Alirocumab - An Adjunct Treatment for High Cholesterol Levels

Overview

Alirocumab is a medication prescribed as the second-line intervention for increased cholesterol concentration in adults with severe hereditary type cholesterol and atherosclerosis, and also unresponsive to diet and statin therapy. It is a human monoclonal antibody and belongs to a novel class of anti-cholesterol drugs, proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors. Also, Alirocumab has been proven to reduce the risks of heart attack, stroke, and angina by lowering the cholesterol concentration in the bloodstream.

Alirocumab is generally administered by subcutaneous injection. The drug received FDA (the United States Food and Drug Administration) approval as a second-line intervention to reduce cholesterol levels in July 2015. Alirocumab is the first drug to get approval among PCSK9 inhibitors. The FDA approval was bound by extensive clinical trials determining its safety and efficacy.

In 2021, the FDA included Alirocumab for indication in treating adults with heterozygous familial hypercholesterolemia (a heritable condition of high cholesterol). Nevertheless, the drug is not meant to be given alone but in conjunction with other interventions.

How Does Alirocumab Work?

Alirocumab is prescribed as a subcutaneous injection. As a PCSK9 inhibitor, Alirocumab inhibits the activity of an enzyme called proprotein convertase subtilisin Kexin type 9 (PCSK9). This enzyme is secreted from the liver, binds to the low-density lipoprotein (LDL) cholesterols, and raises their levels.

Therefore, the drug Alirocumab is effective in blocking the production of LDL cholesterol in the body. Thereby, it reduces the process of atherosclerosis (accumulation of cholesterol buildup in the walls of the blood vessels) and prevents blood clot formation. Alirocumab on appropriate dosage with an appropriate diet prevents heart attacks and other cardiovascular concerns.

Uses

• Homozygous Familial Hypercholesterolemia: It is a genetic condition with markedly high LDL cholesterol concentrations, commonly manifested in the younger adult (20 - 40 years) population. This autosomal dominant disease is due to the single DNA variant.

• Cardiovascular Events: Cholesterol accumulation in the walls of the arteries results in cardiovascular events such as heart attacks, stroke, and angina.

• Primary Hyperlipidemia: Primary hyperlipidemia is a genetic condition with heightened levels of fat or lipid in the system and holds a high risk of cardiovascular attacks and recurrent pancreatitis.

Drug and Its Dosage:

Route of Administration - Subcutaneous (SC) injection, just under the skin.

Drug Form:

Alirocumab injection is in the form of a pre-filled, single-dosed pen or syringe readily available for subcutaneous injection. The liquid solution is clear to pale yellow in color, devoid of floating particles.

Drug Strength:

The drug Alirocumab is available in two strengths: 75 mg/mL (milligram/milliliter) and 150 mg/mL.

Drug Dosages:

The dosages, number of injections, and frequency vary according to the individual's clinical status. Also, the duration of overall drug intervention relies on the person’s condition to be treated. However, the recommended dosage is as below.

Homozygous Familial Hypercholesterolemia

• In Adults, 50 mg subcutaneous injection is given once every two weeks.

Primary Hyperlipidemia and Reducing the Risk of Cardiovascular Events

• Every 2-Week Dose: 75 mg subcutaneous injection is given once in every two weeks. The dosage is increased depending on the patient's response.

• Every Four Weeks: 300 mg subcutaneous injection is administered once every four weeks. The dose adjustments are recommended based on clinical evaluation.

Precaution: The maximum dosage should not be increased by more than 150 mg per two-week duration.

What Are the Warnings and Precautions for Alirocumab?

• Anaphylaxis: In many instances, Alirocumab might result in severe and life-threatening hypersensitivity reactions called anaphylaxis. Discontinue the treatment and rightly seek out the doctor if one encounters signs of allergic reactions. The symptoms include rashes, hives, swelling, and difficulty breathing. Also, one with a history of allergy should not recommence the therapy.

• Pregnancy: Data from studies are inadequate to assess the Alirocumab-related effects on maternal and fetal outcomes. Hence, one should inform the doctor regarding pregnancy and play for pregnancy.

• Breastfeeding: There are inadequate studies about the effects of Alirocumab on infants while breastfeeding. The doctors should consider the potential benefits and risks before prescribing the medication.

• Pediatrics: Clinical trials and studies have not yet been conducted determining the age and the effects of Alirocumab in children. Therefore, the safety and efficacy of the drug in the pediatric population are not established.

• Geriatrics: The existing clinical studies do not document problems resulting from the use of Alirocumab in the geriatric population. Since older people are more sensitive to the effects of the drug, regular monitoring is needed when prescribing the drug to elderly people.

For Patients

What Are the Effects of High Cholesterol on the System?

High concentrations of cholesterol in the blood contribute to life-threatening events with no initial symptoms. High cholesterol level in the bloodstream contributes to the development of fatty deposits in the blood vessels, limiting the blood flow to various organs. The deposits, in turn, can grow or rupture to form a clot in the blood. Eventually, this atherosclerotic effect culminates in heart attack, stroke, or other cardiovascular events.

LDL cholesterol (LDL-C), referred to as bad cholesterol, forms fatty deposits called plaque. The low-density lipoprotein forms most of the body’s cholesterol composition. Therefore, the increased LDL concentration increases the risk of cardiovascular conditions.

Warning Signs of Hypercholesterolemia

• Nausea.

• Distorted speech.

• Increased blood pressure.

• Numbness.

• Extreme degrees of fatigue.

• Angina (intense chest pain).

• Shortness of breath.

• Numbness sensation felt in extremities.

How Does Alirocumab Help With High Cholesterol?

Alirocumab is an injection prescribed for lowering the LDL cholesterol concentration in the system. Alirocumab belongs to the class of proprotein convertase subtilisin Kexin type 9 (PCSK9) inhibitors. PCSK9 is an enzyme responsible for the production of low-density lipoprotein (LDL) cholesterols in the body. So, by inhibiting its action, Alirocumab limits the cholesterol levels in the bloodstream, reducing the risk potential and hazards of fatty deposits, blood clots, and, thus, cardiac illnesses.

How to Use Alirocumab Injection?

Alirocumab is a prescription injection that comes in the form of a liquid solution pre-filled in either a syringe or dosing pen. It is injected just under the skin. The doctor prescribes the drug with a frequency of every two or three weeks. However, the doctors would alter the dosage and duration on the basis of age, the cholesterol range in the blood, and the underlying medical illnesses. One should use the injection as per the prescribed direction. It is given on the prescription label or as directed by the healthcare professional.

What Are the Things to Consider and Inform the Doctor Before Commencement?

• One should inform the doctor if one has had an allergy to Alirocumab. Also, tell the doctor if one is allergic to any ingredients in the prescribed medication.

• Inform the doctor if the person is taking or about to take any medications, vitamins, nutritional intake, or herbal supplements. Hence, the doctors would adjust the dosage or assess attentively for any adverse reaction.

• Inform the doctor about the present and past medical illnesses, diseases, and conditions.

• Report to the doctor if one is pregnant, breastfeeding, or has any plans for pregnancy.

• Call and inform the doctor in case one gets pregnant during Alirocumab injection treatment.

Considerations Before Injecting:

• Alirocumab must be injected into the subcutaneous tissue, fatty tissue beneath the skin.

• One can inject in any injection site, such as the thigh, upper arm, and stomach. Avoid the region near the two-inch part around the navel and proximate to the waistline.

• One should not inject the dosing pen or syringe into the area of skin with redness, soreness, bruising, sunburn, swelling, hardiness, hotness, infection, or injury. Also, the region of visible scars, veins, stretch marks, and rashes should be avoided.

• The doctors may recommend two pens or injections simultaneously to level the dosage. In that case, use the syringe or pen closely but inject them at different injection sites.

• It takes twenty seconds to inject the drug. So, take the do’s and don'ts into consideration.

Directions for Alirocumab Injection:

• Conscientiously, one should read the manufacturer’s instructions that come with labeling.

• The instructions describe the procedure for handling the syringe or dosing pen.

• Before injecting, unload the syringe from the refrigerator where it is usually stored. Nevertheless, the syringe must be allowed to warm at room temperature for about thirty to forty minutes.

• One should not heat the syringe or place it in hot water to make it warm.

• Be sure that one uses the syringe within thirty days after being taken from the refrigerator.

• Never shake the medication. Also, one should assess the solution in the syringe or pen for the presence of any particles, defects, and discoloration. If so, do not proceed.

• Also, avoid injection if the syringe, dosing pen, or cap is damaged.

• Clean and disinfect the injection area with rubbing alcohol or spirit prior to injection.

• Remove the cap or hub before injecting, but be conscious about the needle and do not touch its tip.

• As per the physician’s instruction, slowly and gently inject the injection.

• As soon as after injection, dispose the needle with care.

Disclamation:

Use the Alirocumab injection as per the physician’s instructions. One should not use the medication more or less than the prescribed dosage. Also, the therapy should not be preceded on a longer span than advised.

Dietetic Consideration:

A well-balanced, nutritious diet paves the way for sound health. The doctors advise a diet with limited fat, sugar, and cholesterol. Attentively follow the doctor’s diet regimen. In addition, avoid full-fat dairy products, red meat, processed foods, lean meat, fried items, baked products, and egg yolks. Try to ingest fruits, vegetables, cereals, and fish.

Drug Storage:

• Store the Alirocumab syringe or pen in the refrigerator, but do not freeze.

• The injection can be stored with its actual carton at room temperature (up to 77 degrees Fahrenheit) for up to 30 days.

• Also, use the medication within 30 days after being withdrawn from the refrigerator.

• Dispense safely any outdated or unused medication.

• The medication should be kept out of reach of children.

Drug Disposal:

• Firstly, discard the used needles in a rigid, tight container so the needles cannot poke out.

• Then, safely dispose of them in a way that the children, companions, and pets are prevented from reaching the used needles.

• The syringe and dosing pen should not be flushed in the toilet, thrown in the community garbage, or poured into the channel.

• Instead, dispense safely following the local and state laws.

Missed Drug Dosage:

Every Two Weeks

• If It Is Within the Range of Seven Days of the Missed Dose - For people who miss the dose on the basis of medication every two weeks, take the injection right after the thought. Then, recommence with the actual schedule.

• If It Exceeded Seven Days From the Missed Dose - In this case, skip the missed dose and look for the succeeding date of the regular schedule.

Every Four Weeks

• If It Is Within the Range of Seven Days of the Missed Dose: One can inject the missed dose as soon as the thought and then restart with the original checklist.

• If It Exceeded Seven Days From the Missed Dose: Inject the missed dose and commence a new four-week schedule from this day.

Nevertheless, one should refrain from injecting the double dose as compensation for the missed one. Instead, seek the doctor in case of doubts.

What if One Suddenly Stops Taking Alirocumab?

One should not stop or halt the Alirocumab injection therapy without the doctor’s consent. The Alirocumab drug works on lowering cholesterol levels as far as the person is continuing the medication. But, if one suddenly stops, then the liver is unable to remove LDL cholesterol from the body, resulting in increased cholesterol concentration. So, one must have concerns about a doctor’s advice.

In Cases of Emergency or Overdosage:

Alirocumab overdose leads to dangerous levels of the drug held in the system. The alarming signs include collapse, seizure, difficulty breathing, and inability to wake. Reach out to the doctor or emergency helpline immediately when excessive amounts of the drug are injected.

How Effective Is Alirocumab?

Alirocumab is a safe, sound, and efficient drug. Studies and interventions uncover that Alirocumab injection significantly lowers LDL cholesterol levels, along with dietetic consideration and statin therapy. And higher dose results in profound LDL reductions.

Side Effects:

Pain, redness, swelling, or itching at the injection site is common, though. In addition, Alirocumab has several side effects, which usually subside with the drug therapy as the body adapts. Nevertheless, seek professional help if these signs persist and are distressing.

• Bleeding, bruising, redness, swelling, hives, numbness, infection, itching, inflammation, scarring, rashes, soreness, burning, and ulceration at the injection site.

• Cough.

• Chills.

• Diarrhea.

• Headache.

• Loss of appetite.

• Muscle spasms, pain, and cramps.

• Sore throat.

• Unusual sweating.

• Shivering.

• Vomiting.

• Insufficient sleep.

• Flu-like symptoms.

In addition, people may experience certain harmful signs, that require medical attention at the earliest. So, reach out to the doctor if one has any of the following.

• Chest pain or discomfort.

• Trouble breathing or swallowing.

• Fever.

• Rapid heartbeat.

• Itching, hives, or skin rashes.

• Irritation.

• Dry hoarseness of voice.

• Pain, stiffness, or swelling of the joints.

• Unusual fatigue.

• Nausea.

• Swelling of face, lips, arms, or eyelids.

• Skin redness, particularly of ears.

For Doctors

About Alirocumab

Clinical Data

• Generic Name: Alirocumab.

• Drug Class: Proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitor.

• Formula: C6472H9996N1736O2032S42.

• Molar Mass: 145 983.80 g.mol-1.

Monoclonal Antibody

• Type: Whole antibody.

• Source: Human.

• Target: Proprotein convertase subtilisin/Kexin type 9 (PCSK9).

Indications

• Reducing the risk of hospitalization with certain cardiovascular events, such as myocardial infarction, unstable angina, and stroke in those adults with prevailing cardiovascular disease.

• For lowering low-density lipoprotein (LDL) cholesterol levels in the body as an adjunct drug with other LDL-C therapies, including in the treatment of heterozygous familial hypercholesterolemia.

• Alirocumab alone or in conjugation with lipid-lowering agents is indicated and used as an adjunct to diet in the management of primary hyperlipidemia.

In Associated Conditions

• Cerebrovascular accident.

• Heterozygous familial hypercholesterolemia.

• Homozygous familial hypercholesterolemia.

• Myocardial infarction.

• Primary hyperlipidemia.

• Unstable angina pectoris.

Pharmacology of Alirocumab

Chemistry

Alirocumab is a whole human monoclonal antibody assimilating the type of IgG1 isotype. So, it is composed of two-disulfide linked, human heavy chains, whereas all these disulfides are linked to the light chains. It is processed from Chinese hamster ovary cells and transfected with the rDNA.

Mechanism of Action

Alirocumab is a whole human monoclonal antibody that lowers the LDL cholesterol concentration by binding and inhibiting the enzyme called proprotein convertase subtilisin/Kexin type 9 (PCSK 9). PCSK 9 is an enzyme possessing “gain of function” mutations in autosomal dominant or familial hypercholesterolemia cases. So, the gain of function trait is achieved as PCSK 9 is secreted from the liver and binds to those LDL receptors in the serum and so tends them for lysosomal degradation. As a result, the LDL receptors now lack the ability to recycle to the plasma membrane. Therefore, the binding to LDL cholesterol and LDL-C clearance from plasma is reduced. Hence, Alirocumab, through inhibiting the enzyme PCSK 9, makes allowances for increased LDL-C reuptake by the liver and advancing raised clearance rate.

Pharmacodynamics

Alirocumab diminishes the levels of PCSK9 depending on the concentration.

Absorption

• Alirocumab is administered subcutaneously and absorbed into the bloodstream.

• The maximum concentrations (Peak plasma time) were reached within an average time of three to seven days.

• The absolute bioavailability after subcutaneous administration is 85 percent.

Distribution

• Alirocumab is chiefly and widely distributed through the circulatory system.

• Extravascular distribution is minimal.

• The volume of distribution is 0.04 to 0.05 L/kg.

Metabolism

• Specified metabolism studies for Alirocumab are not yet conducted.

• Preliminary data shows that Alirocumab is a protein, and it gets metabolized by the reticuloendothelial system and degraded into small peptides and distinctive amino acids.

• Alirocumab is not affected by CYP 450 enzymes and transported proteins.

Elimination

Monoclonal antibodies are not excreted by means of hepatic or renal pathways.

Half-life

• 17 to 20 days.

• In monotherapy, the median half-life is 17 to 20 days in individuals with subcutaneous Alirocumab 75 mg or 150 mg every two weeks.

• In statin therapy, the production of PCSK9 is increased, and half-life gets reduced with this statin co-administration. Hence, the half-life was decreased to 12 days.

• However, these differences are minimal, and no changes are required in dosages.

Dosage Considerations

Things to Monitor

The following lab investigations are to be analyzed in relation to the dosage adjustments and clinical requirements.

• Platelet count.

• Prothrombin time.

• Activated partial thromboplastin time.

• Quantitative spot urine protein test.

For Every Two-Week Schedule

Recommended Initial Dose: 75 mg subcutaneous (SC) every two weeks.

• LDL-C should be assessed between four to eight weeks after initiation.

• In cases of inadequate responses, the dosage is recommended to be increased to 150 mg SC every two weeks.

• Remonitor the levels of LDL-C. However, the dosage is not to exceed 150 mg SC every two weeks.

For Every Four-Week Schedule:

The recommended initial dose is 300 mg subcutaneously every four weeks, delivered in two 150 mg dosed injections successively at two different sites.

• On monitoring the LDL-C concentration, the dosage is adjusted to 150 mg SC every two weeks if the response is poor or inadequate.

• Eventually, assess the LDL-C levels prior to scheduling consecutive dates.

For Heterozygous Familial Hypercholesterolemia Under Apheresis

• 150 mg subcutaneously (SC) every two weeks.

• Administered regardless of apheresis timing.

Dosage Revises

• No dosage modification is required in cases of mild and moderate hepatic or renal impairment.

• No studies contribute to the dose adjustments in severe renal or hepatic dysfunction.

Limitation

The effect of Alirocumab on cardiovascular mortality and morbidity is not yet documented.

• The safety and efficacy of the drug Alirocumab in pediatrics are not yet established.

Adverse Effects

• Nasopharyngitis.

• Allergic reactions and anaphylaxis.

• Injection site reactions.

• Influenza.

• Antidrug antibodies.

• Bruising.

• Urinary tract infection (UTI).

• Diarrhea.

• Bronchitis.

• Myalgia.

• Muscle spasms.

• Sinusitis.

• Liver impairments.

• Cough.

• Contusion.

• Musculoskeletal pain.

Contraindications of Alirocumab

Alirocumab is strictly contraindicated in people with a history of severe hypersensitivity reaction to Alirocumab.

• Hypersensitivity vasculitis.

• Angioedema.

• Hypersensitivity requiring hospitalization.

Considerations

• Hypersensitivity reactions and anaphylaxis.

• Local injection site reactions.

• Liver enzyme abnormalities.

Drug Interactions:

The studies show that Alirocumab has no reported mild, moderate, or severe drug interaction with other drugs, herbal supplements, and food. Nevertheless, the risk of adverse effects can be increased with certain medications.

• Interaction with Live Vaccines: The therapeutic efficacy of the live, attenuated vaccine can be decreased when used in conjugation with Alirocumab.

• Interaction with Esterified Estrogens. Esterified estrogens might increase the thrombogenic activity of the drug Alirocumab.

• Interaction with Estetrol: Estetrol might enhance the thrombogenic activity of Alirocumab.

• Interaction with Imlifidase: The therapeutic potential and efficacy of Alirocumab decrease when co-administered with the drug.

Clinical Trial:

A randomized, placebo-controlled, double-blind interventional study was conducted with a number of participants. The study was directed to determine and validate the drop in low-density lipoprotein (LDL) cholesterol concentration by virtue of Alirocumab administration. In the study, Alirocumab was utilized as an adjunct therapy to non-statin lipid-modifying therapy (LMT) that includes diet therapy alone or statin therapy. This clinical trial compared Alirocumab with a placebo therapy in hypercholesterolemic patients after 12 weeks.

Results:

As a result of a placebo-controlled trial, the efficacy of Alirocumab in lowering cholesterol concentration is proven. Other clinical trial-based studies provided data on significant and favorable amendments in LDL-C and HDL-C concentrations with the Alirocumab medication in 12 randomized controlled trials incorporating about 6019 patients.