Crovalimab Administration Guidelines

Crovalimab (PiaSky) is a humanized anti-C5 monoclonal antibody. Crovalimab (PiaSky) binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9 (membrane attack complex MAC).

Bloods should be taken prior to commencement and at review for FBC, Retics, U&Es, LFTs, LDH and PNH clone. Please contact PNH team with any concerns.

Pregnancy test should be performed on females prior to commencement.

Indications for Treatment with crovalimab (PiaSky)

Patients 12 years of age or older with a weight of 40kg fulfilling any of the following categories:

• Thrombosis related to PNH
• Complications associated with haemolysis: Renal failure, Pulmonary hypertension.
• Haemolytic (LDH >1.5xULN) symptomatic PNH with either of the following

With anaemia (Hb <9g/L) or With agreement with Joint Service colleagues at MDT

• Exceptional cases in whom is considered appropriate (not fulfilling the above criteria) will be approved through discussion between the two Nationally Commissioned PNH Services and the National Commissioners.

Important consideration: if a patient is switching from another C5 complement inhibitor to Crovalimab (PiaSky) there is risk of immune complex deposition please discuss with a PNH consultant haematologist.

Risks

Meningococcal Infection:

Due to its mechanism of action, the use of Crovalimab (PiaSky) increases the patient’s susceptibility to meningococcal infection.

To reduce the risk of infection, all patients must be:

1. Vaccinated on the day 1 of receiving Crovalimab (PiaSky) after administration with:

Menveo/Nimenrix  and Bexsero with a second Bexsero dose at 6 weeks post commencement

Then re-vaccinated according to current PNH medical guidelines for vaccination use.

Patients will be revaccinated as per antibody response to MenCWY.

Bexsero second dose 6 weeks later and every 5 years thereafter

It is recommended 3 doses of paracetamol be prescribed around the administration of Bexsero vaccination with one before and 2 to follow at 4 hourly intervals.

2. Prescribed:

• Ciprofloxacin 500mg twice daily for the first 14 days of Crovalimab (PiaSky)
• Followed by Penicillin V 500mg twice daily for the duration of complement inhibition.  Patients who are allergic to penicillin can be prescribed erythromycin 500mg   twice daily.
• Rescue antibiotic to keep at home in case of a possible meningococcal infection ciprofloxacin 500mg twice daily x 10 days. Patients will contact the PNH team for advice if pyrexial.

3. Have a throat swab taken, to rule out if they are a carrier of the meningococcal bacteria at commencement.
4. Educated on the risks and signs and symptoms of possible infection such as a temperature of 38c or above.

If patient shows any signs of meningococcal infection the PNH team should be contacted immediately 0113 2068625 or out of hours 07920535918

Dose

Initial phase

Day 1 – one loading dose administered by intravenous infusion.

Days 2, 8, 15, and 22 – weekly loading doses administered by subcutaneous injection.

Maintenance phase

Day 29 – administered then every 4 weeks by subcutaneous injection.

The Crovalimab (PiaSky) doses to be administered are based on the patient’s body weight, as shown:

Q4W=every 4 weeks

For patients switching from treatment with another complement inhibitor, the first intravenous loading dose of Crovalimab (PiaSky) should be administered at the time of the next scheduled complement inhibitor administration.

Administration window

• There is a +/- 1 or 2 days that the dose can be given but this must be agreed by the prescribing centre.
• Except at Day 1 and Day 2 if this is delayed, the subsequent dose should be administered according to the regular schedule.

Adminstration:

• Crovalimab (PiaSky) should be prepared and administered by a healthcare professional for IV dosing then can be self-administered for subcutaneous doses.

Day 1 IV infusion:

• Baseline observations should be done prior to administration including blood pressure, pulse, and temperature.
• Adherence of aseptic technique should be always followed.
• Crovalimab (PiaSky) must be diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion prior to administration.
• Administered by an intravenous infusion over 90 min via a 2 μ m in-line filter giving set using free flow gravity or pump.
• Patients should be monitored for signs of hypersensitivity during the infusion and one hour following infusion.
• If an adverse event occurs during the administration of Crovalimab (PiaSky) the administration must be stopped the total infusion time may not exceed two hours.
• See below for reconstitution instructions for IV

Day 2, 8, 15, 22, 29 and every 4 weeks thereafter subcutaneous injection:

• Crovalimab (PiaSky) can be self-administered when the patient is confident in administration.
• Day 2 will be given at treating centre or by homecare.
• Homecare is available for 4 doses or until the patient is confident in self-administration.
• Crovalimab (Piasky) is used undiluted and should be prepared using aseptic technique.
• A syringe, a transfer needle and an injection needle are needed to withdraw Crovalimab Piasky solution from the vial and inject it subcutaneously.
• Each injection is of a volume of 2 mL, corresponding to 340 mg.
• A 2 mL-size or 3 mL-size syringes should be used for each injection.
• A dose of 680 mg is achieved by performing two consecutive subcutaneous injections of 340 mg.
• Administer at an angle between 45° to 90° to the skin.

Any adverse events must be documented and reported to the prescribing centre.

• if patient has a temperature of >38^oC contact PNH team
• 0113 2068625 or out of hours 07920535918

Procedure

Preparing the Infusion

The same vials are used for IV loading and S/C administration.

IV loading dose and 1st S/C dose to be given on site always adhering to aseptic technique.

Subcutaneous administration by the patient and/or caregiver: Must be used undiluted.

It is recommended to inject Crovalimab (Piasky) into the abdomen.

Within the abdomen, injection sites should be rotated with every injection.

Injections should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Dosing Table for IV dose

Dilution

1. Withdraw the required volume of Crovalimab Piasky from the vial (see Table below) using a sterile syringe and dilute into the infusion bag. Multiple vials need to be used to meet the required volume of Crovalimab Piasky to be added to the infusion bag. Discard any unused portion left in the vial.

Dilution of Crovalimab Piasky in infusion bags containing sodium chloride 9 mg/mL (0.9%) solution for infusion must be in the range of 4-15 mg/mL (final concentration after dilution).

Intravenous infusion bags of a volume of 100 mL or 250 mL can be used.

Table 5: Dose example volume determination

* Each 340 mg vial contains a nominal fill volume of 2.0 mL

2. Gently mix the infusion bag by slowly inverting the bag. Do not shake.
3. Inspect the infusion bag for particles and discard if present.
4. Flushing of infusion line is required in order to ensure complete administration of the entire dose.
5. Patients are observed for 1 hour post for any signs of reaction.