects on the breastfed infant, or the effects on milk production. Data suggest that IgG antibodies that are present in human milk do not enter the neonatal and infant circulation in substantial amounts. Consider the development and health benefits of breast-feeding along with the mother's clinical need for alirocumab and any potential side effects on the breastfed infant from alirocumab or from the underlying maternal condition.
Due to the risk of serious hypersensitivity reactions or anaphylaxis, alirocumab is contraindicated for use in patients with a known allergic reaction to the drug. Hypersensitivity vasculitis, angioedema, and hypersensitivity reactions resulting in hospitalization have occurred with use. If a serious hypersensitivity reaction or anaphylaxis develops during therapy, immediately discontinue alirocumab and institute appropriate treatment.
-Alirocumab is recommended as second-line therapy in addition to maximally tolerated statin therapy in patients with clinical ASCVD and comorbidities that still require 25% or greater LDL reduction. Factors to consider include cost, benefit of ASCVD risk reduction, dosing frequency requirements, and administration by subcutaneous injection.
-Assess low-density lipoprotein (LDL-C) when clinically appropriate. The LDL-C lowering effect of alirocumab may be measured as soon as 4 weeks after treatment initiation.
For the treatment of primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), as an adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C) lowering therapies to reduce LDL-C:
-for the treatment of primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), in adults:
Subcutaneous dosage:
Adults: 75 mg subcutaneously every 2 weeks or 300 mg subcutaneously every 4 weeks. Monitor LDL-C as clinically appropriate; the LDL-lowering effect may be measured as early as 4 weeks after starting therapy. Measure LDL-C just before next dose in persons receiving 300 mg subcutaneously every 4 weeks. May adjust dose to 150 mg subcutaneously every 2 weeks if response is inadequate.
-for the treatment of heterozygous familial hypercholesterolemia (HeFH) in pediatric patients:
Subcutaneous dosage:
Children and Adolescents 8 to 17 years weighing 50 kg or more: 300 mg subcutaneously every 4 weeks. May adjust dose to 150 mg subcutaneously every 2 weeks if response is inadequate. Monitor LDL-C as clinically appropriate; the LDL-lowering effect may be measured as early as 4 weeks after starting therapy.
Children and Adolescents 8 to 17 years weighing less than 50 kg: 150 mg subcutaneously every 4 weeks. May adjust dose to 75 mg subcutaneously every 2 weeks if response is inadequate. Monitor LDL-C as clinically appropriate; the LDL-lowering effect may be measured as early as 4 weeks after starting therapy.
-for the treatment of heterozygous familial hypercholesterolemia (HeFH) in adults undergoing LDL apheresis:
Subcutaneous dosage:
Adults: 150 mg subcutaneously every 2 weeks. May be administered without regard to the timing of LDL apheresis. Monitor LDL-C as clinically appropriate; the LDL-lowering effect may be measured as early as 4 weeks after starting therapy.
For the treatment of patients with homozygous familial hypercholesterolemia as an adjunct to other LDL-C-lowering therapies to reduce LDL-C:
Subcutaneous dosage:
Adults: 150 mg subcutaneously every 2 weeks. Monitor LDL-C as clinically appropriate; the LDL-lowering effect may be measured as early as 4 weeks after starting therapy.
For myocardial infarction prophylaxis, stroke prophylaxis, and to reduce the risk of unstable angina requiring hospitalization in patients with established cardiovascular disease:
Subcutaneous dosage:
Adults: 75 mg subcutaneously every 2 weeks or 300 mg subcutaneously every 4 weeks. Measure LDL-C prior to next dose for persons receiving 300 mg subcutaneously every 4 weeks and otherwise as clinically appropriate. May adjust dose to 150 mg subcutaneously every 2 weeks for inadequate LDL-C response.
Maximum Dosage Limits:
-Adults
300 mg subcutaneously once every month.
-Geriatric
300 mg subcutaneously once every month.
-Adolescents
Safety and efficacy have not been established.
-Children
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
No dosage adjustment is needed for mild or moderate hepatic impairment. Specific guidelines for dosage adjustments in severe hepatic impairment are not available.
Patients with Renal Impairment Dosing
No dosage adjustment is needed for mild or moderate renal impairment. Specific guidelines for dosage adjustments in severe renal impairment are not available.
*non-FDA-approved indication
There are no drug interactions associated with Alirocumab products.
Alirocumab is a human monoclonal IgG1 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 alirocumab inhibiting the binding of PCSK9 to LDLR, the number of LDLRs available to clear LDL increases and LDL-C concentrations decrease.
Alirocumab is administered subcutaneously. Alirocumab is a protein and is expected to degrade to small peptides and amino acids. At low concentrations, elimination is through saturable binding to proprotein convertase subtilisin/kexin type 9 (PCSK9). At higher concentrations, elimination is mainly through a non-saturable proteolytic pathway. At subcutaneous doses of 75 mg every 2 weeks or 150 mg every 2 weeks, the median apparent half-life of alirocumab at steady state is 17 to 20 days.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Subcutaneous Route
The median time to maximum serum alirocumab concentration (Tmax) following subcutaneous administration of doses of 75 to 150 mg is 3 to 7 days. Following a 2-fold increase in dose from 75 mg every 2 weeks to 150 mg every 2 weeks, there was a slightly greater than dose proportional increase of 2.1- to 2.7-fold in total alirocumab concentrations. Alirocumab reduces free PCSK9 in a concentration-dependent manner; maximal suppression of PCSK9 occurs within 4 to 8 hours of a single subcutaneous dose of alirocumab 75 or 150 mg and returns to baseline once alirocumab concentrations are undetectable. The pharmacokinetics of alirocumab following injection into different anatomical sites (i.e., abdomen, upper arm, thigh) are similar. Steady state is reached after 2 to 3 doses. The absolute bioavailability after subcutaneous administration was approximately 85%.
-Special Populations
Hepatic Impairment
The pharmacokinetics of alirocumab in patients with mild and moderate hepatic impairment were similar to those with normal hepatic function after subcutaneous administration of a single alirocumab 75 mg dose. Alirocumab 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 alirocumab. Patients with severe renal impairment have not been studied.
Pediatrics
The pharmacokinetics of alirocumab were evaluated in 140 pediatric patients aged 8 to 17 years with heterozygous familial hypercholesterolemia. Steady-state alirocumab concentrations were reached at or before week 8 with recommended dosing.
Geriatric
In a population pharmacokinetic analysis, age was not found to significantly influence alirocumab pharmacokinetics.
Gender Differences
In a population pharmacokinetic analysis, gender was not found to significantly influence alirocumab pharmacokinetics.
Ethnic Differences
In a population pharmacokinetic analysis, race was not found to significantly influence alirocumab pharmacokinetics.
Obesity
In a population pharmacokinetic analysis, body weight was not found to significantly influence alirocumab pharmacokinetics.