PIASKY Solution for injection Ref.[110563] Active ingredients: Crovalimab

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 the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of PIASKY.
• Healthcare settings and pharmacies that dispense PIASKY must be certified in the REMS and must verify prescribers are certified.
• Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection.
• Patients must be instructed to carry the Patient Safety Card with them at all times during and for 11 months following treatment with PIASKY.

Further information is available at www.PIASKYREMS.com or 1-866-4My-Skyy (469-7599).

5.3 Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes

Patients who are switching from another C5 inhibitor (e.g., eculizumab or ravulizumab) to PIASKY or from PIASKY to another C5 inhibitor are at risk of serious Type III hypersensitivity reactions related to the formation of drug-target-drug-complexes (DTDCs), because PIASKY and these other C5 inhibitors bind different epitopes of C5 [see Drug Interactions (7)].

In clinical trials, Type III hypersensitivity reactions were reported in 39 of 201 patients (19%) who switched from eculizumab or ravulizumab to PIASKY. Four of these patients (10%) had not fully recovered from symptoms of Type III hypersensitivity reactions at the time of their last follow up visit. In addition, Type III hypersensitivity reactions were reported in 2 of 8 patients (25%) who switched from PIASKY to eculizumab or ravulizumab, including one patient who developed Grade 3 axonal neuropathy [see Adverse Reactions (6)].

Symptoms of Type III hypersensitivity reactions that occurred in more than 2 patients were arthralgia, rash, pyrexia, myalgia, headache, fatigue, petechiae and abdominal pain. Among patients who experienced Type III hypersensitivity reactions, 8 (21%) had events that were considered serious due to hospitalization. Symptoms of serious Type III hypersensitivity reactions included pyrexia and arthralgia. Type III hypersensitivity reactions can also cause renal abnormalities.

Healthcare providers should consider the benefits of the timing of switching C5 inhibitors vs. the risks of Type III hypersensitivity reactions. Patients are expected to no longer be at risk of Type III hypersensitivity reactions if the prior C5 inhibitor has been cleared from the body prior to starting PIASKY or if PIASKY has been cleared from the body prior to starting another C5 inhibitor. Therefore, initiating PIASKY sooner than 5.5 half-lives from the last dose of a C5 inhibitor (e.g., eculizumab or ravulizumab) or initiating a C5 inhibitor (e.g., eculizumab or ravulizumab) sooner than 5.5 half-lives from the last dose of PIASKY increases the risk of Type III hypersensitivity reactions.

Based on time-to-onset of Type III hypersensitivity reactions observed in clinical trials, patients should be monitored for the first 30 days of the new therapy for the occurrence of symptoms of Type III hypersensitivity reactions. For mild or moderate Type III hypersensitivity reactions, administer symptomatic treatment, such as topical corticosteroids, antihistamines, antipyretics, and/or analgesics. For severe reactions, initiate and taper oral or systemic corticosteroid therapy as clinically indicated.

5.4 Other Infections

Due to its mechanism of action, PIASKY may increase susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria spp. but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with PIASKY may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Vaccinate patients against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations.

If PIASKY is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection. If the patient’s infection worsens, consider whether to discontinue PIASKY.

5.5 Infusion- and Injection-Related Reactions

Administration of PIASKY may cause infusion-related reactions or systemic injection-related reactions, depending on the route of administration [see Adverse Reactions (6)]. These may include hypersensitivity reactions (including anaphylaxis) but also a range of other symptoms such as injection site pain, erythema, headache or myalgia. One patient experienced a serious infusion-related reaction that resolved 4 days after interruption of infusion with PIASKY. Instruct patients/caregivers to seek immediate medical attention if the patient develops symptoms of a serious hypersensitivity reaction and to report this reaction to their healthcare provider.

If a serious hypersensitivity reaction (including anaphylaxis) occurs, discontinue PIASKY treatment immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved. PIASKY is contraindicated in patients with a known serious hypersensitivity reaction to crovalimab or any of the excipients.

5.6 Monitoring PNH Manifestations after Discontinuation of PIASKY

In case of PIASKY discontinuation, patients who do not switch to another treatment for PNH, must be closely monitored for at least 20 weeks for signs and symptoms of serious hemolysis, identified by elevated lactate dehydrogenase (LDH) levels, along with a sudden decrease in hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (including thrombosis), dysphagia, erectile dysfunction or renal impairment.

If signs and symptoms of hemolysis occur after discontinuation of PIASKY, consider restarting treatment with PIASKY, if appropriate, or initiating another treatment for PNH.

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)]

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 inhibitornaïve 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:

^* 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.
^** Injection-related reactions are only expected to occur in the PIASKY arm as eculizumab is not given by subcutaneous injection

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 hypersensitivity reaction, infusion-related reaction, peripheral edema, and headache.

Table 5. Adverse Reactions Reported In 5% or More of Complement-Inhibitor Treated Patients with PNH Randomized to PIASKY in COMMODORE 1:

^* Grouped terms
Fatigue includes fatigue, malaise and asthenia.
Injection-related reaction includes injection related reaction and injection site reaction.
Rash includes rash and skin exfoliation.
Peripheral edema includes edema peripheral and peripheral swelling.
Respiratory tract infection includes respiratory tract infection, nasopharyngitis, pneumonia and upper respiratory tract infection.
Viral infection includes viral infection, influenza, COVID-19, and respiratory syncytial virus infection
^** Type III immune complex mediated reaction is only expected to occur in the PIASKY arm as patients in the eculizumab arm did not change C5 inhibitor treatment
^*** Infusion-related reactions are not expected to occur in the eculizumab arm as these patients tolerated eculizumab prior to study initiation
^**** Injection-related reactions are only expected to occur in the PIASKY arm as eculizumab is not given by subcutaneous injection

Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes [see Warnings and Precautions (5.3), and Drug Interactions (7)]

Across the COMMODORE 1 and 2 studies, 39 out of 201 (19.4%) patients who switched from eculizumab or ravulizumab to PIASKY experienced a Type III hypersensitivity reaction (reported as Type III immune complex mediated reaction). A total of 6 patients had switched two times and of the 6 patients, 2 patients experienced a second episode of Type III hypersensitivity reaction after discontinuing PIASKY and switching to ravulizumab. One of these patients developed Grade 3 axonal neuropathy and a Type III hypersensitivity reaction could not be excluded and the other developed Grade 2 arthralgia and myalgia. These two events remained unresolved at the last follow up visit of the clinical studies (the duration of the events until last follow-up was 313 days for the event of Grade 3 axonal neuropathy and 142 days for the event of Grade 2 arthralgia and myalgia, respectively). Two additional patients who experienced Grade 3 rash and Grade 3 arthralgia, respectively, had unresolved Type III hypersensitivity reaction at the last follow-up visit.

The median time to onset of Type III hypersensitivity reaction in patients who switched treatment from eculizumab or ravulizumab to PIASKY was 1.6 weeks (range: 0.7 – 4.4 weeks) and the median duration of Type III hypersensitivity reactions was 1.9 weeks (range 0.4 – 34.1 weeks). The majority of events were Grade 1-2. Grade 3 Type III hypersensitivity reaction occurred in 8% of patients who switched from eculizumab or ravulizumab to PIASKY. Out of 42 Type III hypersensitivity reactions, 37 (88%) resolved, including 1 (2.4%) that resolved with PIASKY discontinuation, 2 (4.8%) that resolved with PIASKY interruption and 34 (81%) that resolved without discontinuation, interruption, or dose change in PIASKY therapy.

Axonal Neuropathy

In COMMODORE 1 and 2, Grade 3 distal axonal demyelinating polyneuropathy and Grade 3 axonal neuropathy were reported, each in 1 patient who switched from another C5 inhibitor to PIASKY or from PIASKY to another C5 inhibitor. The Grade 3 distal axonal demyelinating polyneuropathy occurred 11 weeks after a patient switched from eculizumab to PIASKY (with first dose of PIASKY received 12 days after the last dose of eculizumab treatment) and was preceded by a bacterial respiratory tract infection. The Grade 3 axonal neuropathy occurred in a patient who had switched to ravulizumab treatment after 6 weeks of treatment with PIASKY, and previously received ravulizumab treatment prior to switching to treatment with PIASKY [see Warnings and Precautions (5.3)]. Events associated with the axonal neuropathy included COVID-19, sepsis and administration of a fluoroquinolone. In both cases of axonal neuropathy, a Type III hypersensitivity reaction as a cause of, or contributor to, the axonal neuropathy could not be excluded. Both cases of axonal neuropathy remained unresolved at the last follow up visit of the clinical studies.

Pediatric Population with PNH Treated with PIASKY

Twelve pediatric patients with PNH (9 treatment-naïve patients and 3 patients who switched from another C5 inhibitor) were treated with PIASKY in COMMODORE 1 (n=2), COMMODORE 2 (n=7), and in a single-arm trial [(COMMODORE 3 (n=3)]. The safety profile of PIASKY appeared comparable between adult and pediatric patients, but conclusions are limited by the small number of pediatric patients.

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)].

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 post-natal 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).

Risk Summary

There are no data on the presence of crovalimab-akkz in either human or animal milk, the effects on the breastfed child or on milk production. Endogenous IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to crovalimab-akkz is unknown. Because of the potential for serious adverse reactions in a breastfed child, advise patients that breastfeeding is not recommended during treatment with PIASKY and for 9 months after the final dose.

The safety and effectiveness of PIASKY for the treatment of PNH have been established in pediatric patients 13 years and older with a body weight 40 kg. Use of PIASKY for this indication in pediatric patients is supported by evidence from adequate and well-controlled studies in adults along with additional pharmacokinetic, pharmacodynamic, efficacy and safety data in pediatric patients aged 13 to 17 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

The safety and effectiveness of PIASKY have not been established in pediatric patients less than 13 years of age and in those with body weight <40 kg.

Clinical studies of PIASKY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.

Of the 393 PIASKY-treated patients in COMMODORE 1, 2 and 3, 43 (10.9%) were 65 years of age and older. In patients who were complement inhibitor naïve, serious adverse reactions were reported in 1 patient (8%) who was 65 years or older compared to 6 (4%) patients who were 18 to 64 years of age. In patients who previously received a different C5 inhibitor and switched to PIASKY, serious adverse reactions were reported in 3 (7%) patients who were 65 years or older compared to 12 (4%) patients who were 18 to 64 years of age.