Zilucoplan Sodium (Monograph)

Brand name: Zilbrysq
Drug class: Complement Inhibitors

Medically reviewed by Drugs.com on Dec 10, 2024. Written by ASHP.

[Web]

Introduction

Complement protein C5 inhibitor.

Uses for Zilucoplan Sodium

Myasthenia Gravis

Used for treatment of generalized myasthenia gravis in adults who are anti-acetylcholine receptor (AChR) antibody positive (designated an orphan drug by FDA for this use).

Conventional therapy for generalized myasthenia gravis includes immunosuppressive agents, removal of antibodies by plasma exchange, and, in some cases, thymectomy. Complement inhibitors (e.g., eculizumab, ravulizumab) may be options for AChR-positive disease. Zilucoplan is another complement inhibitor that may be effective in myasthenia gravis. Specific place in therapy for zilucoplan has not yet been established.

Zilucoplan Sodium Dosage and Administration

General

Pretreatment Screening

• Evaluate the need for meningococcal vaccinations according to current immunization guidelines.

• Obtain baseline lipase and amylase levels.

Patient Monitoring

• Monitor patients for early signs and symptoms of meningococcal infection during treatment; evaluate patients immediately if infection is suspected.

Premedication and Prophylaxis

• Vaccinate patients against meningococcal infection (serogroups A, C, W, Y [MenACWY] and serogroup B [MenB]) according to current Advisory Committee on Immunization Practices (ACIP) recommendations ≥2 weeks prior to treatment initiation. If urgent therapy is indicated in a patient not up to date with the MenACWY and MenB vaccines, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible.

REMS

• Because of the risk of meningococcal infections, zilucoplan is available only through a restricted program, the Zilbrysq Risk Evaluation and Mitigation Strategy (REMS). Zilucoplan may be prescribed only by clinicians who are enrolled in the Zilbrysq REMS program. In addition, clinicians must agree to counsel patients regarding the risk of meningococcal infection, provide educational materials, and ensure that patients are compliant with meningococcal vaccinations and antibacterial drug prophylaxis requirements. To obtain additional information or to enroll in the program, clinicians may call 1-877-414-8353 or visit [Web].

Administration

Available in single-dose, preservative-free, prefilled syringes containing zilucoplan 16.6 mg/0.416 mL, 23 mg/0.574 mL, or 32.4 mg/0.81 mL. For one-time use only in a single patient.

Sub-Q Administration

Administer under guidance and supervision of a healthcare professional. Patients may self-inject after proper training. Provide training to patients and/or caregivers on sub-Q injection technique according to manufacturer's instructions for use.

If stored at room temperature and when ready to use, take 1 zilucoplan prefilled syringe from the carton. Do not return to refrigerator after storing at room temperature.

If stored in refrigerator and when ready to use, take 1 prefilled syringe out of refrigerator and place on clean, flat surface. Allow to reach room temperature away from direct sunlight (30–45 minutes) before injection. Do not heat or place in the microwave. Immediately return carton with other prefilled syringes to refrigerator.

Inject full contents of prefilled syringe. Administer at approximately the same time each day. Administer into areas of abdomen, thighs, or back of upper arms that are not tender, bruised, red, or hard. Do not inject into areas with scars or stretch marks. Rotate injection sites for each administration. Administration in upper, outer arm should be performed by a caregiver.

Discard prefilled syringe after use; do not reuse.

If a dose is missed, administer as soon as possible, then resume dosing at regular scheduled time. Do not administer more than 1 dose per day.

Dosage

Dosage of zilucoplan sodium expressed in terms of zilucoplan.

Adults

Generalized Myasthenia Gravis

Sub-Q

Recommended dosage based on patient's actual body weight (See Table 1); administer once daily.

Special Populations

Hepatic Impairment

No dosage adjustment required in mild or moderate hepatic impairment. Not studied in severe hepatic impairment.

Renal Impairment

No dosage adjustment required in renal impairment.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Zilucoplan Sodium

Contraindications

• Unresolved Neisseria meningitidis infection.

Warnings/Precautions

Warnings

Serious Meningococcal Infections

Risk of serious, life-threatening and fatal meningococcal infections caused by any serogroup, including non-groupable strains; can occur in vaccinated and unvaccinated patients. (See Boxed Warning.)

Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

Complete or update meningococcal vaccination (for both serogroups A, C, W, and Y [MenACWY] and serogroup B [MenB]) ≥2 weeks prior to administering the first dose of zilucoplan, according to current Advisory Committee on Immunization Practices (ACIP) recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering duration of zilucoplan therapy.

If urgent zilucoplan therapy indicated in patients not up to date with both MenACWY and MenB vaccines according to ACIP recommendations, provide antibacterial drug prophylaxis and administer vaccine(s) as soon as possible. Consider benefits and risks of zilucoplan therapy and antibacterial drug prophylaxis against known risks for meningococcal infection.

Monitor closely for early signs and symptoms of meningococcal infection; evaluate immediately if infection suspected. Inform patients of signs and symptoms of infection; instruct patients to seek immediate medical care if these occur. Withhold zilucoplan administration in patients undergoing treatment for meningococcal infection until infection is resolved.

Because of risk of serious meningococcal infections, zilucoplan is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. (See REMS under Dosage and Administration.)

Other Warnings and Precautions

Other Infections

May increase susceptibility to infections, especially with encapsulated bacteria, such as Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae.

Vaccinate patients for prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections in accordance with ACIP guidelines. Persons receiving zilucoplan at increased risk for infections due to these bacteria even after vaccination.

Pancreatitis and Other Pancreatic Conditions

Pancreatitis, pancreatic cysts, and increased lipase and/or amylase reported.

Inform patients of this risk before starting zilucoplan. Obtain lipase and amylase levels at baseline. Discontinue zilucoplan if pancreatitis suspected; initiate appropriate management until pancreatitis ruled out or resolved.

Immunogenicity

Potential for immunogenicity. Anti-drug and anti-polyethylene glycol (anti-PEG) antibodies detected.

Available data too limited to make definitive conclusions regarding immunogenicity and its effect on pharmacokinetics, pharmacodynamics, safety, or efficacy of zilucoplan.

Specific Populations

Pregnancy

No available data on zilucoplan use in pregnant women to inform drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Increased embryofetal death observed in animal studies in the absence of maternal toxicity.

Lactation

No data on presence in human milk, effects on breast-fed infant, or effects on milk production.

Consider developmental and health benefits of breast-feeding, along with mother's clinical need for zilucoplan and any potential adverse effects on breast-fed child from drug or underlying maternal condition.

Females and Males of Reproductive Potential

Testicular germ cell depletion/degeneration with evidence of lack of reversibility observed in animals.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.

Hepatic Impairment

Exposure decreased by 24% in individuals with moderate hepatic impairment (Child-Pugh category of moderate [score 7–9]) compared to those with normal hepatic function; this change not expected to be clinically important.

Pharmacokinetics not studied in severe hepatic impairment.

Renal Impairment

Exposure decreased by 13% in individuals with severe renal impairment (Cl_cr <30 mL/min) compared to those with normal renal function; this change not expected to be clinically important.

Common Adverse Effects

Most common adverse effects (≥10%): injection site reactions, upper respiratory tract infection, diarrhea.

Drug Interactions

Not a substrate of major CYP isoenzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A), or transporters including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3.

Clinically important interactions with substrates of CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A, and 4F), UGTs (1A1, 1A3, 1A4, 1A6, 1A9, 2B7, and 2B15), and transporters (P-gp, BCRP, OATP1B1, OATP1B3, organic anion transporter [OAT] 1, OAT3, multidrug and toxin extrusion [MATE] 1, MATE2-K, organic cation transporter [OCT] 1, and OCT2) unlikely.

No clinical drug interaction studies conducted to date.

Zilucoplan Sodium Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics not time dependent.

Following sub-Q administration, increase in peak plasma concentration approximately dose proportional; increase in AUC less than dose proportional.

Time to peak plasma concentration: 3–6 hours.

Following daily sub-Q dosing, peak plasma concentration and systemic exposure increase approximately 3-fold.

Time to steady state: 4 weeks.

Distribution

Extent

Unknown if distributes into human milk.

Plasma Protein Binding

Highly bound to plasma proteins (>99%).

Elimination

Metabolism

Expected to undergo degradation via catabolic pathways into small peptides and amino acids.

Metabolite RA103488 has pharmacological activity similar to zilucoplan but is present at much lower concentration. Metabolite RA102758 pharmacologically inactive. AUCs of both metabolites approximately 10% of parent AUC; contribution of RA103488 to pharmacological activity expected to be low.

Elimination Route

Excretion of zilucoplan and metabolite in urine and feces negligible (<1% of dose).

Half-life

Approximately 172 hours (7–8 days).

Special Populations

Pharmacokinetics not significantly affected by age, sex, or race based on population pharmacokinetics analysis.

Stability

Storage

Parenteral

Injection for Sub-Q Use

Store prefilled syringes at 2–8°C in original container until dispensing. After dispensing, patients or caregivers may store under refrigeration (2–8°C) until expiration date on carton, or at room temperature (≤30°C) for ≤3 months after removing from refrigerator or until expiration date, whichever occurs first. Store in original carton to protect from light until time of use; do not freeze.

Actions

• Complement inhibitor; binds to complement protein C5 and inhibits its cleavage to C5a and C5b, preventing generation of terminal complement complex, C5b-9.

• Exact mechanism of therapeutic effect in generalized myasthenia gravis unknown; presumed to involve reduction of C5b-9 deposition at neuromuscular junction.

• Dose-dependent inhibition of complement observed.

Advice to Patients

• Advise patients and/or caregivers to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

• Advise patients of the risk of meningococcal infection. Inform patients of the need to complete or update meningococcal vaccination for both MenACWY and MenB ≥2 weeks prior to receiving the first dose of zilucoplan. Inform patients of the requirement to be revaccinated according to current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccines while on zilucoplan therapy. Inform patients that they must receive antibiotics as directed by the clinician if they are not up to date on both meningococcal vaccines and have to start zilucoplan immediately.

• Inform patients that vaccination may not prevent meningococcal infection. Inform patients about the signs and symptoms of meningococcal infection, and to seek immediate medical attention if the following signs or symptoms occur: headache with nausea or vomiting; headache and a fever; headache with a stiff neck or stiff back; fever; fever and a rash; confusion; muscle aches with flu-like symptoms; or eye sensitivity to light.

• Inform patients that they will receive a Patient Safety Card for zilucoplan that they should carry with them at all times during treatment and for 2 months following treatment discontinuation. Inform patients that this card describes symptoms which, if experienced, should prompt them to seek immediate medical evaluation.

• Inform patients that zilucoplan is available only through a restricted program called Zilbrysq REMS. Inform patients of the important requirements of the program, including patient counseling (with written educational materials) and compliance with meningococcal vaccinations.

• Advise patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseriaspecies. Advise patients if they should receive the Streptococcus pneumoniae and Haemophilus influenzae type b vaccinations. Counsel patients about gonorrhea prevention and advise regular testing for patients at risk. Advise patients to report any new signs and symptoms of infection.

• Inform patients that pancreatitis and pancreatic cysts have been reported in patients treated with zilucoplan. Inform patients that the hallmark symptom of acute pancreatitis is persistent abdominal pain, sometimes severe or radiating to the back, which may or may not be accompanied by vomiting. Instruct patients to contact their clinician if these symptoms occur to determine if they should discontinue zilucoplan.

• Train patients and/or caregivers on proper subcutaneous injection technique of zilucoplan. Instruct patients to inject the full dose of zilucoplan. Instruct patients or caregivers on proper disposal of needles and syringes.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Zilucoplan is only available through a restricted REMS program (Zilbrysq REMS). For additional information, call 1-877-414-8353 or visit [Web] .

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