Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Les Laboratoires Servier, 50, rue Carnot, 92284, Suresnes cedex, France
Pixuvri is indicated as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHL). The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy.
Pixuvri must be administered by physicians who are familiar with the use of antineoplastic agents and have the facilities for regular monitoring of clinical, haematological, and biochemical parameters during and after treatment (see section 6.6).
The recommended dose is 50 mg/m² of pixantrone on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles.
Please note:
In the EU recommended dose refers to the base of the active substance (pixantrone). Calculation of the individual dose to be administered to a patient must be based on the strength of the reconstituted solution that contains 5.8mg/ml pixantrone and the dose recommendation of 50 mg/m². In some trials and publications, the recommended dose is based on the salt form (pixantrone dimaleate).
However, the dose has to be adjusted before the start of each cycle based on nadir haematologic counts or maximum toxicity from the preceding cycle of therapy. The amount of Pixuvri in milligrams that is to be administered to a patient should be determined on the basis of the patient’s body surface area (BSA).
The BSA should be determined using the institutional standard for BSA calculation and should use a weight measured on day 1 of every cycle.
Some caution is advised in obese patients as data on BSA- based dosing is very limited for this group.
Dose modification and the timing of subsequent doses should be determined by clinical judgement depending on the degree and duration of myelosuppression. For subsequent courses, the prior dose can usually be repeated if white blood cell and platelet counts have returned to acceptable levels.
If on day 1 of any cycle the Absolute Neutrophil Count (ANC) is <1.0 × 109/l or platelet count is <75 × 109/l it is recommended to delay treatment until ANC recovers to ≥1.0 × 109/l and platelet count to ≥75 × 109/l. Table 1 and Table 2 are recommended as guides to dosage adjustments for days 8 and 15 of the 28-day cycles.
Table 1. Dose modifications for hematologic toxicity on days 8 and 15 of any cycle:
| Grade | Platelet count | ANC count | Dose modification |
|---|---|---|---|
| 1-2 | LLN* – 50 × 109/l | LLN – 1.0 × 109/l | No change in dose or schedule. |
| 3 | <50 – 25 × 109/l | <1.0 – 0.5 × 109/l | Delay treatment until recovery to platelet count ≥50 × 109/l and ANC** ≥1.0 × 109/l. |
| 4 | <25 × 109/l | <0.5 × 109/l | Delay treatment until recovery to platelet count ≥50 × 109/l and ANC** ≥1.0 × 109/l. Reduce the dose by 20%. |
* LLN: Lower Limit of the Normal range
** ANC: Absolute Neutrophil Count
Table 2. Treatment modifications for non-hematologic toxicities:
| Toxicity | Modification |
|---|---|
| Any grade 3 or 4 drug-related non cardiac toxicity other than nausea or vomiting | Delay treatment until recovery to grade 1. Reduce the dose by 20%. |
| Any grade 3 or 4 NYHA* cardiovascular toxicity or persistent LVEF** decline | Delay treatment and monitor until recovery.Consider discontinuation for persistent decline in LVEF** of ≥15% of baseline value. |
* NYHA: New York Heart Association
** LVEF: Left Ventricular Ejection Fraction
The safety and efficacy of Pixuvri in children aged <18 years has not yet been established. No data are available.
No specific dose adjustment is required in elderly patients (aged ≥65 years).
The safety and efficacy of Pixuvri has not been established in patients with impaired renal function. Patients with serum creatinine >2 x Upper Limit of the Normal range (ULN) were excluded from the randomised studies. Thus, Pixuvri should be used with caution in patients with renal impairment.
The safety and efficacy of Pixuvri in patients with impaired hepatic function has not been established. Pixuvri should be used with caution in patients with mild or moderate liver impairment. Pixuvri is not recommended for use in patients with severe excretory hepatic impairment, (see section 4.3).
There is currently no information on the safety and efficacy of patients with poor performance status (ECOG >2). Caution should be exercised when treating such patients.
Pixuvri is for intravenous use only. The safety of intrathecal use has not been established.
Pixuvri is intended for administration as a slow intravenous infusion using an in-line filter (over a minimum of 60 minutes) only after reconstitution with 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection and after further dilution with sodium chloride 9 mg/ml (0.9%) solution for injection to a final volume of 250 ml.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
In the clinical trial program, there has been one report of overdose with Pixuvri with no reported concomitant adverse events.
Single doses of pixantrone up to 158 mg/m² have been given in dose-escalation clinical trials without evidence of dose-related toxicity.
If overdose occurs, supportive management is recommended.
Unopened vial: 5 years.
Reconstituted and diluted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (15°C to 25°C) and daylight exposure in polyethylene (PE) standard infusion bags.
From a microbiological point of view, the 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°C to 8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.
Store in a refrigerator (2°C to 8°C).
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
Type I glass vial with grey butyl rubber stopper with aluminium seal and red plastic cap containing 50 mg pixantrone dimaleate equivalent to 29 mg pixantrone.
Pack size of 1 vial.
Aseptically reconstitute each 29 mg vial with 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. The lyophilised powder should completely dissolve in 60 seconds with agitation. This yields a dark blue solution with a pixantrone concentration of 5.8 mg/ml.
Aseptically withdraw the volume needed for the required dose (based on 5.8 mg/ml concentration) and transfer to a 250 ml infusion bag of sodium chloride 9 mg/ml (0.9%) solution for injection. The final concentration of pixantrone in the infusion bag should be less than 580 microgram/ml based upon input of reconstituted medicinal product. Compatibility with other diluents has not been determined. After transferring, thoroughly mix the contents of the infusion bag. The mixture should be a clear and dark blue solution.
Polyethersulfone 0.2 μm pore size in-line filters should be used during administration of the diluted Pixuvri solution.
Pixuvri is a cytotoxic agent. Avoid contact with eyes and skin. Use gloves, masks, and protective eyewear when handling Pixuvri and during decontamination procedures.
Pixuvri is for single use only. Any unused medicinal product or waste material including materials used for reconstitution, dilution, and administration should be disposed of in accordance with local requirements applicable to cytotoxic agents.
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