Consumer medicine information

Repatha

Evolocumab

BRAND INFORMATION

Brand name

Repatha

Active ingredient

Evolocumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Repatha.

SUMMARY CMI

Repatha®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Repatha?

Repatha contains the active ingredient evolocumab. Repatha is used to treat high cholesterol. Repatha is also used to treat high cholesterol in adults and people 12 years and older who have high cholesterol because of a condition that runs in their family. Repatha can be used with other cholesterol lowering medicines in adults with heart disease to reduce the risk of heart attack, stroke, and certain heart procedures to restore blood flow to the heart.

For more information, see Section 1. Why am I using Repatha? in the full CMI.

2. What should I know before I use Repatha?

Do not use if you have ever had an allergic reaction to evolocumab or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Repatha? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Repatha and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Repatha?

  • Repatha is injected under the skin (subcutaneous)
  • Repatha can be self-administered by injection under the skin after training from your doctor or nurse.

More instructions can be found in Section 4. How do I use Repatha? in the full CMI.

5. What should I know while using Repatha?

Things you should do
  • Remind any doctor, dentist, pharmacist or nurse you visit that you are using Repatha.
  • Keep all of your doctor's appointments so that your progress can be monitored.
Things you should not do
  • Do not stop using this medicine or lower your dose without checking with your doctor.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Repatha affects you.
  • Repatha has no known effects on the ability to drive or use machines, but as a general precaution, avoid driving soon after you have an injection.
Looking after your medicine
  • Store in a refrigerator at 2°C to 8°C. Do not freeze. Do not shake.
  • Keep your medicine in the carton in order to protect from light.

For more information, see Section 5. What should I know while using Repatha? in the full CMI.

6. Are there any side effects?

Side effects that require urgent medical attention include: signs of an allergic reaction, such as rash with shortness of breath, wheezing or difficulty breathing, swelling of the face, mouth, lips, tongue, throat or other parts of the body.

Common side effects include: flu or flu-like symptoms, such as high temperature, runny nose, cough and chills, sore throat or sinus infections, nausea, rash, joint pain, back pain, injection site reactions including redness, bruising, pain, swelling or bleeding.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Repatha®

Active ingredient(s): Evolocumab (rch) - e" voe lok' ue mab

Consumer Medicine Information (CMI)

This leaflet provides important information about using Repatha. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Repatha.

Where to find information in this leaflet:

1. Why am I using Repatha?
2. What should I know before I use Repatha?
3. What if I am taking other medicines?
4. How do I use Repatha?
5. What should I know while using Repatha?
6. Are there any side effects?
7. Product details

1. Why am I using Repatha?

Repatha contains the active ingredient evolocumab. Repatha is a protein (human monoclonal antibody) that lowers cholesterol. Repatha is given as an injection under the skin (subcutaneous).

Repatha is used with other cholesterol lowering medicines in adults with heart disease to reduce the risk of heart attack, stroke, and certain heart procedures to restore blood flow to the heart. Risk factors of heart disease include a history of heart attack, stroke or blood vessel disease.

Repatha is used in adults who cannot control their cholesterol levels by cholesterol lowering diet and exercise. You should stay on your cholesterol lowering diet and exercise as directed by your doctor while taking this medicine.

Cholesterol is one of several fatty substances found in the bloodstream. Your total cholesterol is made up mainly of Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL) cholesterol.

Repatha lowers LDL cholesterol and triglycerides. It can raise your HDL cholesterol as well.

LDL cholesterol can build up in the walls of your arteries forming plaque. Eventually this plaque build-up can lead to a narrowing of the arteries. This narrowing can slow or block blood flow to vital organs such as the heart and brain. This blocking of blood flow can result in a heart attack or stroke and can cause other health problems.

HDL cholesterol helps to keep LDL cholesterol from building up in the arteries and protects against heart disease.

Triglycerides are another form of fat in your blood that may increase your risk for heart disease.

Repatha can be used with other cholesterol lowering medicines in adults to treat high cholesterol. When a statin cannot be used or does not work well, Repatha can be used alone or together with other cholesterol lowering medicines.

Repatha can be used with other cholesterol lowering medicines for people 12 years and older who have high cholesterol because of a condition that runs in their family (homozygous familial hypercholesterolaemia).

2. What should I know before I use Repatha?

Warnings

Do not use Repatha if:

  • you are allergic to evolocumab, or any of the ingredients listed at the end of this leaflet or medicines or other products that are produced by DNA technology using Chinese Hamster Ovary cells.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Repatha has not been tested in pregnant women. It is not known if Repatha will affect your unborn baby.

If you are taking another cholesterol lowering medicine with Repatha, read the patient leaflet of that particular medicine as well.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known whether Repatha is found in breast milk.

Your doctor will help you decide whether to stop breast-feeding, or whether to stop using Repatha, considering the benefit of breast-feeding to the baby and the benefit of Repatha to the mother.

Your doctor can discuss with you the risks and benefits involved.

Use in children and adolescents

  • Do not give this medicine to a child under the age of 18 years except for children over 12 years with a rare form of high cholesterol.
  • Repatha has only been studied in children over 12 years with a rare form of high cholesterol which runs in families, called homozygous familial hypercholesterolaemia.
  • Repatha has not been studied in children under 12 years and has not been studied in children with high cholesterol due to other causes.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Repatha can be used with other cholesterol lowering medicines unless they cannot be used or do not work well.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Repatha.

4. How do I use Repatha?

How much to take / use

  • The recommended dose for adults with high cholesterol and heart disease to reduce the risk of heart attack, stroke and certain heart procedures is either 140 mg single SureClick pen every two weeks or 420 mg once monthly.
  • For homozygous familial hypercholesterolaemia the recommended starting dose is 420 mg once monthly. After 12 weeks your doctor may decide to increase the dose to 420 mg every 2 weeks. If you also receive apheresis, a procedure similar to dialysis where cholesterol and other fats are removed from the blood, your doctor may decide to start you on a dose of 420 mg every two weeks to coincide with your apheresis treatment.
  • If you have been prescribed the 420 mg dose, this can be given as three 140 mg SureClick pens. The three injections should be given consecutively within 30 minutes. Alternatively, the single-use automated mini-doser (AMD) can be used.
  • Follow the instructions provided and use Repatha until your doctor tells you to stop.

When to take / use Repatha

  • Before starting Repatha, you should be on a cholesterol lowering diet and regularly exercising to lower your cholesterol.
  • You should stay on your cholesterol lowering diet and exercise as directed by your doctor while taking Repatha.
  • If your doctor has prescribed Repatha along with other cholesterol lowering medicines, follow your doctor's instructions on how to take these medicines together. Please read the patient leaflet for those medicines as well.
  • Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist or nurse if you are not sure.

How to use Repatha

  • Repatha is injected under the skin.
  • If your doctor decides that you or a caregiver can give the injections of Repatha you or your caregiver will receive training on the right way to prepare and inject Repatha.
  • If using the pre-filled pen, place the correct (yellow) end of the pre-filled pen on the skin before injecting
  • Follow the "Instructions for Use" leaflet in the pack which provides instructions about the right way to store, prepare, and give your Repatha injections at home.

If you forget to use Repatha

Repatha should be used regularly at the same time every 2 weeks or once a month. If you miss your dose at the usual time, use Repatha as soon as you can after the missed dose.

Contact your doctor who will tell you when you should schedule your next dose. Follow that schedule exactly as your doctor has told you.

Do not take a double dose to make up for the dose you missed.

If you use too much Repatha

If you think that you have used too much Repatha, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Repatha?

Things you should do

If you are about to be started on any new medicine, remind your doctor, pharmacist or nurse that you are using Repatha.

Tell any other doctor, nurses, and pharmacist who treat you that you are using this medicine.

If you become pregnant while using this medicine, tell your doctor immediately.

Keep all your doctor's appointments so that your progress can be checked.

Things you should not do

  • Do not use Repatha to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop using your medicine or lower the dosage without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Repatha affects you.

Repatha has no known effects on the ability to drive or use machines, but as a general precaution, avoid driving soon after you have an injection.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Store in a refrigerator at 2°C to 8°C. Do not freeze. Do not shake.
  • Keep your medicine in the carton to protect from light.
  • Your medicine may be left outside the refrigerator to reach room temperature (up to 25°C) before injection. This will make the injection more comfortable.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

When to discard your medicine

After removal from the refrigerator, your medicine may be stored at room temperature (up to 25°C) in the original carton and must be used within 30 days.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
General:
  • flu or flu-like symptoms, such as high temperature, sore throat, runny nose, cough and chills
  • headache
  • skin rash
Infection-related:
  • common cold, such as runny nose, sore throat or sinus infections
Gut-related:
  • nausea
Bone-related:
  • back pain
Muscle-related:
  • joint pain
  • muscle pain (myalgia)
Injection site-related:
  • redness
  • bruising
  • pain
  • swelling
  • bleeding
Speak to your doctor if you have any of these less serious side effects and they worry you.

Very serious side effects

Serious side effectsWhat to do
Signs of a serious allergic reaction:
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, mouth, lips, tongue, throat or other parts of the body
  • skin rash with itching, including rash over the whole body, hives
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Repatha contains

Active ingredient
(main ingredient)		evolocumab
Other ingredients
(inactive ingredients)		proline
glacial acetic acid
polysorbate 80
water for injections
sodium hydroxide

Do not take this medicine if you are allergic to any of these ingredients.

What Repatha looks like

Repatha is a solution which is clear to opalescent, colourless to yellowish, and practically free from particles.

Do not use this medicine if you notice it is discoloured or contains large lumps, flakes or coloured particles.

Repatha is available as:

  • A pack that contains one single-use SureClick pre-filled pen with 140 mg of evolocumab in 1 mL of solution (140 mg/mL) (Aust R 231152)
  • A pack that contains one single-use automated mini-doser (AMD) and one pre-filled cartridge with 420 mg of evolocumab in 3.5 mL of solution (120 mg/mL)
    (Aust R 348651).

Who distributes Repatha

Amgen Australia Pty Ltd
Level 11, 10 Carrington St
Sydney NSW 2000
Ph: 1800 803 638
www.amgenmedinfo.com.au

This leaflet was prepared in March 2023.

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Repatha

Active ingredient

Evolocumab

Schedule

S4

 

1 Name of Medicine

Evolocumab.

2 Qualitative and Quantitative Composition

Repatha is a sterile, preservative-free solution for injection containing 140 mg/mL evolocumab in a pre-filled syringe or pre-filled pen or a 420 mg/3.5 mL solution delivering 120 mg/mL evolocumab in a pre-filled cartridge co-packaged with an automated mini-doser (AMD).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Repatha is a sterile, preservative-free solution, clear to opalescent; colourless to yellowish solution for injection, practically free from particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Repatha is indicated as an adjunct to diet and exercise in:

Prevention of cardiovascular events.

Repatha is indicated to reduce the risk of cardiovascular events (myocardial infarction, stroke and coronary revascularisation) in adults with established cardiovascular disease in combination with an optimally dosed statin and/or other lipid-lowering therapies (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Primary hypercholesterolaemia.

Repatha is indicated in adults with primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia and non-familial hypercholesterolaemia) to reduce low-density lipoprotein cholesterol (LDL-C):
in combination with a statin or statin with other lipid lowering therapies; or
alone or in combination with other lipid lowering therapies in patients who are statin intolerant.

Homozygous familial hypercholesterolaemia.

Repatha is indicated in adults and adolescents aged 12 years and over with homozygous familial hypercholesterolaemia in combination with other lipid lowering therapies.

4.2 Dose and Method of Administration

Dosage (dose and interval).

Primary hypercholesterolaemia and prevention of cardiovascular events.

The recommended dose for Repatha is either 140 mg every 2 weeks or 420 mg once monthly; both doses are clinically equivalent.

Homozygous familial hypercholesterolaemia.

The initial recommended dose for Repatha is 420 mg once monthly. The dose can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks. Patients on apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule.

Method of administration.

Administration should be performed by an individual who has been trained to administer the product.
Prior to subcutaneous administration, allow Repatha to sit at room temperature for at least 30 minutes for the prefilled pen or 45 minutes for the automated mini-doser (AMD).
Do not warm in any other way.
Avoid vigorous shaking the product.
Visually inspect the solution for particles and discolouration. Do not use if the solution is discoloured, cloudy, or if flakes or particles are present.
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.
Repatha is for single use in one patient only. Discard any residue.
Comprehensive instructions for the administration of Repatha are provided in the instructions for use. See Table 1.

Dosage adjustment.

Patients with renal impairment.

No dose adjustment is necessary in patients with renal impairment.

Patients with hepatic impairment.

No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Repatha has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Elderly patients.

No dose adjustment is necessary in elderly patients (age ≥ 65 years).

4.3 Contraindications

Known hypersensitivity to evolocumab or any of the excipients found in Repatha.

4.4 Special Warnings and Precautions for Use

Allergic reactions.

Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients treated with Repatha, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with Repatha, treat according to the standard of care, and monitor until signs and symptoms resolve.

Concomitant lipid lowering therapies.

When using Repatha in combination with statins or other lipid lowering therapies (e.g. ezetimibe), the prescriber should refer to the Contraindications and Special Warnings and Precautions sections of the prescribing information for those medications.

Low LDL-C levels.

Although adverse consequences of very low LDL-C were not identified in the clinical trials with an average exposure of 2 years, the long-term effects of very low levels of LDL-C induced by Repatha are unknown.

Immunogenicity.

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

Use in hepatic impairment.

No dose adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh A or B). Repatha has not been studied in patients with severe hepatic impairment (Child-Pugh C).

Use in renal impairment.

No dose adjustment is necessary in patients with chronic kidney disease (CKD).

Use in the elderly.

Of the 18,546 hypercholesterolaemia patients treated with Repatha in double blind clinical studies, 7,656 (41.3%) were ≥ 65 years old, while 1500 (8.1%) were ≥ 75 years old. No overall differences in safety or efficacy were observed between the elderly and younger patients.

Paediatric use.

The safety and effectiveness of Repatha have not been established in paediatric patients with primary hypercholesterolaemia. Fourteen adolescent patients aged 12 years and over have been included in HoFH clinical studies. No overall differences in safety or efficacy were observed between adolescent and adult patients with HoFH. Long-term safety has not been established in children.

Effects on laboratory tests.

An integrated safety analysis of phase 2 and 3 randomised controlled studies of Repatha with statin therapy for up to 52 weeks duration was performed to assess alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and creatine kinase (CK) for patients with normal values at baseline. The incidence of ALT or AST > 5-fold the upper limit of normal was 0.1% in both the Repatha (N=2523) and control (N=1249) groups. In the same studies, CK > 10-fold the upper limit of normal was 0.2% (N=2486) in the Repatha group and 0.1% (N=1217) in the control group.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug-drug interaction studies have been conducted for Repatha.
The pharmacokinetic interaction between statins and Repatha was evaluated in the Repatha clinical trials. An approximate 20% increase in the clearance of Repatha was observed in patients coadministered 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 Repatha on lipids. No statin dose adjustments are necessary when used in combination with Repatha.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data are available on the effect of Repatha on human fertility. In hamsters, there was no effect on male or female fertility (including oestrous cycling, sperm analysis, mating performance and embryonic development) when evolocumab was administered at dose levels up to 100 mg/kg every 2 weeks (AUC exposure estimate 7-fold higher than in patients receiving Repatha at 420 mg once every 2 weeks). In sexually mature cynomolgus monkeys, no effects were observed on reproductive organ histopathology, menstrual cycling, or sperm parameters following administration of evolocumab at dose levels up to 300 mg/kg weekly for 6 months (AUC exposure up to 133-fold higher than in patients receiving Repatha at 420 mg once every 2 weeks).
(Category B1)
Category B1 refers to drugs where animal studies have not shown evidence of an increased occurrence of foetal damage and which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed.
In cynomolgus monkeys, no effects on embryofoetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed throughout pregnancy at AUC exposure levels 5-fold higher than those achieved in patients receiving Repatha 420 mg once every 2 weeks.
Animal studies are not always predictive of human response. Therefore, it is not known whether Repatha can cause foetal harm when administered to a pregnant woman and Repatha should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
When Repatha is administered with a statin or other lipid lowering therapies (e.g. ezetimibe) in women of childbearing potential, refer to the Use in pregnancy section of the prescribing information for those medications.
 It is not known whether Repatha is present in human milk. Many drugs are present in human milk and because of the potential for adverse effects in nursing infants from Repatha, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the potential benefit of the drug to the mother and the potential benefit of breastfeeding to the infant.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The safety of evolocumab was evaluated in 35,141 patients with primary hypercholesterolaemia, 18,546 patients received evolocumab 140 mg every two weeks or 420 mg once monthly representing 32,231 patient-years of exposure with 14,226 patients treated for 12 months or longer. In two clinical studies in 99 patients with homozygous familial hypercholesterolaemia, there were 63 patient-years of exposure to evolocumab 420 mg every two weeks or once monthly; 23 of them were treated for 12 months or longer. In clinical studies, the incidence of adverse events was similar between evolocumab and control groups. The adverse reactions associated with evolocumab were usually mild to moderate.

Summary of adverse events.

Adverse events reported by preferred term for patients treated with evolocumab at an incidence rate ≥ 2.0% compared to any control, are shown in Table 2.

Summary of adverse reactions.

Adverse reactions are displayed by system organ class and frequency in Table 3 using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000).
The safety profile in the HoFH population was consistent with that demonstrated in the primary hypercholesterolaemia population.

Other adverse reactions.

A tabulated listing of adverse reactions reported in < 2% of patients treated with evolocumab to a 0.5% cut off, at an incidence greater than any control, are shown in Table 4.

Post marketing experience.

Hypersensitivity reactions including angioedema, influenza-like illness, myalgia, headache.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no specific treatment for Repatha overdose. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Repatha binds selectively and with high affinity to PCSK9 and inhibits 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 low density lipoprotein cholesterol (LDL-C).

Pharmacodynamics.

Clinical studies have demonstrated that elevated levels of total cholesterol (TC), nonhigh density lipoprotein cholesterol (non-HDL-C), LDL-C and apolipoprotein B (ApoB), the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis.
Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of TC, non-HDL-C, LDL-C, ApoB and lipoprotein(a) [Lp(a)], and inversely with the level of HDL-C. Like LDL, cholesterol enriched triglyceride rich lipoproteins, including very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering triglycerides (TG) or Lp(a) on the risk of cardiovascular morbidity and mortality has not been determined.
In clinical trials, in patients with primary hypercholesterolaemia, Repatha reduced LDL-C, TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/apolipoprotein A1 (ApoA1), VLDL-C, TG and Lp(a), and increased HDL-C and ApoA1.
A single subcutaneous administration of Repatha 140 mg or 420 mg resulted in maximum suppression of circulating unbound PCSK9 by 4 hours followed by a reduction in LDL-C reaching a mean nadir in response by 14 and 21 days, respectively. Changes in unbound PCSK9 and serum lipoproteins were reversible upon discontinuation of Repatha. No increase in unbound PCSK9 or LDL-C above baseline was observed during the washout of evolocumab suggesting that compensatory mechanisms to increase production of PCSK9 and LDL-C do not occur during treatment.
Based on dose range finding studies, subcutaneous regimens of 140 mg every 2 weeks and 420 mg once monthly were identified as the optimal regimens to achieve maximal LDL-C lowering (see Figure 1) and were equivalent in average LDL-C lowering (mean of weeks 10 and 12), resulting in -72% to -57% from baseline compared to placebo.
Treatment with Repatha resulted in a similar reduction of LDL-C when used alone or in combination with other lipid lowering therapy. The effect of LDL-C lowering is sustained.
Doses of 140 mg subcutaneously every 2 weeks and 420 mg subcutaneously once monthly achieve approximately 80% of the theoretical maximal reduction in calculated LDL-C at the mean of weeks 10 and 12 based on exposure response models. Intrinsic and extrinsic covariates, such as demographics, comedications, laboratory variables and disease states are not expected to modify the LDL-C response (see Section 4.2 Dose and Method of Administration).

Clinical trials.

Summary of clinical efficacy.

Prevention of cardiovascular events.

In adults with established cardiovascular disease in combination with a statin and/or other lipid-lowering therapies:
Repatha significantly reduced the risk for the primary composite endpoint (time to cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina, or coronary revascularisation, whichever occurred first) by 15% compared to placebo.
Repatha reduced the risk of the key secondary composite endpoint (time to cardiovascular death, myocardial infarction, or stroke, whichever occurred first) by 20% compared with placebo.
9,518 patients treated with Repatha in the cardiovascular outcomes study, achieved at least one LDL-C value < 0.6 mmol/L. These patients had similar types of adverse events at a similar or lower incidence, compared to patients treated with Repatha or placebo who always had LDL-C ≥ 1.0 mmol/L.

Regression of atherosclerosis.

In adults with coronary artery disease on lipid-lowering therapy, Repatha reduced percent atheroma volume (PAV) and total atheroma volume (TAV) by 1.01% (0.64, 1.38) and 4.89 mm3 (2.53, 7.25) respectively from baseline to week 78 compared to placebo (p < 0.0001).

Primary hypercholesterolaemia.

Repatha reduced LDL-C, TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG, and Lp(a), and increased HDL-C and ApoA1 in patients with primary hypercholesterolaemia.
Repatha was superior to ezetimibe in reducing LDL-C, TC, ApoB, non-HDL-C, Lp(a), TC/HDL-C, and ApoB/ApoA1.
Repatha 140 mg every 2 weeks and 420 mg once monthly dosing regimens are clinically equivalent.
LDL-C reduction of approximately 55% to 75% was achieved with Repatha as early as week 1 and maintained with long-term therapy. Maximal response was generally achieved within 1 to 2 weeks after dosing.
In 80 to 85% of all patients treated with either dose, Repatha demonstrated a ≥ 50% reduction in LDL-C at the mean of weeks 10 and 12.
Up to 99% of patients treated with either dose of Repatha achieved an LDL-C of < 2.6 mmol/L and up to 95% patients treated with either dose of Repatha achieved an LDL-C < 1.8 mmol/L at the mean of weeks 10 and 12.
Repatha was effective in reducing LDL-C regardless of baseline characteristics, with no notable differences observed between subgroups, such as age, race, gender, region, body mass index, National Cholesterol Education Program (NCEP) risk, current smoking status, baseline coronary heart disease (CHD) risk factors, family history of premature CHD, glucose tolerance status (i.e. diabetes mellitus type 2, metabolic syndrome, or neither), hypertension, statin dose and intensity, unbound baseline PCSK9, baseline LDL-C and baseline TG.

Homozygous familial hypercholesterolaemia.

Repatha was effective in reducing LDL-C, TC, ApoB, and non-HDL-C in patients with homozygous familial hypercholesterolaemia (HoFH).
Repatha 420 mg once monthly and 420 mg once every 2 weeks demonstrated a sustained treatment effect as evidenced by a reduction in LDL-C of approximately 20% to 30% in patients with HoFH not on apheresis and approximately 15% to 25% in patients with HoFH on apheresis.
No overall differences in safety or efficacy of Repatha were observed between adolescent and adult patients with HoFH.
Prevention of cardiovascular events. FOURIER was a phase 3, double-blind, randomised, placebo-controlled, event-driven, cardiovascular outcomes study to evaluate the effects of Repatha treatment in adult patients with established cardiovascular disease [prior myocardial infarction (81%), prior non-haemorrhagic stroke (19%), or symptomatic peripheral arterial disease (13%)].
Enrolled patients were on a stable background lipid lowering therapy and had LDL-C values ≥ 1.8 mmol/L or non-HDL-C values ≥ 2.6 mmol/L with at least one major or two minor risk factors. Most patients (99.7%) were on a high (69.3%) or moderate-intensity (30.4%) statin therapy at baseline and most patients (99.6%) were taking at least one other cardiovascular medication such as anti-platelet agents, beta blockers, ACE inhibitors, or angiotensin receptor blockers.
A total of 27,564 patients were randomised 1:1 to receive either Repatha (140 mg every 2 weeks or 420 mg once monthly) or placebo (every 2 weeks or once monthly, respectively) subcutaneously with regular assessments every 12 weeks. Patients were followed for a mean (SD) of 26.1 (6.4) months. A total of 24.6% of patients were female, 85.1% were White, 9.9% were Asian, 2.4% were Black, and 7.9% were Hispanic/Latino. The mean (SD) age was 62.5 (9.0) years. The median (Q1, Q3) LDL-C at baseline was 2.4 (2.1, 2.8) mmol/L.
Repatha significantly reduced the risk for the primary composite endpoint (time to cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina, or coronary revascularisation, whichever occurred first) and the key secondary composite endpoint (time to cardiovascular death, myocardial infarction, or stroke, whichever occurred first). No significant difference was observed on cardiovascular or all-cause mortality; the study was not powered to detect such a difference. The results of primary and secondary efficacy endpoints are shown in Table 5, Figure 2 and Figure 3.
The Kaplan-Meier curves for the primary and key secondary composite endpoints separated at approximately five months and the magnitudes of the absolute risk reductions grew steadily over time.
In an exploratory landmark analysis of post-baseline subgroups, Repatha reduced the risk of the primary and key secondary composite endpoints more after the first year than in the first year of the study.
The efficacy of Repatha on the primary and key secondary composite endpoints was consistent across all pre-specified subgroups (e.g. baseline LDL-C, geographic region, age, sex, race, prior non-haemorrhagic stroke, symptomatic PAD, length of prior myocardial infarction, intensity of statin treatment at baseline, history of type 2 diabetes, ezetimibe use at baseline) relative to placebo.
Repatha reduced LDL-C by a median (Q1, Q3) of 63.8% (32.3, 76.8) to 69.5% (55.7, 79.1). The treatment difference in LDL-C reduction between Repatha and placebo ranged from 52.1% (95% CI: 49.2%, 55.0%) to 60.7% (95% CI: 60.1, 61.3). These reductions were maintained for more than three years. Corresponding median (Q1, Q3) LDL-C concentrations ranged from 0.7 (0.5, 1.1) mmol/L to 0.9 (0.5, 1.7) mmol/L in the Repatha group and 25% of patients achieved a LDL-C concentration < 0.5 mmol/L.
Of the patients treated with Repatha, 9518 achieved at least one LDL-C value < 0.6 mmol/L. These patients had similar or lower incidence and similar type of adverse events, including neurocognitive events and new onset diabetes, compared to patients treated with Repatha or placebo who always had LDL-C ≥ 1.0 mmol/L.
In a separate study of 1974 patients with established cardiovascular disease enrolled in the FOURIER study, evolocumab was non-inferior to placebo for effects on the cognitive domain of executive function and other cognitive domains, assessed by the CANTAB Spatial Working Memory strategy index of executive function. There was no evidence that Repatha had a detrimental effect on cognitive domains based on the analysis of data from 1204 patients (586 Repatha, 618 placebo).
Effect on LDL-C during acute phase of acute coronary syndrome (ACS). EVOPACS was an investigator-sponsored, multicentre, double-blind, randomised, placebo controlled, 8-week study conducted in Switzerland of Repatha in 308 patients admitted to the hospital within 24 to 72 hours of an ACS event who received concomitant atorvastatin. Repatha 420 mg once monthly significantly reduced LDL-C from baseline to week 8 compared with placebo (p < 0.001).
The mean (SD) reduction in calculated LDL-C from baseline at week 8 was 77.1% (15.8%) in the evolocumab group and 35.4% (26.6%) in the placebo group, with a least squares (LS) mean difference (95% CI) of 40.7% (36.2%, 45.2%). Baseline LDL-C values were 3.61 mmol/L in the evolocumab group and 3.42 mmol/L in the placebo group. LDL-C reductions in this study were consistent with previous studies where evolocumab was added to stable lipid-lowering therapy as demonstrated by on-treatment LDL-C levels at week 8 in this study (reflecting steady-state effect of high-intensity statin in both treatment arms) of 0.79 mmol/L and 2.06 mmol/L in the evolocumab plus atorvastatin and the placebo plus atorvastatin groups, respectively.
The effects of evolocumab in this patient population were consistent with those observed in previous studies in the evolocumab clinical development program and no new safety concerns were noted.
Effect on coronary atherosclerotic plaque morphology. HUYGENS was a phase 3, 52-week, double blind, randomised, placebo controlled study to evaluate the effects of Repatha 420 mg once monthly on coronary atherosclerotic plaques as assessed by optical coherence tomography (OCT) including adult patients initiated within 7 days of a non ST segment elevation acute coronary syndrome (NSTEACS) on maximally tolerated statin therapy. For the primary endpoint of absolute change in minimum FCT (fibrous cap thickness) in a matched segment of artery from baseline, least squares (LS) mean (95% CI) increased from baseline by 42.7 micrometer (32.4, 53.1) in the Repatha group and 21.5 micrometer (10.9, 32.1) in the placebo group, an additional 21.2 micrometer (4.7, 37.7) compared to placebo (p = 0.015; 38% difference (p = 0.041)). The reported secondary findings show treatment differences including change in mean minimum FCT (increase 32.5 micrometer (12.7, 52.4); p = 0.016) and absolute change in maximum lipid arc (-26° (49.6, -2.4); p = 0.041).
The contribution of these findings to Repatha's known effect on reducing the risk of CV events is not yet known.
Regression of atherosclerosis. GLAGOV was a phase 3, double-blind, randomised, placebo-controlled study to evaluate the effects of Repatha treatment on coronary atherosclerotic disease as measured by intravascular ultrasound (IVUS).
Enrolled patients were required to be on a stable background lipid-lowering therapy and to have a LDL-C of ≥ 2.1 mmol/L or LDL-C ≥ 1.6 to < 2.1 mmol/L with one major or three minor cardiovascular risk factors. These patients had coronary artery disease and required coronary angiography.
A total of 970 patients were randomised 1:1 into two treatment groups to either receive Repatha 420 mg once monthly or placebo once monthly as subcutaneous injections for 76 weeks. IVUS was performed at baseline and at week 78. A total of 27.8% of patients were female and 93.8% were white. The mean (SD) age was 59.8 (9.2) years. The mean (SD) LDL-C at baseline was 2.4 (0.7) mmol/L.
Repatha reduced the percent atheroma volume (PAV) and total atheroma volume (TAV) by 1.01% (0.64, 1.38) and 4.89 mm3 (2.53, 7.25) respectively from baseline to week 78 compared with placebo (p < 0.0001). Atherosclerosis regression, defined as any reduction in PAV or TAV at week 78, was observed in 17% and 12.5% more patients treated with Repatha than patients treated with placebo for PAV and TAV respectively. The results of the study are shown in Table 6.
Exploratory endpoints showed the treatment difference in LDL-C reduction between Repatha and placebo was 68.7 (95% CI: 64.7, 72.7) from baseline to week 78. These reductions were maintained through the end of the study. Corresponding mean (SD) LDL-C concentrations at week 78 were 0.8 (0.7) mmol/L in the Repatha group.
Clinical trials for primary hypercholesterolaemia.

Combination with statin or statin with other lipid lowering therapies.

LAPLACE-2 was an international, multicentre, double blind, randomised, 12 week study of Repatha in 1896 patients with primary hypercholesterolaemia who were randomised to receive Repatha in combination with statins (rosuvastatin, simvastatin or atorvastatin). Repatha was compared with placebo for the rosuvastatin and simvastatin groups and compared with placebo and ezetimibe for the atorvastatin group.
In LAPLACE-2, Repatha exhibited consistent treatment effects of lowering LDL-C and improving other lipid parameters across all statins and statin doses that were evaluated.
Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 compared with placebo for the rosuvastatin and simvastatin groups and compared to placebo and ezetimibe for the atorvastatin group (p < 0.001) (see Figure 4). Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a) and increased HDL-C from baseline to mean of weeks 10 and 12 as compared with placebo for the rosuvastatin and simvastatin groups (p < 0.05) and significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1 and Lp(a) compared with placebo and ezetimibe for the atorvastatin group (p < 0.001).
In a prespecified analysis of LAPLACE-2, Repatha significantly reduced LDL-C, TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a) and increased HDL-C and ApoA1 from baseline to mean of weeks 10 and 12 compared with placebo for the combined rosuvastatin, simvastatin and atorvastatin groups (p < 0.001) (see Table 7). Consistent treatment effects were observed in an analysis of Repatha compared with ezetimibe for the combined atorvastatin treatment groups (see Table 8).
RUTHERFORD-2 was an international, multicentre, double blind, randomised, placebo controlled, 12 week study of Repatha in 329 patients with heterozygous familial hypercholesterolaemia (HeFH) on lipid lowering therapies. Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12, compared with placebo (p < 0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG, and Lp(a), and increased HDL-C and ApoA1 from baseline to mean of weeks 10 and 12 compared with placebo (p < 0.05) (see Table 7).

Statin intolerant therapy.

GAUSS-2 was an international, multicentre, double blind, randomised, ezetimibe controlled, 12 week study of Repatha in 307 patients who were statin intolerant or unable to tolerate an effective dose of a statin. Repatha significantly reduced LDL-C compared to ezetimibe (p < 0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, and Lp(a) from baseline to mean of weeks 10 and 12 compared with ezetimibe (p < 0.001) (see Table 8).

Monotherapy.

MENDEL-2 was an international, multicentre, double-blind, randomised, placebo and ezetimibe-controlled, 12-week study of Repatha in 614 patients with hypercholesterolaemia. Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 compared with both placebo and ezetimibe (p < 0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, and Lp(a) from baseline to mean of weeks 10 and 12 compared with both placebo and ezetimibe (p < 0.001) (Table 7 and Table 8).

Long-term efficacy in primary hypercholesterolaemia.

DESCARTES was an international, multicentre, double blind, randomised, placebo controlled, 52 week study of Repatha in 901 patients with hypercholesterolaemia who were receiving diet alone, atorvastatin, or a combination of atorvastatin and ezetimibe. Repatha 420 mg once monthly significantly reduced LDL-C from baseline at 52 weeks compared with placebo (p < 0.001). Treatment effects were sustained over 1 year as demonstrated by reduction in LDL-C from week 12 to week 52 (see Figure 5). Reduction in LDL-C from baseline at week 52 compared with placebo was consistent across background lipid lowering therapies optimised for LDL-C and cardiovascular risk. Repatha 420 mg once monthly significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG, and Lp(a), and increased HDL-C at week 52 compared with placebo (p < 0.001) (see Table 9).
OSLER-1 and OSLER-2 were two randomised, controlled, open label extension studies to assess the long-term safety and efficacy of Repatha in patients who completed treatment in a 'parent' study. In each extension study, patients were randomised 2:1 to receive either Repatha plus standard of care (evolocumab group) or standard of care alone (control group) for the first year of the study. At the end of the first year (week 52 in OSLER-1 and week 48 in OSLER-2), patients were eligible to enter the all Repatha period in which all patients could receive open label Repatha for either another 4 years (OSLER-1) or 2 years (OSLER-2).
A total of 1324 patients enrolled in OSLER-1. Repatha 420 mg once monthly reduced LDL-C from baseline at week 12 and week 52 compared with control. Treatment effects were maintained over 272 weeks as demonstrated by a reduction in LDL-C from week 12 in the parent study to week 260 in the open label extension and the safety profile remained the same. A total of 3681 patients enrolled in OSLER-2. Repatha reduced LDL-C from baseline at week 12 and week 48 compared with control. Treatment effects were maintained as demonstrated by reduction in LDL-C from week 12 to week 104 in the open label extension. Repatha reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a), and increased HDL-C and ApoA1 from baseline to week 52 in OSLER-1 and to week 48 in OSLER-2 compared with control. LDL-C and other lipid parameters returned to baseline within 12 weeks after discontinuation of Repatha at the beginning of OSLER-1 without evidence of rebound.
TAUSSIG was a multicentre, open label 5 year extension study to assess the long-term safety and efficacy of Repatha in patients with severe familial hypercholesterolaemia (FH), including homozygous familial hypercholesterolaemia (HoFH), who were treated with Repatha as an adjunct to other lipid lowering therapies. A total of 194 severe FH (non-HoFH) patients and 106 HoFH patients enrolled in TAUSSIG. All patients in the study were initially treated with Repatha 420 mg once monthly except for those receiving lipid apheresis at enrolment, who began with Repatha 420 mg every 2 weeks. Dose frequency in nonapheresis patients could be titrated up to 420 mg once every 2 weeks based on LDL-C response and PCSK9 levels. Repatha demonstrated a sustained treatment effect as evidenced by a reduction of LDL-C in patients with severe FH (non-HoFH) (see Table 10). Changes in other lipid parameters (TC, ApoB, non-HDL-C, TC/HDL-C, and ApoB/ApoA1) also demonstrated a sustained effect of ongoing Repatha administration in patients with severe FH (non-HoFH).

Homozygous familial hypercholesterolaemia.

TESLA was an international, multicentre, double blind, randomised, placebo controlled 12 week study of Repatha in 49 HoFH patients between 12 to 65 years of age (including 10 adolescent patients) evaluated for their response to 420 mg once monthly as an adjunct to other lipid lowering therapies (e.g. statins, bile acid sequestrants). Repatha 420 mg once monthly significantly reduced LDL-C and ApoB at week 12 compared with placebo (p < 0.001) (see Table 11). Changes in other lipid parameters (TC, non-HDL-C, TC/HDL-C, and ApoB/ApoA1) also demonstrated a treatment effect of Repatha administration in patients with HoFH.

Efficacy in homozygous familial hypercholesterolaemia.

In TAUSSIG, Repatha demonstrated a sustained treatment effect as evidenced by reduction of LDL-C in patients with HoFH (overall, nonapheresis, apheresis) (see Table 12). Changes in other lipid parameters (TC, ApoB, non-HDL-C, TC/HDL-C, and ApoB/ApoA1) also demonstrated a sustained effect of Repatha administration in patients with HoFH. Reductions in LDL-C and changes in other lipid parameters in 14 adolescent patients (12 to < 18 years of age) with HoFH were comparable to those in the overall HoFH study population.

5.2 Pharmacokinetic Properties

Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Administration of the 140 mg dose in healthy volunteers resulted in a Cmax mean (standard deviation [SD]) of 18.6 (7.3) microgram/mL and AUClast mean (SD) of 188 (98.6) day.microgram/mL. Administration of the 420 mg dose in healthy volunteers resulted in a Cmax mean (SD) of 59.0 (17.2) microgram/mL and AUClast mean (SD) of 924 (346) day.microgram/mL. Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be 12 (2) mL/hr. An approximate 2 to 3-fold accumulation was observed in trough serum concentrations (Cmin [SD] 7.21 [6.6]) following 140 mg doses administered subcutaneously every 2 weeks or following 420 mg doses administered subcutaneously monthly (Cmin [SD] 11.2 [10.8]), and serum trough concentrations approached steady state by 12 weeks of dosing.

Absorption.

Following a single subcutaneous dose of 140 mg or 420 mg Repatha administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days and estimated absolute bioavailability was 72%.

Distribution.

Following a single 420 mg Repatha intravenous dose, the steady-state volume of distribution was estimated to be 3.3 (0.5) L, suggesting Repatha has limited tissue distribution.

Metabolism.

As a fully human IgG2 antibody, the clearance of Repatha is mediated by specific binding and complex formation with its target ligand, PCSK9, as well as by typical IgG clearance processes in the reticuloendothelial system (RES). Repatha is expected to be degraded into small peptides and amino acids via these catabolic pathways.

Excretion.

Repatha was estimated to have an effective half-life of 11 to 17 days.
No time dependent changes were observed in serum evolocumab concentrations over a period of 124 weeks.
An approximate 20% increase in the clearance of Repatha was observed in patients coadministered 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 Repatha on lipids. Population pharmacokinetic analysis indicated no appreciable differences in evolocumab serum concentrations in hypercholesterolaemic (non-FH or FH) patients taking concomitant statins (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Special populations.

Population pharmacokinetic analyses suggest that no dose adjustments are necessary for age, race or gender. The pharmacokinetics of Repatha were influenced by bodyweight without having any notable impact on LDL-C lowering. Therefore, no dose adjustments are necessary based on bodyweight.

Hepatic impairment.

Single 140 mg subcutaneous doses of Repatha were studied in 8 patients with mild hepatic impairment, 8 patients with moderate hepatic impairment and 8 healthy subjects. The exposure to evolocumab was found to be approximately 40% to 50% lower compared with healthy subjects. However, baseline PCSK9 levels and the degree and time course of PCSK9 neutralisation were found to be similar between patients with mild or moderate hepatic impairment and healthy subjects. This resulted in similar time course and extent of absolute LDL-C lowering.

Renal impairment.

Population pharmacokinetic analysis of integrated data from the Repatha clinical trials did not reveal a difference in pharmacokinetics in Chronic Kidney Disease (CKD) patients with stages 2 and 3 renal impairment relative to nonrenally impaired patients.
In a clinical trial of 18 patients with either normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2), stage 4 CKD (eGFR < 30 mL/min/1.73 m2) or stage 5 CKD (estimated glomerular filtration rate [eGFR] < 15 mL/min/1.73 m2 or on dialysis), exposure, as assessed by Cmax, was found to be approximately 30% to 45% lower in patients with stage 4 or 5 CKD compared with patients with normal renal function. The median tmax was similar across all groups. The pharmacodynamics and safety of Repatha in patients with stage 4 or 5 CKD were similar to patients with normal renal function and there were no clinically meaningful differences in LDL-C lowering.
Therefore, no dose adjustments are necessary in patients with stage 4 or 5 CKD.

5.3 Preclinical Safety Data

Genotoxicity.

The mutagenic potential of Repatha has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.

Carcinogenicity.

The carcinogenic potential of Repatha was evaluated in a lifetime study conducted in the hamster at dose levels up to 100 mg/kg every 2 weeks (AUC exposure 7-fold higher than in patients receiving Repatha at 420 mg once every 2 weeks). There were no evolocumab related tumours. Expected serum LDL-C lowering was observed throughout the study.

6 Pharmaceutical Particulars

6.1 List of Excipients

Repatha is formulated from proline, glacial acetic acid, polysorbate 80, water for injections and sodium hydroxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store refrigerated at 2°C to 8°C in the original carton.
If removed from the refrigerator, Repatha should be kept at controlled room temperature (up to 25°C) in the original carton and must be used within 30 days.
Protect Repatha from direct light and do not expose to temperatures above 25°C.
Do not freeze.
Do not shake.

6.5 Nature and Contents of Container

The needle cover of the glass pre-filled syringe and the pre-filled pen is made from dry natural rubber (a derivative of latex).
Repatha is provided as a:
1 mL solution (140 mg/mL evolocumab) in a single use pre-filled syringe made from type I glass with stainless steel needle, supplied as a 1-pack.*
* Not available in Australia.
1 mL solution (140 mg/mL evolocumab) in a single use pre-filled pen with type 1 glass syringe and stainless steel needle; supplied as a 1-pack, 2-pack*, and 3-pack*.
* Not available in Australia.
3.5 mL solution (420 mg/3.5 mL evolocumab) delivering 120 mg/mL evolocumab in a single-use prefilled cartridge assembly made from Crystal Zenith resin which is co-packaged with an administration device (AMD). The administration device is a compact, sterile, single-use, disposable, injection device intended for use only with the provided 3.5 mL pre-filled cartridge assembly; supplied as a 1-pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Repatha is a fully human immunoglobulin G2 (IgG2) monoclonal antibody with high affinity binding to Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). Repatha has an approximate molecular weight of 144 kDa and is produced using recombinant DNA technology in mammalian (Chinese hamster ovary, CHO) cells.

CAS number.

1256937-27-5.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes