Brand name: Piasky
Drug class: Complement Inhibitor Agents

Medically reviewed by Drugs.com on Dec 10, 2024. Written by ASHP.

Introduction

Terminal complement inhibitor; humanized monoclonal antibody.

Uses for Crovalimab-akkz

Paroxysmal Nocturnal Hemoglobinuria

Treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults and pediatric patients ≥13 years of age and body weight ≥40 kg (designated an orphan drug by FDA for this use).

Options for PNH include supportive care (e.g., iron supplementation, RBC transfusion, antibiotics for bacterial infection, anticoagulation, corticosteroids), allogeneic bone marrow transplantation, and/or terminal complement inhibitors (e.g., eculizumab, ravulizumab); choice of therapy depends on PNH classification and symptom severity.

Crovalimab-akkz Dosage and Administration

General

Pretreatment Screening

• Assess immunization status prior to initiating crovalimab-akkz therapy; ensure patients have received recommended vaccines.

Patient Monitoring

• Closely monitor patients for early signs and symptoms of meningococcal infections during treatment with crovalimab-akkz; evaluate patients immediately if infection is suspected.

• When switching between complement C5 inhibitors, monitor patients for the first 30 days of the new therapy for the occurrence of symptoms of type III hypersensitivity reactions.

• Closely monitor patients for signs and symptoms of worsening infection if crovalimab-akkz is administered to patients with an active systemic infection.

• If crovalimab-akkz is discontinued and the patient is not switched to another treatment for paroxysmal nocturnal hemoglobinuria (PNH), closely monitor the patient for ≥20 weeks for signs and symptoms of serious hemolysis.

• Monitor for infusion- and injection site-related reactions and initiate medical management as indicated.

Premedication and Prophylaxis

• Vaccinate patients for meningococcal infection (serogroups A, C, W, Y, and B) if needed according to current Advisory Committee on Immunization Practices (ACIP) recommendations in patients receiving a complement inhibitor ≥2 weeks prior to initiating crovalimab-akkz. If urgent therapy is indicated in a patient not up to date with these vaccines, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible.

• Vaccinate patients against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) if needed according to current ACIP recommendations.

REMS Program

• Because of the risk of serious meningococcal infections, crovalimab-akkz is only available through a restricted distribution program called the Piasky Risk Evaluation and Mitigation Strategy (REMS). Crovalimab-akkz may be prescribed only by clinicians who are enrolled in the Piasky REMS program. In addition, clinicians must agree to counsel patients regarding the risk of meningococcal infection, provide educational materials, and ensure that patients are compliant with meningococcal vaccine and antibacterial drug prophylaxis requirements. To obtain additional information or to enroll in the program, clinicians may call 1-866-469-7599 or visit [Web].

Administration

Administered as an IV infusion for the first dose and as a sub-Q injection for subsequent doses. Should only be administered by a healthcare provider.

Each single-dose vial contains 340 mg/2mL (170 mg/mL) of crovalimab-akkz.

IV Administration

Must be diluted before IV administration.

Dilution

Dilute in infusion bags containing 0.9% sodium chloride to yield final concentration of 4–15 mg/mL. Use infusion bags of 100 or 250 mL.

To prepare, withdraw required volume of crovalimab-akkz from vial using sterile syringe and dilute into infusion bag. Use multiple vials to meet required volume of drug to be added to infusion bag. Refer to full prescribing information for additional information. Discard any unused portion left in vial.

Gently mix solution by slowly inverting infusion bag; do not shake. Inspect solution for particles; discard if present.

Solution is preservative-free; use immediately after dilution.

Rate of Administration

Administer infusion over 60±10 minutes (1000-mg dose) or 90±10 minutes (1500-mg dose) using a 0.2-micron in-line filter through a dedicated infusion line. Flush infusion line after administration to ensure complete administration of full dose.

No incompatibilities observed with infusion sets or infusion aids containing PVC, polyethylene, polyurethane, polybutadiene, acrylnitrile butadiene styrene, polycarbonate, or polytetrafluorethylene.

Slow or interrupt infusion if infusion-related reaction occurs. Immediately discontinue infusion if serious hypersensitivity reaction develops.

Sub-Q Administration

Use undiluted crovalimab-akkz.

Syringe, transfer needle, and injection needle needed to withdraw solution from crovalimab-akkz vial and inject drug.

Syringe requirements: 2- or 3-mL transparent polypropylene or polycarbonate syringe with Luer-Lock tip (if not available, a Luer Slip tip may be used), sterile, single-use, latex-free, non-pyrogenic.

Transfer needle requirements: transfer needle without a filter, stainless steel, sterile, preferably 18-gauge with a single bevel at approximately 45° (or alternatively, a 21-gauge standard needle), single-use, latex-free, non-pyrogenic.

Injection needle requirements: hypodermic, stainless steel, sterile, single-use, latex-free, non-pyrogenic; 25-, 26-, or 27-gauge needle of 3/8” or 1/2” length; preferably including a safety needle shield.

For specific preparation instructions, refer to full prescribing information.

If dose requires multiple injections, use new vial for each injection.

Each injection is a 2-mL volume (corresponds to 340 mg). Split doses >340 mg into multiple 2-mL injections (a 680-mg dose consists of 2 consecutive 2-mL injections; a 1020-mg dose consists of 3 consecutive 2-mL injections).

Administer into abdominal region as no data on injection into other body sites; separate injection sites by ≥2 inches (for consecutive injections) and rotate sites with each injection. Do not inject into moles, scars, or areas of the skin that are tender, bruised, red, hard, or not intact.

Administer sub-Q doses immediately upon preparation.

Dosage

Pediatric Patients

Paroxysmal Nocturnal Hemoglobinuria (PNH)

IV, then Sub-Q

Dosage in pediatric patients ≥13 years of age weighing ≥40 kg based on actual body weight (ABW) as shown in Table 1. Recommended dosing regimen: 1 loading dose administered by IV infusion (on day 1), followed by 4 additional weekly loading doses administered by sub-Q injection (on days 2, 8, 15, and 22). Starting on day 29, administer maintenance doses every 4 weeks by sub-Q injection.

Adjust maintenance dosage if body weight changes to consistently >100 kg or <100 kg during course of treatment.

When switching to crovalimab-akkz from another complement C5 inhibitor (e.g., eculizumab, ravulizumab), administer first loading dose of crovalimab-akkz no earlier than the time of next scheduled dose of eculizumab or ravulizumab.

Except for days 1 and 2, dosing schedule may occasionally vary within 2 days of scheduled administration day. If this occurs, administer subsequent dose on next regularly scheduled administration day.

Adults

PNH

IV, then Sub-Q

Dosage in adults weighing ≥40 kg based on ABW as shown in Table 1. Recommended dosing regimen: 1 loading dose administered by IV infusion (day 1), followed by 4 additional weekly loading doses administered by sub-Q injection (on days 2, 8, 15, and 22). Starting on day 29, administer maintenance doses every 4 weeks by sub-Q injection.

Adjust maintenance dosage if body weight changes to consistently >100 kg or <100 kg during course of treatment.

When switching to crovalimab-akkz from another complement C5 inhibitor (e.g., eculizumab, ravulizumab), administer first loading dose of crovalimab-akkz no earlier than the time of next scheduled dose of eculizumab or ravulizumab.

Except for days 1 and 2, dosing schedule may occasionally vary within 2 days of the scheduled administration day. If this occurs, administer subsequent dose on next regularly scheduled administration day.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time. Not eliminated via hepatic pathways.

Renal Impairment

No specific dosage recommendations at this time. Not eliminated via renal pathways.

Geriatric Patients

No specific dosage recommendations at this time. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and greater frequency of concomitant disease or other drug therapy.

Cautions for Crovalimab-akkz

Contraindications

• Initiation in patients with unresolved serious Neisseria meningitidis infection.

• Known serious hypersensitivity to crovalimab-akkz or any ingredient in the formulation.

Warnings/Precautions

Warnings

Serious Meningococcal Infections

Risk of serious and life-threatening infections caused by N. meningitidis. (See Boxed Warning.) Increased susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria in any serogroup, including non-groupable strains. Infections reported in both vaccinated and unvaccinated patients.

Complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) ≥2 weeks prior to first dose of crovalimab-akkz in accordance with current Advisory Committee on Immunization Practices (ACIP) recommendations for patients receiving a complement inhibitor. Revaccinate patients according to ACIP recommendations considering duration of crovalimab-akkz therapy.

If urgent crovalimab-akkz therapy indicated in patients not up to date with meningococcal vaccines, initiate antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Optimal prophylactic drug regimen and duration unknown in unvaccinated or vaccinated patients receiving complement inhibitors. Consider benefits and risks of crovalimab-akkz therapy, and benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, against known risks for serious infections caused by N. meningitidis.

Risk of meningococcal infection not fully eliminated with vaccination.

Closely monitor for early signs and symptoms of meningococcal infection; evaluate immediately if infection suspected. Inform patients of signs and symptoms of infection; instruct patients to seek immediate medical care if these occur. Promptly treat known infections; can develop rapidly into life-threatening or fatal infection if not recognized and treated early. Consider interrupting crovalimab-akkz in patients receiving treatment for serious meningococcal infection.

Due to risk of meningococcal infections, crovalimab-akkz is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. For further information, call 1-866-469-7599 or consult[Web]. (See REMS Program under Dosage and Administration.)

Other Warnings/Precautions

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

When switching to or from another complement C5 inhibitor (e.g., eculizumab or ravulizumab), risk of serious type III hypersensitivity reactions related to formation of drug-target-drug complexes (DTDCs). Signs and symptoms, including arthralgia, rash, pyrexia, myalgia, headache, fatigue, petechiae, abdominal pain, and renal abnormalities, reported.

Consider benefits of timing of switching C5 inhibitors versus risks of developing type III hypersensitivity reactions. Manufacturer states risk not increased once prior C5 inhibitor is cleared from body prior to starting crovalimab-akkz (5.5 half-lives from last dose of eculizumab or ravulizumab) or after crovalimab-akkz is cleared from body prior to starting eculizumab or ravulizumab (5.5 half-lives from last dose of crovalimab-akkz).

Monitor patients for the first 30 days of new C5 inhibitor therapy for occurrence of symptoms. If mild or moderate type III hypersensitivity reactions occur, may administer symptomatic treatment (e.g., topical corticosteroids, antihistamines, antipyretics, and/or analgesics). For severe type III hypersensitivity reactions, initiate and taper oral or systemic corticosteroid therapy as clinically indicated.

Other Infections

May increase susceptibility to infections, especially those caused by encapsulated bacteria such as Neisseria spp, Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. Pediatric patients may be at increased risk for serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).

Vaccinate patients against S. pneumoniae and Hib infections in accordance with current ACIP recommendations.

Closely monitor for signs and symptoms of worsening infection if crovalimab-akkz is administered to patients with active systemic infections. If infection worsens, consider discontinuation of crovalimab-akkz.

Infusion- and Injection-related Reactions

Serious hypersensitivity reactions (including anaphylaxis) and/or injection-related reactions (e.g., injection site pain, erythema, headache, myalgia) can occur.

Instruct patients/caregivers to seek immediate medical attention if symptoms of serious hypersensitivity reaction occur and to report reaction to their clinician.

If serious hypersensitivity reaction (including anaphylaxis) occurs, immediately discontinue crovalimab-akkz and initiate standard of care treatment. Monitor until signs and symptoms have resolved.

Monitoring Disease Manifestations After Treatment Discontinuation

If crovalimab-akkz is discontinued and patient not switched to another treatment for paroxysmal nocturnal hemoglobinuria (PNH), closely monitor for ≥20 weeks for signs and symptoms of serious hemolysis. Hemolysis identified by elevations in LDH levels, sudden decreases in hemoglobin, or the reappearance 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, consider reinitiating crovalimab-akkz therapy, if appropriate, or switching to another treatment for PNH.

Immunogenicity

Potential for immunogenicity.

Anti-crovalimab-akkz antibodies observed in studies. Few patients with anti-drug antibodies had loss of pharmacological activity coinciding with loss of exposure/efficacy, manifesting as sustained loss of hemolysis control. No evidence for clinical impact of anti-drug antibodies on safety of crovalimab-akkz.

Specific Populations

Pregnancy

Data insufficient in pregnancy to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Since human IgG antibody crosses placenta, possible that crovalimab-akkz may be transmitted from mother to developing fetus.

Untreated PNH in pregnancy associated with risks to mother and fetus.

Lactation

No data on presence in human or animal milk, effects on breast-fed children, or effects on milk production. Endogenous IgG and monoclonal antibodies transfer into human milk. Effects of local GI exposure to crovalimab-akkz and limited systemic exposure in breast-fed children unknown.

Advise patients to avoid breast-feeding during treatment and for 9 months following the last dose.

Pediatric Use

Safety and efficacy for treatment of PNH established in pediatric patients ≥13 years of age weighing ≥40 kg.

Safety and efficacy not established in pediatric patients <13 years of age and in those weighing <40 kg.

Similar exposure to crovalimab-akkz observed in pediatric patients with PNH weighing ≥40 kg and in adult patients.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to assess differences in response compared to younger adults. Serious adverse reactions reported more frequently in complement inhibitor-naïve and experienced patients ≥65 years of age compared to patients 18–64 years of age.

Hepatic Impairment

No clinically important changes in pharmacokinetics observed in patients with mild hepatic impairment. Not evaluated in moderate or severe hepatic impairment.

Renal Impairment

No clinically important changes in pharmacokinetics observed in patients with mild, moderate, or severe renal impairment.

Common Adverse Effects

Adverse effects (≥10%): Infusion-related reactions, respiratory tract infections, viral infections, type III hypersensitivity reactions.

Drug Interactions

Expected to undergo metabolism via lysosomal proteolysis into small peptides and amino acids.

Other Complement C5 Inhibitors

Possible formation of drug-target-drug complexes (DTDCs) when switching between crovalimab-akkz and eculizumab or ravulizumab; may result in type III hypersensitivity reactions. Clearance of DTDCs expected after approximately 8 weeks with eculizumab and longer with ravulizumab. Patients considered no longer at risk for type III hypersensitivity reactions after the prior C5 inhibitor fully cleared from body (i.e., 5.5 half-lives of prior C5 inhibitor have elapsed).

Monitor patients for occurrence of type III hypersensitivity symptoms for first 30 days of new C5 inhibitor therapy.

Crovalimab-akkz Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration, bioavailability is 83%.

Peak plasma concentration and AUC dose proportional over dosage range of 75–1500 mg when given as a single IV infusion and 100–1020 mg when given as a sub-Q injection.

Following administration of first IV loading dose, target threshold concentration for complete terminal complement inhibition exceeded. Subsequent sub-Q doses result in steady-state concentrations after approximately 12 weeks.

Special Populations

Mild to severe renal impairment: Pharmacokinetics not substantially altered.

Mild hepatic impairment: Pharmacokinetics not substantially altered.

Moderate to severe hepatic impairment: Pharmacokinetics not studied.

Age (13–85 years), gender, and race do not substantially affect pharmacokinetics.

Distribution

Extent

Not known if excreted into human milk; however, endogenous IgG and monoclonal antibodies known to transfer into milk.

Human IgG antibody crosses placenta.

Elimination

Metabolism

Expected catabolism via lysosomal proteolysis into small peptides and amino acids.

Elimination Route

Not eliminated via renal or hepatic pathways.

Half-life

53.1 days.

Special Populations

Patients being switched from another C5 inhibitor (e.g., eculizumab or ravulizumab) to crovalimab-akkz: Transient increase in elimination (due to the formation of transient immune complexes) observed.

Stability

Storage

Parenteral

Injection for IV Use

Store vials at 2–8°C in original carton to protect from light. Do not freeze or shake. Once removed from refrigeration, unopened vials may be kept in original carton at room temperature (≤30°C) for ≤7 days if needed and returned to refrigeration; if stored at room temperature for a total combined time of >7 days, discard vials.

If diluted solution not immediately used, PVC infusion bags may be stored at 2–8°C for ≤12 hours protected from light and at 30°C for ≤6 hours (including infusion time) under ambient light conditions.

If the diluted solution not immediately used, polyolefin (PO), polyethylene (PE), or polypropylene (PP) infusion bags may be stored at 2–8°C for ≤64 hours protected from light and at 30°C for ≤6 hours (including infusion time) under ambient light conditions.

Protect diluted solution from direct sunlight.

Injection for Sub-Q Use

Store vials at 2–8°C in original carton to protect from light. Do not freeze or shake. Once removed from refrigeration, unopened vials may be kept in original carton at room temperature (≤30°C) for ≤7 days if needed and returned to refrigeration; if stored at room temperature for a total combined time of >7 days, discard vials.

If prepared dose not immediately used, capped syringes may be stored refrigerated at 2–8°C for ≤64 hours protected from light, and stored at room temperature ≤30°C for ≤5 hours under ambient light conditions. Protect from direct sunlight.

Actions

• Binds with high affinity to the complement protein C5, inhibiting its cleavage into C5a and C5b and thereby preventing formation of the membrane attack complex (MAC).

• Through terminal complement inhibition, inhibits intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Inform patients of the risk of serious meningococcal infection, and the need to complete or update their meningococcal vaccinations ≥2 weeks prior to the first dose of crovalimab-akkz. If vaccines are not updated ≥2 weeks prior, inform patients that they must receive antibiotic prophylaxis if urgent crovalimab-akkz treatment is initiated. Inform patients that they must continue to be revaccinated according to current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal infection while on crovalimab-akkz therapy.

• Inform patients that vaccination does not fully eliminate the risk of serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur: fever; fever and a rash; headache with nausea or vomiting; fever with a high heart rate; headache and a fever; headache with a stiff neck or stiff back; confusion; muscle aches with flu-like symptoms; or eye sensitivity to light.

• Inform patients that they will be given a Patient Safety Card that they should carry with them at all times during treatment with crovalimab-akkz and for 11 months following discontinuance of treatment. Inform patients that this card describes symptoms of meningococcal infection which, if experienced, should prompt them to immediately seek medical evaluation.

• Inform patients that crovalimab-akkz is available only through a restricted program called the Piasky Risk Evaluation and Mitigation Strategy (REMS), and that this program requires patients to receive counseling (including educational materials) about the risk of serious meningococcal infections, as well as to comply with the most current recommendations for meningococcal vaccination.

• Inform patients of the risk of experiencing a type III hypersensitivity reaction in the first 30 days after switching from another complement C5 inhibitor to crovalimab-akkz (or if they are planning to switch from crovalimab to another C5 inhibitor). Inform patients about the signs and symptoms of a type III hypersensitivity reaction, and advise patients to seek immediate medical attention if the following signs or symptoms occur: rash; itching; joint pain; or numbness and tingling or a feeling of pins and needles, especially of the hands and feet.

• Advise patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species. Advise patients of the need for vaccination against Streptococcus pneumoniae infections according to current ACIP recommendations. Inform parents or caregivers of children receiving crovalimab-akkz that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to current medical guidelines. Advise patients to report any new signs or symptoms of infection.

• Advise patients that administration of crovalimab-akkz may result in infusion-related reactions or systemic injection-related reactions, depending on the route of administration. Advise patients to seek immediate medical attention if symptoms of a serious allergic reaction occur.

• Inform patients that they may develop hemolysis due to paroxysmal nocturnal hemoglobinuria when crovalimab-akkz is discontinued and that they will be closely monitored by their clinician for ≥20 weeks following treatment discontinuation.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise patients it is not recommended to breast-feed during treatment with crovalimab-akkz and for 9 months after the final dose.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of crovalimab-akkz is restricted. (See REMS Program under Dosage and Administration.)

Reload page with references included

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