Evkeeza Drug Information

EVKEEZA is indicated as an adjunct to diet and exercise and other low-density lipoprotein-cholesterol (LDL-C) lowering therapies to reduce LDL-C in adults and pediatric patients, aged 1 year and older, with homozygous familial hypercholesterolemia (HoFH).

Recommended Dosage

The recommended dosage of EVKEEZA is 15 mg/kg administered by intravenous (IV) infusion over 60 minutes once monthly (every 4 weeks). If a dosage of EVKEEZA is missed, administer as soon as possible. Thereafter, EVKEEZA should be scheduled monthly from the date of the last dosage.

Assess LDL-C when clinically appropriate. The LDL-lowering effect of EVKEEZA may be measured as early as 2 weeks after initiation.

Preparation Instructions for Intravenous Infusion Calculate the dosage (mg), total volume (mL) of EVKEEZA required, and the number of vials required based on the patient's current body weight. Visually inspect the solution for cloudiness, discoloration, and particulate matter prior to administration. EVKEEZA is a clear to slightly opalescent, colorless to pale-yellow solution.

Do not administer if the solution is cloudy, discolored, or contains particulate matter. EVKEEZA is supplied as single-dose vials and does not contain a preservative. Prepare the diluted infusion using aseptic technique.

Do not shake the vial. Withdraw the required volume from the vial(s) of EVKEEZA and transfer into an IV infusion bag of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Discard any unused portion left in the vials.

Mix the diluted solution by gentle inversion; do not shake. Maximum diluent volume by patient weight is summarized in Table 1. Table 1: The final concentration of the diluted solution should be between 0.5 mg/mL and 20 mg/mL depending on the patient's current body weight.

Administer the diluted solution immediately after preparation and discard any unused portion left in the vial. Do not freeze the diluted solution.

Administration Instructions for Intravenous Infusion

If refrigerated, allow the diluted solution to come to room temperature prior to administration. Administer EVKEEZA diluted solution via IV infusion through an IV line containing a sterile, in-line or add-on, 0.2-micron to 5-micron filter over 60 minutes. Do not mix other medications with EVKEEZA or administer other medications concomitantly via the same infusion line.

The rate of infusion may be slowed, interrupted or discontinued if the patient develops any signs of adverse reactions, including infusion or hypersensitivity reactions. EVKEEZA can be administered without regard to the timing of lipoprotein apheresis.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adult and Pediatric Patients (aged 12 to 17 years) with HoFH Safety data are based on pooled results from two randomized, double-blind, placebo-controlled trials that included 81 patients treated with EVKEEZA. Forty-four (54%) EVKEEZA-treated patients had HoFH.

Patients received EVKEEZA as add-on therapy to other lipid-lowering therapies, including maximally tolerated statin, ezetimibe, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, lomitapide, and apheresis. The most common adverse reactions (reported in greater than 3% of EVKEEZA-treated patients and more frequently than in placebo) are shown in Table 2. Table 2: Adverse Reactions Occurring in >3% of Adult and Pediatric Patients Aged 12 to 17 Years Treated with EVKEEZA and Greater than Placebo in 24-Week, Pooled, Placebo-Controlled Trials 0 4 Other adverse reactions occurring in less than 3% of patients treated with EVKEEZA and greater than placebo included constipation, upper respiratory tract infection, nasal congestion, and abdominal pain.

Transient, mild to moderate decreases in diastolic blood pressure and increases in heart rate occurred in clinical trials of EVKEEZA infusion but did not require intervention and resolved post-infusion. Serious Hypersensitivity Reactions Anaphylaxis was reported in 0% patients who received placebo and 1 (1%) patient treated with EVKEEZA. The following infusion reactions occurred in EVKEEZA-treated patients: infusion site pruritus, pyrexia, muscular weakness, nausea, and nasal congestion.

Part A was a trial of 6 patients who received a single intravenous dose of EVKEEZA 15 mg/kg to determine the dosage for the rest of the trial. Part B was a single-arm, 24-week trial of EVKEEZA 15 mg/kg given intravenously every 4 weeks in 14 unique patients. Part C was a 48-week extension trial of EVKEEZA 15 mg/kg given intravenously every 4 weeks that consisted of 20 patients who entered directly from Parts A or B.

The safety profile of EVKEEZA observed in these patients was consistent with the safety profile observed in adults and pediatric patients aged 12 years and older, with the additional adverse reaction of fatigue. Fatigue was reported in 3 (15%) patients.

Pregnancy Risk Summary Based on data from animal reproduction studies, EVKEEZA may cause fetal harm when administered to pregnant patients. Available human data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Evinacumab-dgnb is a human IgG4 monoclonal antibody, and human IgG is known to cross the placental barrier; therefore, evinacumab-dgnb has the potential to be transmitted from the mother to the developing fetus.

Subcutaneous administration of evinacumab-dgnb to pregnant rabbits during the period of organogenesis resulted in fetal malformations (domed head, hydrocephalus, and flexed limbs) at doses below the maximum recommended human dose (MRHD). No adverse embryofetal effects were observed with subcutaneous administration of evinacumab-dgnb to pregnant rats during the period of organogenesis at doses below the MRHD. Measurable evinacumab-dgnb serum concentrations were observed in fetal rabbit and rat sera at birth, indicating that evinacumab-dgnb, like other IgG antibodies, crosses the placental barrier (see Data ).

Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. 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.

If a patient becomes pregnant while receiving EVKEEZA, healthcare providers should report EVKEEZA exposure by calling 1-833-385-3392. Data Animal Data In an embryo-fetal development study in pregnant rabbits, evinacumab-dgnb was administered subcutaneously at doses of mg/kg every 3 days (Q3D) during the period of organogenesis from gestation day 7 to day 19. Evinacumab-dgnb was teratogenic in rabbits, causing domed head, dilation of the lateral and third ventricles of the brain, and flexed fore/hind paws at maternal evinacumab-dgnb exposures below human exposure at the MRHD of 15 mg/kg every 4 weeks, based on AUC.

Other fetal malformations, consisting of irregular and abnormal ossification in the skull, palate, and metacarpal, and enlarged anterior and/or posterior fontanelles occurred and were consistent with significant maternal toxicity (including early deaths due to abortion and premature delivery at all doses, reduction in maternal body weight gains, and reduced maternal food consumption). Increased incidences of post-implantation losses, resorptions (total, early, and late), and decreased fetal body weight were also consistent with maternal toxicity. Evinacumab-dgnb was present in the sera of fetuses born from mothers at 10 and 30 mg/kg/Q3D at levels higher than in maternal serum.

In an embryo-fetal development study in pregnant rats, evinacumab-dgnb was administered subcutaneously at doses of mg/kg/Q3D during the period of organogenesis from gestation day 6 to day 18. Maternal exposures to evinacumab-dgnb were below the human exposure measured at the MRHD. Evinacumab-dgnb resulted in unexplained maternal deaths at 100 mg/kg/Q3D.

Evinacumab-dgnb crossed the placenta and was present at ratios (C Fetal /C Maternal ) ranging from 0.42 to 0.65. No adverse effects on embryofetal development were observed at any dose. In a combined fertility, embryofetal, and pre- and postnatal development study, female rats were administered evinacumab-dgnb via subcutaneous injection at doses of 30 and 100 mg/kg/Q3D beginning 2 weeks prior to mating and continuing to gestation day 21 or lactation day 21.

Mean maternal systemic exposures were below the human exposure at the MRHD throughout the study. No maternal or developmental toxicity was observed.

Pediatric Use The safety and effectiveness of EVKEEZA as an adjunct to other LDL-C-lowering therapies for the treatment of HoFH have been established in pediatric patients aged 1 year and older. Use of EVKEEZA for this indication is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, efficacy, and safety data in pediatric patients aged 1 year and older. The safety profile of EVKEEZA in pediatric patients aged 1 to 11 years was similar to the safety profile in adults and pediatric patients aged 12 years and older, with the additional adverse reaction of fatigue in patients aged 5 to 11 years.

The safety and effectiveness of EVKEEZA have not been established in pediatric patients younger than 1 year of age.

EVKEEZA is contraindicated in patients with a history of serious hypersensitivity reaction to evinacumab-dgnb or to any of the excipients in EVKEEZA. Serious hypersensitivity reactions, including anaphylaxis, have occurred.