REPATHA 140mg injection for pre-filled pen medication leaflet

Repatha 140 mg solution for injection in pre-filled syringe

Repatha 140 mg solution for injection in pre-filled pen

Repatha 420 mg solution for injection in cartridge

Repatha 140 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 140 mg of evolocumab in 1 mL of solution.

Repatha 140 mg solution for injection in pre-filled pen

Each pre-filled pen contains 140 mg of evolocumab in 1 mL of solution.

Repatha 420 mg solution for injection in cartridge

Each cartridge contains 420 mg of evolocumab in 3.5 mL of solution (120 mg/mL).

Repatha is a human IgG2 monoclonal antibody produced in Chinese hamster ovary (CHO) cells byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Solution for injection (injection) in pre-filled pen (SureClick).

Solution for injection (injection) (automated mini-doser).

The solution is clear to opalescent, colourless to yellowish, and practically free from particles.

Hypercholesterolaemia and mixed dyslipidaemia

Repatha is indicated in adults with primary hypercholesterolaemia (heterozygous familial andnon-familial) or mixed dyslipidaemia, and in paediatric patients aged 10 years and over withheterozygous familial hypercholesterolaemia, as an adjunct to diet:

* in combination with a statin or statin with other lipid-lowering therapies in patients unable toreach 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.

Homozygous familial hypercholesterolaemia

Repatha is indicated in adults and paediatric patients aged 10 years and over with homozygousfamilial hypercholesterolaemia in combination with other lipid-lowering therapies.

Established atherosclerotic cardiovascular disease

Repatha is indicated in adults with established atherosclerotic cardiovascular disease (myocardialinfarction, stroke or peripheral arterial disease) to reduce cardiovascular risk by lowering LDL-Clevels, as an adjunct to correction of other risk factors:

* in combination with the maximum tolerated dose of a statin with or without other lipid-loweringtherapies or,

* alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant,or for whom a statin is contraindicated.

For study results with respect to effects on LDL-C, cardiovascular events and populations studied seesection 5.1.

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

Primary hypercholesterolaemia and mixed dyslipidaemia (including heterozygous familialhypercholesterolaemia)

Adults and paediatric patients (aged 10 years and over)

The recommended dose of evolocumab is either 140 mg every two weeks or 420 mg once monthly;both doses are clinically equivalent.

Homozygous familial hypercholesterolaemia in adults and paediatric patients aged 10 years and over

The initial recommended dose is 420 mg once monthly. After 12 weeks of treatment, dose frequencycan be up-titrated to 420 mg once every 2 weeks if a clinically meaningful response is not achieved.

Patients on apheresis may initiate treatment with 420 mg every two weeks to correspond with theirapheresis schedule.

Established atherosclerotic cardiovascular disease in adults

The recommended dose of evolocumab is either 140 mg every two weeks or 420 mg once monthly;both doses are clinically equivalent.

Elderly patients (age ≥ 65 years)

No dose adjustment is necessary in elderly patients.

No dose adjustment is necessary in patients with renal impairment (see section 5.2).

No dose adjustment is necessary in patients with mild hepatic impairment, see section 4.4 for patientswith moderate and severe hepatic impairment.

The safety and effectiveness of Repatha have not been established in paediatric patients withheterozygous familial hypercholesterolaemia (HeFH) or homozygous familial hypercholesterolaemia(HoFH) who are younger than 10 years old or in paediatric patients with other types ofhyperlipidaemia.

Subcutaneous use.

Evolocumab is for subcutaneous injection into the abdomen, thigh or upper arm region. Injection sitesshould be rotated and injections should not be given into areas where the skin is tender, bruised, red,or hard.

Evolocumab must not be administered intravenously or intramuscularly.

Repatha 140 mg solution for injection in pre-filled syringe

The 140 mg dose should be delivered using a single pre-filled syringe.

The 420 mg dose should be delivered using three pre-filled syringes administered consecutively within30 minutes.

Repatha 140 mg solution for injection in pre-filled pen

The 140 mg dose should be delivered using a single pre-filled pen.

The 420 mg dose should be delivered using three pre-filled pens administered consecutively within30 minutes.

Repatha 420 mg solution for injection in cartridge

The 420 mg dose should be delivered using a single cartridge with the automated mini-doser.

Repatha is intended for patient self-administration after proper training. Administration of evolocumabcan also be performed by an individual who has been trained to administer the product.

For single use only.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

In patients with moderate hepatic impairment, a reduction in total evolocumab exposure was observedthat may lead to a reduced effect on LDL-C reduction. Therefore, close monitoring may be warrantedin these patients.

Patients with severe hepatic impairment (Child-Pugh class C) have not been studied (see section 5.2).

Evolocumab should be used with caution in patients with severe hepatic impairment.

Dry natural rubber

Repatha 140 mg solution for injection in pre-filled syringe

The needle cover of the glass pre-filled syringe is made from dry natural rubber (a derivative of latex),which may cause severe allergic reactions.

Repatha 140 mg solution for injection in pre-filled pen

The needle cover of the pre-filled pen is made from dry natural rubber (a derivative of latex), whichmay cause severe allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

No interaction studies have been performed.

The pharmacokinetic interaction between statins and evolocumab was evaluated in the clinical trials.

An approximately 20% increase in the clearance of evolocumab was observed in patients co-administered statins. This increased clearance is in part mediated by statins increasing theconcentration of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) which did not adverselyimpact the pharmacodynamic effect of evolocumab on lipids. No statin dose adjustments are necessarywhen used in combination with evolocumab.

No studies on pharmacokinetic and pharmacodynamics interaction between evolocumab and lipid-lowering medicinal products other than statins and ezetimibe have been conducted.

There are no or limited amount of data from the use of Repatha in pregnant women.

Animal studies do not indicate direct or indirect effects with respect to reproductive toxicity (seesection 5.3).

Repatha should not be used during pregnancy unless the clinical condition of the woman requirestreatment with evolocumab.

It is unknown whether evolocumab is excreted in human milk.

A risk to breastfed newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or discontinue/abstain from Repathatherapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for thewoman.

No data on the effect of evolocumab on human fertility are available. Animal studies did not show anyeffects on fertility endpoints at area under the concentration time curve (AUC) exposure levels muchhigher than in patients receiving evolocumab at 420 mg once monthly (see section 5.3).

Repatha has no or negligible influence on the ability to drive and use machines.

The most commonly reported adverse reactions at the recommended doses are nasopharyngitis (7.4%),upper respiratory tract infection (4.6%), back pain (4.4%), arthralgia (3.9%), influenza (3.2%), andinjection site reactions (2.2%). The safety profile in the homozygous familial hypercholesterolaemiapopulation was consistent with that demonstrated in the primary hypercholesterolaemia and mixeddyslipidaemia population.

Adverse reactions reported in pivotal, controlled clinical studies, and spontaneous reporting, aredisplayed by system organ class and frequency in table 1 below using the following convention: verycommon (≥ 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).

Table 1. Adverse reactions

MedDRA system organ class Adverse reactions Frequency category(SOC)

Infections and infestations Influenza Common

Nasopharyngitis Common

Upper respiratory tract Commoninfection

Immune system disorders Hypersensitivity Common

Rash Common

Urticaria Uncommon

Nervous system disorders Headache Common

Gastrointestinal disorders Nausea Common

Skin and subcutaneous tissue Angioedema Raredisorders

Musculoskeletal and connective Back pain Commontissue disorders Arthralgia Common

Myalgia Common

General disorders and Injection site reactions1 Commonadministration site conditions Influenza-like illness Uncommon1 See section Description of selected adverse reactions.

The safety profile was consistent between subjects with post-baseline LDL-C < 25 mg/dL(0.65 mmol/L) or < 40 mg/dL(1.03 mmol/L) compared to subjects with higher post-baseline LDL-C(≥ 40 mg/dL[1.03 mmol/L]), with median (Q1, Q3) Repatha exposure of 84.2 (78.1, 89.8) months insubjects who continued on Repatha and 59.8 (52.8, 60.3) months in subjects on placebo who switchedto Repatha in an open-label extension study.

The most frequent injection site reactions were injection site bruising, erythema, haemorrhage,injection site pain, and swelling.

The safety and effectiveness of Repatha have been established in paediatric patients with heterozygousand homozygous familial hypercholesterolaemia. A clinical study to evaluate the effects of Repathawas conducted in 158 paediatric patients aged ≥ 10 to < 18 years old with heterozygous familialhypercholesterolaemia. No new safety concerns were identified and the safety data in this paediatricpopulation was consistent with the known safety profile of the product in adults with heterozygousfamilial hypercholesterolaemia. Twenty-six paediatric patients with homozygous familialhypercholesterolaemia have been treated with Repatha in clinical studies conducted in patients aged≥ 10 to < 18 years. No difference in safety was observed between paediatric and adult patients withhomozygous familial hypercholesterolaemia.

Of the 18,546 patients treated with evolocumab in double-blind clinical studies 7,656 (41.3%) were≥ 65 years old, while 1,500 (8.1%) were ≥ 75 years old. No overall differences in safety or efficacywere observed between these patients and younger patients.

In clinical studies, 0.3% of patients (48 out of 17,992 patients) treated with at least one dose ofevolocumab tested positive for binding antibody development. The patients whose sera tested positivefor binding antibodies were further evaluated for neutralising antibodies and none of the patients testedpositive for neutralising antibodies. The presence of anti-evolocumab binding antibodies did notimpact the pharmacokinetic profile, clinical response, or safety of evolocumab.

The development of anti-evolocumab antibodies was not detected in clinical trials of paediatricpatients treated with Repatha.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No adverse effects were observed in animal studies at exposures up to 300-fold higher than those inpatients treated with 420 mg evolocumab once monthly.

There is no specific treatment for evolocumab overdose. In the event of an overdose, the patientshould be treated symptomatically, and supportive measures instituted as required.

Pharmacotherapeutic group: lipid modifying agents, other lipid modifying agents. ATC code:

C10AX13

Evolocumab binds selectively to PCSK9 and prevents circulating PCSK9 from binding to the lowdensity lipoprotein receptor (LDLR) on the liver cell surface, thus preventing PCSK9-mediated LDLRdegradation. Increasing liver LDLR levels results in associated reductions in serum LDL-cholesterol(LDL-C).

In clinical trials, evolocumab reduced unbound PCSK9, 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 primaryhypercholesterolaemia and mixed dyslipidaemia.

A single subcutaneous administration of 140 mg or 420 mg evolocumab resulted in maximumsuppression of circulating unbound PCSK9 by 4 hours followed by a reduction in LDL-C reaching amean nadir in response by 14 and 21 days, respectively. Changes in unbound PCSK9 and serumlipoproteins were reversible upon discontinuation of evolocumab. No increase in unbound PCSK9 or

LDL-C above baseline was observed during the washout of evolocumab suggesting that compensatorymechanisms to increase production of PCSK9 and LDL-C do not occur during treatment.

Subcutaneous regimens of 140 mg every 2 weeks and 420 mg once monthly were equivalent inaverage LDL-C lowering (mean of weeks 10 and 12) resulting in -72% to -57% from baselinecompared with placebo. Treatment with evolocumab resulted in a similar reduction of LDL-C whenused alone or in combination with other lipid-lowering therapies.

Clinical efficacy in primary hypercholesterolaemia and mixed dyslipidaemia

LDL-C reduction of approximately 55% to 75% was achieved with evolocumab as early as week 1and maintained during long-term therapy. Maximal response was generally achieved within 1 to2 weeks after dosing with 140 mg every 2 weeks and 420 mg once monthly. Evolocumab waseffective in all subgroups relative to placebo and ezetimibe, with no notable differences observedbetween subgroups, such as age, race, gender, region, body-mass index, National Cholesterol

Education Program 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, metabolicsyndrome, or neither), hypertension, statin dose and intensity, unbound baseline PCSK9, baseline

LDL-C and baseline TG.

In 80-85% of all primary hyperlipidaemia patients treated with either dose, evolocumab demonstrateda ≥ 50% reduction in LDL-C at the mean of weeks 10 and 12. Up to 99% of patients treated witheither dose of evolocumab achieved an LDL-C of < 2.6 mmol/L and up to 95% achieved an LDL-C< 1.8 mmol/L at the mean of weeks 10 and 12.

Combination with a statin and statin with other lipid-lowering therapies

LAPLACE-2 was an international, multicentre, double-blind, randomised, 12-week study in1,896 patients with primary hypercholesterolaemia or mixed dyslipidaemia who were randomised toreceive evolocumab in combination with statins (rosuvastatin, simvastatin or atorvastatin).

Evolocumab was compared to placebo for the rosuvastatin and simvastatin groups and compared withplacebo and ezetimibe for the atorvastatin group.

Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 compared withplacebo for the rosuvastatin and simvastatin groups and compared with placebo and ezetimibe for theatorvastatin group (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 from baseline to mean of weeks 10and 12 as compared to placebo for the rosuvastatin and simvastatin groups (p < 0.05) and significantlyreduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1 and Lp(a), compared with placebo andezetimibe for the atorvastatin group (p < 0.001) (see tables 2 and 3).

RUTHERFORD-2 was an international, multicentre, double-blind, randomised, placebo-controlled,12-week study in 329 patients with heterozygous familial hypercholesterolaemia on lipid-loweringtherapies. Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 comparedwith 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 ofweeks 10 and 12 compared to placebo (p < 0.05) (see table 2).

Table 2. Treatment effects of evolocumab compared with placebo in patients with primaryhypercholesterolaemia and mixed dyslipidaemia - mean percent change from baseline to averageof weeks 10 and 12 (%, 95% CI)

Study Dose LDL-C Non- ApoB TC Lp(a) VLDL HDL TG ApoA1 TC/ ApoB/regimen (%) HDL-C (%) (%) (%) -C -C (%) (%) HDL-C ApoA1(%) (%) (%) ratio ratio% %

LAPLACE-2 140 mg

- 72b -60b -56b -41b -30b -18b 6b -17b 3b -45b -56b(HMD) Q2W(combined (-75,-69) (-63,-58) (-58,-53) (-43,-39) (-35,-25) (-23,-14) (4,8) (-22,-13) (1,5) (-47,-42) (-59,-53)(N = 555)rosuvastatin,simvastatin, & 420 mg

- 69b -60b -56b -40b -27b -22b 8b -23b 5b -46b -58batorvastatin QM(-73,-65) (-63,-57) (-58,-53) (-42,-37) (-31,-24) (-28,-17) (6,10) (-28,-17) (3,7) (-48,-43) (-60,-55)groups) (N = 562)140 mg

- 61b -56b -49b -42b -31b -22b 8b -22b 7a -47b -53

Q2W

RUTHERFO (-67,-55) (-61,-51) (-54,-44) (-46,-38) (-38,-24) (-29,-16) (4,12) (-29,-15) (3,12) (-51,-42) (-58,-48)(N = 110)

RD-2420 mg(HeFH) -66b -60b -55b -44b -31b -16b 9b -17b 5a -49b -56b

QM(-72,-61) (-65,-55) (-60,-50) (-48,-40) (-38,-24) (-23,-8) (5,14) (-24,-9) (1,9) (-54,-44) (-61,-50)(N = 110)

Key: Q2W = once every 2 weeks, QM = once monthly, HMD = Primary hypercholesterolaemia and mixeddyslipidaemia, HeFH = Heterozygous familial hypercholesterolaemia, a p value < 0.05 when compared withplacebo, b p value < 0.001 when compared with placebo.

Statin intolerant patients

GAUSS-2 was an international, multicentre, double-blind, randomised, ezetimibe-controlled, 12-weekstudy in 307 patients who were statin-intolerant or unable to tolerate an effective dose of a statin.

Repatha significantly reduced LDL-C compared with ezetimibe (p < 0.001). Repatha significantlyreduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1 and Lp(a), from baseline to mean ofweeks 10 and 12 compared to ezetimibe (p < 0.001) (see table 3).

Treatment in the absence of a statin

MENDEL-2 was an international, multicentre, double-blind, randomised, placebo and ezetimibe-controlled, 12-week study of Repatha in 614 patients with primary hypercholesterolaemia and mixeddyslipidaemia. Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12compared 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 12compared with both placebo and ezetimibe (p < 0.001) (see table 3).

Table 3. Treatment effects of evolocumab compared with ezetimibe in patients with primaryhypercholesterolaemia and mixed dyslipidaemia - mean percent change from baseline to averageof weeks 10 and 12 (%, 95% CI)

Study Dose LDL-C Non- ApoB TC Lp(a) VLDL HDL- TG ApoA1 TC/ ApoB/regimen (%) HDL- (%) (%) (%) -C C (%) (%) HDL- ApoA1

C (%) (%) C ratio ratio(%) % %140 mg

- 43c -34c -34c -23c c c

LAPLACE-2 -30 -1 7 -2 7c -27c -38c

Q2W(HMD) (-50, -37) (-39, -30) (-38, -30) (-26, -19) (-35, -25) (-7, 5) (4, 10) (-9, 5) (4, 9) (-30, -23) (-42, -34)(N = 219)(combinedatorvastatin 420 mg

- 46c -39c -40c -25c -33c -7 8c -8 7c -30c -42cgroups) QM(-51, -40) (-43, -34) (-44, -36) (-29, -22) (-41, -26) (-20, 6) (5, 12) (-21, 5) (2, 11) (-34, -26) (-47, -38)(N = 220)

Study Dose LDL-C Non- ApoB TC Lp(a) VLDL HDL- TG ApoA1 TC/ ApoB/regimen (%) HDL- (%) (%) (%) -C C (%) (%) HDL- ApoA1

C (%) (%) C ratio ratio(%) % %140 mg

- 38b -32b -32b -24b -24b -2 5 -3 5a -27b -35b

Q2W(-44, -33) (-36, -27) (-37, -27) (-28, -20) (-31, -17) (-10, 7) (1, 10) (-11, 6) (2, 9) (-32, -23) (-40, -30)

GAUSS-2 (N = 103)(statin-intolerant) 420 mg

- 39b -35b -35b -26b -25b -4 6 -6 3 -30b -36b

QM(-44, -35) (-39, -31) (-40, -30) (-30, -23) (-34, -17) (-13, 6) (1, 10) (-17, 4) (-1, 7) (-35, -25) (-42, -31)(N = 102)140 mg

- 40b -36b -34b -25b -22b -7 6a -9 3 -29b -35b

MENDEL-2 Q2W(-44, -37) (-39, -32) (-37, -30) (-28, -22) (-29, -16) (-14, 1) (3, 9) (-16, -1) (0, 6) (-32, -26) (-39, -31)(treatment in the (N = 153)absence of a 420 mg b bstatin) -41 -35 -35b -25b -20b -10 4 -9 4a -28b -37b

QM(-44, -37) (-38, -33) (-38, -31) (-28, -23) (-27, -13) (-19, -1) (1, 7) (-18, 0) (1, 7) (-31, -24) (-41, -32)(N = 153)

Key: Q2W = once every 2 weeks, QM = once monthly, HMD = Primary hypercholesterolaemia and mixeddyslipidaemia, a p value < 0.05 when compared with ezetimibe, b p value < 0.001 when compared withezetimibe, c nominal p value < 0.001 when compared with ezetimibe.

Long-term efficacy in primary hypercholesterolaemia and mixed dyslipidaemia

DESCARTES was an international, multicentre, double-blind, randomised, placebo-controlled,52-week study in 901 patients with hyperlipidaemia who received diet alone, atorvastatin, or acombination 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 weresustained over 1 year as demonstrated by reduction in LDL-C from week 12 to week 52. 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 significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and

Lp(a), and increased HDL-C and ApoA1 at week 52 compared with placebo (p < 0.001) (see table 4).

Table 4. Treatment effects of evolocumab compared with placebo in patients with primaryhypercholesterolaemia and mixed dyslipidaemia - mean percent change from baseline toweek 52 (%, 95% CI)

Study Dose LDL-C Non- ApoB TC Lp(a) VLDL HDL- TG ApoA1 TC/ ApoB/regimen (%) HDL- (%) (%) (%) -C C (%) (%) HDL- ApoA1

C (%) (%) C ratio ratio(%) % %420 mg

- 59b -50b -44b -33b -22b -29b 5b -12b 3a -37b -46b

DESCARTES QM(-64, -55) (-54, -46) (-48, -41) (-36, -31) (-26, -19) (-40, -18) (3, 8) (-17, -6) (1, 5) (-40, -34) (-50, -43)(N = 599)

Key: QM = once monthly, a nominal p value < 0.001 when compared with placebo, b p value < 0.001 whencompared with placebo.

OSLER and OSLER-2 were two randomised, controlled, open-label extension studies to assess thelong-term safety and efficacy of Repatha in patients who completed treatment in a ‘parent’ study. Ineach 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 endof the first year (week 52 in OSLER and week 48 in OSLER-2), patients entered the all Repathaperiod in which all patients received open-label Repatha for either another 4 years (OSLER) or 2 years(OSLER-2).

A total of 1,324 patients enrolled in OSLER. Repatha 420 mg once monthly significantly reduced

LDL-C from baseline at week 12 and week 52 compared with control (nominal p < 0.001). Treatmenteffects were maintained over 272 weeks as demonstrated by reduction in LDL-C from week 12 in theparent study to week 260 in the open-label extension. A total of 3,681 patients enrolled in OSLER-2.

Repatha significantly reduced LDL-C from baseline at week 12 and week 48 compared with control(nominal p < 0.001). Treatment effects were maintained as demonstrated by reduction in LDL-C fromweek 12 to week 104 in the open-label extension. Repatha significantly reduced TC, ApoB,non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a), and increased HDL-C and ApoA1from baseline to week 52 in OSLER and to week 48 in OSLER-2 compared with control (nominalp < 0.001). LDL-C and other lipid parameters returned to baseline within 12 weeks afterdiscontinuation of Repatha at the beginning of OSLER or OSLER-2 without evidence of rebound.

TAUSSIG was a multicentre, open-label, 5-year extension study to assess the long-term safety andefficacy of Repatha, as an adjunct to other lipid-lowering therapies, in patients with severe familialhypercholesterolaemia (FH), including homozygous familial hypercholesterolaemia. A total of 194severe familial hypercholesterolaemia (non-HoFH) patients and 106 homozygous familialhypercholesterolaemia patients enrolled in TAUSSIG. All patients in the study were initially treatedwith Repatha 420 mg once monthly, except for those receiving lipid apheresis at enrolment who beganwith Repatha 420 mg once every 2 weeks. Dose frequency in non-apheresis patients could be titratedup to 420 mg once every 2 weeks based on LDL-C response and PCSK9 levels. Long-term use of

Repatha demonstrated a sustained treatment effect as evidenced by reduction of LDL-C in patientswith severe familial hypercholesterolaemia (non-HoFH) (see table 5).

Changes in other lipid parameters (TC, ApoB, non-HDL-C, TC/HDL-C, and ApoB/ApoA1) alsodemonstrated a sustained effect of long-term Repatha administration in patients with severe familialhypercholesterolaemia (non-HoFH).

Table 5. Effect of evolocumab on LDL-C in patients with severe familial hypercholesterolaemia(non-HoFH) - mean percent change from baseline to OLE week 216 (and associated 95% CI)

Patient OLE OLE OLE OLE OLE OLE OLE OLE

Population Week 12 Week 24 Week 36 Week 48 Week 96 Week 144 Week 192 Week 216(N) (n = 191) (n = 191) (n = 187) (n = 187) (n = 180) (n = 180) (n = 147) (n = 96)

Severe FH

- 54.9 -54.1 -54.7 -56.9 -53.3 -53.5 -48.3 -47.2(non-HoFH)(N = 194) (-57.4, -52.4) (-57.0, -51.3) (-57.4, -52.0) (-59.7, -54.1) (-56.9, -49.7) (-56.7, -50.2) (-52.9, -43.7) (-52.8, -41.5)

Key: OLE = open-label extension, N (n) = Number of evaluable patients (N) and patients with observed LDL-Cvalues at specific scheduled visit (n) in the severe familial hypercholesterolaemia (non-HoFH) final analysis set.

Treatment of heterozygous familial hypercholesterolaemia in paediatric patients

HAUSER-RCT was a randomized, multicentre, placebo-controlled, double-blind, parallel-group,24-week trial in 158 paediatric patients aged 10 to < 18 years with heterozygous familialhypercholesterolaemia. Patients were required to be on a low-fat diet and must have been receivingoptimized background lipid-lowering therapy (statin at optimal dose, not requiring up titration).

Enrolled patients were randomized in a 2:1 ratio to receive 24 weeks of subcutaneous once monthly420 mg Repatha or placebo.

The primary efficacy endpoint in this trial was percent change from baseline to week 24 in LDL-C.

The difference between Repatha and placebo in mean percent change in LDL-C from baseline toweek 24 was 38% (95% CI: 45%, 31%; p < 0.0001). The least squares mean Standard Error (SE)reduction (p < 0.0001) in LDL-C from baseline at week 24 was 44% (2%) in the Repatha group and6% (3%) in the placebo group. Mean absolute LDL-C values at week 24 were 104 mg/dL in the

Repatha group and 172 mg/dL in the placebo group. Reductions in LDL-C were observed by the firstpost-baseline assessment at the week 12 time point and were maintained throughout the trial.

The secondary endpoint of this trial was mean percent change from baseline to weeks 22 and 24 in

LDL-C, where week 22 reflects the peak and week 24 the trough of the subcutaneous once monthlydosing interval, and provides information about the time-averaged effect of Repatha therapy over theentire dosing interval. The least squares mean treatment difference between Repatha and placebo inmean percent change in LDL-C from baseline to the mean of week 22 and week 24 was 42% (95% CI:

48%, 36%; p < 0.0001). For additional results, see table 6.

Table 6. Treatment effects of Repatha compared with placebo in paediatric patients withheterozygous familial hypercholesterolaemia - mean percent change from baseline to week 24(%, 95% CI)

TC/ ApoB/

Dose LDL-C Non-HDL-C ApoB HDL-C ApoA1

Studyregimen (%) (%) (%) Ratio Ratio(%) (%)

HAUSER-RCT(HeFH 420 mg QM -38.3 -35.0 -32.5 -30.3 -36.4

Paediatric (N = 104) (-45.5, -31.1) (-41.8, -28.3) (-38.8, -26.1) (-36.4, -24.2) (-43.0, -29.8)

Patients)

QM = monthly (subcutaneous); CI = Confidence Interval; LDL-C = low density lipoprotein cholesterol; HDL-C= high density lipoprotein cholesterol; ApoB = apolipoprotein B; ApoA1 = apolipoprotein A1, TC = totalcholesterol

All adjusted p-values <0.0001

N = number of patients randomized and dosed in the full analysis set.

HAUSER-OLE was an open-label, single-arm, multicentre, 80 week study of Repatha in150 paediatric patients aged 10 to 17 years with HeFH that rolled-over from HAUSER-RCT andenrolled 13 de novo paediatric HoFH patients. Patients had to be on a low-fat diet and receivingbackground lipid-lowering therapy. All HeFH patients in this study received 420 mg Repathasubcutaneously once monthly (median exposure duration: 18.4 months). The mean (SE) percentchanges in calculated LDL-C from baseline were: -44.4% (1.7%) at week 12, -41.0% (2.1%) atweek 48, and -35.2% (2.5%) at week 80.

The mean (SE) percent change from baseline to week 80 in other lipid endpointswere: -32.1% (2.3%) non-HDL-C, -25.1% (2.3%) ApoB, -28.5% (2.0%) TC/HDL-Cratio, -30.3% (2.2%) ApoB/ApoA1 ratio, and -24.9% (1.9%) TC.

Treatment of homozygous familial hypercholesterolaemia

TESLA was an international, multicentre, double-blind, randomised, placebo-controlled 12-weekstudy in 49 homozygous familial hypercholesterolaemia patients aged 12 to 65 years. Repatha 420 mgonce monthly, as an adjunct to other lipid-lowering therapies (e.g., statins, bile-acid sequestrants),significantly reduced LDL-C and ApoB at week 12 compared with placebo (p < 0.001) (see table 7).

Changes in other lipid parameters (TC, non-HDL-C, TC/HDL-C, and ApoB/ApoA1) alsodemonstrated a treatment effect of Repatha administration in patients with homozygous familialhypercholesterolaemia.

Table 7. Treatment effects of evolocumab compared with placebo in patients with homozygousfamilial hypercholesterolaemia - mean percent change from baseline to week 12 (%, 95% CI)

Study Dose LDL-C Non- ApoB TC Lp(a) VLDL- HDL-C TG TC/ ApoB/regimen (%) HDL-C (%) (%) (%) C (%) (%) HDL-C ApoA1(%) (%) ratio ratio% %420 mg

TESLA -32b -30a -23b -27a -12 -44 -0.1 0.3 -26a -28a

QM(HoFH) (-45, -19) (-42, -18) (-35, -11) (-38, -16) (-25, 2) (-128, 40) (-9, 9) (-15, 16) (-38, -14) (-39, -17)(N = 33)

Key: HoFH = homozygous familial hypercholesterolaemia, QM = once monthly, a nominal p value < 0.001when compared with placebo, b p value < 0.001 when compared with placebo.

Long-term efficacy in homozygous familial hypercholesterolaemia

In TAUSSIG, long-term use of Repatha demonstrated a sustained treatment effect as evidenced byreduction of LDL-C of approximately 20% to 30% in patients with homozygous familialhypercholesterolaemia not on apheresis and approximately 10% to 30% in patients with homozygousfamilial hypercholesterolaemia on apheresis (see table 8). Changes in other lipid parameters (TC,

ApoB, non-HDL-C, TC/HDL-C, and ApoB/ApoA1) also demonstrated a sustained effect of long-term

Repatha administration in patients with homozygous familial hypercholesterolaemia. Reductions in

LDL-C and changes in other lipid parameters in 14 adolescent patients (aged ≥ 12 to < 18 years) withhomozygous familial hypercholesterolaemia are comparable to those in the overall population ofpatients with homozygous familial hypercholesterolaemia.

Table 8. Effect of evolocumab on LDL-C in patients with homozygous familialhypercholesterolaemia - mean percent change from baseline to OLE week 216 (and associated95% CI)

Patient OLE OLE OLE OLE OLE OLE OLE OLE

Population (N) Week 12 Week 24 Week 36 Week 48 Week 96 Week 144 Week 192 Week 216

- 21.2 -21.4 -27.0 -24.8 -25.0 -27.7 -27.4 -24.0

HoFH(-26.0, -16.3) (-27.8, -15.0) (-32.1, -21.9) (-31.4, -18.3) (-31.2, -18.8) (-34.9, -20.5) (-36.9, -17.8) (-34.0, -14.0)(N = 106)(n = 104) (n = 99) (n = 94) (n = 93) (n = 82) (n = 79) (n = 74) (n = 68)

- 22.7 -25.8 -30.5 -27.6 -23.5 -27.1 -30.1 -23.4

Non-apheresis(-28.1, -17.2) (-33.1, -18.5) (-36.4, -24.7) (-35.8, -19.4) (-31.0, -16.0) (-35.9, -18.3) (-37.9, -22.2) (-32.5, -14.2)(N = 72)(n = 70) (n = 69) (n = 65) (n = 64) (n = 62) (n = 60) (n = 55) (n = 50)

- 18.1 -11.2 -19.1 -18.7 -29.7 -29.6 -19.6 -25.9

Apheresis(-28.1, -8.1) (-24.0, 1.7) (-28.9, -9.3) (-29.5, -7.9) (-40.6, -18.8) (-42.1, -17.1) (-51.2, 12.1) (-56.4, pct. 4.6)(N = 34)(n = 34) (n = 30) (n = 29) (n = 29) (n = 20) (n = 19) (n = 19) (n = 18)

Key: OLE = open-label extension. N (n) = Number of evaluable patients (N) and patients with observed LDLvalues at specific schedule visit (n) in the HoFH final analysis set.

HAUSER-OLE was an open-label, single-arm, multicentre, 80-week trial in 12 HofH subjects toevaluate the safety, tolerability and efficacy of Repatha for LDL-C reduction in paediatric patientsfrom aged ≥ 10 to < 18 years of age with homozygous familial hypercholesterolaemia. Patients had tobe on a low-fat diet and receiving background lipid-lowering therapy. All patients in the studyreceived 420 mg Repatha subcutaneously once monthly. Median (Q1, Q3) LDL-C at baseline was 398(343, 475) mg/dL. The median (Q1, Q3) percent change in LDL-C from baseline to week 80was -14% (-41, 4). Reductions in LDL-C were observed by the first assessment at week 12 and wasmaintained throughout the trial, median (Q1, Q3) reductions ranging between 12% (-3, 32) and 15%(-4, 39). For additional results, please see table 9.

Table 9. Treatment effects of evolocumab compared with placebo in patients with homozygousfamilial hypercholesterolaemia - median (Q1, Q3) percent change from baseline to week 80

TC/ ApoB/

Dose LDL-C Non-HDL-C ApoB HDL-C ApoA1

Studyregimen (%) (%) (%) Ratio Ratio(%) (%)

HAUSER-

OLE (HoFH 420 mg QM -14.3 -13 -19.1 -3.7 -3

Paediatric (N = 12) (-40.6, 3.5) (-40.7, 2.7) (-33.3, 11.6) (-41.6, 7.6) (-35.7, 9.3)

Patients)

QM = monthly (subcutaneous); LDL-C = low density lipoprotein cholesterol; HDL-C = high density lipoproteincholesterol; ApoB = apolipoprotein B; ApoA1 = apolipoprotein A1, TC = total cholesterol

N = number of patients randomized and dosed in the interim analysis set.

Effect on atherosclerotic disease burden

The effects of Repatha 420 mg once monthly on atherosclerotic disease burden, as measured byintravascular ultrasound (IVUS), were evaluated in a 78-week double-blind, randomised, placebocontrolled study in 968 patients with coronary artery disease on a stable background of optimal statintherapy. Repatha reduced both percent atheroma volume (PAV; 1.01% [95% CI 0.64, 1.38],p < 0.0001) and total atheroma volume (TAV; 4.89 mm3 [95% CI 2.53, 7.25], p < 0.0001) comparedwith placebo. Atherosclerotic regression was observed in 64.3% (95% CI 59.6, 68.7) and 47.3%(95% CI 42.6, 52.0) of patients who received Repatha or placebo respectively, when measured by

PAV. When measured by TAV, atherosclerotic regression was observed in 61.5% (95% CI 56.7, 66.0)and 48.9% (95% CI 44.2, 53.7) of patients who received Repatha or placebo respectively. The studydid not investigate the correlation between atherosclerotic disease regression and cardiovascularevents.

Effect on coronary atherosclerotic plaque morphology

The effects of Repatha 420 mg once monthly on coronary atherosclerotic plaques as assessed byoptical coherence tomography (OCT), were evaluated in a 52-week double-blind, randomised, placebocontrolled study including adult patients initiated within 7 days of a non-ST-segment elevation acutecoronary syndrome (NSTEACS) on maximally tolerated statin therapy. For the primary endpoint ofabsolute change in minimum FCT (fibrous cap thickness) in a matched segment of artery frombaseline, least squares (LS) mean (95% CI) increased from baseline by 42.7 μm (32.4, 53.1) in the

Repatha group and 21.5 μm (10.9, 32.1) in the placebo group, an additional 21.2 μm (4.7, 37.7)compared to placebo (p = 0.015; 38% difference (p = 0.041)). The reported secondary findings showtreatment differences including change in mean minimum FCT (increase 32.5 µm (12.7, 52.4);p = 0.016) and absolute change in maximum lipid arc (-26° (-49.6, -2.4); p = 0.041).

Cardiovascular risk reduction in adults with established atherosclerotic cardiovascular disease

The Repatha Outcomes Study (FOURIER) was a randomised, event-driven, double-blind study of27,564 subjects, aged between 40 and 86 years (mean age 62.5 years), with established atherosclerotic

CV disease; 81% had a prior MI event, 19% had a prior stroke event and 13% had peripheral arterialdisease. Over 99% of patients were on moderate to high intensity statin and at least one othercardiovascular medicine such as anti-platelet agents, beta blockers, Angiotensin-Converting Enzyme(ACE) inhibitors, or angiotensin receptor blockers; median (Q1, Q3) baseline LDL-C was 2.4 mmol/L(2.1, 2.8). Absolute CV risk was balanced between treatment groups, in addition to the index event allpatients had at least 1 major or 2 minor CV risk factors; 80% had hypertension, 36% had diabetesmellitus, and 28% were daily smokers. Patients were randomised 1:1 to either Repatha (140 mg everytwo weeks or 420 mg once every month) or matching placebo; the mean duration of patient follow-upwas 26 months.

A substantial reduction of LDL-C was observed throughout the study, with achieved median LDL-Cranges of 0.8 to 0.9 mmol/L at each assessment; 25% of patients achieved a LDL-C concentration lessthan 0.5 mmol/L. Despite the very low levels of LDL-C achieved, no new safety issues were observed(see section 4.8); the frequencies of new onset diabetes and cognitive events were comparable inpatients who achieved LDL-C levels < 0.65 mmol/L and those with higher LDL-C.

Repatha significantly reduced the risk of cardiovascular events defined as the composite of time tofirst CV death, MI, stroke, coronary revascularisation, or hospitalisation for unstable angina (seetable 10); the Kaplan-Meier curves for the primary and key secondary composite endpoints separatedat approximately 5 months (see figure 1 for the MACE three year Kaplan-Meier curve). The relativerisk of the MACE composite (CV death, MI, or stroke) was significantly reduced by 20%. Thetreatment effect was consistent across all subgroups (including age, type of disease, baseline LDL-C,baseline statin intensity, ezetimibe use, and diabetes) and was driven by a reduction in the risk ofmyocardial infarction, stroke and coronary revascularisation; no significant difference was seen oncardiovascular or all-cause mortality however the study was not designed to detect such a difference.

Table 10. Effect of evolocumab on major cardiovascular events

Placebo Evolocumab(N = 13,780) (N = 13,784) Hazard ratioan (%) n (%) (95% CI) p valueb

MACE+ (composite of MACE, 1,563 (11.34) 1,344 (9.75) 0.85 (0.79, 0.92) < 0.0001coronary revascularisation, orhospitalisation for unstable angina)

MACE (composite of CV death, MI, or 1,013 (7.35) 816 (5.92) 0.80 (0.73, 0.88) < 0.0001stroke)

Cardiovascular death 240 (1.74) 251 (1.82) 1.05 (0.88, 1.25) 0.62

All-cause mortality 426 (3.09) 444 (3.22) 1.04 (0.91, 1.19) 0.54

Myocardial infarction (fatal/non-fatal) 639 (4.64) 468 (3.40) 0.73 (0.65, 0.82) < 0.0001c

Stroke (fatal/non-fatal) d 262 (1.90) 207 (1.50) 0.79 (0.66, 0.95) 0.0101c

Coronary revascularisation 965 (7.00) 759 (5.51) 0.78 (0.71, 0.86) < 0.0001c

Hospitalisation for unstable anginae 239 (1.7) 236 (1.7) 0.99 (0.82, 1.18) 0.89a Based on a Cox model stratified by the randomisation stratification factors collected via Interactive Voice

Response System (IVRS).b 2-sided log-rank test stratified by randomisation stratification factors collected via IVRS.c Nominal significance.d The treatment effect on stroke was driven by a reduction in risk of ischaemic stroke; there was no effect onhaemorrhagic or undetermined stroke.e Assessment of time to hospitalisation for unstable angina was ad-hoc.

Figure 1. Time to a MACE event (composite of CV death, MI, or stroke); 3-year Kaplan-Meier

Hazard Ratio, 0.80 (95% CI, 0.73, 0.88)9.910 P<0.0001 Placebo8 Repatha6.8 7.95 5.54 3.73.10 6 12 18 24 30 36

Months

Patients at Risk

Placebo 13780 13447 13140 12257 7923 3785 717

Repatha 13784 13499 13240 12422 8066 3837 713

FOURIER-OLE (study 1 and study 2) consisted of two open-label, single-arm, multicenter, extensionstudies to evaluate the long-term safety, tolerability, and efficacy of Repatha in patients withestablished cardiovascular disease who completed the FOURIER study. Enrolled patients received

Repatha 140 mg every 2 weeks or 420 mg once monthly for approximately 5 years and continuedmoderate- (22.2%) or high-intensity (74.8%) background statin therapy. Of the 5 031 patients whoreceived at least one dose of Repatha in study 1, 2 499 patients received Repatha and 2 532 patientsreceived placebo in the FOURIER study. Of the 1 599 patients who received at least one dose of

Repatha in study 2 854 patients received Repatha and 745 patients received placebo in the FOURIERstudy. Upon completion of study 1 and study 2, patients randomized to Repatha in the FOURIERstudy had up to 8.4 years (median 85.4 months) and 8.0 years of total Repatha exposure median

Cumulative Incidence (%)

GRH0465 v180.2 months) and patients randomized to placebo had up to 5.25 years (median 60.0 months) and 4.9years of total Repatha exposure (median 55.1 months), respectively.

In study 1 and 2 combined, 72.4% (n = 4 802) of patients achieved a lowest post-baseline

LDL-C < 25 mg/dL (0.65 mmol/L), 87.0% (n = 5 765) of patients achieved an LDL-C < 40 mg/dL(1.03 mmol/L), and 11.9% (n = 792) of patients had an all post-baseline LDL-C ≥ 40 mg/dL (1.03mmol/L). Of the patients who achieved post-baseline low LDL-C (< 25 mg/dL or < 40 mg/dL), theoverall subject incidences of treatment emergent adverse events were 80.0% patients who achieved

LDL-C < 25 mg/dL and 82.7% in patients who achieved LDL-C < 40 mg/dL compared to 85.0% inpatients with LDL-C ≥ 40 mg/dL. The overall subject incidences of serious treatment emergentadverse events were 37.7% in patients who achieved LDL-C < 25 mg/dL and 40.0% in patients whoachieved LDL-C < 40 mg/dL compared to 41.5% in patients with LDL-C ≥ 40 mg/dL.

The mean percent reduction from baseline in LDL-C was stable during the OLE study period andranged from 53.4% to 59.1% for study 1 and 62.5% to 67.2% for study 2, regardless of the patient’soriginal randomised treatment group in the FOURIER study. This appears to translate into anumerically lower subject incidence rate of adjudicated exploratory CV endpoints of the composite of

CV death, MI and stroke for patients who had received Repatha in both the FOURIER and FOURIER

OLE studies compared with patients who had received placebo in the FOURIER study and Repatha inthe FOURIER OLE studies.

Overall, no new safety findings were identified in these studies.

Effect on LDL-C during acute phase of Acute Coronary Syndromes (ACS)

EVOPACS was a single country, multicentre, double-blind, randomized, placebo-controlled, 8-weekstudy on 308 ACS patients with evolocumab initiated in-hospital within 24 to 72 hours of presentation.

If patients were not on a statin or were on statin treatment other than atorvastatin 40 mg prior toscreening, this was stopped and atorvastatin 40 mg once daily was initiated. Randomisation wasstratified by study centre and presence of stable statin treatment within ≥ 4 weeks prior to enrolment.

Most subjects (241 [78%]) were not on stable statin treatment for ≥ 4 weeks prior to screening andmost (235 [76%]) were not taking a statin at baseline. By week 4, 281 (97%) subjects were receivinghigh-intensity statins. Evolocumab 420 mg once monthly significantly reduced LDL-C from baselineto week 8 compared with placebo (p < 0.001). The mean (SD) reduction in calculated LDL-C frombaseline at week 8 was 77.1% (15.8%) in the evolocumab group and 35.4% (26.6%) in the placebogroup with a least squares (LS) mean difference (95% CI) of 40.7% (36.2%, 45.2%). Baseline LDL-Cvalues were 3.61 mmol/L (139.5 mg/dL) in the evolocumab group and 3.42 mmol/L (132.2 mg/dL) inthe placebo group. LDL-C reductions in this study were consistent with previous studies whereevolocumab was added to stable lipid-lowering therapy as demonstrated by on-treatment LDL-Clevels at week 8 in this study (reflecting steady-state effect of high-intensity statin in both treatmentarms) of 0.79 mmol/L (30.5 mg/dL) and 2.06 mmol/L (79.7 mg/dL) in the evolocumab plusatorvastatin and the placebo plus atorvastatin groups, respectively.

The effects of evolocumab in this patient population were consistent with those observed in previousstudies in evolocumab clinical development program and no new safety concerns were noted.

Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthyadults, median peak serum concentrations were attained in 3 to 4 days. Administration of singlesubcutaneous dose of 140 mg resulted in a Cmax mean (SD) of 13.0 (10.4) μg/mL and AUClast mean(SD) of 96.5 (78.7) day*μg/mL. Administration of single subcutaneous dose 420 mg resulted in a Cmaxmean (SD) of 46.0 (17.2) μg/mL and AUClast mean (SD) of 842 (333) day*μg/mL. Three subcutaneous140 mg doses were bioequivalent to a single subcutaneous 420 mg dose. The absolute bioavailabilityafter SC dosing was determined to be 72% from pharmacokinetic models.

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

Evolocumab is composed solely of amino acids and carbohydrates as native immunoglobulin and isunlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination areexpected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptidesand individual amino acids.

Evolocumab was estimated to have an effective half-life of 11 to 17 days.

In patients with primary hypercholesterolaemia or mixed dyslipidaemia on high dose statin, thesystemic exposure of evolocumab was slightly lower than in subjects on low-to-moderate dose statin(the ratio of AUClast 0.74 [90% CI 0.29; 1.9]). An approximately 20% increase in the clearance is inpart mediated by statins increasing the concentration of PCSK9 which did not adversely impact thepharmacodynamic effect of evolocumab on lipids. Population pharmacokinetic analysis indicated noappreciable differences in evolocumab serum concentrations in hypercholesterolaemic patients (non-familial hypercholesterolaemia or familial hypercholesterolaemia) taking concomitant statins.

Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be12 (2) mL/hr. In clinical studies with repeated subcutaneous dosing over 12 weeks, dose proportionalincreases in exposure were observed with dose regimens of 140 mg and greater. An approximate twoto three-fold accumulation was observed in trough serum concentrations (Cmin (SD) 7.21 (6.6))following 140 mg doses every 2 weeks or following 420 mg doses administered monthly (Cmin (SD)11.2 (10.8)), and serum trough concentrations approached steady-state by 12 weeks of dosing.

No time dependent changes were observed in serum concentrations over a period of 124 weeks.

No dose adjustment is necessary in patients with renal impairment. Data from the evolocumab clinicaltrials did not reveal a difference in pharmacokinetics of evolocumab in patients with mild or moderaterenal impairment relative to non-renally 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, n = 6), severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2,n = 6), or end-stage renal disease (ESRD) receiving haemodialysis (n = 6), exposure to unboundevolocumab as assessed by Cmax after a single 140 mg subcutaneous dose was decreased by 30% inpatients with severe renal impairment and by 45% in patients with ESRD receiving haemodialysis.

Exposure as assessed by AUClast was decreased by approximately 24% in patients with severe renalimpairment and by approximately 45% in patients with ESRD receiving haemodialysis. The exactmechanism of PK differences is unknown; however, differences in body weight could not explainthese differences. Some factors including small sample size and large inter-subject variability shouldbe considered when interpreting the results. The pharmacodynamics and safety of evolocumab inpatients with severe renal impairment and ESRD were similar to patients with normal renal function,and there were no clinically meaningful differences in LDL-C lowering. Therefore, no doseadjustments are necessary in patients with severe renal impairment or ESRD receiving haemodialysis.

No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A).

Single 140 mg subcutaneous doses of evolocumab were studied in 8 patients with mild hepaticimpairment, 8 patients with moderate hepatic impairment and 8 healthy subjects. The exposure toevolocumab was found to be approximately 40-50% lower compared to healthy subjects. However,baseline PCSK9 levels and the degree and time course of PCSK9 neutralisation were found to besimilar between patients with mild or moderate hepatic impairment and healthy volunteers. Thisresulted in similar time course and extent of absolute LDL-C lowering. Evolocumab has not beenstudied in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.4).

Body weight was a significant covariate in population PK analysis impacting evolocumab troughconcentrations, however there was no impact on LDL-C reduction. Following repeat subcutaneousadministration of 140 mg every 2 weeks, the 12-week trough concentrations were 147% higher and70% lower in patients of 69 kg and 93 kg respectively, than that of the typical 81 kg subject. Lessimpact from body weight was seen with repeated subcutaneous evolocumab 420 mg monthly doses.

Population pharmacokinetic analyses suggest that no dose adjustments are necessary for age, race orgender. The pharmacokinetics of evolocumab were influenced by body weight without having anynotable effect on LDL-C lowering. Therefore, no dose adjustments are necessary based on bodyweight.

The pharmacokinetics of Repatha were evaluated in 103 paediatric patients aged ≥ 10 to < 18 yearswith heterozygous familial hypercholesterolaemia (HAUSER-RCT). Following subcutaneousadministration of 420 mg Repatha once monthly, mean (SD) trough serum concentrations were 22.4(14.7) mcg/mL, 64.9 (34.4) mcg/mL and 25.8 (19.2) mcg/mL over the Week 12, Week 22 and

Week 24 time points, respectively. The pharmacokinetics of Repatha were evaluated in 12 paediatricpatients aged ≥ 10 to < 18 years with homozygous familial hypercholesterolaemia (HAUSER-OLE).

Following subcutaneous administration of 420 mg Repatha once monthly, mean (SD) serum troughconcentrations were 20.3 (14.6) mcg/mL and 17.6 (28.6) mcg/mL at Week 12 and Week 80,respectively.

Evolocumab was not carcinogenic in hamsters at exposures much higher than patients receivingevolocumab at 420 mg once monthly. The mutagenic potential of evolocumab has not been evaluated.

In hamsters and cynomolgus monkeys at exposures much higher than patients receiving 420 mgevolocumab once monthly, no effect on male or female fertility was observed.

In cynomolgus monkeys at exposures much higher than patients receiving 420 mg evolocumab oncemonthly, no effects on embryo-foetal or postnatal development (up to 6 months of age) were observed.

Apart from a reduced T-cell Dependent Antibody Response in cynomolgus monkeys immunised withkeyhole limpet haemocyanin (KLH) after 3 months of treatment with evolocumab, no adverse effectswere observed in hamsters (up to 3 months) and cynomolgus monkeys (up to 6 months) at exposuresmuch higher than patients receiving evolocumab at 420 mg once monthly. The intendedpharmacological effect of decreased serum LDL-C and total cholesterol were observed in these studiesand was reversible upon cessation of treatment.

In combination with rosuvastatin for 3 months, no adverse effects were observed in cynomolgusmonkeys at exposures much higher than patients receiving 420 mg evolocumab once monthly.

Reductions in serum LDL-C and total cholesterol were more pronounced than observed previouslywith evolocumab alone, and were reversible upon cessation of treatment.

Proline

Glacial acetic acid

Polysorbate 80

Sodium hydroxide (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Repatha 140 mg solution for injection in pre-filled syringe3 years.

Repatha 140 mg solution for injection in pre-filled pen3 years.

Repatha 420 mg solution for injection in cartridge2 years.

If removed from the refrigerator, Repatha may be stored at room temperature (up to 25°C) in theoriginal carton and must be used within 1 month.

Store in a refrigerator (2°C - 8°C). Do not freeze.

Repatha 140 mg solution for injection in pre-filled syringe

Store in the original carton in order to protect from light.

Repatha 140 mg solution for injection in pre-filled pen

Store in the original carton in order to protect from light.

Repatha 420 mg solution for injection in cartridge

Store in the original carton in order to protect from light and moisture.

Repatha 140 mg solution for injection in pre-filled syringe

One mL solution in a single use pre-filled syringe made from type I glass with stainless steel 27 gaugeneedle.

The needle cover of the pre-filled syringe is made from dry natural rubber (a derivative of latex, seesection 4.4).

Pack size of one pre-filled syringe.

Repatha 140 mg solution for injection in pre-filled pen

One mL solution in a single use pre-filled pen made from type I glass with stainless steel 27 gaugeneedle.

The needle cover of the pre-filled pen is made from dry natural rubber (a derivative of latex, seesection 4.4).

Pack sizes of one, two, three pre-filled pens or multipacks containing 6 (3 packs of 2) pre-filled pens.

Repatha 420 mg solution for injection in cartridge

A 3.5 mL solution in a single use cartridge made from cyclic olefin polymer with elastomer septumand piston as product-contact materials, and a resin cap. The pre-filled cartridge is assembled with atelescopic screw device component. The cartridge assembly is co-packed with an administrationdevice. The fluid path within the administration device is made from stainless steel and non-DEHPpolyvinyl chloride, with a stainless steel 29 gauge needle. The administration device contains silveroxide-zinc batteries and includes an adhesive patch made from polyester tape with an acrylateadhesive. The administration device is designed for use only with the provided 3.5 mL pre-filledcartridge assembly.

Pack sizes of one cartridge/automated mini-doser or multipack of three (3x1) cartridges/automatedmini-dosers.

Not all pack sizes may be marketed.

Before administration, the solution should be inspected. The solution should not be injected if itcontains particles, or is cloudy or discoloured. To avoid discomfort at the site of injection, themedicinal product should be allowed to reach room temperature (up to 25°C) before injecting. Theentire contents should be injected.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amgen Europe B.V.

Minervum 70614817 ZK Breda

The Netherlands

Repatha 140 mg solution for injection in pre-filled syringe

EU/1/15/1016/001 - 1 pre-filled syringe

Repatha 140 mg solution for injection in pre-filled pen

EU/1/15/1016/002 - 1 pre-filled pen

EU/1/15/1016/003 - 2 pre-filled pens

EU/1/15/1016/004 - 3 pre-filled pens

EU/1/15/1016/005 - 6 (3x2) pre-filled pens (multipack)

Repatha 420 mg solution for injection in cartridge

EU/1/15/1016/006 - 1 cartridge with co-packed automated mini-doser

EU/1/15/1016/007 - 3 (3x1) cartridges with co-packed automated mini-dosers (multipack)

Date of first authorisation: 17 July 2015

Date of latest renewal: 14 April 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.