Pharmacy Practice in Focus: Health Systems
This case report depicts a probable infusion reaction in a 61-year-old woman prescribed evinacumab for the treatment of familial hypercholesterolemia.
This case report depicts a probable infusion reaction in a 61-year-old woman prescribed evinacumab for the treatment of familial hypercholesterolemia.
Familial hypercholesteremia (FH) is a genetic disorder that affects the metabolism of low-density lipoprotein particles and leads to abnormally high levels of cholesterol earlier in a patient’s life. Evinacumab-dgnb (Evkeeza; Regeneron Pharmaceuticals, Inc) is an angiopoietin-like 3 inhibitor approved in 2021 for the treatment of patients with homozygous familial hypercholesterolemia. This case report depicts a probable infusion reaction in a 61-year-old woman prescribed evinacumab for treatment of FH. During the first infusion, the patient experienced a drop in both heart rate and blood pressure, accompanied by dizziness and shortness of breath. This report reveals potential safety concerns with the administration of this novel cholesterol-lowering agent. Given that the medication has limited use because of its specific indication and that there is little literature available regarding that use, this case report emphasizes the need for more clinical practice examples regarding infusion reactions with evinacumab and highlights potential safety considerations with its administration.
Hyperlipidemia is an asymptomatic condition of high levels of fat particles in the blood.1 If hyperlipidemia is left untreated, over time the fat particles deposit in blood vessel walls and increase the risk of heart attack and stroke.
Familial hypercholesteremia (FH) is a genetic disorder that affects the metabolism of low-density lipoprotein (LDL) particles, leading to abnormally high levels of cholesterol earlier in life, increasing the likelihood of heart attacks and stroke at a younger age.2
Historically, FH has been thought to occur in 1 in every 500 individuals. However, more recent data estimate that FH occurs in 1 in every 200 to 300 individuals.2 There are 2 types of FH: heterozygous FH (HeFH) and homozygous FH (HoFH). HeFH refers to FH when only 1 defective copy of the gene is inherited; in HoFH, both inherited copies are mutated. FH can be monogenic (only 1 lipid-lowering gene is defective) or polygenic (multiple lipid-lowering genes are defective). HoFH is much rarer than HeFH. Individuals with HoFH tend to present with higher LDL levels (> 400 mg/dL vs > 190 mg/dL) at a younger age (childhood) and have poorer or no response to standard lipid-lowering medications.
With no gold standard for diagnosis, the presence of a positive mutation on genetic testing is the most widely acknowledged means of diagnosis. There are 3 genetic variants associated with FH: the LDL receptor (LDLR), APOB, and PCSK9 genes. All 3 encode proteins that play key roles in the regulation of cholesterol.3 Even with these identified genes, it is estimated that approximately 30% to 40% of patients with a diagnosis of FH have negative genetic testing. This is likely attributed to the wide range of unknown genetic mutations that cause FH that are still undiscovered; a patient with a yet-to-be-discovered FH genetic mutation would appear to have a negative genetic test result.2,3 For this reason, a clinical diagnosis of FH is frequently given in practice.
A clinical diagnosis of FH is based on a combination of several factors, including response to certain cholesterol-lowering medications, such as a diminished or no response to PCSK9 inhibitors; untreated LDL greater than 200 mg/dL; and a positive family history of premature heart disease. When genetic testing is unavailable or inconclusive, clinicians often rely on clinical diagnosis for FH. Tools such as the Simon-Broome Diagnostic Criteria or Dutch Lipid Clinic Network Score also aid clinicians when making a clinical diagnosis.
Evinacumab-dgnb (Evkeeza; Regeneron Pharmaceuticals, Inc) is an angiopoietin-like 3 (ANGPTL3) inhibitor approved in 2021 for the treatment of patients with HoFH. It is indicated as adjunct therapy to other maximally tolerated LDL-lowering therapies for the treatment of patients 5 years or older with HoFH. Evinacumab is a weight-based intravenous (IV) infusion dosed at 15 mg/kg that is mixed in a maximum volume of 250 mL of 0.9% normal saline or 5% dextrose. The final concentration of the diluted solution ranges between 0.5 mg/mL and 20 mg/mL, depending on patient weight, and is administered over 60 minutes every 4 weeks. The LDL-lowering effects can be seen as early as 2 weeks after initiation.
The most common adverse effect (AE) of evinacumab is nasopharyngitis; its frequency is greater than 10%.5 Safety data are based on pooled results from 2 clinical trials that included 81 patients treated with evinacumab 15 mg/kg every 4 weeks.5-7 Anaphylaxis was reported in 1 patient (1.2%) in the treatment group and 0 (0%) patients in the placebo group.5,7 Furthermore, infusion reactions occurred in 6 patients treated with evinacumab (7%) compared with 2 patients (4%) in the control group.5-7 Manufacturer labeling recommends slowing or discontinuing the infusion if hypersensitivity reactions occur.
Based on the low number of patients receiving this therapy, evinacumab’s specific indication, the lack of literature on its use outside of manufacturer labeling, and the lack of clinical data, this case aids in the awareness of potential safety considerations with the administration of evinacumab.
The patient was a 61-year-old White woman referred by her cardiologist to a pharmacist-run lipid clinic. She had elevated LDL despite having received PCSK9 inhibitor therapy; she also was to be assessed for HoFH.
At her initial lipid visit, genetic testing for FH was requested because of the patient’s partial response to PCSK9 inhibitor therapy (22% reduction in LDL rather than the expected approximately 60% reduction based on package insert) and untreated LDL greater than 400 mg/dL (LDL 430; 01/2019). Genetic testing could not be obtained because it was denied by the insurance company (estimated out-of-pocket expense for the patient was $1200). Therefore, clinical diagnosis of HoFH was designated in the setting of untreated LDL greater than 400 mg/dL and the patient’s partial response to evolocumab. The patient was deemed a candidate for evinacumab therapy by meeting the criteria for a clinical diagnosis of HoFH.
Approved for infusion at an independent location outside of the health system or home infusion, the patient elected for home infusion. At the time of first infusion, the patient weighed 58 kg, resulting in an evinacumab dose of approximately 866 mg. The medication was supplied by Orsini Specialty Pharmacy. Premedications were not selected for administration because the patient did not have a history of infusion reactions and premedications are not recommended by package labeling.
Forty-five minutes into the first infusion of evinacumab, the patient experienced decreases in her heart rate (from 84 to 64 bpm) and blood pressure, which were noted by the home infusion nurse. The patient reported feeling dizzy and short of breath. Infusion subsequently was stopped due to the concern for hypersensitivity and infusion reaction. Normal saline and 1 injection of intramuscular epinephrine were administered.
Patient was brought to the emergency department (ED) via ambulance. Emergency medical services (EMS) gave the patient 25 mg of diphenhydramine.
The patient received IV famotidine 20 mg once and methylprednisolone 125 mg once while in the ED. After observation and being deemed stable, she was discharged home.
The patient elected to discontinue treatment with evinacumab but continued taking evolocumab every 14 days.
According to current evinacumab clinical trial data, anaphylaxis was reported in 1 patient in the intravenous treatment group (n = 73). According to the trial investigators, during the second infusion of 15 mg/kg, the patient experienced “dizziness, chest pressure, tingling in the arms and legs, shortness of breath, pruritus, decreased blood pressure, and increased heart rate.” The infusion was discontinued and treated with oral diphenhydramine. No patients with adverse events in the intravenous treatment group died.7 Based on the pooled safety data (n = 81), infusion reactions occurred in 6 (7%) of the treatment group vs 2 (4%) in the placebo group. Infusion reactions included infusion site pruritus, pyrexia, muscular weakness, nausea, and nasal congestion.5-7 Manufacturer labeling recommends slowing infusion, at a rate designated by prescriber, if infusion reactions occur.5 Use of premedications to mitigate potential infusion reactions is up to the provider. Gaudet et al sought to assess the long-term safety and efficacy of evinacumab in adults and adolescents with HoFH.8 This was an open-label, single-arm, phase 3 trial that included 116 patients 12 years or older who were evinacumab naive or had received evinacumab in prior clinical trials. Trial investigators reported that most treatment-emergent adverse events (TEAEs) were mild or moderate in severity and the safety profile was consistent with the phase 3 ELIPSE trial (NCT03399786). The most common TEAEs were nasophyngitis (n = 23), influenza-like illness (n = 16), and headache (n = 19).8
Utilization of the Naranjo Scale leads to the conclusion that a drug-related AE was possible in this case report. With this conjecture, there are multiple limitations to consider. Because the patient received the infusion and rescue medications through a home infusion company, the authors were unable to gain access to the administering nurse’s encounter notes and recorded blood pressures, but they did have access to the patient’s heart rate data. The supplying drug company was also unable to provide any written infusion reaction protocols regarding the use of this medication.
The use of evinacumab in clinical practice is limited. Due to its low utilization, the existing data to reference regarding infusion reactions and/or the use of premedications are limited beyond the manufacturer labeling data and initial clinical trials. Other limiting factors include that this case was heavily based on patient-reported synopsis of events and subjective symptoms depicted in limited medical record documentation from various providers. Although this reaction may have been drug induced, we cannot eliminate the possibility that the patient’s symptoms could have been a vasovagal response to the infusion or IV access itself. Additional factors to note include that the patient had a past medical history of being positive for PCC and anxiety, both of which may have contributed to the patient’s constellation of symptoms during infusion.
Although the patient had been approved for infusion at an independent location outside of the health system or home infusion, the patient could not receive infusion at an independent infusion center because of institutional policies that prevent medications from an outside pharmacy to be received or administered, thus forcing the patient to receive this medication via home infusion. Evinacumab can be dispensed only through the Orsini Specialty Pharmacy for home infusions. In addition to patient preference, patient coverage plans and benefits help determine the treatment setting (home vs clinical setting) and acquisition channel (specialty distributor vs contracted specialty pharmacy). The authors would like to point out that home infusions can come with additional risks, especially when administering first doses of IV medications. The risk to patients is thought to revolve around the home environment having less intensive monitoring, less access to a collaborative health care team, and a lack of immediate access to urgent medical treatment in the event of an acute reaction, which may result in delayed care or increased need for escalation of care. Baker et al also found that infusion reactions administered at home were more likely to occur after the first infusion and result in increased escalation of care due to AEs and increased ED visits or hospital admissions.9
Jordan Krumanocker, PharmD, CPP, BCACP, is a PGY-2 ambulatory care pharmacy resident at Novant Health New Hanover Regional Medical Center in Wilmington, North Carolina.
Geena Eglin, PharmD, BCACP, CSP, CPP, is a specialty clinical pharmacist practitioner at Novant Health New Hanover Regional Medical Center in Wilmington, North Carolina.
This case depicts a likely infusion reaction to evinacumab. Based on the available literature, a retrial could be considered with the use of premedications and a slowed infusion time to mitigate the potential of another infusion reaction occurring. Minor infusion reactions that are nonfatal, such as infusion site pruritus and vasovagal responses, can be avoided by using premedications or administering the infusions in health care settings. Based on our speculation of infusion reaction and the patient’s preference, a retrial was not pursued. This report reveals potential safety concerns with the administration of a novel cholesterol-lowering agent. It also emphasizes the need for more clinical practice examples, given the limited information regarding infusion reactions and use of premedications with this agent, as well as bringing awareness to potential safety considerations with the administration of evinacumab.
The authors have nothing to disclose.
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