Repatha

Repatha

evolocumab

Manufacturer:

Amgen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Evolocumab.
Description
Repatha solution for injection in pre-filled syringe 140 mg: Each pre-filled syringe contains 140 mg of evolocumab in 1 mL of solution.
Repatha solution for injection in pre-filled autoinjector 140 mg: Each pre-filled autoinjector contains 140 mg of evolocumab in 1 mL of solution.
Repatha is a human IgG2 monoclonal antibody produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells.
Excipients/Inactive Ingredients: Proline, Glacial acetic acid, Polysorbate 80, Sodium hydroxide (for pH adjustment), Water for injections.
Action
Pharmacotherapeutic group: Other lipid modifying agents. ATC code: C10AX13.
Pharmacology: Pharmacodynamics: Mechanism of action: Evolocumab binds selectively to PCSK9 and prevents circulating PCSK9 from binding to the low density lipoprotein receptor (LDLR) on the liver cell surface, thus preventing PCSK9-mediated LDLR degradation. Increasing liver LDLR levels results in associated reductions in serum LDL-cholesterol (LDL-C).
Pharmacodynamic effects: In clinical trials, Repatha 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 primary hypercholesterolaemia and mixed dyslipidaemia.
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.
Subcutaneous regimens of 140 mg every 2 weeks and 420 mg once monthly were equivalent in average LDL-C lowering (mean of weeks 10 and 12) resulting in -72 to -57% from baseline compared with placebo. Treatment with Repatha resulted in a similar reduction of LDL-C when used alone or in combination with other lipid-lowering therapy.
Clinical efficacy in primary hypercholesterolaemia and mixed dyslipidaemia: LDL-C reduction of approximately 55% to 75% was achieved with Repatha as early as week 1 and maintained during long-term therapy. Maximal response was generally achieved within 1 to 2 weeks after dosing with 140 mg every 2 weeks and 420 mg once monthly. Repatha was effective in all subgroups relative to placebo and ezetimibe, with no notable differences observed between 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, metabolic syndrome, 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, 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% 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 in 1,896 patients with primary hypercholesterolaemia or mixed dyslipidaemia who were randomised to receive Repatha in combination with statins (rosuvastatin, simvastatin, or atorvastatin). Repatha was compared to placebo for the rosuvastatin and simvastatin groups and compared with placebo and ezetimibe for the atorvastatin group. 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 with placebo and ezetimibe for the atorvastatin 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 10 and 12 as compared to 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) (see Tables 1 and 2).
RUTHERFORD-2 was an international, multicentre, double-blind, randomised, placebo-controlled, 12-week study in 329 patients with heterozygous familial hypercholesterolaemia 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 to placebo (p < 0.05) (see Table 1.)

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Statin-intolerant patients: GAUSS-2 was an international, multicentre, double-blind, randomised, ezetimibe-controlled, 12-week study 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 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 to ezetimibe (p < 0.001) (see Table 2).
Monotherapy: 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 mixed dyslipidaemia. 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) (see Tables 1 and 2). (See Table 2.)

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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 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. 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 3).

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OSLER 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 and week 48 in OSLER-2), patients entered the all Repatha period 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). Treatment effects were maintained over 272 weeks as demonstrated by reduction in LDL-C from week 12 in the parent 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 from week 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 ApoA1 from baseline to week 52 in OSLER and to week 48 in OSLER-2 compared with control (nominal p < 0.001). LDL-C and other lipid parameters returned to baseline within 12 weeks after discontinuation 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 and efficacy of Repatha, as an adjunct to other lipid-lowering therapies, in patients with severe familial hypercholesterolaemia (FH), including homozygous familial hypercholesterolaemia. A total of 194 severe familial hypercholesterolaemia (non-HoFH) patients and 106 homozygous familial hypercholesterolaemia 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 once every 2 weeks. Dose frequency in non-apheresis patients could be titrated up 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 patients with severe familial hypercholesterolaemia (non-HoFH) (Table 4).
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 severe familial hypercholesterolaemia (non-HoFH). (See Table 4.)

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The long-term safety of sustained very low levels of LDL-C (i.e. < 0.65 mmol/L [< 25 mg/dL]) has not yet been established. Available data demonstrate that there are no clinically meaningful differences between the safety profiles of patients with LDL-C levels < 0.65 mmol/L and those with higher LDL-C, see Adverse Reactions.
Treatment of homozygous familial hypercholesterolaemia: TESLA was an international, multicentre, double-blind, randomised, placebo-controlled 12-week study in 49 homozygous familial hypercholesterolaemia patients aged 12 to 65 years. Repatha 420 mg once 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) (Table 5). 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 homozygous familial hypercholesterolaemia. (See Table 5.)

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Long-term efficacy in homozygous familial hypercholesterolaemia: In TAUSSIG, long-term use of Repatha demonstrated a sustained treatment effect as evidenced by reduction of LDL-C of approximately 20% to 30% in patients with homozygous familial hypercholesterolaemia not on apheresis and approximately 10% to 30% in patients with homozygous familial hypercholesterolaemia on apheresis (Table 6). 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) with homozygous familial hypercholesterolaemia are comparable to those in the overall population of patients with homozygous familial hypercholesterolaemia. (See Table 6.)

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Effect on atherosclerotic disease burden: The effects of Repatha 420 mg once monthly on atherosclerotic disease burden, as measured by intravascular ultrasound (IVUS), were evaluated in a 78-week double-blind, randomised, placebo-controlled study in 968 patients with coronary artery disease on a stable background of optimal statin therapy. 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) compared with 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 study did not investigate the correlation between atherosclerotic disease regression and cardiovascular events.
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 ≥ 70 mg/dL (1.8 mmol/L) or non-HDL-C values ≥ 100 mg/dL (2.6 mmol/L) with at least one major or at least 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 91.5 (79.5, 108.5) mg/dL (2.4 [2.0, 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).
The results of primary and secondary efficacy endpoints are shown in Table 7 and Figures 1 and 2 as follows: (See Table 7 and Figures 1 and 2.)

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The Kaplan-Meier curves for the primary and key secondary composite endpoints separated at approximately 5 months, and the magnitudes of the absolute risk reductions grew steadily over time.
In an exploratory landmark analysis of post-baseline subgroups, Repatha further reduced risk of the primary and key secondary composite endpoints after the first year than observed 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 3 years. Corresponding median (Q1, Q3) LDL-C concentrations ranged from 29 (19, 43) mg/dL to 35 (21, 64) mg/dL in the Repatha group, and 25% of patients achieved a LDL-C concentration < 20 mg/dL.
Of the patients treated with Repatha, 9518 achieved at least one LDL-C value < 25 mg/dL. 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 ≥ 40 mg/dL. Lower LDL-C concentrations achieved during the study were associated with lower rates of cardiovascular events for the primary and secondary composite endpoint.
In a separate study of 1,974 patients with established cardiovascular disease enrolled in the FOURIER study, no clinically meaningful effect of Repatha was observed on cognitive function domains.
Other Supportive Clinical Information: In an integrated analysis of phase 2 and 3 randomised placebo and active controlled studies of Repatha for up to 52 weeks duration, adverse events were reported in 51% (N = 1,609) of patients in the Repatha group who achieved an LDL < 25 mg/dL and 51% (N = 2,565) of patients in the Repatha group who achieved an LDL < 40 mg/dL compared with 52% (N = 1,339) of patients in the Repatha group with an LDL ≥ 40 mg/dL and 50% (N = 2,038) of patients in the control group with LDL ≥ 40 mg/dL.
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 > 5x upper limit of normal was 0.1% in both the Repatha (N = 2,523) and control (N = 1,249) groups. In the same studies, CK > 10 x upper limit of normal was 0.2% (N = 2,486) in the Repatha group and 0.1% (N = 1,217) in the control group.
The safety of Repatha in the long-term, controlled studies was similar to the findings in the integrated analysis of phase 2 and 3 placebo and active controlled studies.
Paediatric population: There are limited data available on the use of Repatha in the paediatric population. Fourteen adolescent patients aged ≥ 12 to < 18 years with homozygous familial hypercholesterolaemia have been included in clinical trials. No overall differences in safety or efficacy were observed between adolescent and adult patients with homozygous familial hypercholesterolaemia.
See Dosage & Administration for information on paediatric use.
Pharmacokinetics: Absorption and distribution: 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. Administration of single subcutaneous 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 Cmax mean (SD) of 46.0 (17.2) μg/mL and AUClast mean (SD) of 842 (333) day·μg/mL. Three subcutaneous 140 mg doses were bioequivalent to a single subcutaneous 420 mg dose. The absolute bioavailability after SC dosing was determined to be 72% from pharmacokinetic models.
Following a single 420 mg Repatha intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L, suggesting evolocumab has limited tissue distribution.
Biotransformation: Repatha is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.
Elimination: 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, the systemic 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 in part mediated by statins increasing the concentration of PCSK9 which did not adversely impact the pharmacodynamic effect of evolocumab on lipids. Population pharmacokinetic analysis indicated no appreciable differences in evolocumab serum concentrations in hypercholesterolaemic patients (non-familial hypercholesterolaemia or familial hypercholesterolaemia) taking concomitant statins.
Linearity/non-linearity: Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be 12 (2) mL/hr. In clinical studies with repeated subcutaneous dosing over 12 weeks, dose proportional increases in exposure were observed with dose regimens of 140 mg and greater. An approximate two to 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.
Renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment. Population pharmacokinetic analysis of integrated data from the Repatha clinical trials did not reveal a difference in pharmacokinetics of evolocumab in patients with mild or moderate renal impairment relative to non-renally impaired patients. There is limited experience with Repatha in patients with severe renal impairment (see Precautions).
Hepatic impairment: No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). 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 40-50% lower compared to 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 volunteers. This resulted in similar time course and extent of absolute LDL-C lowering. Repatha has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see Precautions).
Body weight: Body weight was a significant covariate in population PK analysis impacting evolocumab trough concentrations, however there was no impact on LDL-C reduction. Following repeat subcutaneous administration of 140 mg every 2 weeks, the 12-week trough concentrations were 147% higher and 70% lower in patients of 69 kg and 93 kg respectively, than that of the typical 81 kg subject. Less impact from body weight was seen with repeated subcutaneous evolocumab 420 mg monthly doses.
Other special populations: Population pharmacokinetic analyses suggest that no dose adjustments are necessary for age, race or gender. The pharmacokinetics of evolocumab were influenced by body weight without having any notable effect on LDL-C lowering. Therefore, no dose adjustments are necessary based on body weight.
Toxicology: Preclinical safety data: Evolocumab was not carcinogenic in hamsters at exposures much higher than patients receiving evolocumab 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 mg evolocumab once monthly, no effect on male or female fertility was observed.
In cynomolgus monkeys at exposures much higher than patients receiving 420 mg evolocumab once monthly, 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 with keyhole limpet haemocyanin (KLH) after 3 months of treatment with evolocumab, no adverse effects were observed in hamsters (up to 3 months) and cynomolgus monkeys (up to 6 months) at exposures much higher than patients receiving evolocumab at 420 mg once monthly. The intended pharmacological effect of decreased serum LDL-C and total cholesterol were observed in these studies and was reversible upon cessation of treatment.
In combination with rosuvastatin for 3 months, no adverse effects were observed in cynomolgus monkeys 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 previously with evolocumab alone, and were reversible upon cessation of treatment.
Indications/Uses
Prevention of Cardiovascular Events: In adults with established cardiovascular disease, Repatha in combination with an optimally dosed statin and/or other lipid-lowering therapies is indicated to reduce the risk of myocardial infarction, stroke, and coronary revascularisation (see Pharmacology: Pharmacodynamics under Actions).
Primary Hyperlipidaemia (Including Heterozygous Familial Hypercholesterolaemia): Repatha is indicated as an adjunct to diet, for the treatment of adults with primary hyperlipidaemia to reduce low density lipoprotein cholesterol (LDL-C): In combination with a statin or statin with other lipid-lowering therapies (e.g. statins, ezetimibe) in patients who are unable to reach LDL-C goals with 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 adolescents aged 12 years and over with homozygous familial hypercholesterolaemia in combination with other lipid-lowering therapies.
Dosage/Direction for Use
Prior to initiating Repatha, secondary causes of hyperlipidaemia or mixed dyslipidaemia (e.g., nephrotic syndrome, hypothyroidism) should be excluded.
Posology: Primary Hyperlipidaemia (Including Heterozygous Familial Hypercholesterolaemia) and Prevention of Cardiovascular Events: The recommended dose of Repatha is either 140 mg every 2 weeks or 420 mg once monthly; both doses are clinically equivalent.
When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.
Homozygous familial hypercholesterolaemia in adults and adolescents aged 12 years and over: The initial recommended dose is 420 mg once monthly. Patients on apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule.
Missed dose: If a dose is missed, instruct the patient to administer Repatha within 7 days from the missed dose and resume the patient's original schedule.
If an every-2-week dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
If a once-monthly dose is not administered within 7 days, instruct the patient to administer the dose and start a new schedule based on this date.
Patients with renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment, see Precautions for patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2).
Patients with hepatic impairment: No dose adjustment is necessary in patients with mild hepatic impairment, see Precautions for patients with moderate and severe hepatic impairment.
Elderly patients (age ≥ 65 years): No dose adjustment is necessary in elderly patients.
Paediatric population: The safety and efficacy of Repatha in children aged less than 18 years has not been established in the indication for primary hypercholesterolaemia and mixed dyslipidaemia. No data are available.
The safety and efficacy of Repatha in children aged less than 12 years has not been established in the indication for homozygous familial hypercholesterolaemia. No data are available.
Method of administration: Subcutaneous use.
Repatha is for subcutaneous injection into the abdomen, thigh, or upper arm region. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red, or hard. Repatha must not be administered intravenously or intramuscularly.
Repatha solution for injection in pre-filled syringe 140 mg: 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 within 30 minutes.
Repatha solution for injection in pre-filled autoinjector 140 mg: The 140 mg dose should be delivered using a single pre-filled autoinjector. The 420 mg dose should be delivered using three pre-filled autoinjectors administered consecutively within 30 minutes.
Repatha is intended for patient self-administration after proper training. Administration of Repatha can also be performed by an individual who has been trained to administer the product.
or single use only.
For instructions on administration, see Special precautions for disposal and other handling under Cautions for Usage and the 'Instructions for Use' provided in the carton.
Overdosage
No adverse effects were observed in animal studies at exposures up to 300-fold higher than those in patients treated with Repatha at 420 mg once monthly.
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.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Special Precautions
Dry natural rubber: Repatha solution for injection in pre-filled syringe 140 mg: The needle cover of the glass pre-filled syringe is made from dry natural rubber (a derivative of latex), which may cause allergic reactions.
Repatha solution for injection in pre-filled autoinjector 140 mg: The needle cover of the glass pre-filled autoinjector is made from dry natural rubber (a derivative of latex), which may cause allergic reactions.
Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 'sodium-free'.
Effects on ability to drive and use machines: Repatha has no known influence on the ability to drive and use machines.
Renal impairment: There is limited experience with Repatha in patients with severe renal impairment (defined as eGFR 30 mL/min/1.73 m2) (see Pharmacology: Pharmacokinetics under Actions). Repatha should be used with caution in patients with severe renal impairment.
Hepatic impairment: In patients with moderate hepatic impairment, a reduction in total evolocumab exposure was observed that may lead to a reduced effect on LDL-C reduction. Therefore, close monitoring may be warranted in these patients.
Patients with severe hepatic impairment (Child-Pugh C) have not been studied (see Pharmacology: Pharmacokinetics under Actions). Repatha should be used with caution in patients with severe hepatic impairment.
Use In Pregnancy & Lactation
Pregnancy: 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 (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Repatha should not be used during pregnancy unless the clinical condition of the woman requires treatment with evolocumab.
Breast-feeding: 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 Repatha therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: No data on the effect of evolocumab on human fertility are available. Animal studies did not show any effects on fertility endpoints at area under the concentration time curve (AUC) exposure levels much higher than in patients receiving evolocumab at 420 mg once monthly (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Adverse Reactions
Summary of the safety profile: The most commonly reported adverse reactions during pivotal trials, at the recommended doses, were nasopharyngitis (7.4%), upper respiratory tract infection (4.6%), back pain (4.4%), arthralgia (3.9%), influenza (3.2%), and injection site reactions (2.2%). The safety profile in the homozygous familial hypercholesterolaemia population was consistent with that demonstrated in the primary hypercholesterolaemia and mixed dyslipidaemia population.
Tabulated summary of adverse reactions: Adverse reactions reported in pivotal, controlled clinical studies, and spontaneous reporting, are displayed by system organ class and frequency in Table 8 as follows 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). (See Table 8.)

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Description of selected adverse reactions: Injection site reactions: The most frequent injection site reactions were injection site bruising, erythema, haemorrhage, injection site pain, and swelling.
Paediatric population: There is limited experience with Repatha in paediatric patients. Fourteen patients aged ≥ 12 to < 18 years with homozygous familial hypercholesterolaemia were included in clinical studies. No difference in safety was observed between adolescent and adult patients with homozygous familial hypercholesterolaemia.
The safety and effectiveness of Repatha in paediatric patients with primary hypercholesterolaemia and mixed dyslipidaemia has not been established.
Elderly population: Of the 18,546 patients treated with Repatha 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 efficacy were observed between these patients and younger patients.
Immunogenicity: In clinical studies, 0.3% of patients (48 out of 17,992 patients) treated with at least one dose of Repatha tested positive for binding antibody development. 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 Repatha.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation 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 as per local regulations.
Drug Interactions
No formal drug-drug interaction studies have been conducted for Repatha.
The pharmacokinetic interaction between statins and evolocumab was evaluated in the Repatha 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 the concentration of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) which did not adversely impact the pharmacodynamic effect of evolocumab on lipids. No statin dose adjustments are necessary when used in combination with Repatha.
No studies on pharmacokinetic and pharmacodynamics interaction between Repatha and lipid-lowering drugs other than statins and ezetimibe have been conducted.
Caution For Usage
Special precautions for disposal and other handling: Before administration, the solution should be inspected. Do not inject the solution if it contains particles, or is cloudy or discoloured. To avoid discomfort at the site of injection, allow the medicine to reach room temperature (up to 25°C) before injecting. Inject the entire contents.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Storage
Store in a refrigerator (2°C - 8°C). Do not freeze or shake.
Repatha solution for injection in pre-filled syringe 140 mg: Keep in the original carton in order to protect from light.
Repatha solution for injection in pre-filled autoinjector 140 mg: Keep in the original carton in order to protect from light.
If removed from the refrigerator, Repatha may be stored at room temperature (up to 25°C) in the original carton and must be used within 1 month.
ATC Classification
C10AX13 - evolocumab ; Belongs to the class of other lipid modifying agents.
Presentation/Packing
Soln for inj (pre-filled syringe, pre-filled autoinjector) 140 mg/mL (sterile and preservative-free, clear to opalescent, colourless to yellowish, and practically free from particles) x 1's.
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