ARZERRA Concentrate for solution for infusion Ref.[8957] Active ingredients: Ofatumumab

Arzerra should be administered under the supervision of a physician experienced in the use of cancer therapy and in an environment where full resuscitation facilities are immediately available.

Monitoring

Patients should be closely monitored during administration of ofatumumab for the onset of infusion-related reactions, including cytokine release syndrome, particularly during the first infusion.

Pre-medication

Patients should receive the following pre-medication medicinal products 30 minutes to 2 hours prior to each Arzerra infusion according to the following dosing schedules:

Premedication schedule for Arzerra:

* Up to 13 infusions in previously untreated CLL; up to 7 infusions in relapsed CLL.
** Corticosteroid may be either reduced or omitted for subsequent infusions at the discretion of the physician, if a severe infusion-related adverse drug reaction (ADR) did not occur with the preceding infusion(s).
*** Corticosteroid may be reduced for subsequent infusions at the discretion of the physician, if a severe infusion-related ADR did not occur with the preceding infusion(s).

Posology

Previously untreated CLL

For previously untreated CLL, the recommended dosage and schedule is:

• Cycle 1: 300 mg on day 1 followed 1 week later by 1000 mg on day 8
• Subsequent cycles (until best response or a maximum of 12 cycles): 1000 mg on day 1 every 28 days.

Each cycle lasts 28 days and is counted from day 1 of the cycle.

Best response is a clinical response that did not improve with 3 additional cycles of treatment.

Relapsed CLL

For relapsed CLL, the recommended dosage and schedule is:

• Cycle 1: 300 mg on day 1 followed 1 week later by 1000 mg on day 8
• Subsequent cycles (up to a maximum of 6 cycles in total): 1000 mg on day 1 every 28 days.

Each cycle lasts 28 days and is counted from day 1 of the cycle.

Previously untreated CLL and relapsed CLL

First infusion

The initial rate of the first infusion of Arzerra should be 12 ml/h. During infusion, the rate should be increased every 30 minutes to a maximum of 400 ml/h (see section 6.6). If an infusion-related ADR is observed during infusion, see below section “Dose modification and reinitiation of therapy after infusion-related ADRs”.

Subsequent infusions

If the preceding infusion(s) has (have) been completed without severe infusion related ADRs, the subsequent infusions can start at a rate of 25 ml/h and should be increased every 30 minutes up to a maximum of 400 ml/h (see section 6.6). If an infusion-related ADR is observed during infusion, see below section “Dose modification and reinitiation of therapy after infusion-related ADRs”. ge

Dose modification and reinitiation of therapy after infusion-related ADRs

In the event of a mild or moderate ADR, the infusion should be interrupted and restarted at half of the infusion rate at the time of interruption once the patient’s condition is stable. If the infusion rate had not been increased from the starting rate of 12 ml/hour prior to interrupting due to an ADR, the infusion should be restarted at 12 ml/hour, the standard starting infusion rate. The infusion rate can continue to be increased according to standard procedures, to physician discretion and to patient tolerance (not to exceed doubling the rate every 30 minutes).

In the event of a severe ADR, the infusion should be interrupted and restarted at 12 ml/hour when the patient’s condition is stable. The infusion rate can continue to be increased according to standard procedures, to physician discretion and to patient tolerance (not to exceed increasing the rate every 30 minutes).

Arzerra should be permanently discontinued in patients who develop an anaphylactic reaction to the medicinal product.

Refractory CLL

The recommended dose and schedule is 12 doses administered as follows:

• 300 mg on day 1 followed 1 week later by
• 2000 mg weekly for 7 doses (infusions 2 to 8) followed 4-5 weeks later by
• 2000 mg every 28 days for 4 doses (infusions 9 to 12)

First and second infusions

The initial rate of the first and second infusion of Arzerra should be 12 ml/hour. During infusion, the rate should be increased every 30 minutes to a maximum of 200 ml/hour (see section 6.6). If an infusion-related ADR is observed during an infusion, see below section “Dose modification and reinitiation of therapy after infusion-related ADRs”.

Subsequent infusions

If the preceding infusion(s) has (have) been completed without severe infusion-related ADRs, the subsequent infusions can start at a rate of 25 ml/hour and should be increased every 30 minutes up to a maximum of 400 ml/hour (see section 6.6). If an infusion-related ADR is observed during an infusion, see below section “Dose modification and reinitiation of therapy after infusion-related ADRs”.

Dose modification and reinitiation of therapy after infusion-related ADRs

In the event of a mild or moderate ADR, the infusion should be interrupted and restarted at half of the infusion rate at the time of interruption, once the patient’s condition is stable. If the infusion rate had not been increased from the starting rate of 12 ml/hour prior to interrupting due to an ADR, the infusion should be restarted at 12 ml/hour, the standard starting infusion rate. The infusion rate can continue to be increased according to standard procedures, to physician discretion and to patient tolerance (not to exceed doubling the rate every 30 minutes).

In the event of a severe ADR, the infusion should be interrupted and restarted at 12 ml/hour, once the patient’s condition is stable. The infusion rate can continue to be increased according to standard procedures, to physician discretion and to patient tolerance (not to exceed increasing the rate every 30 minutes).

Arzerra should be permanently discontinued in patients who develop an anaphylactic reaction to the medicinal product.

Special populations

Paediatric population

The safety and efficacy of Arzerra in children aged below 18 years have not been established. Arzerra is therefore not recommended for use in this patient population. ge

Elderly

No substantial differences related to age were seen in safety and efficacy (see section 5.1). Based on available safety and efficacy data in the elderly, no dose adjustment is required (see section 5.2).

Renal impairment

No formal studies of Arzerra in patients with renal impairment have been performed. No dose adjustment is recommended for mild to moderate renal impairment (creatinine clearance >30 ml/min) (see section 5.2).

Hepatic impairment

No formal studies of Arzerra in patients with hepatic impairment have been performed. However, patients with hepatic impairment are unlikely to require dose modification (see section 5.2).

Method of administration

Arzerra is for intravenous infusion and must be diluted prior to administration. For instructions on dilution of the medicinal product before administration, see section 6.6.

No case of overdose has been reported.

Shelf life

Vial: 3 years.

Diluted infusion solution: Chemical and physical in-use stability has been demonstrated for 48 hours at ambient conditions (less than 25°C).

From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8ºC, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Store and transport refrigerated (2°C–8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Arzerra 100 mg concentrate for solution for infusion:

Clear Type I glass vial with a bromobutyl rubber stopper and aluminium over-seal, containing 5 ml of concentrate for solution for infusion.

Arzerra is available in packs of 3 vials.

Arzerra 1000 mg concentrate for solution for infusion:

Clear Type I glass vial with a bromobutyl rubber stopper and aluminium over-seal, containing 50 ml of concentrate for solution for infusion.

Arzerra is available in packs of 1 vial.

Dilution

Arzerra concentrate for solution for infusion does not contain a preservative; therefore dilution should be carried out under aseptic conditions. The diluted solution for infusion must be used within 24 hours of preparation. Any unused solution remaining after this time should be discarded.

Before diluting Arzerra

Check the Arzerra concentrate for particulate matter and discolouration prior to dilution. Ofatumumab should be a colourless to pale yellow solution. Do not use the Arzerra concentrate if there is discolouration.

Do not shake the ofatumumab vial for this inspection.

How to dilute the solution for infusion

The Arzerra concentrate must be diluted in sodium chloride 9 mg/ml (0.9%) solution for injection prior to administration, using aseptic technique.

Arzerra 100 mg concentrate for solution for infusion:

300 mg dose: Use 3 vials (15 ml total, 5 ml per vial):

• Withdraw and discard 15 ml from a 1000 ml bag of sodium chloride 9 mg/ml (0.9%) solution for injection;
• Withdraw 5 ml of ofatumumab from each of 3 vials and inject into the 1000 ml bag;
• Do not shake; mix diluted solution by gentle inversion.

Arzerra 1000 mg concentrate for solution for infusion:

1000 mg dose: Use 1 vial (50 ml total, 50 ml per vial):

• Withdraw and discard 50 ml from a 1000 ml bag of sodium chloride 9 mg/ml (0.9%) solution for injection;
• Withdraw 50 ml of ofatumumab from the vial and inject into the 1000 ml bag;
• Do not shake; mix diluted solution by gentle inversion.

2000 mg dose: Use 2 vials (100 ml total, 50 ml per vial):

• Withdraw and discard 100 ml from a 1000 ml bag of sodium chloride 9 mg/ml (0.9%) solution for injection;
• Withdraw 50 ml of ofatumumab from each of 2 vials and inject into the 1000 ml bag;
• Do not shake; mix diluted solution by gentle inversion.

How to administer the diluted solution

Arzerra must not be administered as an intravenous push or bolus. Administer using an intravenous infusion pump.

The infusion must be completed within 24 hours after preparation. Discard any unused solution after this time.

Arzerra must not be mixed with, or administered as an infusion with other medicinal products or intravenous solutions. Flush line before and after ofatumumab administration with sodium chloride 9 mg/ml (0.9%) solution for injection to avoid this.

Previously untreated CLL and relapsed CLL

For the first infusion, administer over 4.5 hours (see section 4.2), through a peripheral line or indwelling catheter, according to the schedule below:

If the first infusion was completed without a severe adverse reaction, the remaining infusions of 1000 mg should be administered over 4 hours (see section 4.2), through a peripheral line or indwelling catheter, according to the schedule below. If any infusion-related adverse reactions are observed, infusion should be interrupted and restarted when the patient’s condition is stable (see section 4.2 for further information).

Infusion schedule:

* If the previous infusion was completed without severe infusion-related ADRs. If any infusion-related ADRs are observed, infusion should be interrupted and restarted when the patient’s condition is stable (see section 4.2 of the SmPC)

Refractory CLL

For the first and second infusion, administer over 6.5 hours (see section 4.2), through a peripheral line or indwelling catheter, according to the schedule below:

If the second infusion was completed without a severe adverse reaction, the remaining infusions (3-12) should be administered over 4 hours (see section 4.2), through a peripheral line or indwelling catheter, according to the schedule below. If any infusion-related adverse reactions are observed, infusion should be interrupted and restarted when the patient’s condition is stable (see section 4.2 for further information).

Infusion schedule:

* If the second infusion is completed without severe infusion-related ADRs. If any infusion-related ADRs are observed, infusion should be interrupted and restarted when the patient’s condition is stable (see section 4.2).

If any adverse reactions are observed, infusion rates should be reduced (see section 4.2).

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.