Pegcetacoplan is a parenteral complement (C3) inhibitor indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH) and geographic atrophy (GA) secondary to age-related macular degeneration (AMD). For PNH, pegcetacoplan was studied in a randomized, open-label, active comparator phase 3 trial (16 weeks) that enrolled patients with PNH who had been treated with a stable dose of eculizumab for at least 3 months. Pegcetacoplan was superior to eculizumab for the change from baseline in hemoglobin at week 16 (p less than 0.0001). Non-inferiority was demonstrated with transfusion avoidance and change from baseline absolute reticulocyte count (ARC). The use of pegcetacoplan for PNH may predispose patients to serious, life-threatening, or fatal infections caused by encapsulated bacteria; vaccinate for these bacteria prior to starting pegcetacoplan. Patients with PNH switching from eculizumab or ravulizumab to pegcetacoplan require a cross-over treatment period to avoid the risk of hemolysis due to therapy disruption.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Pegcetacoplan is available as a solution for injection for subcutaneous use (Empaveli) and a solution for injection for intravitreal use (Syfovre). These medications are not interchangeable. Do not substitute the subcutaneous injection with the intravitreal injection. Do not administer the subcutaneous injection for the intravitreal injection.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Pegcetacoplan is a clear, colorless to slightly yellowish solution. Do not use if the liquid looks cloudy, contains particles, or is dark yellow.
-Missed dose: Administer as soon as possible after a missed dose. Resume the regular dosing schedule after administration of the missed dose.
Subcutaneous Administration
NOTE: Subcutaneous pegcetacoplan (Empaveli) is intended for use under the guidance of a health care professional. After proper training in subcutaneous infusion, a patient may self-administer, or the patient's caregiver may administer pegcetacoplan.
Preparation of vial
-Remove a single pegcetacoplan vial carton from the refrigerator. Keep the vial in the original carton at room temperature and allow it to reach room temperature for approximately 30 minutes. Do not speed up the warming process.
-Remove the vial from the carton. Carefully inspect the liquid in the pegcetacoplan vial. Do not use the vial and call ApellisAssist at 1-866-692-7527 if the liquid looks cloudy, contains particles, or is dark yellow, the protective flip cap is missing, or the expiration date is passed.
-Remove the protective flip cap from the top of the vial to show the middle part of the gray rubber stopper of the pegcetacoplan vial. Dispose of the protective flip cap.
-Clean the gray rubber stopper with a new alcohol wipe and allow the gray rubber stopper to dry for at least 30 seconds. Do not touch the exposed gray rubber stopper after wiping.
Subcutaneous Administration via Infusion Pump
Preparation of syringe
-If using a needleless transfer device (e.g., a vial adapter), follow the instructions provided by the device manufacturer.
-If transfer is done using a transfer needle and a syringe, follow the instructions outlined below:-Attach a sterile transfer needle to a sterile syringe.
-Pull back the plunger to the 20-mL mark to fill the syringe with air.
-Push the air-filled syringe with transfer needle attached down through the center of the pegcetacoplan vial gray rubber stopper. Ensure the tip of the transfer needle is not in the solution to avoid creating air bubble(s).
-Gently push the air from the syringe into the vial.
-Turn the vial upside down and insert the transfer needle in the pegcetacoplan solution.
-Slowly pull the plunger back to fill the syringe with all the pegcetacoplan solution.
-Remove the filled pegcetacoplan syringe and the transfer needle from the vial.
-Remove the transfer needle by using 1 hand to slide the needle into the needle cap and scoop upwards to cover the needle.
-After the needle is covered, push the needle cap down towards the syringe to fully attach it with 1 hand to prevent an accidental stick with the needle. Twist off and remove the transfer needle.
Administration
-Administer via a commercially available infusion pump with a reservoir of at least 20 mL. Follow the device manufacturer's instructions to prepare the pump and tubing.
-Select an area on the abdomen, thighs, hips, or upper arms for the infusion(s). Avoid infusing into areas where the skin is tender, bruised, red, hard, tattooed, scarred, or has stretch marks.
-Use a different site from the time of the last pegcetacoplan infusion. Space infusion sites at least 3 inches apart if there are multiple infusion sites. Rotate infusion sites in between each infusion.
-Clean the skin at each infusion site(s) with a new alcohol wipe, starting at the center of each infusion site and working outward in a circular motion. Allow the skin to dry.
-Pinch the skin between the thumb and forefinger around the infusion site and insert the needle into the skin. Secure the needle(s) using gauze and tape or place a transparent dressing over the infusion site(s).
-Follow the device manufacturer's instructions to start and complete the infusion. Start the infusion immediately after drawing pegcetacoplan into the syringe. Pegcetacoplan infusion requires about 30 minutes if using 2 infusion sites or 60 minutes if using 1 infusion site.
-After the infusion is complete, remove the dressing and slowly take out the needle(s). Cover the infusion site with a new dressing.
-Remove the infusion set from the pump.
-Dispose of the used infusion set, needles, syringes, and tubing in an appropriate sharps container immediately after use.
Subcutaneous Administration via On-Body Injector
Preparation of syringe
-Prepare and fill the syringe with pegcetacoplan using a needleless transfer device (e.g., a vial adapter).
--Always follow the Instructions for Use provided by the needleless transfer device's manufacturer (as they may differ).
-Do not remove the needleless transfer device from the blister package, touch the spike or the inside of the needleless transfer device, or use the needleless transfer device if it comes out or is dropped out of the package, or if the package is opened.
-Remove the cover of the needleless transfer device package. Place the vial on a clean, flat surface and hold the vial by the base with 1 hand.
-Using the outside of the blister package to firmly hold the needleless transfer device, push the needleless transfer device straight down onto the vial top until it snaps securely into place.
-Remove the blister package from the needleless transfer device and throw the blister package away. Do not touch the connector at the top of the transfer device.
-Remove the syringe from its packaging. Do not touch the tip of the syringe.
-Attach the syringe to the needleless transfer device by twisting the tip of the syringe to the right (clockwise) onto the top of the needleless transfer device.
-Turn the pegcetacoplan vial upside down. Slowly pull the syringe plunger down to fill the syringe with pegcetacoplan.
-Withdraw all pegcetacoplan from the vial into the syringe; ensure there is 20 mL of pegcetacoplan in the syringe. Remove air from the syringe by gently pushing on the plunger.
-While holding the pegcetacoplan vial and syringe, turn the pegcetacoplan vial and filled syringe upright and place the bottom of the pegcetacoplan vial on a flat surface.
-Remove the filled syringe from the needleless transfer device with 1 hand while holding the pegcetacoplan vial with the other hand and twisting the filled syringe to the left (counterclockwise).
-Place the syringe on a clean, flat surface while preparing the pegcetacoplan injector. The syringe will not leak when set down. Do not touch the tip of the filled syringe.
-Discard of the vial with the attached needleless transfer device in the trash.
Preparation of on-body injector
-Peel back the injector cover and remove the clear packaging insert. Remove the pegcetacoplan injector and the surrounding filling base from the packaging; place it on a clean, flat, surface.
-Pick up the syringe filled with pegcetacoplan and twist the filled syringe tip to the right (clockwise) into the fill port until it is tight.
-Firmly push the syringe plunger down. Watch the fill gauge move as pegcetacoplan is pushed into the injector.
--Ensure that the syringe is empty. If needed, press firmly down on the syringe plunger again.
-Do not remove the syringe from the filling base.
Administration
-Use the pegcetacoplan injector where the temperature is between 41 and 104 degrees F (5 and 40 degrees C).
-Select an area of the stomach to place the pegcetacoplan injector. Use the pegcetacoplan injector on the stomach only.
--Select an injection site at least 1 inch from the edge of the belly button and the edge of the pegcetacoplan injector and 1 inch from the last injection site.
-Avoid an injection site that is tender, bruised, red, hard, irritated, tattooed, or has stretch marks.
-Do not apply the pegcetacoplan injector along the belt line or on areas where the pegcetacoplan injector will be affected by folds in the skin.
-Wearing loose clothes is recommended so that clothes do not get in the way of the pegcetacoplan injector.
-Clean the injection site with an alcohol wipe. Allow the injection site to dry for at least 30 seconds. Do not allow clothes to touch the clean injection site.
-Hold and pull the gray pull tab. Allow both the gray and clear pull tabs to fall to the side. Both tabs may fall to the side or come off completely.
--Do not remove the red safety tab until the pegcetacoplan injector is attached to the body.
-Hold the sides of the pegcetacoplan injector and pull it straight up to remove it from the filling base.
--Do not touch the adhesive on the bottom of the pegcetacoplan injector or fold the adhesive onto itself. The white adhesive will stay attached to the pegcetacoplan injector and the clear liner will stay attached to the filling base.
-Position the pegcetacoplan injector so that the fill window is pointed up toward the face. Press firmly on the clear portion of the pegcetacoplan injector to attach to stomach. Do not use anything to hold the pegcetacoplan injector in place.
-Hold the pegcetacoplan injector with 1 hand. Use the other hand to pull the red safety tab off. The pegcetacoplan infusion will not start until the red safety tab is removed.
-Immediately press the button in firmly until it stays in place to start the pegcetacoplan infusion. Pushing the button in will insert the needle into the skin.
--Holding down the button will stop the flow of medication. Infusion will begin again when the button is released.
-The pegcetacoplan infusion will continue as long as the button is pushed in. The estimated infusion time is 30 to 60 minutes.
--To track progress, watch the fill gauge move across the fill window toward empty. It may take some time to move and may move slowly.
-Light daily activities can be done during the pegcetacoplan infusion. Do not bump or knock the pegcetacoplan injector or button during the pegcetacoplan infusion.
-Keep the stomach dry. Avoid intense physical activity. Do not sleep or bathe during the pegcetacoplan infusion.
-When the button pops out, the pegcetacoplan infusion is done. The needle will be pulled out of the skin and back into the pegcetacoplan injector. The button popping out is the only way to know if the pegcetacoplan infusion is complete. Do not remove the pegcetacoplan injector until the button pops out.
-If the button does not pop out after 2 hours, press and hold the button while removing the pegcetacoplan injector from the skin. Do not touch the bottom of the pegcetacoplan injector as the needle will be exposed. Set the pegcetacoplan injector aside and call ApellisAssist at 1-866-692-7527.
-To remove the pegcetacoplan injector, use the thumb to lift the adhesive tab. Hold the adhesive tab against the pegcetacoplan injector. Slowly peel the pegcetacoplan injector away from the skin.
-Dispose of the used pegcetacoplan injector in an appropriate sharps container immediately after use. Do not throw the pegcetacoplan injector in the trash. The filling base (with the syringe attached), alcohol wipe, and packaging may be placed in the trash.
-If the pegcetacoplan injector falls off of the body, pick it up carefully. Do not touch the needle or any medication that may be on the pegcetacoplan injector. Set the pegcetacoplan injector aside and out of reach of children. Immediately call ApellisAssist at 1-866-692-7527.
Other Injectable Administration
Intravitreal Administration
NOTE: Intravitreal pegcetacoplan (Syfovre) must be administered by a qualified health care professional trained in these specialized administration techniques.
Preparation of vial and syringe
-Remove the carton from the refrigerator for at least 15 minutes prior to injection, but not longer than 8 hours.
-Remove the flip-off cap from the vial and clean the vial septum with an alcohol swab and wait for the alcohol to dry out.
-Attach a 5-micron filter needle onto a 1 mL Luer-lock syringe by twisting it onto the Luer-lock syringe tip.
-Push the filter needle into the center of the vial septum until the needle is submerged in the drug product to prevent withdrawal of air. To withdraw the entire contents of the vial into the syringe, hold the vial at a slightly inclined position. Withdraw the drug product slowly to prevent air bubbles. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid until all the fluid is withdrawn from the vial. Do not tap the syringe to remove air bubbles. While maintaining the filter needle within the vial, invert the syringe and move the plunger down and up until bubbles move to the top.
-Disconnect the filter needle from the syringe and dispose of it. Do not use the filter needle for injection.
-Aseptically and firmly attach the injection needle onto the 1 mL Luer-lock syringe.
-Check for air bubbles by holding the syringe with the needle pointing up. Do not tap the syringe to remove air bubbles. If there are any air bubbles, remove the needle cap and with the needle end facing up gently advance the plunger to the 0.1 mL dose mark.
Intravitreal Administration
-Only 0.1 mL (15 mg) should be administered to deliver a single dose. Any excess volume should be disposed. Ensure that the injection is given immediately after the preparation of the dose.
-Prior to the intravitreal injection, monitor for elevated intraocular pressure (IOP) using tonometry. If necessary, ocular hypotensive medication can be given to lower the IOP.
-The intravitreal injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid, and ocular surface should be administered prior to the injection.
-Inject intravitreally slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.1 mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel.
-Immediately after the intravitreal injection, monitor for elevations in IOP. Additional evaluation may include checking for perfusion of the optic nerve head and tonometry.
-Instruct patients to report without delay any symptoms suggestive of endophthalmitis (e.g., eye pain, redness of the eye, photophobia, blurring of vision).
-Each vial should only be used for the treatment of a single eye. If the fellow eye requires treatment, a new sterile, vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before pegcetacoplan administration. Repeat same procedure steps as above.
-Any unused medicinal product or waste material should be disposed of in accordance with local regulations.
Infusion-related reactions, including systemic hypersensitivity reactions (e.g., facial swelling, rash, urticaria), have occurred in persons treated with pegcetacoplan. Hypersensitivity pneumonitis was reported in less than 5% of subjects in clinical trials. A single subject (less than 1% of subjects in clinical trials) experienced a serious allergic reaction which resolved after treatment with antihistamines. Discontinue pegcetacoplan infusion immediately if a severe hypersensitivity reaction, including anaphylactoid reactions, occurs. Institute appropriate treatment and monitor until signs and symptoms are resolved. Dermatologic adverse reactions reported with use of pegcetacoplan in clinical trials include ecchymosis (7%), erythema (7%), and rash (11%).
Pegcetacoplan use increases susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria, including S. pneumoniae, N. meningitidis (any serogroup, including non-groupable strains), and H. influenzae type B. Ensure persons are appropriately vaccinated. Closely monitor for early signs and symptoms of serious infection and evaluate immediately if infection is suspected. Instruct persons to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of pegcetacoplan in persons who are undergoing treatment for serious infections. Serious infection was reported in 5% of subjects during clinical trials. Infections (20% to 29%) reported with pegcetacoplan during clinical trials include bacterial infection, biliary sepsis (less than 5%), sepsis, septic shock, fungal infection, vulvovaginal mycotic infection, vaginal infection, gastrointestinal infection, esophageal candidiasis, gastroenteritis, Helicobacter gastritis, pustular acne, anal abscess, bronchitis, cellulitis, dental pulpitis, ear infection, otitis externa, furuncle, hordeolum, pharyngitis, respiratory tract infection (15%, including influenza-like illness, nasopharyngitis, rhinitis, tonsillitis, bacterial tonsillitis, viral upper respiratory tract infection, sinusitis), Pneumocystis jirovecii pneumonia, pulmonary tuberculosis, tuberculosis, urinary tract infection, and viral infection (12% to 13%, including oral herpes, COVID-19, COVID-19 pneumonia, influenza, gastrointestinal viral infection, rhinovirus infection). Fever (8% to 9%) and cough (9% to 12%) were also reported with pegcetacoplan in clinical trials.
Injection site reaction/infusion site reaction (26% to 39%) was reported with pegcetacoplan during clinical trials. These reactions were mild or moderate in severity and include erythema, swelling, induration, pruritus, pain, bruising, bleeding, edema, warmth, injection-site mass, rash, application site reaction, and puncture site reaction. Vaccination-site reaction, including pain, was also reported.
Gastrointestinal adverse events, including mild or moderate diarrhea (22%) abdominal pain (11% to 20%), and abdominal distension (5%), were reported in pegcetacoplan clinical trials. Abdominal pain included upper abdominal pain, abdominal discomfort, lower abdominal pain, abdominal tenderness, and epigastric discomfort.
Fatigue, including asthenia and lethargy, occurred in 12% of subjects treated with pegcetacoplan in clinical trials. Chest pain (unspecified), including chest discomfort, non-cardiac chest pain, and musculoskeletal chest pain, was reported in 7% of subjects treated with pegcetacoplan in clinical trials.
Back pain (7%, including sciatica), musculoskeletal pain (7%), arthralgia (8% to 11%), myalgia (5%), pain in the extremity (7% to 13%), and oropharyngeal pain (8%) were reported with pegcetacoplan during clinical trials.
Anxiety (5%), dizziness (11%), drowsiness (7%), and headache (7% to 11%) were reported with pegcetacoplan in clinical trials.
Systemic hypertension (7%) and bowel ischemia (less than 5%) were reported with pegcetacoplan in clinical trials.
As with all therapeutic peptides, there is a potential for immunogenicity with pegcetacoplan. The available methodology and data on anti-pegcetacoplan antibody formation were not adequate to fully assess the incidence of anti-drug antibodies or their effect on pharmacokinetics, pharmacodynamics, safety, or effectiveness of pegcetacoplan.
Acute renal failure (5%) and increased serum creatinine (7%) were reported with pegcetacoplan in clinical trials.
Epistaxis (7%) and thrombocytopenia (7%) were reported with pegcetacoplan in clinical trials.
Hypokalemia was reported in 13% of subjects treated with pegcetacoplan in clinical trails.
Peripheral edema was reported in 7% of subjects treated with pegcetacoplan in clinical trials.
During clinical trials, ocular inflammation was observed in 4% of patients receiving monthly, 2% of patients receiving every other month and less than 1% in the control group. Ocular inflammation was defined as anterior chamber flare, iridocyclitis, iritis, vitreal cells, anterior chamber cells, uveitis, and vitritis.
The most common adverse reactions (greater than 5%) reported in patients receiving pegcetacoplan for intravitreal use every month vs every other month were ocular discomfort (13% vs 10%) including ocular pain, ocular irritation, foreign body sensation in eyes, and abnormal sensation in eye, neovascular age-related macular degeneration (12% vs 7%) including exudative age-related macular degeneration and choroidal neovascularization, vitreous floaters (10% vs 7%), and conjunctival or ocular hemorrhage (8%) during clinical trials. Retinal hemorrhage (4% vs 5%), vitreous detachment (4% vs 6%), and punctate keratitis/keratitis (5% vs 3%) were also reported during clinical trials.
Intravitreal injections of pegcetacoplan have been associated with endophthalmitis, retinal detachment, hyphema, and retinal tears in less than 1% of patients.
Increased intraocular pressure (ocular hypertension) was reported in 2% of patients receiving monthly injections and in 3% of patients receiving every other month injections of intravitreal pegcetacoplan. After the injection, monitor intraocular pressure and optic nerve head perfusion; medically manage any abnormality as needed.
Non-arteritic anterior ischemic optic neuropathy was reported in 1.7% of patients treated monthly, 0.2% of patients treated every other month and 0.0% of patients assigned to sham. Deaths were reported in 6.7% of patients treated monthly, 3.6% of patients treated every other month and 3.8% of patients assigned to sham. The rates and causes of death were consistent with the elderly study population.
Retinal vasculitis with or without retinal vascular occlusion, typically associated with intraocular inflammation, has been reported with postmarketing use of pegcetacoplan. Retinal vasculitis may occur with the first pegcetacoplan dose and may cause severe vision loss. Instruct patients to promptly report any change in vision and discontinue therapy if these events develop.
Pegcetacoplan is contraindicated in patients with a hypersensitivity to pegcetacoplan or any of the excipients.
Pegcetacoplan is contraindicated in persons with paroxysmal nocturnal hemoglobinuria (PNH) and unresolved serious encapsulated bacteria infection, including infections caused by S. pneumoniae, N. meningitidis (any serogroup, including non-groupable strains), and H. influenzae type B. Pegcetacoplan increases the risk of serious, life-threatening, or fatal infections caused by encapsulated bacteria. Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of pegcetacoplan, according to current Advisory Committee on Immunization Practices (ACIP) recommendations for persons receiving a complement inhibitor. Revaccinate considering the duration of pegcetacoplan therapy. Note that ACIP recommends an administration schedule in persons receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent pegcetacoplan therapy is indicated in persons who are not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, administer these vaccines as soon as possible and provide antibacterial medication prophylaxis. The optimal durations and medication regimens for antibacterial medication prophylaxis and their efficacy have not been studied in persons receiving complement inhibitors, including pegcetacoplan. Consider the benefits and risks of treatment with pegcetacoplan in addition to the benefits and risks of antibacterial medication prophylaxis in unvaccinated or vaccinated persons against the known risks for serious infections caused by encapsulated bacteria. Closely monitor for early signs and symptoms of serious infection and evaluate immediately if infection is suspected. Instruct persons to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of pegcetacoplan in persons who are undergoing treatment for serious infections. Vaccination does not eliminate the risk for infections due to these organisms, despite development of antibodies after vaccination.
To reduce the risk of hemolysis due to abrupt discontinuation of treatment when switching drug therapy for paroxysmal nocturnal hemoglobinuria (PNH) from eculizumab to pegcetacoplan, start pegcetacoplan while continuing eculizumab at its current dose and discontinue eculizumab after 4 weeks before continuing on monotherapy with pegcetacoplan; for patients switching from ravulizumab, initiate pegcetacoplan no more than 4 weeks after the last dose of ravulizumab. After discontinuing treatment with pegcetacoplan, closely monitor for signs and symptoms of hemolysis, identified by elevated lactate dehydrogenase (LDH) concentrations along with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues pegcetacoplan for at least 8 weeks to detect hemolysis and other reactions. If hemolysis, including elevated LDH, occurs after discontinuation of pegcetacoplan, consider restarting treatment with pegcetacoplan.
Administration of pegcetacoplan for paroxysmal nocturnal hemoglobinuria (PNH) may result in laboratory test interference. Avoid the use of silica reagents in coagulation panels. There may be interference between silica reagents in coagulation panels and pegcetacoplan that results in artificially elevated prolonged activated partial thromboplastin time (aPTT).
There are insufficient data on pegcetacoplan use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Systemic exposure of pegcetacoplan following ocular administration is low. There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy. Adverse maternal outcomes associated with PNH in pregnancy include worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality. Adverse fetal outcomes associated with PNH in pregnancy include fetal death and premature delivery. The use of pegcetacoplan may be considered following an assessment of the risks and benefits. Animal studies using a dose 2.9 times human exposure based on AUC from the gestation period through parturition resulted ina statistically significant increase in abortions or stillbirths compared to controls. No increase in abortions or stillbirths occurred at a dose of 1.3 times human exposure based on AUC. No maternal toxicity or teratogenic effects were observed in offspring delivered at term. No developmental effects were observed up to 6 months postpartum. Systemic exposure to pegcetacoplan of less than 1% was detected in animal fetuses treated with a dose of 2.9 times human exposure from the period of organogenesis through the second trimester.
Discontinue breast-feeding during pegcetacoplan treatment for paroxysmal nocturnal hemoglobinuria and for 40 days after the last dose. It is not known whether pegcetacoplan is secreted in human breast milk or whether there is potential for absorption and harm to the infant. There are no data on the effects of pegcetacoplan on milk production when used for treatment of paroxysmal nocturnal hemoglobinuria. Many drugs are secreted into human breast milk, and there is potential for serious adverse reactions in the breast-feeding child. Pegcetacoplan is present in milk in animal studies at less than 1% of serum concentrations but was not detectable in the serum of nursing infants. Animal studies with use of intravitreal pegcetacoplan suggest that the risk of clinically relevant exposure to the infant following maternal intravitreal treatment is minimal. Intravitreal pegcetacoplan should be administered with caution during breast-feeding due to the potential for absorption and harm to infant growth and development.
Pegcetacoplan may be associated with reproductive risk. Obtain pregnancy testing before prescribing pegcetacoplan for paroxysmal nocturnal hemoglobinuria to females of reproductive potential. Discuss contraception requirements with the patient. Advise women of reproductive potential to use effective contraception during pegcetacoplan treatment and for 40 days after the final dose.
Pegcetacoplan is contraindicated in patients with ocular infection or periocular infection and active intraocular or ocular inflammation. In clinical trials, use of pegcetacoplan was associated with episodes of intraocular inflammation including: vitritis, vitreal cells, iridocyclitis, uveitis, anterior chamber cells, iritis, and anterior chamber flare. After inflammation resolves, patients may resume treatment with pegcetacoplan. Acute increased intraocular pressure (IOP) may develop within minutes of intravitreal injections, including with pegcetacoplan. Monitor for increased IOP and perfusion of the optic nerve head and manage as needed.
Intravitreal injections, including those with pegcetacoplan, may be associated with endophthalmitis and retinal detachments. Proper aseptic injection technique must always be used when administering pegcetacoplan in order to minimize the risk of endophthalmitis. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately.
In clinical trials, use of pegcetacoplan was associated with increased rates of neovascular (wet) age-related macular degeneration (AMD) or choroidal neovascularization (12% when administered monthly, 7% when administered every other month and 3% in the control group) by month 24. Patients receiving pegcetacoplan should be monitored for signs of neovascular AMD. In case anti-Vascular Endothelial Growth Factor (anti-VEGF) is required, it should be given separately from pegcetacoplan administration.
Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of pegcetacoplan. Retinal vasculitis may occur with the first pegcetacoplan dose and may cause severe vision loss. Patients who develop these events should discontinue treatment with pegcetacoplan and report any changes in vision without delay.
General Dosing Information
-Vaccinate persons against encapsulated bacteria, including S. pneumoniae and N. meningitidis (serogroups A, C, W, Y, and B), at least 2 weeks prior to initiation of pegcetacoplan and according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations.
--If urgent pegcetacoplan treatment is indicated in persons not up to date with vaccines for S. pneumoniae and N. meningitidis according to ACIP recommendations, administer these vaccines as soon as possible and provide antibacterial medication prophylaxis.
-Conversion from eculizumab: Administer pegcetacoplan loading dose while continuing eculizumab at its current dose. After 4 weeks, discontinue eculizumab and continue pegcetacoplan monotherapy.
-Conversion from ravulizumab: Start pegcetacoplan no more than 4 weeks after the last dose of ravulizumab.
For the treatment of paroxysmal nocturnal hemoglobinuria (PNH):
Subcutaneous dosage:
Adults: 1,080 mg subcutaneously twice weekly.
For the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD):
Intravitreal dosage:
Adults: 15 mg (0.1 mL of 150 mg/mL solution) administered by intravitreal injection to each affected eye once every 25 to 60 days.
Therapeutic Drug Monitoring:
Dosage adjustment for elevated lactate dehydrogenase (LDH)
LDH more than 2 times the upper limit of normal (ULN): Adjust the dosing regimen to 1,080 mg subcutaneously every 3 days. Monitor LDH twice weekly for at least 4 weeks.
Maximum Dosage Limits:
-Adults
For paroxysmal nocturnal hemoglobinuria, 1,080 mg subcutaneously twice weekly. For geographic atrophy, 15 mg intravitreally once every 25 days.
-Geriatric
For paroxysmal nocturnal hemoglobinuria, 1,080 mg subcutaneously twice weekly. For geographic atrophy, 15 mg intravitreally once every 25 days.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Pegcetacoplan is a complement (C3) inhibitor that binds to complement protein (C3) and its activation fragment C3b, thereby regulating the cleavage of C3 and the generation of downstream complement activation. In paroxysmal nocturnal hemoglobinuria (PNH), extravascular hemolysis (EVH) is facilitated by C3b opsonization while intravascular hemolysis (IVH) is mediated by the downstream membrane attach complex (MAC). Pegcetacoplan acts proximally in the complement cascade controlling both C3b-mediated EVH and terminal complement-mediated IVH.
Pegcetacoplan is administered by subcutaneous infusion for paroxysmal nocturnal hemoglobinuria (PNH) and by intravitreal injection for geographic atrophy (GA). The mean (CV%) Vd of pegcetacoplan is approximately 3.98 L (32%) in persons with PNH after subcutaneous infusion. The estimated mean (CV%) of clearance is 0.36 L/day (30%), and the median effective half-life of elimination (T1/2) is 8.6 days in persons with PNH. Pegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways. The geometric mean (95% CI) Vd of pegcetacoplan is approximately 1.85 L (1.62 to 2.12) in persons with GA following intravitreal administration. The estimated geometric mean (CV%) of clearance is 0.284 L/day (21.1%) and the geometric mean half-life of elimination (T1/2) is 4.5 days in persons with GA.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Subcutaneous Route
The median Tmax of pegcetacoplan is between 108 and 144 hours (4.5 to 6 days) after a single dose. Steady-state serum pegcetacoplan concentrations were achieved approximately 4 to 6 weeks after the first dose and the mean (CV%) trough serum concentration was 706 (15.1%) mcg/mL in persons with paroxysmal nocturnal hemoglobinuria (PNH) at week 16 and sustained through week 48. Exposure increased proportionally over a dosage range from 45 mg to 1,440 mg (0.04 to 1.33 times the approved recommended dose). In another pegcetacoplan clinical trial, the mean (CV%) trough serum concentration was 744 (25.5%) mcg/mL at week 26.
The mean C3 concentration increased from 0.94 g/L at baseline to 3.8 g/L at week 16 in persons with PNH administered multiple doses of pegcetacoplan. The baseline percentage of PNH Type II + III red blood cells (RBCs) was 66.2%, which increased to 93.9% at week 16. The mean percentage of PNH Type II + III RBCs with C3 deposition was 17.8% at baseline and decreased to 0.2% at week 16 and sustained through week 48. In another pegcetacoplan clinical trial, the mean C3 concentration increased from 0.95 g/L at baseline to 3.56 g/L and the mean percentage of PNH Type II + III RBCs increased from 42.4% at baseline to 90% at week 26. The mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 2.85% at baseline to 0.09% at week 26.
Other Route(s)
Intravitreal route
Following intravitreal administration of pegcetacoplan, the systemic median Tmax of pegcetacoplan is between 7 and 14 days. Following intravitreal treatment, systemic exposure of pegcetacoplan increases approximately proportionally over a dosage range of 4 to 20 mg. Following repeat intravitreal administration of pegcetacoplan at a dose of 15 mg, geometric mean (CV%) serum Cmax value at steady state was 2.2 mcg/mL (28.7%) and 1.5 mcg/mL (58.1%) for GA patients dosed monthly and every other month, respectively. The steady state geometric mean (CV%) serum trough concentrations were 1.0 mcg/mL (52.3%) and 0.2 mcg/mL (89.6%) for patients treated monthly and every other month, respectively.
-Special Populations
Hepatic Impairment
There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on hepatic function as evaluated by total bilirubin (0.06 to 8.8 mg/dL), albumin (3 to 5.5 g/dL), aspartate aminotransferase (6 to 302 International Units/L), or alanine aminotransferase (4 to 209 International Units/L) in patients with PNH and total bilirubin (0.05 to 1.7 mg/dL), albumin (2.96 to 5.38 g/dL), aspartate aminotransferase (8.7 to 101 International Units/L), or alanine aminotransferase (5.9 to 136 International Units/L) in patients with GA.
Renal Impairment
There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on renal impairment.
Geriatric
There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on age (19 to 81 years) in persons with PNH and age (60 to 97 years) in persons with GA.
Gender Differences
There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on sex.
Ethnic Differences
There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on race (Asian vs. non-Asian).