Pegcetacoplan Adverse Events: What the Label and Studies Report

Pegcetacoplan is a prescription pegylated peptide that binds complement component C3 and C3b, a mechanism summarised in a review of peptide and oligonucleotide approvals that listed pegcetacoplan among the agents cleared by the FDA in 2021 (PMID 35215334). Because the molecule acts upstream in the complement cascade, its reported adverse event profile differs by route of administration and by the disease setting studied. This page describes what product labeling and published trials have reported, grouped by body system, and does not offer guidance on use. This page is for educational purposes only and is not medical advice; consult a licensed physician or the prescribing clinician about any symptom, medicine or treatment decision.

Two routes, two safety profiles

The subcutaneous formulation is approved in the United States for paroxysmal nocturnal hemoglobinuria (PNH) and, more recently, for complement 3 glomerulopathy (C3G) and primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN). The intravitreal formulation is approved for geographic atrophy secondary to age-related macular degeneration (AMD). Any other application, including use after kidney transplantation for recurrent glomerular disease, is investigational and has been examined only in small published series. The warnings attached to each formulation reflect the route: systemic complement inhibition is dominated by infection risk, while intravitreal injection is dominated by ocular risks.

Boxed Warning on the Systemic Product

The United States prescribing information for the subcutaneous formulation carries a boxed warning for serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b and Escherichia coli. The label states that such infections may become rapidly life threatening or fatal if not recognised and treated early, directs that patients be vaccinated against these organisms before starting therapy, and describes a restricted distribution program (REMS) in the United States. The intravitreal product does not carry a boxed warning.

The biological rationale behind that warning is described in reviews of complement therapeutics, which explained that blocking C3 removes opsonisation as well as terminal pathway activity and therefore broadens susceptibility to encapsulated organisms compared with terminal inhibitors (PMID 40354320). A review of emerging PNH drugs likewise reported that vaccination requirements and infection surveillance accompany proximal complement inhibitors in clinical development and practice (PMID 35078384).

Serious Warnings and Precautions on the Labels: What Studies Report

Systemic formulation

• Serious infections with encapsulated bacteria. Labeled as a boxed warning and discussed in complement inhibition reviews that described infection monitoring as a standing requirement of C3 blockade (PMID 40354320).
• Monitoring after discontinuation in PNH. The label describes monitoring for signs of hemolysis after stopping therapy. A review of pegcetacoplan in PNH reported that intravascular and extravascular hemolysis can resume when C3 inhibition is withdrawn, and described laboratory monitoring in that period (PMID 37016661).
• Injection site reactions and hypersensitivity. The pivotal randomised trial comparing pegcetacoplan with eculizumab reported injection site reactions as the most frequent adverse event in the pegcetacoplan group (PMID 33730455).
• Interference with laboratory tests. The label notes that the polyethylene glycol component may interfere with certain assays, including silica-based coagulation tests.

Intravitreal formulation

• Endophthalmitis and retinal detachment. These are standard labeled risks of any intravitreal injection and were discussed in a review of the safety of recently approved AMD therapeutics (PMID 39710898).
• Retinal vasculitis with or without retinal vascular occlusion. The label describes postmarketing reports of retinal vasculitis, typically occurring within the first weeks after an initial injection; the same review summarised these postmarketing ocular inflammatory events (PMID 39710898).
• Neovascular (exudative) AMD. The phase 3 OAKS and DERBY trials reported new-onset exudative AMD more often in pegcetacoplan treated eyes than in sham treated eyes (PMID 37865470), and a Cochrane review of complement inhibitors for AMD reported an increased risk of macular neovascularisation with complement inhibition relative to control (PMID 37314061).
• Increased intraocular pressure and intraocular inflammation. Both appear in the labeled warnings and in trial safety reporting for the intravitreal product (PMID 37865470).

Common Adverse Reactions in PNH Trials: What Studies Report

The head to head phase 3 trial known as PEGASUS randomised adults with PNH and persistent anemia to subcutaneous pegcetacoplan 1080 mg twice weekly or to continued intravenous eculizumab over a 16 week randomised period (PMID 33730455). Researchers reported that the most common adverse events in that trial included injection site reactions, diarrhea, breakthrough hemolysis, headache and fatigue, with injection site reactions and diarrhea more frequent in the pegcetacoplan group and headache and fatigue more frequent in the eculizumab group (PMID 33730455). The study also reported that no cases of meningococcal infection occurred during the randomised period (PMID 33730455).

Breakthrough hemolysis deserves separate mention because it is a disease related event rather than a classic drug reaction. A review of pegcetacoplan in PNH reported that breakthrough hemolysis can follow complement amplifying conditions such as infection and that it has been described during proximal complement inhibition (PMID 37016661). A broader review of complement inhibition for PNH and complement mediated thrombotic microangiopathy reported that management of breakthrough events and of infection risk remains a central safety consideration across this drug class (PMID 40354320). An earlier review of emerging PNH therapies reported that subcutaneous administration shifted the tolerability discussion toward local injection site effects compared with intravenous terminal inhibitors (PMID 35078384).

Ocular Adverse Events in Geographic Atrophy Trials: What Studies Report

OAKS and DERBY were two multicentre, randomised, double masked, sham controlled phase 3 trials that evaluated intravitreal pegcetacoplan 15 mg given monthly or every other month in people with geographic atrophy secondary to AMD (PMID 37865470). Researchers reported that new-onset exudative AMD occurred more frequently in treated eyes than in sham eyes and that ocular adverse events in the study eye were more common with active treatment, while rates of serious systemic adverse events were broadly comparable across groups (PMID 37865470).

The Cochrane systematic review of complement inhibitors for AMD pooled randomised evidence and reported a small slowing of geographic atrophy lesion growth alongside an increased risk of macular neovascularisation, concluding that the balance of benefit and harm required careful interpretation (PMID 37314061). A 2025 review of the safety of recently approved AMD therapeutics described postmarketing reports of intraocular inflammation, including occlusive retinal vasculitis, following intravitreal complement inhibition (PMID 39710898). General background on the pharmacology of macular degeneration agents and the procedural risks attached to intravitreal therapy has also been summarised in the drug monograph literature (PMID 31643677).

Kidney Disease Studies: What Studies Report

A 2025 randomised trial published in the New England Journal of Medicine evaluated subcutaneous pegcetacoplan 1080 mg twice weekly against placebo in patients with C3 glomerulopathy or primary immune-complex membranoproliferative glomerulonephritis and reported a reduction in proteinuria with active treatment, with adverse events described in the trial report (PMID 41337715). Readers comparing safety across settings should note that the trial population differed from the PNH population in age, kidney function and concomitant immunosuppression, which affects how adverse event frequencies translate between indications (PMID 41337715).

In an investigational setting, a study of kidney transplant recipients with recurrent C3 glomerulopathy or primary immune-complex MPGN reported efficacy and safety observations for pegcetacoplan in that small transplant population (PMID 39810766). Transplant recipients already receive immunosuppression, so infection related events in that group cannot be attributed to complement inhibition alone, a limitation the published report addressed (PMID 39810766).

Pregnancy and Other Special Situations

Controlled pregnancy data are limited. A 2025 case report described a pregnancy in a patient with PNH treated with pegcetacoplan and included a pharmacokinetic analysis of drug exposure during gestation (PMID 41268092). A single case report cannot establish frequency or causality for any outcome, and questions about pregnancy, breastfeeding, vaccination timing or planned surgery go to the prescribing clinician.

Reported Events by Body System

How to Read These Numbers

Adverse event frequencies reported in a trial describe what happened in that trial population over that follow up period and under that monitoring intensity. The PNH comparison was open label against an active comparator over a defined randomised period (PMID 33730455), while the geographic atrophy trials were sham controlled and double masked with monthly or every other month injections (PMID 37865470). Pooled analyses such as the Cochrane review can detect signals that individual trials are underpowered to show, which is why its finding on macular neovascularisation carries separate weight (PMID 37314061). Postmarketing reports, by contrast, lack a denominator and establish that an event has been observed rather than how often it occurs (PMID 39710898).

Questions That Belong With a Prescriber

• Fever, chills, severe headache with neck stiffness, confusion or other signs of infection in a person receiving systemic complement inhibition.
• Vaccination status and timing relative to therapy, as described in the labeled boxed warning.
• New or worsening eye pain, redness, floaters or vision change after an intravitreal injection.
• Dark urine, increasing fatigue or other signs of hemolysis, including after any interruption of therapy (PMID 37016661).
• Pregnancy planning, where published human data remain limited to case level reporting (PMID 41268092).

Talk to your prescriber about any of these situations. This page summarises published literature and labeling and makes no judgement about whether the medicine is appropriate for any individual.

References

• Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (The New England Journal of Medicine, 2021)
• Trial of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN (The New England Journal of Medicine, 2025)
• Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials (Lancet, 2023)
• Complement inhibitors for age-related macular degeneration (Cochrane Database of Systematic Reviews, 2023)
• The Safety of Recently Approved Therapeutics in Age-Related Macular Degeneration (International Ophthalmology Clinics, 2025)
• Pegcetacoplan: A New Opportunity for Complement Inhibition in PNH (Journal of Blood Medicine, 2023)
• Emerging drugs for the treatment of paroxysmal nocturnal hemoglobinuria (Expert Opinion on Emerging Drugs, 2022)
• Advancements in complement inhibition for PNH and primary complement-mediated thrombotic microangiopathy (Blood Advances, 2025)
• Efficacy and Safety of Pegcetacoplan in Kidney Transplant Recipients With Recurrent Complement 3 Glomerulopathy or Primary Immune Complex Membranoproliferative Glomerulonephritis (Kidney International Reports, 2025)
• Paroxysmal Nocturnal Hemoglobinuria in Pregnancy Treated With Pegcetacoplan: Case Report and Pharmacokinetic Analysis (EJHaem, 2025)
• 2021 FDA TIDES (Peptides and Oligonucleotides) Harvest (Pharmaceuticals, 2022)
• Macular Degeneration Agents (2012)