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WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA EMPAVELI increases the risk of serious and life-threatening infections caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type B.
EMPAVELI is available only through a restricted program called EMPAVELI REMS. |
EMPAVELI contains pegcetacoplan, a complement inhibitor. Pegcetacoplan is a symmetrical molecule comprised of two identical pentadecapeptides covalently bound to the ends of a linear 40-kiloDalton (kDa) PEG molecule. The peptide portions of pegcetacoplan contain 1-methyl-L-tryptophan (Trp(Me)) in position 4 and amino(ethoxyethoxy)acetic acid (AEEA) in position 14.
The molecular weight of pegcetacoplan is approximately 43.5 kDa. The molecular formula is C1970H3848N50O947S4. The structure of pegcetacoplan is shown below.
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EMPAVELI injection is a sterile, clear, colorless to slightly yellowish aqueous solution for subcutaneous use and is supplied in a 20-mL single-dose vial. Each 1 mL of solution contains 54 mg of pegcetacoplan, 41 mg of sorbitol, 0.384 mg of glacial acetic acid, 0.490 mg of sodium acetate trihydrate, and Water for Injection USP. EMPAVELI may also contain sodium hydroxide and/or additional glacial acetic acid for adjustment to a target pH of 5.
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
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.
Paroxysmal Nocturnal Hemoglobinuria
Study in Complement-Inhibitor Experienced Adult Patients with PNH (Study APL2-302)
The data described below reflect the exposure in 80 adult patients with PNH who received EMPAVELI (n=41) or eculizumab (n=39) at the recommended dosing regimens for 16 weeks. Serious adverse reactions were reported in 7 (17%) patients with PNH receiving EMPAVELI. The most common serious adverse reaction in patients treated with EMPAVELI was infections (5%). The most common adverse reactions (≥10%) with EMPAVELI were injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue.
Table 2 describes the adverse reactions that occurred in ≥5% of patients treated with EMPAVELI in Study APL2-302.
Table 2: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-302
| Adverse Reaction | EMPAVELI (N=41) n (%) |
Eculizumab (N=39) n (%) |
|
| General disorders and administration site conditions | |||
| Injection-site reaction*a | 16 (39) | 2 (5) | |
| Fatigue* | 5 (12) | 9 (23) | |
| Chest pain* | 3 (7) | 1 (3) | |
| Infections and infestations | |||
| Infections* | 12 (29) | 10 (26) | |
| Respiratory tract infection* | 6 (15) | 5 (13) | |
| Viral Infection* | 5 (12) | 3 (8) | |
| Gastrointestinal disorders | |||
| Diarrhea | 9 (22) | 1 (3) | |
| Abdominal pain* | 8 (20) | 4 (10) | |
| Musculoskeletal disorders | |||
| Back pain* | 3 (7) | 4 (10) | |
| Nervous system disorders | |||
| Headache | 3 (7) | 9 (23) | |
| Vascular disorders | |||
| Systemic hypertension* | 3 (7) | 1 (3) | |
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* Grouped terms a Term includes injection-site erythema, injection-site reaction, injection-site swelling, injection-site induration, injection-site bruising, injection-site pain, injection-site pruritus, vaccination site reaction, administration site swelling, injection-site hemorrhage, injection -site edema, injection-site warmth, administration site pain, application site pain, injection-site mass, injection-site rash, vaccination site pain |
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After the randomized control period, 77 patients continued the study, and all were treated with EMPAVELI monotherapy at the recommended dosing regimen for up to 48 weeks. Serious adverse reactions were reported in 18 patients (23%). Additional adverse reactions reported in >5% of patients treated with EMPAVELI during the open-label part of the study compared to the randomized controlled part in Table 1 were cough (12%), arthralgia (8%), oropharyngeal pain (8%), pyrexia (8%), pain in extremity (7%), thrombocytopenia (7%), abdominal distension (5%), acute kidney injury (5%), anxiety (5%), and myalgia (5%). One patient (1%) died due to COVID-19 infection.
Injection-Site Reactions
Injection/infusion-site reactions (e.g., erythema, swelling, induration, pruritus, and pain) have been reported during Study APL2-302. These reactions were mild or moderate in severity.
Diarrhea
Seventeen cases of diarrhea have been reported during the 48 weeks. Fifteen of the cases were mild and two were moderate.
Study in Complement-Inhibitor NaÏve Adult Patients with PNH (Study APL2-308)
The data described below reflect the exposure in adult patients with PNH who received EMPAVELI (n=46) or the control arm (supportive care excluding complement inhibitors) (n=18) in Study APL2-308 [see Clinical Studies (14.1)]. One patient (2%) who received EMPAVELI died due to septic shock. Serious adverse reactions were reported in 6 (13%) patients with PNH receiving EMPAVELI. The most common adverse reaction (≥10%) in patients treated with EMPAVELI were injection site reactions, infections, viral infection, pain in extremity, hypokalemia, arthralgia, dizziness, abdominal pain, rash, and headache.
Table 3 describes the adverse reactions that occurred in ≥5% of patients treated with EMPAVELI in Study APL2-308.
Table 3: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-308
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Adverse Reaction |
EMPAVELI Exposure Adjusted Rate (per 100 pt yrs) |
Control Arma Exposure Adjusted Rate (per 100 pt yrs) |
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| General disorders and administration site conditions | |||
| Injection-site reaction*b | 12 (26) | 0 | |
| 42 | 0 | ||
| Pyrexia | 4(9) | 0 | |
| 14 | 0 | ||
| Peripheral edema* | 3 (7) | 0 | |
| 11 | 0 | ||
| Infections and Infestations | |||
| Infections* | 9 (20) | 4 (22) | |
| 32 | 74 | ||
| Viral infection* | 6 (13) | 2 (11) | |
| 21 | 37 | ||
| Musculoskeletal and connective tissue disorders | |||
| Pain in extremity | 6 (13) | 0 | |
| 21 | 0 | ||
| Arthralgia | 5 (11) | 0 | |
| 18 | 0 | ||
| Musculoskeletal pain | 3 (7) | 0 | |
| 11 | 0 | ||
| Metabolism and nutrition disorders | |||
| Hypokalemia | 6 (13) | 2 (11) | |
| 21 | 37 | ||
| Nervous system disorders | |||
| Dizziness | 5 (11) | 0 | |
| 18 | 0 | ||
| Headache | 5 (11) | 0 | |
| 18 | 0 | ||
| Somnolence | 3 (7) | 0 | |
| 11 | 0 | ||
| Gastrointestinal disorders | |||
| Abdominal pain* | 5 (11) | 1 (6) | |
| 18 | 18 | ||
| Skin and subcutaneous tissue disorders | |||
| Rash* | 5(11) | 0 | |
| 18 | 0 | ||
| Ecchymosis | 3 (7) | 0 | |
| 11 | 0 | ||
| Erythema | 3 (7) | 0 | |
| 11 | 0 | ||
| Blood and lymphatic system disorders | |||
| Thrombocytopenia | 3 (7) | 1 (6) | |
| 11 | 18 | ||
| Respiratory, thoracic and mediastinal disorders | |||
| Cough* | 4 (9) | 0 | |
| 14 | 0 | ||
| Epistaxis | 3 (7) | 0 | |
| 11 | 0 | ||
| Investigations | |||
| Blood creatinine increased | 3 (7) | 0 | |
| 11 | 0 | ||
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aControl Arm = supportive care (excluding complement inhibitors) EMPAVELI (N=46) group includes patients who received EMPAVELI at any point during the study, including patients randomized to EMPAVELI (N=35) and patients randomized to the control arm and crossed over to EMPAVELI treatment (N=11). *Grouped terms b Term includes injection-site bruising, injection-site hemorrhage, injection-site swelling, application site reaction, infusion-site pruritus, injection-site erythema, injection-site rash, puncture site reaction. |
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C3 Glomerulopathy or Primary IC-MPGN
Study in Adult and Pediatric Patients 12 Years of age and older with C3G or primary IC-MPGN (Study APL2-C3G-310)
The data described below reflects the exposure in adult (n=35) and pediatric patients 12 years of age and older (n=28) with native kidney C3G (n=46), native kidney primary IC-MPGN (n=12), or recurrent C3G following kidney transplant (n=5) who received EMPAVELI at the recommended dosing regimens during the 26-week placebo-controlled period of APL2-C3G-310. Serious adverse reactions due to viral infections resulting in hospitalizations occurred in 2 (3%) patients with C3G or primary IC-MPGN receiving EMPAVELI and 1 (2%) patient on placebo. One patient (2%) on EMPAVELI with native kidney C3G died because of respiratory failure due to COVID-19 pneumonia; there were no deaths in the placebo arm.
Table 4 describes the adverse reactions that were reported in ≥5% of patients (adults and pediatric patients 12 years of age and older) treated with EMPAVELI and at a greater incidence than placebo in APL2-C3G-310. Adverse reactions in pediatric patients were similar to those seen in adults.
The placebo-controlled period of APL2-C3G-310 was followed by a 26-week open-label period. During the open-label period, one patient with native kidney C3G had a serious adverse event of pneumonia secondary to Streptococcus pneumoniae, and one patient with recurrent C3G following kidney transplant developed herpes zoster meningoencephalitis while on concomitant immunosuppression, leading to treatment discontinuation.
Table 4: Adverse Reactions Reported in ≥5% of Patients (adult and pediatric) Treated with EMPAVELI and Greater than Placebo in Study APL2-C3G-310
| Adverse Reaction | EMPAVELI (N=63) n (%) |
Placebo (N=61) n (%) |
|
| General disorders and administration site conditions | |||
| Infusion-site reactions* | 16 (25) | 14 (23) | |
| Pyrexia | 12 (19) | 6 (10) | |
| Fatigue | 4 (6) | 1 (2) | |
| Infections and infestations | |||
| Nasopharyngitis | 11 (18) | 7 (12) | |
| Influenza | 7 (11) | 3 (5) | |
| Gastrointestinal disorders | |||
| Nausea | 6 (10) | 4 (7) | |
| Respiratory, thoracic and mediastinal disorders | |||
| Cough | 6 (10) | 1 (2) | |
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* Term includes the following reactions at the infusion site: erythema, pruritus, swelling, bruising, induration, pain, hemorrhage, discomfort, oedema, rash, and hypoaesthesia. |
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Study in Adult recurrent C3G or primary IC-MPGN following kidney transplant (Study APL2-C3G-204)
In a study in 13 adults with recurrent C3G or primary IC-MPGN after kidney transplant (NCT#04572854), one patient with primary IC-MPGN experienced a serious adverse event of Pneumocystis jirovecii pneumonia while on EMPAVELI and concurrent immunosuppressive medications.
The following adverse reactions have been identified during post-approval use of EMPAVELI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to EMPAVELI exposure.
No information provided
Included as part of the PRECAUTIONS section.
EMPAVELI, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis (caused by any serogroup, including non-groupable strains), and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initation of EMPAVELI treatment is contraindicated in patients with unresolved serious infection caused by encapsulated bacteria.
Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of EMPAVELI, according to the most current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with EMPAVELI. 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 EMPAVELI therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. 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 EMPAVELI. The benefits and risks of treatment with EMPAVELI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria.
Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients 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 EMPAVELI in patients who are undergoing treatment for serious infections.
EMPAVELI is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)].
EMPAVELI is available only through a restricted program under a REMS called EMPAVELI REMS, because of the risk of serious infections caused by encapsulated bacteria [see Warnings and Precautions (5.1)].
Notable requirements of the EMPAVELI REMS include the following:
Further information is available at www.empavelirems.com or 1-888-343-7073
Systemic hypersensitivity reactions (e.g., facial swelling, rash, urticaria, pyrexia) have occurred in patients treated with EMPAVELI, which may resolve after treatment with antihistamines. Cases of anaphylaxis leading to treatment discontinuation have been reported. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue EMPAVELI infusion immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved.
After discontinuing treatment with EMPAVELI, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH levels 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 EMPAVELI for at least 8 weeks to detect hemolysis and other reactions. If hemolysis, including elevated LDH, occurs after discontinuation of EMPAVELI, consider restarting treatment with EMPAVELI.
There may be interference between silica reagents in coagulation panels and EMPAVELI that results in artificially prolonged activated partial thromboplastin time (aPTT); therefore, avoid the use of silica reagents in coagulation panels.
Long-term animal carcinogenicity studies of pegcetacoplan have not been conducted.
Pegcetacoplan was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) and was not genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice.
Effects of pegcetacoplan on fertility have not been studied in animals. There were no microscopic abnormalities in male or female reproductive organs in toxicity studies in rabbits and monkeys.
In toxicology studies in rabbits and cynomolgus monkeys, epithelial vacuolation and infiltrates of vacuolated macrophages were observed in multiple tissues, including the renal tubules, following daily subcutaneous doses of pegcetacoplan up to 7 times the human dose. These findings are attributable to uptake of the PEG moieties of pegcetacoplan. Renal degeneration was observed microscopically in rabbits at exposures (Cmax and AUC) less than those for the human dose, and in monkeys at exposures approximately 2.7-fold those for the human dose. The clinical significance of these findings is uncertain.
No information provided.
EMPAVELI is contraindicated:
Pegcetacoplan binds to complement protein C3 and its activation fragment C3b, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation.
In PNH, extravascular hemolysis (EVH) is facilitated by C3b opsonization while intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan acts proximally in the complement cascade controlling both C3b-mediated EVH and terminal complement-mediated IVH.
In C3G and primary IC-MPGN, complement dysregulation and overactivation causes deposition of C3 fragments in glomeruli, which contributes to the pathogenesis of C3G and is thought to contribute to the pathogenesis of IC-MPGN. Pegcetacoplan binds C3 and its activation fragment C3b, therefore inhibiting C3 activation, decreasing C3 glomerular fragment deposition, and decreasing C5 convertase activity and subsequent assembly of C5b-9.
In patients with PNH administered multiple doses of pegcetacoplan, the mean C3 concentration increased from 94 mg/dL at baseline to 380 mg/dL at Week 16 and sustained through Week 48 (Study APL2-302). In study APL2-308, the mean C3 concentration increased from 95 mg/dL at baseline to 356 mg/dL at Week 26 [see Clinical Studies (14.1)].
The percentage of PNH Type II + III RBCs increased from 66.2% at baseline to 93.9% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, 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 17.8% at baseline to 0.2% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 2.85% at baseline to 0.09% at Week 26.
In patients with C3G or primary IC-MPGN administered pegcetacoplan SC infusion twice weekly, mean (SD) serum C3 levels increased from 62 (48) mg/dL at baseline to 371 (120) mg/dL at Week 26 compared to no change with placebo. Mean (SD) plasma soluble C5b-9 levels decreased from 903 (698) ng/mL at baseline to 290 (249) ng/mL at Week 26 with EMPAVELI compared to no change with placebo. Of patients with evaluable kidney biopsies (n=69), 74% of patients on pegcetacoplan had a decrease in C3 complement staining by at least 2 orders of magnitude from baseline to Week 26 compared to 12% on placebo.
At the recommended dose of EMPAVELI, no large mean increases in QTc interval (i.e., greater than 20 msec) were observed.
In patients with PNH, the serum pegcetacoplan concentrations achieved steady-state approximately 4 to 6 weeks following the first dose. The exposure of pegcetacoplan increased proportionally over a dose range from 45 to 1,440 mg (0.04 to 1.33 times the approved recommended dose). The mean (CV%) trough serum concentration observed at Week 16 was 706 (15.1%) mcg/mL and sustained through Week 48 (Study APL2-302). In Study APL2-308, mean (CV%) trough serum concentration was 744 (25.5%) mcg/mL at Week 26.
In patients with C3G or primary IC-MPGN, serum pegcetacoplan concentrations reached steady state approximately 4 to 8 weeks following twice weekly SC infusion. The mean (CV%) trough serum concentrations ranged between 716 (31%) and 766 (23%) mcg/mL from Week 4 to Week 26.
The median Tmax of pegcetacoplan is between 108 and 144 hours (4.5 to 6 days) after a single dose.
The mean (CV%) volume of distribution of pegcetacoplan is approximately 3.98 L (32%) in patients with PNH.
The estimated mean (CV%) volume of distribution of pegcetacoplan is approximately 4.79 L (38%) and 4.58 L (29%) in patients with C3G or primary IC-MPGN, respectively.
The estimated mean (CV%) of clearance (CL) is 0.36 L/day (30%) and median effective half-life of elimination (t1/2) is 8.6 days in patients with PNH.
The estimated mean (CV%) of clearance (CL) is 0.32 L/day (54%) and median t1/2 is 10.2 days in patients with C3G. The estimated mean (CV%) of clearance (CL) is 0.3 L/day (51%) and median t1/2 is 10.8 days in patients with primary IC-MPGN.
Metabolism
Pegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways.
There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on age (19 to 81 years old), sex, race (Asian vs. non‑Asian), renal impairment, and hepatic function as evaluated by total bilirubin (0.06‑8.8 mg/dL), albumin (1.8‑5.5 g/dL), aspartate aminotransferase (6‑302 IU/L), or alanine aminotransferase (4‑209 IU/L).
In patients with C3G or primary IC-MPGN, there were no clinically significant differences in pharmacokinetics of pegcetacoplan based on age (12 to 74 years old), diagnosis (C3G vs primary IC- MPGN), and urine protein-to-creatinine ratio (UPCR) (133-13300 mg/g).
There is insufficient information to characterize the anti-drug antibody response to EMPAVELI and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of pegcetacoplan products in PNH patients.
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 study described below with the incidence of anti-drug antibodies in other studies.
During the 26-week placebo-controlled period in Study APL2-C3G-310, 14 of 62 participants (23%) with C3G or primary IC-MPGN randomized to pegcetacoplan developed anti–pegcetacoplan peptide antibodies. Two of 62 participants (3%) developed anti–pegcetacoplan peptide neutralizing antibodies. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of pegcetacoplan over the treatment duration of 26 weeks.
In toxicology studies in rabbits and cynomolgus monkeys, epithelial vacuolation and infiltrates of vacuolated macrophages were observed in multiple tissues, including the renal tubules, following daily subcutaneous doses of pegcetacoplan up to 7 times the human dose. These findings are attributable to uptake of the PEG moieties of pegcetacoplan. Renal degeneration was observed microscopically in rabbits at exposures (Cmax and AUC) less than those for the human dose, and in monkeys at exposures approximately 2.7-fold those for the human dose. The clinical significance of these findings is uncertain.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
For weight-based dosing, instruct caregivers and patients on the proper techniques for preparing, storing, measuring, and administering EMPAVELI via EMPAVELI Injector or commercially available infusion pump.
Advise patients of the risk of serious infection. Inform patients of the need to complete or update their vaccinations against encapsulated bacteria at least 2 weeks prior to receiving the first dose of EMPAVELI or receive antibacterial drug prophylaxis if EMPAVELI treatment must be initiated immediately and they have not been previously vaccinated. Inform the patient that they are required to be revaccinated according to current ACIP recommendations for encapsulated bacteria while on EMPAVELI therapy [see Warnings and Precautions (5.1)].
Inform patients that vaccination may not prevent serious infection and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms include the following:
Inform patients that they will be given a Patient Safety Card for EMPAVELI that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to seek immediate medical evaluation.
EMPAVELI is available only through a restricted program called EMPAVELI REMS [see Warnings and Precautions (5.2)].
Inform the patient of the following notable requirements:
Advise patients of the risk of anaphylaxis and infusion-related reactions. Inform patients that anaphylaxis is life-threatening and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms include the following:
Inform patients with PNH that they may develop hemolysis due to PNH when EMPAVELI is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following discontinuation of EMPAVELI.
Inform patients who discontinue EMPAVELI to keep the Patient Safety Card with them for 2 months after the last dose of EMPAVELI, because the increased risk of serious infection persists for several weeks following discontinuation of EMPAVELI.
