Evolocumab

Registered South African indications:

• Primary hyperlipidaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL- C), total cholesterol (TC), apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), TC/HDL-C, ApoB/apolipoprotein A1 (ApoA1), very low-density lipoprotein cholesterol (VLDL-C), triglycerides (TG) and lipoprotein(a) (Lp[a]), and to increase HDL-C and ApoA1
  - In combination with a statin or statin with other lipid-lowering therapies
  - Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant
  - Alone or in combination with other lipid-lowering therapies in patients for whom a statin is not considered clinically appropriate
• Homozygous familial hypercholesterolaemia
  - To reduce LDL-C, TC, ApoB, and non-HDL-C in combination with other lipid-lowering therapies

Contraindications

South African recommendations

• None

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

South African recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment (Child-Pugh class C)

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Moderate to severe hepatic impairment (Child-Pugh class C)
• Latex allergy (See additional prescribing points)

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

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Primary hyperlipidaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL- C), total cholesterol (TC), apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), TC/HDL-C, ApoB/apolipoprotein A1 (ApoA1), very low-density lipoprotein cholesterol (VLDL-C), triglycerides (TG) and lipoprotein(a) (Lp[a]), and to increase HDL-C and ApoA1 (Additional agent(s) may be required)
- In combination with a statin or statin with other lipid-lowering therapies (e.g. ezetimibe)
- Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant
- Alone or in combination with other lipid-lowering therapies in patients for whom a statin is not considered clinically appropriate

• SC: 140mg, every 2 weeks OR 420mg, once monthly, both doses are clinically equivalent 

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Evolocumab is administered subcutaneously

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Evolocumab is intended for patient self-administration

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Administration should be performed by an individual who has been trained to administer the product

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One pre-filled syringe (PFS) or pre-filled pen delivers the 140mg every 2 week dose, and 3 pre-filled syringes or 3 pre-filled pens administered consecutively within 30 minutes delivers the 420mg once monthly dose

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Homozygous familial hypercholesterolaemia (Additional agents required)
- To reduce LDL-C, TC, ApoB, and non-HDL-C in combination with other lipid-lowering therapies (e.g., statins, LDL apheresis)

• SC: 420mg, once monthly OR 420mg, every 2 weeks

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Patients on apheresis may initiate treatment with 420mg every 2 weeks to correspond with their apheresis schedule

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3 pre-filled syringes or 3 pre-filled pens administered consecutively within 30 minutes delivers the 420mg once monthly or 420mg every 2 weeks dose

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See additional prescribing points for special instructions for administration and handling

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See additional prescribing points for use with other lipid-lowering therapies

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Indications and dosages registered in other jurisdictions

Primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia) and mixed dyslipidaemia as an adjunct to diet (Additional agent(s) may be required)
- 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
- Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated

• SC: 140mg, every 2 weeks OR 420mg, once monthly, both doses are clinically equivalent

Homozygous familial hypercholesterolaemia (Additional agents required)
- In combination with other lipid-lowering therapies

• SC: Initial: 420mg, once monthly; Titrate after 12 weeks to 420mg, every 2 weeks (if a clinically meaningful response is not achieved)

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Patients on apheresis may initiate treatment with 420mg every 2 weeks to correspond with their apheresis schedule

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Established atherosclerotic cardiovascular disease (myocardial infarction, stroke or peripheral arterial disease) to reduce cardiovascular risk by lowering LDL-C levels, as an adjunct to correction of other risk factors (Additional agent(s) may be required)
- 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

• SC: 140mg, every 2 weeks OR 420mg, once monthly, both doses are clinically equivalent

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Evolocumab is administered subcutaneously. It must not be administered intravenously or intramuscularly

Paed. forms avail. in SA and covered in this monograph: inj

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Homozygous familial hypercholesterolaemia (Additional agents required)
- To reduce LDL-C, TC, ApoB, and non-HDL-C in combination with other lipid-lowering therapies (e.g., statins, LDL apheresis)

Younger than 12 years

• No information available

12 years and older

• See adult dosage

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Evolocumab is administered subcutaneously

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Evolocumab is intended for patient self-administration

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Administration should be performed by an individual who has been trained to administer the product

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Safety and effectiveness of evolocumab in paediatric patients with primary hyperlipidaemia and mixed dyslipidaemia have not been established

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14 adolescent patients aged 12 years and over have been included in homozygous familial hypercholesterolaemia clinical studies. No overall differences in safety and efficacy were observed between adolescent and adult patients

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See additional prescribing points for special instructions for administration and handling

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See additional prescribing points for use with other lipid-lowering therapies

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Indications and dosages registered in other jurisdictions

Primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia) and mixed dyslipidaemia as an adjunct to diet (Additional agent(s) may be required)
- 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
- Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated

Younger than 10 years

• Not established for use

10 years and older

• See adult dosage

Homozygous familial hypercholesterolaemia (Additional agents required)
- In combination with other lipid-lowering therapies

Younger than 10 years

• Not established for use

10 years and older

• See adult dosage

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Evolocumab is administered subcutaneously. It must not be administered intravenously or intramuscularly

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Safety and effectiveness of evolocumab in paediatric patients with other types of hyperlipidaemia have not been established

Pregnancy

South African recommendations

• Caution; no information available
• There are no adequate and well-controlled studies of evolocumab in pregnant women 
• In cynomolgus monkeys, no effects on embryo-foetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed throughout pregnancy at exposure levels 12-fold higher than those achieved in patients receiving evolocumab at the 420mg once monthly clinical dosing regimen based on area under the concentration curve (AUC). Animal studies are not always predictive of human response
• Therefore, it is not known whether evolocumab can cause foetal harm when administered to a pregnant woman and it should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus
• See additional prescribing points for use with other lipid-lowering therapies

Recommendations in other jurisdictions

• Caution; not recommended
• There are no or limited amount of data from the use of evolocumab in pregnant women
• Animal studies do not indicate direct or indirect effects with respect to reproductive toxicity
• Should not be used during pregnancy unless the clinical condition of the woman requires treatment with evolocumab

Breastfeeding

South African recommendations

• Caution 
• It is not known whether evolocumab is present in human breast milk. As numerous agents can be present in breast milk and because of the potential adverse effects in breastfeeding infants from evolocumab, a decision should be made whether to discontinue it or discontinue breastfeeding, taking into account the potential benefit of drug therapy to the mother, or breastfeeding to the infant

Recommendations in other jurisdictions

• Caution 
• It is not known whether evolocumab is excreted in human breast milk. A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or discontinue/abstain from evolocumab therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

South African recommendations

• Animal studies did not show any effects on fertility endpoints at AUC exposure levels up to 300-fold higher than in patients receiving evolocumab at 420mg once monthly 

Recommendations in other jurisdictions

• No data on the effect of evolocumab on human fertility are available
• Animal studies did not show any effects on fertility endpoints at area under the concentration time curve (AUC) exposure levels much higher than in patients receiving evolocumab at 420mg once monthly
• In hamsters and cynomolgus monkeys at exposures much higher than patients receiving 420mg evolocumab once monthly, no effect on male or female fertility was observed

Renal Impairment

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available

Recommendations in other jurisdictions

• No dose adjustment recommended

Hepatic Impairment

South African recommendations

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

Recommendations in other jurisdictions

• Mild (Child-Pugh class A): No dose adjustment recommended
• Moderate (Child-Pugh class B): Caution; no dose adjustment recommended
• Severe (Child-Pugh class C): Caution; no information available

Elderly

• No dose adjustment recommended

Drugs in Sport

•  Permitted - No warnings

Central Nervous System Disorders

• Headache

Respiratory Disorders

• Influenza
• Nasopharyngitis
• Upper respiratory tract infection

Gastrointestinal Disorders

• Nausea

Musculoskeletal Disorders

• Back pain
• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Angioedema
• Rash
• Urticaria
• Injection site reactions
  - Bruising
  - Erythema
  - Haemorrhage
  - Injection site pain
  - Swelling

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Influenza-like illness
• Anti-evolocumab antibodies (See additional prescribing points)

• No significant interactions
  (See additional prescribing points)

• Lipid profile (fasting or non-fasting)
  - Before initiating treatment
  - 4-12 weeks after starting treatment and every 3-12 months thereafter
• Low-density lipoprotein-cholesterol (LDL-C)
  - 4 weeks after starting therapy and just prior to the next scheduled dose

Additional observations

• Signs and symptoms of hypersensitivity reactions
  - Angioedema
  - Urticaria
  - Rash mimicking atopic dermatitis
  - Maculopapular exanthema
  - Bruising
  - Erythema of the skin
  - Swelling at the site of injection
  - Nasopharyngitis
  - Flu-like symptoms

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

Special instructions for administration and handling

• Prior to subcutaneous administration, allow evolocumab to sit at room temperature for at least 30 minutes. Do not warm in any other way
• Avoid vigorous shaking of the product
• Visually inspect the solution for particles and discolouration. Do not use if the solution is cloudy or discoloured or contains large lumps, flakes or coloured particles
• Doses may be administered in the upper arm, thigh, or abdomen. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red, or hard
• Any unused product or waste material should be disposed of in accordance with local requirements

Use with other lipid-lowering therapies

• An approximately 20% increase in the clearance of evolocumab was observed when co-administered with statins. This increased clearance is in part mediated by statins increasing the concentration of PCSK9 which did not adversely impact the pharmacodynamic effect of evolocumab on lipids. However, no statin dose adjustments are necessary when used in combination with evolocumab
• When using evolocumab in combination with statins or other lipid-lowering therapies
  - The prescriber should refer to the contraindications and the warnings and precautions sections of the prescribing information for those medications
  - In women of childbearing potential, refer to the pregnancy section of the prescribing information for those medications

Dry natural rubber

• The needle covers of both the pre-filled pen and glass pre-filled syringe are made from dry natural rubber (a derivative of latex), which may cause severe allergic reactions

Anti-evolocumab antibodies

• In clinical studies, 0.3% of patients (48 out of 17,992 patients) treated with at least one dose of evolocumab tested positive for binding antibody development
• Those whose sera tested positive for binding antibodies were further evaluated for neutralising antibodies and none of them tested positive for neutralising antibodies
• The presence of anti-evolocumab binding antibodies did not impact the pharmacokinetic profile, clinical response, or safety of evolocumab 
• The development of anti-evolocumab antibodies was not detected in clinical trials of paediatric patients treated with evolocumab

Evolocumab is a fully human monoclonal IgG2 that binds selectively to human proprotein convertase subtilisin kexin type 9 (PCSK9) and prevents circulating PCSK9 from binding to the low density lipoprotein receptor (LDLR) on the liver cell surface, thus preventing PCSK9-mediated LDLR degradation. Increasing liver LDLR levels results in associated reductions in serum LDL-cholesterol (LDL-C).

Injection (per ml) 140mg 

• Repatha (Amgen South Africa) originator