Crovalimab-akkz
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]
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Black Box Warning
|
SERIOUS MENINGOCOCCAL INFECTIONS
See full prescribing information for complete Boxed Warning.
Condition Name: (PIASKY increases the risk of serious and life-threatening infections caused by Neisseria meningitidis.
Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of PIASKY, unless the risks of delaying PIASKY outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor (5.1). Patients receiving PIASKY are at increased risk for invasive disease caused by N. meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected (5.1). PIASKY is available only through a restricted program called the PIASKY REMS) |
Overview
Crovalimab-akkz is a complement C5 inhibitor that is FDA approved 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.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include *infusion-related reaction,
- respiratory tract infection,
- viral infection, and
- Type III hypersensitivity reactions..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- 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.
- Injection: 340 mg/2 mL (170 mg/mL) in a single-dose vial.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Crovalimab-akkz in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crovalimab-akkz in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Crovalimab-akkz FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Crovalimab-akkz in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crovalimab-akkz in pediatric patients.
Contraindications
PIASKY is contraindicated:
- For initiation in patients with an unresolved serious Neisseria meningitidis infection.
- In patients with a known serious hypersensitivity reaction to crovalimab or any of the excipients.
Warnings
|
SERIOUS MENINGOCOCCAL INFECTIONS
See full prescribing information for complete Boxed Warning.
Condition Name: (PIASKY increases the risk of serious and life-threatening infections caused by Neisseria meningitidis.
Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of PIASKY, unless the risks of delaying PIASKY outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor (5.1). Patients receiving PIASKY are at increased risk for invasive disease caused by N. meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected (5.1). PIASKY is available only through a restricted program called the PIASKY REMS) |
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.
PIASKY REMS
- PIASKY is available only through a restricted program under a REMS called PIASKY REMS, because of the risk of serious meningococcal infections.
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).
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.
- 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.
- 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.
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.
Infusion- and Injection-Related Reactions
- Administration of PIASKY may cause infusion-related reactions or systemic injection-related reactions, depending on the route of administration.
- 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.
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.
Adverse Reactions
Clinical Trials Experience
The following clinically significant adverse reactions are discussed in greater detail in other sections of the label:
- Serious Meningococcal Infection.
- Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes.
- Other Infections.
- Infusion- and Injection-Related Reactions.
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.
- 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.
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.
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.
Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes
- 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. 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.
Postmarketing Experience
There is limited information regarding Crovalimab-akkz Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Crovalimab-akkz Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Crovalimab-akkz in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Crovalimab-akkz in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Crovalimab-akkz during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Crovalimab-akkz in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Crovalimab-akkz in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Crovalimab-akkz in geriatric settings.
Gender
There is no FDA guidance on the use of Crovalimab-akkz with respect to specific gender populations.
Race
There is no FDA guidance on the use of Crovalimab-akkz with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Crovalimab-akkz in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Crovalimab-akkz in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Crovalimab-akkz in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Crovalimab-akkz in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Crovalimab-akkz Administration in the drug label.
Monitoring
There is limited information regarding Crovalimab-akkz Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Crovalimab-akkz and IV administrations.
Overdosage
There is limited information regarding Crovalimab-akkz overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Crovalimab-akkz Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Crovalimab-akkz Mechanism of Action in the drug label.
Structure
There is limited information regarding Crovalimab-akkz Structure in the drug label.
Pharmacodynamics
There is limited information regarding Crovalimab-akkz Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Crovalimab-akkz Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Crovalimab-akkz Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Crovalimab-akkz Clinical Studies in the drug label.
How Supplied
There is limited information regarding Crovalimab-akkz How Supplied in the drug label.
Storage
There is limited information regarding Crovalimab-akkz Storage in the drug label.
Images
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Patient Counseling Information
There is limited information regarding Crovalimab-akkz Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Crovalimab-akkz interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Crovalimab-akkz Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Crovalimab-akkz Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.