Zilucoplan (Monograph)

Drug class: Complement Inhibitors

Introduction

Zilucoplan sodium is a complement protein C5 inhibitor.

Uses for Zilucoplan

Zilucoplan has the following uses:

Zilucoplan is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.

Zilucoplan Dosage and Administration

General

Zilucoplan sodium is available in the following dosage form(s) and strength(s):

Injection: 16.6 mg/0.416 mL, 23 mg/0.574 mL, or 32.4 mg/0.81 mL of zilucoplan in single-dose prefilled syringes.

Administration

For subcutaneous injection only.

Zilucoplan is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject zilucoplan after appropriate training on the subcutaneous injection technique is provided.

Administer zilucoplan subcutaneously into areas of the abdomen, thighs, or back of the upper arms that are not tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. Rotate injection sites for each administration. Administration of zilucoplan in the upper, outer arm should be performed by a caregiver.

When using zilucoplan prefilled syringes, inject the full contents of the single-dose prefilled syringe.

Discard the prefilled syringe after use. Do not reuse.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Obtain baseline amylase and lipase before initiating zilucoplan.

• Recommended dosage is given once daily as a subcutaneous injection and is dependent on actual body weight; daily dose should be administered at approximately the same time each day.

• For patients weighing less than 56 kg, recommended dosage is 16.6 mg once daily using the red colored prefilled syringe.

• For patients weighing 56 kg to less than 77 kg, recommended dosage is 23 mg once daily using the orange colored prefilled syringe.

• For patients weighing 77 kg and above, recommended dosage is 32.4 mg once daily using the dark blue colored prefilled syringe.

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

• See Full Prescribing Information for instructions on preparation and administration.

Cautions for Zilucoplan

Contraindications

Zilucoplan is contraindicated in patients with unresolved Neisseria meningitidis infection.

Warnings/Precautions

Serious Meningococcal Infections

Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors; zilucoplan is a complement inhibitor. The use of zilucoplan increases a patient’s susceptibility to serious and life-threatening meningococcal infections (septicemia and/or meningitis) caused by any serogroup, including non-groupable strains.

Complete or update meningococcal vaccination (for both serogroups A, C, W, and Y [MenACWY] and serogroup B [MenB]) at least 2 weeks prior to administering the first dose of zilucoplan, according to current ACIP recommendations for meningococcal vaccinations in patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of zilucoplan therapy. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information.

If urgent zilucoplan therapy is indicated in a patient who is not up to date with both MenACWY and MenB vaccines according to ACIP recommendations, administer meningococcal vaccine(s) as soon as possible and provide the patient with antibacterial drug prophylaxis. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including zilucoplan. The benefits and risks of treatment with zilucoplan and the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for meningococcal infection.

Because of inhibition of complement activity by zilucoplan and risk of infection caused by non-groupable strains of N. meningitidis, vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Withhold administration of zilucoplan in patients who are undergoing treatment for meningococcal infection until the infection is resolved.

REMS Program

Zilucoplan is available only through a restricted program, called ZILBRYSQ REMS, due to the risk of meningococcal infections. Notable requirements of the REMS program include the following:

Prescribers must enroll in the REMS.

Prescribers must counsel patients about the risk of meningococcal infection.

Prescribers must provide the patients with the REMS educational materials.

Prescribers must assess patient vaccination status for both meningococcal vaccines (MenACWY and MenB) and vaccinate if needed according to current ACIP recommendations for meningococcal vaccinations in patients receiving a complement inhibitor 2 weeks prior to the first dose of zilucoplan.

Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with both MenACWY and MenB vaccines according to current ACIP recommendations at least 2 weeks prior to the first dose of zilucoplan.

Pharmacies that dispense zilucoplan must be certified in the REMS and must verify prescribers are certified.

Patients must receive counseling from the prescriber about the need to receive both meningococcal vaccines (MenACWY and MenB) per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection.

Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 months following treatment discontinuation with zilucoplan.

Further information is available at [Web] or 1-877-414-8353.

Other Infections

Zilucoplan blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. Persons receiving zilucoplan are at increased risk for infections due to these bacteria, even after vaccination.

Pancreatitis and Other Pancreatic Conditions

Pancreatitis and pancreatic cysts have been reported in patients treated with zilucoplan. During the open-label extension studies, 7 (3.3%) patients experienced pancreatic events, including 4 (1.9%) patients with pancreatitis and 3 (1.4%) with pancreatic cysts. In the 3-month, double-blind, Study 1, adverse reactions of increased lipase were reported in 6 (6.9%) patients treated with zilucoplan compared to no patients on placebo, and adverse reactions of increased amylase were reported in 4 (4.7%) patients treated with zilucoplan compared to a single (1.1%) patient on placebo. Lipase levels exceeded 3 times the upper limit of normal in 6 (7%) patients after being started on zilucoplan compared to no patients on placebo. Patients should be informed of this risk before starting zilucoplan. Obtain lipase and amylase levels at baseline before starting treatment with zilucoplan. Discontinue therapy in patients with suspected pancreatitis and initiate appropriate management until pancreatitis is ruled out or has resolved.

Specific Populations

Pregnancy

There are no available data on zilucoplan use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Administration of zilucoplan to pregnant monkeys resulted in increases in embryofetal death at maternal exposures similar to those in humans at therapeutic doses.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of zilucoplan in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for zilucoplan and any potential adverse effects on the breastfed infant from zilucoplan or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of zilucoplan did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Common Adverse Effects

The most common adverse reactions (≥10%) in patients with generalized myasthenia gravis were injection site reactions, upper respiratory tract infection, and diarrhea.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosageadjustments. Interaction highlights:

Clinical drug interaction studies have not been performed with zilucoplan.

Actions

Mechanism of Action

Zilucoplan binds to the complement protein C5 and inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9.

The precise mechanism by which zilucoplan exerts its therapeutic effect in generalized myasthenic gravis is unknown but is presumed to involve reduction of C5b-9 deposition at the neuromuscular junction.

Advice to Patients

• Advise the patients and/or caregivers to read 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 at least 2 weeks prior to receiving the first dose of zilucoplan and to be revaccinated according to current ACIP recommendations for meningococcal vaccines while on zilucoplan therapy. Inform patients that vaccination may not prevent meningococcal infection. Inform patients about the signs and symptoms of meningococcal infection, and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms include 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; and eyes sensitive to light.

• Inform patients that they will be given a Patient Safety Card that they should carry with them at all times and for 2 months following treatment with zilucoplan. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation.

• Zilucoplan is available only through a restricted program called ZILBRYSQ REMS. Patients must receive counseling about the risk of serious meningococcal infections. Patients must receive written educational materials about this risk.

• Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species. 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 taking zilucoplan. Inform patients that persistent abdominal pain, sometimes severe or radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to contact their healthcare provider if these symptoms occur to determine if they should discontinue the drug.

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

• Remind patients if they forget to take their dose of zilucoplan to inject their dose as soon as they remember. They should then take their next dose at the appropriate scheduled time. They should not take more than 1 dose per day.

Additional Information

AHFSfirstRelease™. For additional information until a moredetailed monograph is developed and published, the manufacturer'slabeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

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