Alirocumab

Registered South African indications:

• Primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet 
  - In combination with a statin or statin with other lipid-lowering therapies in patients unable to reach low-density lipoprotein-cholesterol (LDL-C) goals with the maximum tolerated dose of a statin
  - Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated
• Established atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels, as an adjunct to correction of other risk factors
  - In combination with the maximum tolerated dose of a statin with or without other lipid-lowering therapies
  - Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated

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Safety and efficacy beyond 18 months have not been demonstrated

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Children <18 years

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment (eGFR <30ml/min/1.73m²)
• Severe hepatic impairment (Child-Pugh Class C)

South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment (eGFR <30ml/min/1.73m²)
• Severe hepatic impairment (Child-Pugh Class C)
• Very low levels of LDL-C
• Diabetes mellitus
• Fructose intolerance
• Glucose-galactose malabsorption
• Sucrose-isomaltase insufficiency

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet
- In combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,
- Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated
Established atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels, as an adjunct to correction of other risk factors
- In combination with the maximum tolerated dose of a statin with or without other lipid-lowering therapies or,
- Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated

Usual starting dose 

• SC: Initial: 75mg, every 14 days; Titrate according to patient response; Max: 150mg, every 14 days

Patients requiring larger LDL-C reduction (>60%) 

• SC: Initial: 150mg, every 14 days
  OR
• SC: Initial: 300mg, every 28 days; Titrate according to patient response; Max: 150mg, every 14 days

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Prior to initiating alirocumab secondary causes of hyperlipidaemia or mixed dyslipidaemia (e.g., nephrotic syndrome, hypothyroidism) should be excluded

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The dose of alirocumab can be individualised based on patient characteristics such as baseline LDL-C level, goal of therapy, and response. Lipid levels can be assessed 4-8 weeks after treatment initiation or titration, and dose adjusted accordingly (up-titration or down-titration)

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Alirocumab is injected as an SC injection into the thigh, abdomen or upper arm

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To administer the 300mg dose, two 150mg injections should be given consecutively at two different injection sites

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See additional prescribing points for precautions for administration and handling 

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If a dose is missed, the patient should administer the injection as soon as possible and thereafter resume treatment on the original schedule

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South African manufacturer recommendations

Primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet 
- In combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or
- Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated
Established atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels, as an adjunct to correction of other risk factors
- In combination with the maximum tolerated dose of a statin with or without other lipid-lowering therapies, or
- Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated

Usual starting dose 

• SC: Initial: 75mg, every 2 weeks; Titrate according to patient response; Max: 150mg/2 weeks  

Patients requiring larger LDL-C reduction (>60%) 

• SC: Initial: 150mg, every 2 weeks OR 300mg, every 4 weeks; Titrate according to patient response

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Prior to initiating alirocumab, secondary causes of hyperlipidaemia or mixed dyslipidaemia (e.g. nephrotic syndrome, hypothyroidism) should be excluded

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The dose of alirocumab can be individualised based on patient characteristics such as baseline LDL-C level, goal of therapy and response. Lipid levels can be assessed 4-8 weeks after treatment initiation or titration, and dose adjusted accordingly (up-titration or down-titration) 

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If a dose is missed, the patient should administer the injection as soon as possible and thereafter resume treatment on the original schedule 

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Alirocumab is administered as an SC injection into the thigh, abdomen or upper arm, using a single-use pre-filled pen or single use pre-filled syringe

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See additional prescribing points for precautions for administration and handling 

Not established for use in children below 18 years

Pregnancy

• Caution; not recommended
• There are no data from the use of alirocumab in pregnant women. Alirocumab is a recombinant IgG1 antibody, therefore it is expected to cross the placental barrier
• Animal studies do not indicate direct or indirect harmful effects with respect to maintenance of pregnancy or embryo-foetal development; maternal toxicity was noted in rats, but not in monkeys at doses in excess of the human dose, and a weaker secondary immune response to antigen challenge was observed in the offspring of monkeys
• The use of alirocumab is not recommended during pregnancy unless the clinical condition of the woman requires treatment with alirocumab

Breastfeeding

• Caution; not recommended
• It is not known whether alirocumab is excreted in human milk. Human immunoglobulin G (IgG) is excreted in human milk, in particular in colostrum; the use of alirocumab is not recommended in breastfeeding women during this period. For the remaining duration of breastfeeding, exposure is expected to be low
• Since the effects of alirocumab on the breastfed infant are unknown, a decision should be made whether to discontinue breastfeeding or to discontinue alirocumab during this period

Fertility

• In animal studies, there were no adverse effects on surrogate markers of fertility. There are no data on adverse effects on fertility in humans

Renal Impairment

• Mild to moderate (eGFR ≥30ml/min/1.73m²): No dose adjustment recommended
• Severe (eGFR <30ml/min/1.73m²): Caution; no information available
  Limited data are available in patients with severe renal impairment; in these patients the exposure to alirocumab was approximately 2-fold higher compared with subjects with normal renal function

Hepatic Impairment

• Mild to moderate (Child-Pugh Classes A&B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; no information available

Elderly

• No dose adjustment recommended

Body weight

• No dose adjustment is needed in patients based on weight

Drugs in Sport

• Permitted - No warnings

Respiratory Disorders

• Upper respiratory tract signs and symptoms
  - Oropharyngeal pain
  - Rhinorrhea
  - Sneezing

Skin and Subcutaneous Tissue Disorders

• Injection site reactions
  - Erythema/ redness
  - Itching
  - Swelling
  - Pain/ tenderness
• Pruritus
• Urticaria
• Nummular eczema
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Hypersensitivity vasculitis
• Flu-like illness

• Statins
• Other lipid-modifying therapy
• Ezetimibe
• Fenofibrate
  (See additional prescribing points)

• Lipid profile
  - Low-density lipoprotein-cholesterol (LDL-C) level

Additional observations

• Hypersensitivity reactions

Traceability

• In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

Method of administration

• It is recommended to rotate the injection site with each injection
• Alirocumab should not be injected into areas of active skin disease or injury such as sunburns, skin rashes, inflammation, or skin infections
• Alirocumab must not be coadministered with other injectable medicinal products at the same injection site
• The patient may either self-inject alirocumab, or a caregiver may administer alirocumab after guidance has been provided by a healthcare professional on proper subcutaneous injection technique
• The solution should be allowed to warm to room temperature prior to use

Effects of other medicinal products on alirocumab

• Statins and other lipid-modifying therapy are known to increase production of PCSK9, the protein targeted by alirocumab
• This leads to the increased target-mediated clearance and reduced systemic exposure of alirocumab
• Compared to alirocumab monotherapy, the exposure to alirocumab is about 40%, 15%, and 35% lower when used concomitantly with statins, ezetimibe, and fenofibrate, respectively
• However, reduction of LDL-C is maintained during the dosing interval when alirocumab is administered every two weeks

Alirocumab is a fully human IgG1 monoclonal antibody that binds with high affinity and specificity to proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.

The LDLR also binds triglyceride-rich VLDL remnant lipoproteins and intermediate-density lipoprotein (IDL). Therefore, alirocumab treatment can produce reductions in these remnant lipoproteins as evidenced by its reductions in apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TG). Alirocumab also results in reductions in lipoprotein (a) [Lp(a)], which is a form of LDL that is bound to apolipoprotein (a). However, the LDLR has been shown to have a low affinity for Lp(a), therefore the exact mechanism by which alirocumab lowers Lp(a) is not fully understood.

Injection (per ml) 75mg

• Praluent (Sanofi) originator

Injection (per ml) 150mg

• Praluent (Sanofi) originator