Repatha

Repatha

evolocumab

Manufacturer:

Amgen

Distributor:

Zuellig
Full Prescribing Info
Contents
Evolocumab.
Description
Each pre-filled syringe contains 140 mg of evolocumab in 1 mL of solution.
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. The effect of LDL-C lowering is sustained; the longest duration measured was 112 weeks.
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.
In 80-85% of all patients treated with either dose, Repatha demonstrated a ≥ 50% reduction in LDL-C at the mean of weeks 10 and 12. Up to 99% of patients treated with either dose of Repatha achieved an LDL-C of < 2.6 mmol/L and up to 95% achieved an LDL-C < 1.8 mmol/L at the mean of weeks 10 and 12.
Repatha at either dose 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.
Repatha reduced LDL-C, non-HDL-C, ApoB, TC, Lp(a), VLDL-C, TG, TC/HDL-C, and ApoB/ApoA1and increased HDL-C in patients with mixed dyslipidaemia.
Repatha was superior to ezetimibe in reducing LDL-C, TC, ApoB, non-HDL-C, Lp(a), TC/HDL-C, and ApoB/ApoA1.
Combination with a statin and statin with other lipid-lowering therapies: LAPLACE-2 was an international, multicentre, double-blind, randomised, 12-week study in 1896 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).
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 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 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 are two ongoing, 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 were eligible to enter the all Repatha period in which all patients could receive open-label Repatha for either another 4 years (OSLER) or 1 year (OSLER-2).
A total of 1324 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 124 weeks as demonstrated by reduction in LDL-C from week 12 in the parent study to week 112 in the open-label extension. A total of 2928 patients enrolled in OSLER-2. Repatha significantly reduced LDL-C from baseline at week 12 compared with control (nominal p < 0.001). Treatment effects were maintained as demonstrated by reduction in LDL-C from week 12 to week 24 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 24 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 is an ongoing 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, including homozygous familial hypercholesterolaemia. A total of 102 severe familial hypercholesterolaemia patients and 96 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 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 (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.

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The clinical relevance, including the long-term safety, of sustained very low levels of LDL-C (i.e., <0.65 mmol/L [<25 mg/dL]) have 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.
Clinical efficacy in 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.

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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 15% to 25% 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 13 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.

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The effect of Repatha on cardiovascular morbidity and mortality has not yet been established.
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 heterozygous familial hypercholesterolaemia (HeFH) 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. Repatha has not been studied 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 immunized with 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
Hypercholesterolaemia and mixed dyslipidaemia: Repatha is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet: in combination with a statin or statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or; alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.
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.
The effect of Repatha on cardiovascular morbidity and mortality has not yet been determined.
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 hypercholesterolaemia and mixed dyslipidaemia in adults: The recommended dose of Repatha is either 140 mg every two weeks or 420 mg once monthly; both doses are clinically equivalent.
Homozygous familial hypercholesterolaemia in adults and adolescents aged 12 years and over: The initial recommended dose is 420 mg once monthly. After 12 weeks of treatment, dose frequency can 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 their apheresis schedule.
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.
The 420 mg dose once monthly or every 2 weeks should be delivered using three pre-filled syringes/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.
Each pre-filled syringe/autoinjector is for single use only.
For instructions on administration, see Special precautions for disposal and 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
Renal impairment: Patients with severe renal impairment (defined as eGFR <30 mL/min/1.73 m2) have not been studied (see Pharmacology: Toxicology: Preclinical safety data 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: Toxicology: Preclinical safety data under Actions). Repatha should be used with caution in patients with severe hepatic impairment.
Dry natural rubber: The needle cover of the glass pre-filled syringe/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.
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 drug reactions during primary hypercholesterolaemia and mixed dyslipidaemia pivotal trials, at the recommended doses, were nasopharyngitis (4.8%), upper respiratory tract infection (3.2%), back pain (3.1%), arthralgia (2.2%), influenza (2.3%), and nausea (2.1%). 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 in patients with primary hypercholesterolaemia and mixed dyslipidaemia and homozygous familial hypercholesterolaemia are displayed by system organ class and frequency in Table 7 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).

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Description of selected adverse reactions: Injection site reactions: The most frequent injection site reactions were injection site erythema, injection site pain and injection site bruising.
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: Although no safety issues were observed in patients over 75 years, data are limited in this age subgroup.
Of the 6026 total number of patients in clinical studies of Repatha, 1779 (30%) were ≥65 years old, while 223 (4%) were ≥75 years old. No overall differences in safety or efficacy were observed between these patients and younger patients.
Immunogenicity: In clinical studies, 0.1% of patients (7 out of 4846 patients with primary hyperlipidaemia and mixed dyslipidaemia and 0 out of 80 patients with homozygous familial hypercholesterolaemia) treated with at least one dose of Repatha tested positive for binding antibody development (4 of these patients had transient antibodies). The patients whose sera tested positive for binding antibodies were further evaluated for neutralising antibodies and none of the patients tested positive for neutralising antibodies. The presence of anti-evolocumab binding antibodies did not impact the pharmacokinetic profile, clinical response, or safety of Repatha.
Reports of suspected adverse reactions: Seek medical attention immediately at the first sign of any adverse drug reactions.
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
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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 pre-filled syringe/autoinjector to reach room temperature (up to 25°C) before injecting. Inject the entire contents of the pre-filled syringe/autoinjector.
The pre-filled autoinjector is designed to deliver the entire contents as a fixed dose.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Storage
Keep the pre-filled syringe/autoinjector 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.
Shelf-life: Prefilled syringe: 36 months.
Pre-filled autoinjector: 36 months.
Store in a refrigerator (2°C-8°C). Do not freeze.
Patient Counseling Information
Important: Before you use the Repatha pre-filled autoinjector, read this important information: Your healthcare provider will tell you how many Repatha pre-filled autoinjectors are needed for your dose. If injecting more than one Repatha pre-filled autoinjector, after reaching room temperature, all injections should be given within a 30 minute period.
Keep the Repatha pre-filled autoinjector in original carton to protect it from light.
The Repatha pre-filled autoinjector is to be stored in the refrigerator (2°C to 8°C).
It is important that you do not try to give yourself the injection unless you have received training from your healthcare provider.
The orange cap on a Repatha pre-filled autoinjector contains a needle cover (located inside the cap) that is composed of dry natural rubber, which is made from latex. Tell your healthcare provider if you are allergic to latex.
Keep the Repatha pre-filled autoinjector out of the sight and reach of children.
DO NOT: freeze or use the Repatha pre-filled autoinjector if it has been frozen; shake the Repatha pre-filled autoinjector; remove the orange cap from the Repatha pre-filled autoinjector until you are ready to inject; use the Repatha pre-filled autoinjector if it has been dropped on a hard surface. Part of the Repatha pre-filled autoinjector may be broken even if you cannot see the break; use the Repatha pre-filled autoinjector after the expiration date.
Step 1: Prepare.
A. Remove one Repatha pre-filled autoinjector from the package.
1. Carefully lift the pre-filled autoinjector straight up out of the box.
2. Put the original package with any unused pre-filled autoinjectors back in the refrigerator.
3. Wait at least 30 minutes for the pre-filled autoinjector to naturally reach room temperature before injecting.
DO NOT: try to warm the pre-filled autoinjector by using a heat source such as hot water or microwave; leave the pre-filled autoinjector in direct sunlight; shake the pre-filled autoinjector; remove the orange cap from the pre-filled autoinjector yet.
B. Inspect the Repatha pre-filled autoinjector.
Make sure the medicine in the window is clear and colourless to slightly yellow.
Check the expiration date.
DO NOT use pre-filled autoinjector if: medicine is cloudy or discoloured or contains large lumps, flakes, or particles; any part appears cracked or broken; the pre-filled autoinjector has been dropped; the orange cap is missing or not securely attached; the expiration date has passed.
In all cases, use a new pre-filled autoinjector.
C. Gather all materials needed for your injection.
Wash your hands thoroughly with soap and water.
On a clean, well-lit work surface, place the: New pre-filled autoinjector, alcohol wipes, cotton ball or gauze pad, plaster, sharps disposal container.
D. Prepare and clean your injection site.
You can use: Thigh; belly, except for a 2 inch (5 centimetres) area around your belly button; outer area of upper arm (only if someone else is giving you the injection).
Clean the injection site with an alcohol wipe. Let your skin dry.
DO NOT touch this area again before injecting.
Choose a different site each time you give yourself an injection. If you need to use the same injection site, just make sure it is not the same spot on that site you used last time.
DO NOT inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.
Step 2: Get ready.
A. Pull the orange cap straight off, only when you are ready to inject. Do not leave the orange cap off for more than 5 minutes. This can dry out the medicine.
It is normal to see a drop of liquid at the end of the needle or yellow safety guard.
DO NOT: twist, bend or wiggle the orange cap; put the orange cap back onto the pre-filled autoinjector; put fingers into the yellow safety guard.
DO NOT remove the orange cap from the pre-filled autoinjector until you are ready to inject.
B. Stretch or pinch your injection site to create a firm surface.
Stretch method: Stretch skin firmly by moving your thumb and fingers in the opposite direction, creating an area about 2 inches (5 centimetres) wide.
Pinch method: Pinch skin firmly between your thumb and fingers, creating an area about 2 inches (5 centimetres) wide.
It is important to keep skin stretched or pinched while injecting.
Step 3: Inject.
A. Hold the stretch or pinch. With the orange cap off, PLACE the pre-filled autoinjector on the skin at 90 degrees.
DO NOT touch the grey start button yet.
B. Firmly PUSH down the pre-filled autoinjector onto the skin until it stops moving.
You must push all the way down but DO NOT touch the grey start button until you are ready to inject.
C. When you are ready to inject, PRESS the grey start button. You will hear a click.
D. Keep PUSHING down on the skin. Then LIFT thumb. Your injection could take about 15 seconds.
Window turns yellow when the injection is done.
NOTE: After you remove the pre-filled autoinjector from your skin, the needle will be automatically covered.
Step 4: Finish.
A. Discard the used pre-filled autoinjector and orange needle cap.
Discard the used pre-filled autoinjector and the orange cap in a sharps disposal container.
Talk with your healthcare provider about proper disposal. There may be local guidelines for disposal.
Keep the pre-filled autoinjector and the sharps disposal container out of the sight and reach of children.
DO NOT: reuse the pre-filled autoinjector, recap the pre-filled autoinjector or put fingers into the yellow safety guard, recycle the pre-filled autoinjector or sharps disposal container or throw them into household rubbish.
B. Examine the injection site.
If there is blood, press a cotton ball or gauze pad on your injection site. DO NOT rub the injection site.
Apply a plaster if needed.
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 mL x 1's.
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