Drug Detail:Evkeeza (Evinacumab-(e vin ak ue mab) [ e-vin-ak-ue-mab ])
Drug Class: Miscellaneous antihyperlipidemic agents
Highlights of Prescribing Information
EVKEEZA® (evinacumab-dgnb) injection, for intravenous use
Initial U.S. Approval: 2021
Recent Major Changes
| Indications and Usage (1) | 03/2023 |
Indications and Usage for Evkeeza
EVKEEZA is an angiopoietin-like 3 (ANGPTL3) inhibitor indicated as an adjunct to other low-density lipoprotein-cholesterol (LDL-C) lowering therapies for the treatment of adult and pediatric patients, aged 5 years and older, with homozygous familial hypercholesterolemia (HoFH). (1)
Limitations of Use:
- The safety and effectiveness of EVKEEZA have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH). (1)
- The effects of EVKEEZA on cardiovascular morbidity and mortality have not been determined. (1)
Evkeeza Dosage and Administration
- The recommended dosage of EVKEEZA is 15 mg/kg administered by intravenous (IV) infusion once monthly (every 4 weeks). (2.1)
- See the Full Prescribing Information for preparation instructions for the intravenous infusion. (2.2)
- Administer the diluted solution via IV infusion over 60 minutes through an IV line containing a sterile, in-line or add-on, 0.2-micron to 5-micron filter. (2.3)
- Do not mix other medications with EVKEEZA or administer other medications concomitantly via the same infusion line. (2.3)
- The rate of infusion may be slowed, interrupted or discontinued if the patient develops any signs of adverse reactions, including infusion or hypersensitivity reactions. (2.3)
Dosage Forms and Strengths
- Injection: 345 mg/2.3 mL (150 mg/mL) and 1,200 mg/8 mL (150 mg/mL) solution in single-dose vials. (3)
Contraindications
- History of serious hypersensitivity reactions to evinacumab-dgnb or to any of the excipients in EVKEEZA. (4)
Warnings and Precautions
- Serious Hypersensitivity Reactions: Have occurred with EVKEEZA in clinical trials. If a serious hypersensitivity reaction occurs, discontinue EVKEEZA, treat according to standard-of-care and monitor until signs and symptoms resolve. (5.1)
- Embryo-Fetal Toxicity: EVKEEZA may cause fetal harm based on animal studies. Advise patients who may become pregnant of the risk to a fetus. Consider obtaining a pregnancy test prior to initiating treatment with EVKEEZA. Advise patients who may become pregnant to use contraception during treatment and for at least 5 months following the last dosage. (5.2, 8.1, 8.3)
Adverse Reactions/Side Effects
Common adverse reactions (≥5%) were nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, nausea, and fatigue. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-833-385-3392 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 3/2023
Full Prescribing Information
1. Indications and Usage for Evkeeza
EVKEEZA is indicated as an adjunct to other low-density lipoprotein-cholesterol (LDL-C) lowering therapies for the treatment of adult and pediatric patients, aged 5 years and older, with homozygous familial hypercholesterolemia (HoFH).
2. Evkeeza Dosage and Administration
2.1 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.
2.2 Preparation Instructions for Intravenous Infusion
- Calculate the dose (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 or discolored or contains particulate matter.
- EVKEEZA vials are single-dose containers and do not contain a preservative. Observe aseptic technique when preparing EVKEEZA.
- Do not shake the vial. Withdraw the required volume from the vial(s) of EVKEEZA and transfer into an IV infusion bag containing a maximum volume of 250 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix the diluted solution by gentle inversion; do not shake.
- 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.
- If not used immediately, store the diluted solution refrigerated at 2 °C to 8 °C (36 °F to 46 °F) for no more than 24 hours from the time of preparation OR at room temperature up to 25 °C (77 °F) for no more than 6 hours from the time of infusion preparation to the end of the infusion. Do not freeze the diluted solution.
2.3 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 over 60 minutes through an IV line containing a sterile, in-line or add-on, 0.2-micron to 5-micron filter.
- 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 [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
- EVKEEZA can be administered without regard to the timing of lipoprotein apheresis.
3. Dosage Forms and Strengths
EVKEEZA is a clear to slightly opalescent, colorless to pale yellow solution available as follows:
- Injection: 345 mg/2.3 mL (150 mg/mL) and 1,200 mg/8 mL (150 mg/mL) in single-dose vials.
4. Contraindications
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 [see Warnings and Precautions (5.1)].
5. Warnings and Precautions
5.1 Serious Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylaxis, have occurred with EVKEEZA [see Adverse Reactions (6.1)]. If signs or symptoms of serious hypersensitivity reactions occur, discontinue EVKEEZA infusion, treat according to the standard-of-care, and monitor until signs and symptoms resolve. EVKEEZA is contraindicated in patients with a history of serious hypersensitivity reaction to evinacumab-dgnb.
5.2 Embryo-Fetal Toxicity
Based on the findings in animal reproduction studies, EVKEEZA may cause fetal harm when administered to pregnant patients. Administration of evinacumab-dgnb to rabbits during organogenesis caused increases in fetal malformations at doses below the human exposure. Advise patients who may become pregnant of the risk to a fetus. Consider obtaining a pregnancy test prior to initiating treatment with EVKEEZA. Advise patients who may become pregnant to use effective contraception during treatment with EVKEEZA and for at least 5 months following the last dosage of EVKEEZA [see Use in Specific Populations (8.1, 8.3)].
6. Adverse Reactions/Side Effects
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
6.1 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. The mean age of EVKEEZA-treated patients was 48 years (range: 15 to 75 years), 52% were women, 5% were Hispanic, 82% were White, 7% Asian, 3% Black or African American, and 9% other races. 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.
Adverse reactions led to discontinuation of treatment in 1 (2%) patient who received placebo, and 2 (2%) patients treated with EVKEEZA, including 1 case of anaphylaxis. The most common adverse reactions (reported in greater than 3% of EVKEEZA-treated patients and more frequently than in placebo) are shown in Table 1.
| Adverse Reactions | Placebo (N = 54) % | EVKEEZA (N = 81) % |
|---|---|---|
| Nasopharyngitis | 13 | 16 |
| Influenza like illness | 6 | 7 |
| Dizziness | 0 | 6 |
| Rhinorrhea | 0 | 5 |
| Nausea | 2 | 5 |
| Pain in extremity | 0 | 4 |
| Asthenia | 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.
8. Use In Specific Populations
8.4 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 5 years and older. Use of EVKEEZA for this indication is supported by evidence from adequate and well-controlled trials in adults with additional efficacy and safety data in pediatric patients aged 5 years and older [see Adverse Reactions (6.1) and Clinical Studies (14)]. The safety profile of EVKEEZA in pediatric patients aged 5 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.
The safety and effectiveness of EVKEEZA have not been established in pediatric patients with HoFH who are younger than 5 years old.
11. Evkeeza Description
Evinacumab-dgnb is an angiopoietin-like protein 3 (ANGPTL3) inhibitor monoclonal antibody (IgG4 isotype) produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture. Evinacumab-dgnb has an approximate molecular weight of 146 kDa.
EVKEEZA (evinacumab-dgnb) injection is a sterile, preservative-free solution for intravenous use. The solution is clear to slightly opalescent, colorless to pale-yellow, and free from visible particles.
Each vial contains 345 mg/2.3 mL or 1,200 mg/8 mL. Each mL contains 150 mg of evinacumab-dgnb, and L-arginine hydrochloride (14.8 mg), L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.1 mg), L-proline (30 mg), polysorbate 80 (1 mg) and Water for Injection, USP. The pH is 6.
12. Evkeeza - Clinical Pharmacology
12.1 Mechanism of Action
Evinacumab-dgnb is a recombinant human monoclonal antibody that binds to and inhibits ANGPTL3. ANGPTL3 is a member of the angiopoietin-like protein family that is expressed primarily in the liver and plays a role in the regulation of lipid metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). Evinacumab-dgnb inhibition of ANGPTL3 leads to reduction in LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Evinacumab-dgnb reduces LDL-C independent of the presence of LDL receptor (LDLR) by promoting very low-density lipoprotein (VLDL) processing and clearance upstream of LDL formation. Evinacumab-dgnb blockade of ANGPTL3 lowers TG and HDL-C by rescuing LPL and EL activities, respectively.
12.2 Pharmacodynamics
Administration of evinacumab-dgnb in HoFH patients resulted in reductions in LDL-C, total cholesterol (TC), HDL-C, apolipoprotein B and TG [see Clinical Studies (14)].
12.3 Pharmacokinetics
The pharmacokinetic parameters described in this section are presented following administration of evinacumab-dgnb 15 mg/kg intravenously every 4 weeks, unless otherwise specified.
Steady-state is reached after 4 doses, and the accumulation ratio is 2. According to population pharmacokinetic modeling, the mean (standard deviation) steady-state trough concentration is 266 (120) mg/L in adult patients, whereas the mean (standard deviation) Cmax at the end of infusion is 718 (183) mg/L in adult patients. Due to non-linear clearance, a 4.3-fold increase in area under the concentration-time curve at steady-state (AUCtau.ss) for a 3-fold increase in evinacumab-dgnb dose up to 15 mg/kg IV every 4 weeks was predicted in patients with HoFH.
12.6 Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the trials described below with the incidence of anti-drug antibodies in other trials, including those of EVKEEZA or of other evinacumab-dgnb products. During the 24-week treatment period in the trials in:
- Adult and pediatric patients aged 12 years and older with HoFH (Trials 1 and 2) [see Clinical Studies (14)], the incidence of anti-evinacumab-dgnb antibody formation was 0% (0 of 56) in EVKEEZA-treated patients.
- Pediatric patients aged 5 to 11 years with HoFH (Trial 3) [see Clinical Studies (14)], the incidence of anti-evinacumab-dgnb antibody formation was 5% (1 of 20) in EVKEEZA-treated patients. In the one patient that developed anti-evinacumab-dgnb antibodies, there were no effects on efficacy or evinacumab-dgnb concentrations.
- Because of the low occurrence of anti-evinacumab-dgnb antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of evinacumab products is unknown.
14. Clinical Studies
Adult and Pediatric Patients Aged 12 Years and Older with HoFH
Trial ELIPSE-HoFH (NCT03399786; Trial 1) was a multicenter, double-blind, randomized, placebo-controlled trial that evaluated the efficacy of EVKEEZA compared to placebo in 65 patients with HoFH (63 adult patients and 2 pediatric patients). During the 24-week, double-blind treatment period, patients were randomized to receive EVKEEZA 15 mg/kg given intravenously every 4 weeks (n=43) or placebo given intravenously every 4 weeks (n=22). After the double-blind treatment period, 64 of 65 patients entered a 24-week open-label extension period in which all patients received EVKEEZA 15 mg/kg given intravenously every 4 weeks.
Patients were on a background of other lipid-lowering therapies, including maximally tolerated statins, ezetimibe, PCSK9 inhibitor antibodies, lomitapide, and lipoprotein apheresis. Enrollment was stratified by apheresis status and geographical region. The diagnosis of HoFH was determined by genetic testing or by the presence of the following clinical criteria: history of an untreated total cholesterol (TC) >500 mg/dL and either xanthoma before 10 years of age or evidence of TC >250 mg/dL in both parents.
Endpoint Results
The primary efficacy endpoint was percent change in LDL-C from baseline to Week 24. At Week 24, the least squares (LS) mean treatment difference between the EVKEEZA and placebo groups in mean percent change in LDL-C from baseline was −49% (95% confidence interval: −65% to −33%; p <0.0001). After 24 weeks of open-label EVKEEZA treatment (Week 24 to Week 48), the observed LDL-C reduction from baseline was similar in patients who crossed over from placebo to EVKEEZA and was maintained in patients who remained on EVKEEZA for 48 weeks. For efficacy results see Table 2.
At Week 24, the observed reduction in LDL-C with EVKEEZA was similar across predefined subgroups, including age, sex, limited LDLR activity, concomitant treatment with lipoprotein apheresis, and concomitant background lipid-lowering medications (statins, ezetimibe, PCSK9 inhibitor antibodies, and lomitapide).
| LDL-C | ApoB | Non-HDL-C | TC | TG* | HDL-C* | |
|---|---|---|---|---|---|---|
| Abbreviations: HoFH=homozygous familial hypercholesterolemia, ITT=intent-to-treat, LS mean=least squares mean, N=number of randomized patients, CI=confidence interval | ||||||
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| Baseline (mean), mg/dL (N=65) | 255 | 171 | 278 | 322 | 124 | 44 |
| LS Mean: EVKEEZA (N = 43) | −47% | −41% | −50% | −47% | −55% | −30%† |
| LS Mean: Placebo (N = 22) | +2% | −5% | +2% | +1% | −5% | +1%† |
| LS Mean Difference from Placebo (95% CI) | −49% (−65 to −33) | −37% (−49 to −25) | −52% (−65 to −39) | −48% (−59 to −38) | −50% (−66 to −35) | -† |
The LS mean LDL-C percent changes over time are presented in Figure 1.
| Abbreviations: LS mean=least squares mean, HoFH=homozygous familial hypercholesterolemia, DBTP=double-blind treatment period, SE=standard error |
| Figure 1: Calculated LDL-C LS Mean Percent Change from Baseline Over Time Through Week 24 in Patients (63 Adults and 2 Pediatric Patients) with HoFH in Trial ELIPSE-HoFH (Trial 1) |
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Pediatric Patients (aged 5 to 11 years) with HoFH
Trial R1500-CL-17100 (NCT04233918; Trial 3) was a multicenter, three-part, single-arm, open-label trial in pediatric patients aged 5 to 11 years with HoFH [see Adverse Reactions (6.1)]. Part B of this trial evaluated the efficacy of EVKEEZA 15 mg/kg given intravenously every 4 weeks as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe, lomitapide, and lipoprotein apheresis) for 24 weeks in 14 patients with HoFH.
Endpoint Results
The primary efficacy endpoint was percent change in calculated LDL-C from baseline to Week 24. At Week 24, the mean percent change in calculated LDL-C from baseline was −48% (95% confidence interval: −69% to −28%). For efficacy results see Table 3. HDL-C and TG reductions observed in this trial were similar to changes seen in Trial 1, see Table 2.
At Week 24, the reduction in LDL-C with EVKEEZA was similar across baseline characteristics, including age, sex, limited LDLR activity, concomitant treatment with lipoprotein apheresis, and concomitant background lipid-lowering medications (statins, ezetimibe, and lomitapide).
| LDL-C | ApoB | Non-HDL-C | TC | ||
|---|---|---|---|---|---|
| Abbreviations: HoFH=homozygous familial hypercholesterolemia, N=number of randomized patients, CI=confidence interval | |||||
| Baseline (mean) (N=14) | 264 mg/dL | 168 mg/dL | 282 mg/dL | 316mg/dL | |
| Percent Change from Baseline at Week 24 (95% CI) | -48 (-69 to -28) | -41(-59 to -24) | -49 (-68 to -30) | -49 (-65 to -33) | |
16. How is Evkeeza supplied
EVKEEZA (evinacumab-dgnb) injection is a clear to slightly opalescent, colorless to pale yellow solution. It is supplied as one single-dose vial per carton.
- 345 mg/2.3 mL (150 mg/mL) NDC 61755-013-01
- 1,200 mg/8 mL (150 mg/mL) NDC 61755-010-01
17. Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Revised: March 2023 | ||
| Patient Information EVKEEZA® (ev-kee'-zah) (evinacumab-dgnb) injection, for intravenous use |
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| What is EVKEEZA?
EVKEEZA is an injectable prescription medicine used along with other low-density lipoprotein (LDL) lowering medicines in people 5 years of age and older with a type of high cholesterol called homozygous familial hypercholesterolemia (HoFH). It is not known if EVKEEZA is safe and effective in people with other causes of high cholesterol. The effect of EVKEEZA on heart problems such as heart attacks, stroke, or death is not known. It is not known if EVKEEZA is safe and effective in children with HoFH under 5 years of age. |
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| Who should not use EVKEEZA? Do not use EVKEEZA if you are allergic to evinacumab-dgnb or to any of the ingredients in EVKEEZA. See the end of this leaflet for a complete list of ingredients in EVKEEZA. |
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Before receiving EVKEEZA, tell your healthcare provider about all of your medical conditions, including if you:
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How will I receive EVKEEZA?
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| What are the possible side effects of EVKEEZA? EVKEEZA can cause serious side effects, including:
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| The most common side effects of EVKEEZA include: | |||
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| Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of EVKEEZA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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| General information about the safe and effective use of EVKEEZA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. If you would like more information about EVKEEZA, talk with your healthcare provider. You can ask your healthcare provider for information about EVKEEZA that is written for health professionals. |
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| What are the ingredients in EVKEEZA?
Active ingredient: evinacumab-dgnb Inactive ingredients: L-arginine hydrochloride, L-histidine, L-histidine monohydrochloride monohydrate, L-proline, polysorbate 80, and Water for Injection, USP. |
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| Manufactured by: Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road Tarrytown, NY 10591-6707 U.S. License No. 1760 © 2023 Regeneron Pharmaceuticals, Inc. All rights reserved. For more information about EVKEEZA, go to www.EVKEEZA.com or call 1-833-EVKEEZA (833-385-3392) |
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| EVKEEZA
evinacumab injection, solution, concentrate |
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| EVKEEZA
evinacumab injection, solution, concentrate |
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| Labeler - Regeneron Pharmaceuticals, Inc. (194873139) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
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| Regn Ireland DAC | 986063166 | ANALYSIS(61755-013, 61755-010) | |
