Low LDL-C Levels
In a pool of placebo- and active-controlled trials , as well as open-label extension studies that followed them , a total of 1988 patients treated with REPATHA had at least one LDL-C value < 25 mg / dL . Changes to background lipid-altering therapy were not made in response to low LDL-C values , and REPATHA dosing was not modified or interrupted on this basis . Although adverse consequences of very low LDL-C were not identified in these trials , the long-term effects of very low levels of LDL-C induced by REPATHA are unknown .
Musculoskeletal Events
Musculoskeletal adverse reactions were reported in 14.3 % of REPATHA-treated patients and 12.8 % of placebo-treated patients . The most common adverse reactions that occurred at a rate greater than placebo were back pain ( 3.2 % versus 2.9 % for REPATHA and placebo , respectively ), arthralgia ( 2.3 % versus 2.2 %), and myalgia ( 2.0 % versus 1.8 %).
Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia
In a 12-week , double-blind , randomized , placebo-controlled trial of 49 patients with HoFH ( Study 4 ), 33 patients received 420 mg of REPATHA subcutaneously once monthly [ see Clinical Studies ( 14.3 )]. The mean age was 31 years ( range : 13 to 57 years ), 49 % were women , 90 % White , 4 % Asian , and 6 % other . The adverse reactions that occurred in at least two ( 6.1 %) REPATHA-treated patients , and more frequently than in placebo-treated patients , included :
• Upper respiratory tract infection ( 9.1 % versus 6.3 %)
• Influenza ( 9.1 % versus 0 %)
• Gastroenteritis ( 6.1 % versus 0 %)
• Nasopharyngitis ( 6.1 % versus 0 %) 6.2 Immunogenicity
As with all therapeutic proteins , there is potential for immunogenicity . The immunogenicity of REPATHA has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies . For patients whose sera tested positive in the screening immunoassay , an in vitro biological assay was performed to detect neutralizing antibodies .
In a pool of placebo- and active-controlled clinical trials , 0.1 % of patients treated with at least one dose of REPATHA tested positive for binding antibody development . Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies ; none of the patients tested positive for neutralizing antibodies .
There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile , clinical response , or safety of REPATHA , but the longterm consequences of continuing REPATHA treatment in the presence of anti-drug binding antibodies are unknown .
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , comparison of the incidence of antibodies to REPATHA with the incidence of antibodies to other products may be misleading .
8 . USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary
There are no data available on use of REPATHA in pregnant women to inform a drugassociated risk . In animal reproduction studies , there were no effects on pregnancy or neonatal / infant development when monkeys were subcutaneously administered evolocumab from organogenesis through parturition at dose exposures up to 12 times the exposure at the maximum recommended human dose of 420 mg every month . In a similar study with another drug in the PCSK9 inhibitor antibody class , humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses . The exposures where immune suppression occurred in infant monkeys were greater than those expected clinically . No assessment for immune suppression was conducted with evolocumab in infant monkeys . Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum , indicating that evolocumab , like other IgG antibodies , crosses the placental barrier . FDA ’ s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester ; however , they are likely to cross the placenta in increasing amounts in the second and third trimester . Consider the benefits and risks of REPATHA and possible risks to the fetus before prescribing REPATHA to pregnant women .
In the U . S . general population , the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively .
Data Animal Data
In cynomolgus monkeys , no effects on embryo-fetal or postnatal development ( up to 6 months of age ) were observed when evolocumab was dosed during organogenesis to parturition at 50 mg / kg once every 2 weeks by the subcutaneous route at exposures 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly , respectively , based on plasma AUC . No test of humoral immunity in infant monkeys was conducted with evolocumab .
8.2 Lactation Risk Summary
There is no information regarding the presence of evolocumab in human milk , the effects on the breastfed infant , or the effects on milk production . The development and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for REPATHA and any potential adverse effects on the breastfed infant from REPATHA or from the underlying maternal condition . Human IgG is present in human milk , but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts .
8.4 Pediatric Use
The safety and effectiveness of REPATHA in combination with diet and other LDL-Clowering therapies in adolescents with HoFH who require additional lowering of LDL-C were established based on data from a 12-week , placebo-controlled trial that included 10 adolescents ( ages 13 to 17 years old ) with HoFH [ see Clinical Studies ( 14.3 )]. In this trial , 7 adolescents received REPATHA 420 mg subcutaneously once monthly and 3 adolescents received placebo . The effect of REPATHA on LDL-C was generally similar to that observed among adult patients with HoFH . Including experience from openlabel , uncontrolled studies , a total of 14 adolescents with HoFH have been treated with REPATHA , with a median exposure duration of 9 months . The safety profile of REPATHA in these adolescents was similar to that described for adult patients with HoFH .
The safety and effectiveness of REPATHA have not been established in pediatric patients with HoFH who are younger than 13 years old .
The safety and effectiveness of REPATHA have not been established in pediatric patients with primary hyperlipidemia or HeFH .
8.5 Geriatric Use
In controlled studies , 1420 patients treated with REPATHA were ≥ 65 years old and 171 were ≥ 75 years old . No overall differences in safety or effectiveness were observed between these patients and younger patients , and other reported clinical experience has not identified differences in responses between the elderly and younger patients , but greater sensitivity of some older individuals cannot be ruled out .
8.6 Renal Impairment
No dose adjustment is needed in patients with mild to moderate renal impairment . No data are available in patients with severe renal impairment [ see Clinical Pharmacology ( 12.3 )].
8.7 Hepatic Impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment ( Child-Pugh A or B ). No data are available in patients with severe hepatic impairment [ see Clinical Pharmacology ( 12.3 )].
13 . NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis , Mutagenesis , Impairment of Fertility
The carcinogenic potential of evolocumab was evaluated in a lifetime study conducted in the hamster at dose levels of 10 , 30 , and 100 mg / kg administered every 2 weeks . There were no evolocumab-related tumors at the highest dose at systemic exposures up to 38- and 15-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly , respectively , based on plasma AUC . The mutagenic potential of evolocumab has not been evaluated ; however , monoclonal antibodies are not expected to alter DNA or chromosomes .
There were no adverse effects on fertility ( including estrous cycling , sperm analysis , mating performance , and embryonic development ) at the highest dose in a fertility and early embryonic developmental toxicology study in hamsters when evolocumab was subcutaneously administered at 10 , 30 , and 100 mg / kg every 2 weeks . The highest dose tested corresponds to systemic exposures up to 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly , respectively , based on plasma AUC . In addition , there were no adverse evolocumabrelated effects on surrogate markers of fertility ( reproductive organ histopathology , menstrual cycling , or sperm parameters ) in a 6-month chronic toxicology study in sexually mature monkeys subcutaneously administered evolocumab at 3 , 30 , and 300 mg / kg once weekly . The highest dose tested corresponds to 744- and 300-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly , respectively , based on plasma AUC .
13.2 Animal Toxicology and / or Pharmacology
During a 3-month toxicology study of 10 and 100 mg / kg once every 2 weeks evolocumab in combination with 5 mg / kg once daily rosuvastatin in adult monkeys , there were no effects of evolocumab on the humoral immune response to keyhole limpet hemocyanin ( KLH ) after 1 to 2 months exposure . The highest dose tested corresponds to exposures 54- and 21-fold higher than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly , respectively , based on plasma AUC . Similarly , there were no effects of evolocumab on the humoral immune response to KLH ( after 3 to 4 months exposure ) in a 6-month study in cynomolgus monkeys at dose levels up to 300 mg / kg once weekly evolocumab corresponding to exposures 744- and 300-fold greater than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly , respectively , based on plasma AUC .
This Brief Summary is based on the REPATHA ® Prescribing Information v2 , 09 / 15
REPATHA ® ( evolocumab ) Manufactured by : Amgen Inc . One Amgen Center Drive Thousand Oaks , California 91320-1799 U . S . License Number 1080 Patent : http :// pat . amgen . com / repatha /
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