Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Oncopeptides AB (publ), Luntmakargatan 46, 111 37 Stockholm, Sweden
Pepaxti is indicated, in combination with dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least three prior lines of therapies, whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 monoclonal antibody, and who have demonstrated disease progression on or after the last therapy. For patients with a prior autologous stem cell transplantation, the time to progression should be at least 3 years from transplantation (see section 4.4).
Treatment with Pepaxti must be initiated and supervised by physicians experienced in the treatment of multiple myeloma.
The recommended starting dose of Pepaxti is 40 mg on Day 1 of each 28-day treatment cycle. For patients with a body weight of 60 kg or less the recommended starting dose is 30 mg on Day 1 of each 28-day cycle. It is recommended that treatment should be continued until disease progression or unacceptable toxicity (see section 5.1).
The recommended dose of dexamethasone is 40 mg orally on Days 1, 8, 15 and 22 of each 28-day treatment cycle. For patients 75 years of age and older the recommended dose of dexamethasone is 20 mg. For additional information regarding administration of dexamethasone, see section 5.1 and the corresponding Summary of Product Characteristics.
Pepaxti must be withheld if the neutrophil count is less than 1 × 109/L or the platelet count is less than 50 × 109/L.
The recommended dose reduction and dosage modifications for adverse reactions of Pepaxti are presented in Table 1 and Table 2, respectively.
Table 1. Recommended dose reduction for adverse reactions of Pepaxti:
| Dose reduction | Dose* in patients with body weight greater than 60 kg | Dose* in patients with body weight of 60 kg or less |
|---|---|---|
| 40 mg | 30 mg | |
| First | 30 mg | 20 mg |
| Second | 20 mg | 15 mg |
| Third | 15 mg | Permanently discontinue Pepaxti in patients who are unable to tolerate 15 mg |
| Subsequent | Permanently discontinue Pepaxti in patients who are unable to tolerate 15 mg | - |
* Administered intravenously on Day 1 of each 28-day cycle. For dose modifications, see Table 2
Table 2. Recommended dose modifications for adverse reactions of Pepaxti (Grading of adverse reaction according to CTCAE v 5.0):
| Adverse reaction | Severity | Dose modification |
|---|---|---|
| Haematologic adverse reaction (see section 4.4) | Platelet count less than 50 × 109/L on an intended Pepaxti dosing day | • Withhold Pepaxti and monitor platelet count weekly until platelet count is 50 × 109/L or greater. • Resume Pepaxti at 1 dose level lower. |
| Absolute neutrophil count less than 1 × 109/L on an intended Pepaxti dosing day | • Withhold Pepaxti and monitor neutrophil count weekly until neutrophil count is 1 × 109/L or greater. • Resume Pepaxti at 1 dose level lower. | |
| Non-haematologic adverse reaction (see section 4.8) | Grade 2 | • Consider withholding Pepaxti until resolved to at least Grade 1 or baseline. • Consider resuming Pepaxti at 1 dose level lower. |
| Grade 3 or 4 | • Withhold Pepaxti until resolved to at least Grade 1 or baseline. • Consider resuming Pepaxti at 1 dose level lower. |
Consideration should be taken if prophylactic concomitant treatment with antimicrobials should be administered to reduce the risk of infections (see section 4.8).
Anti-emetic agents should be administered prior to and during the treatment with Pepaxti at the discretion of the physician and in accordance with local practice (see section 4.4).
No dose adjustment is recommended for elderly patients.
No dose adjustment of Pepaxti is required in patients with estimated glomerular filtration rate (eGFR) above 45 mL/min/1.73 m². A dose of 30 mg is recommended in patients with eGFR 30-45 mL/min/1.73 m². There are insufficient data in patients with eGFR below 30 mL/min/1.73 m² to support a dose recommendation (see section 4.4 and 5.2).
No dose adjustment of Pepaxti is required for patients with mild hepatic impairment (see section 5.2). There are insufficient data in patients with moderate or severe hepatic impairment to support a dose recommendation.
The safety and efficacy of Pepaxti in children below 18 years of age have not been established. No data are available.
Pepaxti is for intravenous use.
Pepaxti should be administered as a 30-minute infusion via a peripheral venous route or a central venous access device, such as a peripherally inserted central catheter (PICC) or a tunnelled central venous catheter. If administered peripherally, it is recommended to alternate veins for infusion. In case of extravasation, the administration should be interrupted immediately and a central venous line should be used.
Pepaxti must be reconstituted and diluted by a healthcare professional prior to administration. Infusion of the diluted solution must begin within 60 minutes of start of initial reconstitution or be placed in a refrigerator within 30 minutes from start of initial reconstitution. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
In the event of overdose, gastrointestinal events like nausea and vomiting, and haematological events due to bone marrow suppression are likely to occur. The patient should be monitored for any signs or symptoms of adverse reactions, including complete blood counts weekly for at least 4 weeks, and appropriate supportive treatment, such as blood transfusion, antimicrobials and/or haematopoietic growth factors should be instituted if needed. There is no known specific antidote to melphalan flufenamide.
Unopened vial: 4 years.
Diluted solution: From a microbiological point of view the product should be used immediately. If not used immediately, the diluted solution can be stored in a refrigerator (2 °C-8 °C) prior to administration for up to 6 hours. Do not freeze. If refrigerated, allow the diluted solution to equilibrate to room temperature (20 °C-25 °C) for maximum 30 minutes prior to administration.
The diluted solution for infusion may be kept at room temperature for up to 1.5 hours (including infusion time).
Store in a refrigerator (2 °C-8 °C). Do not freeze.
Store in the original package in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
50 mL Type 1 glass vial sealed with chlorobutyl rubber stopper and aluminium overseal with a plastic removable cap containing 20 mg powder. Pack size of 1 vial.
Pepaxti should be prepared by a healthcare professional using aseptic technique to ensure the sterility of the prepared solution.
5% glucose solution for injection/infusion (room temperature).
250 mL bag of cold (2 °C-8 °C) sodium chloride 9 mg/mL (0.9%) solution for injection (refrigerate for at least 4 hours).
Table 6. Dilution volumes per Pepaxti dose:
| Volume description | Pepaxti dose | |||
| 40 mg (2 vials) | 30 mg (1.5 vials) | 20 mg (1 vial) | 15 mg (0.75 vial) | |
| Volume of reconstituted Pepaxti solution needed for final product | 80 mL | 60 mL | 40 mL | 30 mL |
| Final total volume of infusion bag after dilution | 250 mL | 230 mL | 210 mL | 200 mL |
| Pepaxti concentration after dilution | 0.16 mg/mL | 0.13 mg/mL | 0.10 mg/mL | 0.08 mg/mL |
Read the complete instructions prior to starting preparation. Steps 3 to 5 must be completed within 30 minutes.
Determine the number of vials needed for the dose as per Table 6 “Dilution volumes per Pepaxti dose”. Place vial(s) at room temperature for at least 30 minutes.
Shake the vial(s) vigorously or vortex to disintegrate the lyophilised powder cake into a loose powder.
Steps 3 to 5 must be completed within 30 minutes
| For a Pepaxti dose of 40 mg | For a Pepaxti dose of 30 mg | For a Pepaxti dose of 20 mg | For a Pepaxti dose of 15 mg |
| Aseptically reconstitute each of the 2 vials with 40 mL of 5% glucose solution for infusion to obtain a final concentration of 0.5 mg/mL. | Aseptically reconstitute each of the 2 vials with 40 mL of 5% glucose solution for infusion to obtain a final concentration of 0.5 mg/mL. | Aseptically reconstitute 1 vial with 40 mL of 5% glucose solution for infusion to obtain a final concentration of 0.5 mg/mL. | Aseptically reconstitute 1 vial with 40 mL of 5% glucose solution for infusion to obtain a final concentration of 0.5 mg/mL. |
Ensure the 5% glucose solution for infusion is at room temperature (20 °C-25 °C). Shake the vial(s) vigorously until solution is clear.
Let the vial(s) stand to allow air bubbles to dissipate to confirm a clear solution.
Withdraw 80 mL from a refrigerated (2 °C-8 °C) 250 mL bag of sodium chloride 9 mg/mL (0.9%) solution for injection. Discard the withdrawn 80 mL.
| For a Pepaxti dose of 40 mg | For a Pepaxti dose of 30 mg | For a Pepaxti dose of 20 mg | For a Pepaxti dose of 15 mg |
| Withdraw 80 mL of reconstituted solution from the Pepaxti vials and transfer into an intravenous (IV) solution for injection containing sodium chloride 9 mg/mL (0.9%) to obtain a final concentration of 0.16 mg/mL. | Withdraw 60 mL of reconstituted solution from the Pepaxti vials and transfer into an intravenous (IV) solution for injection containing sodium chloride 9 mg/mL (0.9%) to obtain a final concentration of 0.13 mg/mL. | Withdraw 40 mL of reconstituted solution from the Pepaxti vial and transfer into an intravenous (IV) solution for injection containing sodium chloride 9 mg/mL (0.9%) to obtain a final concentration of 0.10 mg/mL. | Withdraw 30 mL of reconstituted solution from the Pepaxti vial and transfer into an intravenous (IV) solution for injection containing sodium chloride 9 mg/mL (0.9%) to obtain a final concentration of 0.08 mg/mL. |
Discard any unused portion left in the vial(s).
Gently invert the bag to mix the solution. Do not shake. Check that the solution is clear and colourless to pale yellow. Do not use if solution discolouration or particles are observed.
Pepaxti degrades in solution, especially at room temperature, and the storage timelines for diluted solution should not be exceeded.
Infusion of the diluted solution must begin within 60 minutes of start of reconstitution (step 3).
If not used for immediate administration, the diluted solution should be placed in a refrigerator (2 °C-8 °C) within 30 minutes after initial reconstitution (step 3) and can be stored for up to 6 hours.
Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. Do not use if visibly opaque particles, discolouration or foreign particles are observed.
Administer Pepaxti as a 30-minute intravenous infusion via peripheral venous route or a central venous access device, for example PICC or tunnelled central venous catheter. If the infusion bag has been stored in a refrigerator, allow to reach to room temperature (20 °C-25 °C). Start infusion within 30 minutes of removing the diluted solution from the refrigerator.
Upon completion of Pepaxti infusion, flush the catheter with sodium chloride 9 mg/mL (0.9%) solution for injection.
Pepaxti is a cytotoxic medicinal product for single use only. The procedure for the safe handling and disposal of nitrogen mustard analogues must be followed by healthcare professionals or medical personnel and should comply with the current recommendations for cytotoxic medicinal products. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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