Dosage & Administration
See Full Prescribing Information for instructions on preparation, dosage, and administration.
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
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PiaSky Prescribing Information
PIASKY, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)]. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.
- Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of PIASKY, unless the risks of delaying therapy with PIASKY outweigh the risk 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. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria.
- 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 serious meningococcal infections and evaluate immediately if infection is suspected.
Because of the risk of serious meningococcal infections, PIASKY is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called PIASKY REMS [see Warnings and Precautions (5.2)].
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.
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)].
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.
| 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 * 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.
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.
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.
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 clear to opalescent, and an almost colorless to brownish-yellow solution. PIASKY should be discarded if the medicine looks cloudy, discolored, or has particles in it.
Preparation of Intravenous Infusion
- Use aseptic technique to prepare PIASKY for intravenous administration. PIASKY must be diluted and administered as an intravenous infusion over 60 minutes ± 10 minutes (1,000 mg) or 90 minutes ± 10 minutes (1,500 mg).
- PIASKY solution must be diluted in 0.9% Sodium Chloride Injection prior to administration. A 0.2 micron in-line filter must be used with the infusion set during administration. A dedicated infusion line must be used during intravenous administration.
- Only dilute PIASKY in 0.9% Sodium Chloride Injection.
Dilution of Intravenous Infusion
- Withdraw the required volume of PIASKY from the vial (see Table 2) using a sterile syringe and dilute into the infusion bag. Use multiple vials to meet the required volume of PIASKY to be added to the infusion bag. Discard any unused portion left in the vial.
Dilution of PIASKY in infusion bags containing 0.9% Sodium Chloride Injection must be in the range of 4-15 mg/mL (final concentration after dilution) (see Table 2).
Intravenous infusion bags of a volume of 100 mL or 250 mL can be used.
| Dose (mg) | Volume of Piasky (mL) | Size of 0.9% Sodium Chloride Injection Bag (mL) | Concentration in Bag (mg/mL) |
|---|---|---|---|
| 1,000 | 5.9 | 250 | 4 |
| 1,500 | 8.8 | 250 | 6 |
| 1,000 | 5.9 | 100 | 10 |
| 1,500 | 8.8 | 100 | 15 |
- Gently mix the infusion bag by slowly inverting the bag. Do not shake.
- Inspect the infusion bag for particles and discard if present.
- Flushing of infusion line is required to ensure complete administration of the entire dose.
Storage of Diluted Solution for Infusion
The diluted solution for intravenous infusion should be used immediately because PIASKY does not contain any antimicrobial preservative. If immediate use is not possible, see Table 3 for detailed storage conditions of the prepared solution for infusion, which depends on the type of infusion bags used.
| Infusion bags | Storage conditions |
|---|---|
| polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) | |
| PO/PE/PP | Refrigerate at 2°C to 8°C (36°F to 46°F) for up to 64 hours protected from light, and store at room temperature up to 30°C (86°F) for up to 6 hours including infusion time under ambient light conditions. Protect from direct sunlight. |
| PVC | Refrigerate at 2°C to 8°C (36°F to 46°F) for up to 12 hours protected from light, and store at room temperature up to 30°C (86°F) for up to 6 hours including infusion time under ambient light conditions. Protect from direct sunlight. |
No incompatibilities have been observed between PIASKY and intravenous infusion bags with product-contacting materials made of polyvinyl chloride, or polyolefins such as polyethylene and polypropylene. In addition, no incompatibilities have been observed with infusion sets or infusion aids with product-contacting materials made of polyvinyl chloride, polyethylene, polyurethane, polybutadiene, acrylonitrile butadiene styrene, polycarbonate, or polytetrafluorethylene.
The infusion of PIASKY may be slowed or interrupted if the patient develops an infusion-related reaction. The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction [see Warnings and Precautions (5.5)].
Preparation of the Subcutaneous Injection
For subcutaneous injection, PIASKY must be used undiluted.
- Remove the vial cap and clean the vial rubber stopper.
- Attach the transfer needle on the syringe.
- Withdraw all the medicine from the vial.
- Remove air bubbles if any.
- Remove the transfer needle from the vial.
- Recap the transfer needle using a one-handed scoop technique.
- Detach the transfer needle.
- Attach the injection needle on the syringe.
- Clean the injection site with an alcohol pad and let air dry.
- Inject the medicine subcutaneously.
If the dose requires multiple injections, perform a new injection using a new PIASKY vial.
A syringe, a transfer needle and an injection needle are needed to withdraw PIASKY solution from the vial and inject it subcutaneously.
- A 2 mL or 3 mL syringe fulfilling the following criteria are recommended: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip (if not available, a syringe with Luer Slip tip can be used), sterile, single-use, latex-free and non-pyrogenic, and commercially available in the US.
- A transfer needle without a filter fulfilling the following criteria may be used: Stainless steel, sterile, preferably gauge 18 G with single bevel at approximately 45 degrees to reduce risk of needle stick injury (or gauge 21 G standard needle as an alternative), single-use, latex-free and non-pyrogenic, and commercially available in the US.
- An injection needle fulfilling the following criteria may be used: Hypodermic needle, stainless steel, sterile, gauge 25 G, 26 G or 27 G, length 3/8'' to 1/2'', single-use, latex-free and non-pyrogenic, preferably including safety needle shield, and commercially available in the US.
- Each injection is a volume of 2 mL PIASKY, corresponding to 340 mg. A 2 mL-size or 3 mL-size syringe should be used for each injection. A dose of 680 mg is achieved by performing two consecutive subcutaneous injections of 340 mg. A dose of 1020 mg is achieved by performing three consecutive subcutaneous injections of 340 mg.
- Inject PIASKY subcutaneously in the abdomen region and rotate abdominal injection sites with every injection. Consecutive injections must be at least 2 inches apart. No data are available on injection at other sites of the body. Injections should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
Storage of Solution for Injection
Once transferred from the vial to the syringe, PIASKY should be injected immediately because PIASKY does not contain any antimicrobial-preservative. If immediate use is not possible, the capped syringe can be refrigerated at 2°C to 8°C (36°F to 46°F) for up to 64 hours protected from light and stored at room temperature up to 30°C (86°F) for up to 5 hours under ambient light conditions.
Protect from direct sunlight.
Injection: 340 mg/2 mL (170 mg/mL) as a clear to opalescent and almost colorless to brownish-yellow solution in a single-dose vial.
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).
Lactation
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.
Pediatric Use
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.
Geriatric Use
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.
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)].