Alirocumab

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Mechanism of Action

Monoclonal antibody that binds to PCSK9 (proprotein convertase subtilisin/kexin type 9)

LDL-C is cleared from the circulation preferentially through the LDL receptor (LDLR) pathway

PCSK9 is a serine protease that destroys LDLR in the liver, resulting in decreased LDL-C clearance and increased plasma LDL-C

PCSK9 inhibitors decrease LDLR degradation by PCSK9, and thereby improve LDL-C clearance and lower plasma LDL-C

Absorption

Absolute bioavailability: 85%

Peak plasma time: 3-7 days

Distribution

Vd: 0.04-0.05 L/kg

Distributed primarily in circulatory system

Metabolism

Specific metabolism studies were not conducted because alirocumab is a protein and is expected to degrade to small peptides and individual amino acids

Does not affect P450 enzymes, P-gp, and OATP

Elimination

Half-life: 17-20 days

Alirocumab may be found in some form under the following brand names:

• Praluent

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use alirocumab if you are allergic to it.

To make sure alirocumab is safe for you, tell your doctor about all your medical conditions or allergies.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether alirocumab passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Alirocumab is not approved for use by anyone younger than 18 years old.

If you inject once every 2 weeks: Use the missed dose within 7 days after the injection was due. Then go back to your original schedule and use the medicine again when your next scheduled dose is due.

If you inject once every 4 weeks: Use the missed dose within 7 days after the injection was due. Then give the next injection 4 weeks later to start a new schedule based on the date you used the missed injection.

Skip the missed dose if you are more than 7 days late for the injection. Do not use extra medicine to make up a missed dose.

Contraindications

• History of serious hypersensitivity reaction to alirocumab.1 (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Serious hypersensitivity reactions, including angioedema, vasculitis, and nummular eczema, reported; in some cases, hospitalization was required.1 18

If a serious hypersensitivity reaction occurs, discontinue drug and initiate standard of care treatment; monitor patient until signs and symptoms resolve.1 (See Contraindications under Cautions.)

Immunogenicity

Development of anti-alirocumab antibodies reported, some of which were neutralizing.1 A higher incidence of injection site reactions observed in antibody-positive patients.1 Some patients who developed neutralizing antibodies exhibited a transient or prolonged loss of efficacy.1

Long-term effects of continued alirocumab therapy in the presence of such antibodies not known.1

Specific Populations

No adequate and well-controlled studies of alirocumab in pregnant women.1 Weigh potential benefits versus possible risk to fetus.1

Adverse embryofetal effects not observed in animal studies with alirocumab; however, some evidence of humoral immune suppression demonstrated in infant monkeys exposed to the drug in utero.1

Not known whether distributed into human milk.1 Human IgG is distributed into human milk; however, published data suggest that IgG antibodies in human milk are not substantially distributed into the circulation of neonates and infants.1

Weigh known benefits of breastfeeding against potential adverse effects of the drug on the infant, taking into account the importance of the drug to the woman.1

Safety and efficacy not established.1

No overall differences in efficacy or safety relative to younger adults; however, possibility of increased sensitivity cannot be ruled out.1

Pharmacokinetics of alirocumab not substantially altered by mild or moderate hepatic impairment.1

Safety and efficacy not established in patients with severe hepatic impairment.1

Renal function not expected to affect pharmacokinetics of alirocumab.1

Safety and efficacy not established in patients with severe renal impairment.1

Common Adverse Effects

Nasopharyngitis,1 3 injection site reactions (e.g., erythema/redness, itching, swelling, pain/tenderness),1 2 3 influenza,1 urinary tract infection,1 3 diarrhea,1 bronchitis,1 myalgia,1 2 muscle spasms,1 sinusitis,1 3 cough,1 contusion,1 musculoskeletal pain.1

Very low levels of LDL cholesterol (e.g., <25 mg/dL) occurred in clinical studies.1 32 Although adverse consequences were not identified, long-term effects not known.1

Storage

Parenteral

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

Use within 24 hours after removal from refrigeration.1

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nose or throat irritation.
• Redness or swelling where the shot is given.
• Itching where the shot is given.
• Pain where the shot was given.
• Flu-like signs.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• REGN727
• SAR236553

Store at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Time out of refrigeration should not exceed 24 hours at 25°C (77°F). Do not freeze. Do not expose to extreme heat. Do not shake.

1% to 10%

Gastrointestinal: Diarrhea (5%)

Hepatic: Liver enzyme disorder (3%), increased serum transaminases (>3 X ULN; 2%)

Immunologic: Immunogenicity (5% to 6%; neutralizing: ≤1%; loss of efficacy: <1%)

Infection: Influenza (6%)

Local: Injection site reaction (7% to 17%)

Neuromuscular & skeletal: Myalgia (4%), muscle spasm (3%)

Respiratory: Cough (3%)

Frequency not defined: Endocrine & metabolic: Decreased LDL cholesterol (<25 mg/dL)

<1% (Limited to important or life-threatening): Confusion, hypersensitivity reaction (including hypersensitivity angiitis, pruritus, severe hypersensitivity, skin rash, urticaria), memory impairment

In animal reproduction studies, there were no effects on embryo-fetal development when rats were subcutaneously administered this drug during organogenesis at dose higher than the maximum recommended human dose. In monkeys, suppression of the humoral immune response was observed in infant monkeys when this drug was dosed during organogenesis to parturition at dose higher than the maximum recommended human dose. Measurable serum concentrations of this drug were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that this drug, like other IgG antibodies, crosses the placenta. Experience with monoclonal antibodies in humans indicates that IgG antibodies are unlikely to cross the placenta during the first trimester; however, during the second and third trimester, increased amounts of this drug are likely to cross the placenta. There are no available data on use of this drug in pregnant women. . US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus. US FDA pregnancy category: Not Assigned Risk Summary: There are no available data on use of this drug in pregnant women to inform a drug associated risk.