Piasky

1 INDICATIONS AND USAGE PIASKY is indicated for the treatment of adult and pediatric patients 13 years and older with paroxysmal nocturnal hemoglobinuria (PNH) and body weight of at least 40 kg. PIASKY is a complement C5 inhibitor indicated for the treatment of adult and pediatric patients 13 years and older with paroxysmal nocturnal hemoglobinuria (PNH) and body weight of at least 40 kg ( 1 )

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for instructions on preparation, dosage, and administration. ( 2.2 , 2.3 , 2.4 , 2.5 ) Start with one loading dose administered by intravenous infusion, followed by 4 additional loading doses administered by subcutaneous injection. Then administer a maintenance dose every 4 weeks by subcutaneous injection. For patients switching from another complement inhibitor, the first loading dose of PIASKY should be administered no sooner than the time of the next scheduled complement inhibitor administration. See Full Prescribing Information for considerations when switching from another C5 inhibitor. Administer doses based on the patient's actual body weight ( 2.2 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients for meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of PIASKY [see Warnings and Precautions (5.1) ] . If urgent PIASKY therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe PIASKY must enroll in the PIASKY REMS [see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage Regimen The recommended dosage regimen consists of one loading dose administered by intravenous (IV) infusion (on Day 1), followed by four additional weekly loading doses administered by subcutaneous (SUBQ) injection (on Days 2, 8, 15, and 22). The maintenance dose starts on Day 29 and is then administered every 4 weeks by subcutaneous injection. Administer doses based on the patient's actual body weight, as shown in Table 1 . Table 1 PIASKY Dosage Regimen Based on Body Weight Body Weight ≥ 40 kg to < 100 kg ≥ 100 kg IV = intravenous, SUBQ = subcutaneous Loading Dose Day 1 Day 2, 8, 15, 22 1,000 mg (IV) 340 mg (SUBQ) 1,500 mg (IV) 340 mg (SUBQ) Maintenance Dose Day 29 and Q4W Q4W=every 4 weeks thereafter 680 mg (SUBQ) 1,020 mg (SUBQ) The dosing schedule is allowed to occasionally vary within 2 days of the scheduled administration day (except at Day 1 and Day 2). If this occurs, the subsequent dose should be administered according to the regular schedule. Modification of the maintenance dose is required if the patient's body weight changes to become consistently greater than or lower than 100 kg during the course of therapy. 2.3 Recommended Timing for Switching to PIASKY from Another C5 Inhibitor Healthcare providers should consider the benefits of the timing of switching C5 inhibitors vs. the risks of Type III hypersensitivity reactions [see Warnings and Precautions (5.3) ] . For patients switching from another C5 inhibitor (e.g., eculizumab or ravulizumab), the first intravenous loading dose of PIASKY should be administered no sooner than the time of the next scheduled complement inhibitor administration. The administration of the additional subcutaneous loading doses and maintenance doses of PIASKY should follow as per the schedule shown in Table 1 . 2.4 Delayed or Missed Dose If an entire planned dose or part of a planned dose of PIASKY is missed, administer the missed dose or remainder of the missed dose as soon as possible before the day of the next scheduled dose. Then administer the next dose on the regularly scheduled dosing day. Do not administer two doses or more than the prescribed dose on the same day to make up for a missed dose. 2.5 Preparation and Administration Each vial of PIASKY is for one-time use in only one patient. PIASKY is administered as an intravenous infusion (first dose) and as a subcutaneous injection (subsequent doses). Only healthcare providers should administer PIASKY. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. PIASKY is cle…

5 WARNINGS AND PRECAUTIONS Type III hypersensitivity reactions: Monitor patients switching from another C5 inhibitor to PIASKY or from PIASKY to another C5 inhibitor as they are at risk of Type III hypersensitivity reactions related to the formation of drug-target-drug complexes ( 5.3 ) Other Infections: PIASKY can increase susceptibility to serious infections especially those caused by encapsulated bacteria. ( 5.4 ) Infusion- and Injection-Related Reactions: Monitor for these reactions and initiate medical management as needed ( 5.5 ) 5.1 Serious Meningococcal Infection PIASKY, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (meningococcemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of PIASKY is contraindicated in patients with a serious unresolved Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) at least 2 weeks prior to administration of the first dose of PIASKY, according to the current Advisory Committee on Immunization Practices (ACIP) recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of PIASKY 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 PIASKY therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal 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 PIASKY. The benefits and risks of treatment with PIASKY, 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 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. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of PIASKY in patients who are undergoing treatment for serious meningococcal infection. PIASKY is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 PIASKY REMS PIASKY is available only through a restricted program under a REMS called PIASKY REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1) ] . Notable requirements of the PIASKY REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of PIASKY. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and t…

4 CONTRAINDICATIONS PIASKY is contraindicated: For initiation in patients with an unresolved serious Neisseria meningitidis infection [see Warnings and Precautions (5.1) ]. In patients with a known serious hypersensitivity reaction to crovalimab or any of the excipients [see Warnings and Precautions (5.5) ] . Initiation during unresolved serious Neisseria meningitidis infection ( 4 ) Serious hypersensitivity to crovalimab or any of the excipients ( 4 )

7. DRUG INTERACTIONS PIASKY binds different epitopes on C5 compared to eculizumab and ravulizumab, which can lead to the formation of DTDCs when patients switch between PIASKY and either eculizumab or ravulizumab. These DTDCs comprise one or more units of C5 bound to both PIASKY and to eculizumab or ravulizumab. These DTDCs are expected to be cleared within approximately 8 weeks (in the case of eculizumab) or longer (in the case of ravulizumab) and can result in Type III hypersensitivity reactions [see Warnings and Precautions (5.3) , Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Available data on PIASKY use in pregnant women are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Human IgG antibody is known to cross the placenta and its transport increases as pregnancy progresses and peaks during the third trimester; therefore, PIASKY may be transmitted from the mother to the developing fetus. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations ). In an enhanced pre- and postnatal development study, no adverse developmental outcomes were observed when monkeys were exposed to crovalimab-akkz during the period of organogenesis through parturition at doses that produced maternal exposures 14-times the exposures at the maximum recommended human dose (MRHD), (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal data In an enhanced pre- and post-natal development study, pregnant cynomolgus monkeys were given an intravenous loading dose of crovalimab-akkz 100 mg/kg on gestation day (GD) 20 followed by weekly subcutaneous injections of up to 100 mg/kg up to parturition. The dams and infants were then observed untreated for 6 months. There were no adverse effects of crovalimab-akkz on pregnancy or on the viability, growth, and development of the infants up to 100 mg/kg at exposures 14-times the human exposure at the MRHD, based on area under the concentration-time curve (AUC).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Serious Meningococcal Infection [see Warnings and Precautions (5.1) ] Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes [see Warnings and Precautions (5.3) ] Other Infections [see Warnings and Precautions (5.4) ] Infusion- and Injection-Related Reactions [see Warnings and Precautions (5.5) ] The most common adverse drug reactions (incidence ≥10%) were infusion-related reaction, respiratory tract infection, viral infection, and Type III hypersensitivity reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience 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. Patients Who are Complement Inhibitor-Naïve The data described below reflect exposure of 204 patients with PNH who were complement inhibitor-naïve and who were randomized in COMMODORE 2 to receive PIASKY (n = 135) or eculizumab (n = 69) at the recommended dosing regimen for 24 weeks [see Clinical Studies (14) ] . Serious adverse reactions occurred in 6% of patients receiving PIASKY in the COMMODORE 2 study, including epistaxis and pneumonia, which occurred in 2 patients each, and infusion related reaction, pyelonephritis, COVID-19, and hypovolemic shock which were reported in 1 patient each. Table 4 lists adverse reactions that occurred at a rate of 5% or more among patients randomized to PIASKY treatment for 24 weeks in the COMMODORE 2 study. The most common adverse reactions (≥10%) in patients treated with PIASKY were infusion related reaction, respiratory tract infection, and viral infection. Table 4 Adverse Reactions Reported In 5% or More of Complement-Inhibitor Naïve Patients with PNH Randomized to PIASKY in COMMODORE 2 Adverse reactions PIASKY (N = 135) % ECULIZUMAB (N = 69) % Infusion-related reaction 16 13 Respiratory tract infection Grouped terms. Diarrhea includes diarrhea and diarrhea infectious. Headache includes headache and migraine. Injection-related reaction includes injection related reaction and injection site reaction. Respiratory tract infection includes nasopharyngitis, pharyngitis, rhinitis, rhinitis allergic, upper respiratory tract infection and pneumonia. Viral infection includes viral infection, COVID-19, influenza, herpes virus infection and oral herpes. 13 20 Viral infection 11 7 Hyperuricemia 8 9 Headache 8 6 Diarrhea 7 1 Injection-related reaction Injection-related reactions are only expected to occur in the PIASKY arm as eculizumab is not given by subcutaneous injection 6 0 Patients Previously Treated with a Complement C5 Inhibitor The data described below reflect exposure of 86 patients with PNH who received PIASKY (n=44) or eculizumab (n=42) at the recommended dosing regimen for 24 weeks in COMMODORE 1, an open-label, active-controlled, multicenter study conducted in patients switching from eculizumab. The median age was 47 years (range: 21 to 85); 52% were female, and race included White (73%), Asian (19%), unknown (5%), and Black/African-American (3%). The population ethnicities were 17% Hispanic or Latino and 76% not Hispanic or Latino. Serious adverse reactions in COMMODORE 1 were reported in 3 patients (7%) with PNH receiving PIASKY. Serious adverse reactions included pneumonia, nasopharyngitis, and urinary tract infection, which occurred in 1 patient each. Table 5 lists adverse reactions that occurred at a rate of 5% or more among patients randomized to PIASKY treatment for 24 weeks in the COMMODORE 1 study. The most common adverse reactions (≥10%) in patients treated with PIASKY were viral infections, respiratory tract infection, Type III hypersensi…