PEPAXTI Powder for concentrate for solution for infusion Ref.[109368] Active ingredients: Melphalan

Melphalan flufenamide can cause local tissue damage. Should extravasation occur, it should not be administered by direct infusion into a peripheral vein (see section 4.2).

Thrombocytopenia

Pepaxti may cause thrombocytopenia. Thrombocytopenia (including platelet count decreased) was frequently reported in clinical studies (see section 4.8). As thrombocytopenia may increase the risk for serious bleeding events, patients should be advised to contact a physician if signs or symptoms of bleeding and bruising occur.

Platelet counts should be monitored at baseline, during treatment, and as clinically indicated. Patients should be monitored more frequently during the first two months of treatment. Pepaxti should not be administered if the platelet count is less than 50 × 109 /L. Treatment should be withheld until platelet count is 50 × 109 /L or greater (without recent transfusions) and resume treatment at one dose level lower. The dose and/or dose schedule should be adjusted based on signs and symptoms of bleeding (see section 4.2). Treating thrombocytopenia with transfusions and/or other treatments should be considered as clinically indicated.

Neutropenia

Pepaxti may cause neutropenia. Neutropenia (including neutrophil count decreased) was frequently reported in clinical studies (see section 4.8). As neutropenia may increase the risk for infections, patients should be advised to contact a physician if signs or symptoms of infection occur.

Neutrophil count should be monitored at baseline, during treatment, and as clinically indicated. Patients should be monitored more frequently during the first two months of treatment. Pepaxti should not be administered if absolute neutrophil count is less than 1 × 109 /L. Treatment should be withheld until absolute neutrophil count is 1 × 109 /L or greater and resume treatment at one dose level lower. The dose and/or dose schedule should be adjusted based on signs and symptoms of infection (see section 4.2). Treating neutropenic patients with haematopoietic growth factors and/or prophylactic antimicrobials should be considered as clinically indicated (see section 4.2).

Anaemia

Anaemia was frequently reported in clinical studies (see section 4.8). Red blood cell counts should be monitored at baseline, during treatment, and as clinically indicated. Patients should be monitored more frequently during the first two months of treatment. Treating anaemia with transfusions and/or erythropoietin should be considered as clinically indicated.

Infections

Pepaxti may cause infections, including Grade ≥ 3 infections such as pneumonia and upper respiratory tract infection (see section 4.8). Patients should be closely monitored for signs of infection. Treating infections with antimicrobials should be considered as clinically indicated.

Gastrointestinal events

Nausea and diarrhoea are very common and vomiting is common during treatment with Pepaxti (see section 4.8). Prophylaxis with anti-emetic agents should be considered prior to and during infusion with melphalan flufenamide (see section 4.2).

Thromboembolic events

Venous thromboembolic events have been observed in patients receiving Pepaxti in combination with dexamethasone (see section 4.8). Patients with known risk factors for thromboembolism, including prior thrombosis, should be closely monitored. A decision to take prophylactic measures should be made after a careful assessment of the individual patient’s underlying risk factors, including the occurrence of thrombocytopenia. In high-risk patients, anti-thrombotic prophylaxis can be considered.

Mutagenicity

Melphalan, a metabolite of melphalan flufenamide, is mutagenic in animals and chromosome aberrations have been observed in patients being treated with melphalan.

Carcinogenicity

Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS)

AML and MDS have occurred in patients with multiple myeloma who have received Pepaxti (see section 4.8). The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan flufenamide. Patients should be monitored closely before and during treatment for occurrence of AML and MDS.

Second primary malignancies (SPM)

The use of alkylating agents has been linked to the development of a SPM and SPMs have been reported also after use of Pepaxti, see section 4.8. When the melphalan flufenamide metabolite melphalan is used in combination with lenalidomide and prednisone, and to a lesser extent in combination with thalidomide and prednisone, it has been linked to an increased risk of solid SPMs for elderly patients with newly diagnosed multiple myeloma. Melphalan flufenamide is not indicated in combination with lenalidomide or thalidomide. Patients should be monitored closely before and during treatment for occurrence of SPM.

Prior autologous stem cell transplant

Pepaxti is not recommended in patients who have progressed within 36 months after an ASCT (see section 4.1). This is based on results from study OP-103 (OCEAN), a randomised phase 3 trial in patients with relapsed or refratory multiple myeloma following 2 to 4 lines of prior therapy and refractory to lenalidomide and the last line of therapy. Post-hoc analyses showed that patients on melphalan flufenamide/dexamethasone who had progressed less than 36 months after an ASCT had a lower survival compared to the pomalidomide/dexamethasone comparator arm, with a median OS of 15.7 months (95% CI: 11.9, 20.5, n=101) compared to 28.7 months (95% CI: 20.2, 34.1; n=101), respectively. For patients who had no prior ASCT or progressed more than 36 months after an ASCT, median OS was 23.6 months (95% CI: 18.9, 28.0; n=145) on melphalan flufenamide/dexamethasone vs. 19.8 months (95% CI: 12.6, 26.5; n=148) in the pomalidomide/dexamethasone arm.

Myeloablative conditioning treatment

The efficacy and safety of Pepaxti at doses required for myeloablation have not been studied in humans. Pepaxti should not be used for conditioning treatment prior to stem cell transplantation.

Renal impairment

Since patients with renal impairment may have marked bone marrow suppression, these patients should be closely monitored. There are insufficient data in patients with eGFR below 30 mL/min/1.73 m² to support a dose recommendation (see section 4.2).

Attenuated live vaccines

A risk of severe illness that may lead to fatal outcome has been described with the metabolite melphalan in patients receiving attenuated live vaccines. This risk is increased in patients who are already immunosuppressed by their underlying disease. An inactivated or mRNA based vaccine should be used when such a vaccine exists.

No interaction studies have been performed with melphalan flufenamide. Based on available in vitro and clinical data, there is a low risk of pharmacokinetic or pharmacodynamic drug interactions for melphalan flufenamide (see section 5.2).

Women of childbearing potential/Contraception in males and females As with all cytotoxic treatments, male and female patients who use melphalan flufenamide should use effective and reliable contraceptive methods until six months after cessation of treatment.

Pregnancy

There are no data from the use of melphalan flufenamide in pregnant women. Studies in animals with the melphalan flufenamide metabolite melphalan have shown reproductive toxicity (see section 5.3). Due to the genotoxic properties and structural similarity of melphalan flufenamide with known teratogenic compounds, it is possible that melphalan flufenamide can induce congenital malformations in offspring of treated patients. Melphalan flufenamide should not be used during pregnancy unless the clinical condition of the woman requires treatment with melphalan flufenamide.

Breast-feeding

It is unknown whether melphalan flufenamide or its metabolites are excreted in human milk. Due to its genotoxic properties, melphalan flufenamide is contraindicated during breast-feeding (see section 4.3).

Fertility

Melphalan flufenamide, as other agents with alkylating properties, is expected to suppress ovary function in premenopausal women, resulting in amenorrhea in a large number of patients. Studies in animals have shown melphalan flufenamide can have adverse effects on spermatogenesis (see section 5.3). Therefore it is possible that melphalan flufenamide may cause temporary or permanent adverse effects on male fertility.Cryopreservation of semen before treatment is advised.

Pepaxti has moderate influence on the ability to drive and use machines. It is possible that certain adverse reactions of melphalan flufenamide, such as dizziness and nausea, may affect this ability.

Summary of the safety profile

The safety of Pepaxti in combination with dexamethasone has been evaluated in 491 patients with multiple myeloma, including 147 patients with triple-class refractory disease who have received at least three prior lines of therapies. The most frequent adverse reactions are thrombocytopenia (83%), neutropenia (72%), anaemia (66%), nausea (21%), diarrhoea (19%) and pyrexia (19%). The most frequent serious adverse reactions are pneumonia (11%), thrombocytopenia (5%) and respiratory tract infection (4%).

Tabulated list of adverse reactions

Table 3 summarises adverse reactions that were reported in patients receiving Pepaxti. The data reflect exposure of Pepaxti in 13 patients as single agent and in 478 patients in combination with dexamethasone. Adverse reactions are described using MedDRA terms. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3. Adverse reactions reported in patients with multiple myeloma treated with Pepaxti in clinical studies:

¹ Sepsis includes the events sepsis, escherichia sepsis, bacterial sepsis, and urosepsis
² Pneumonia includes the events pneumonia, pneumocystis jirovecii pneumonia, COVID-19 pneumonia, Pneumonia influenzal, and pneumonia viral
³ Respiratory tract infection includes the events respiratory tract infection, respiratory tract infection viral, upper respiratory tract infection, viral upper respiratory tract infection, bronchitis, bronchitis viral, and lower respiratory tract infection
⁴ Thrombocytopenia includes the events thrombocytopenia and platelet count decreased
⁵ Neutropenia includes the events neutropenia and neutrophil count decreased

Description of selected adverse reactions

Thrombocytopenia

Thrombocytopenia was reported in 83% of patients, Grade ¾ thrombocytopenia was reported in 74% of patients treated with Pepaxti. 33% of patients experienced Grade ¾ thrombocytopenia during the first treatment cycle. Median time to onset of Grade 3 or 4 thrombocytopenia was 43 days from first dose. Grade ¾ thrombocytopenia resulted in dose delay, dose reduction and dose discontinuation of Pepaxti in 41%, 23% and 12%, respectively.

Bleeding

Any Grade bleeding was reported in 21% of patients. Grade 3 bleeding was reported in 2% and Grade 4 bleeding was reported in <1% of patients. The most commonly reported bleedings were epistaxis, affecting 6% of patients, and unspecified haematoma, affecting 2% of patients. Bleedings starting in cycle concomitant with Grade ¾ thrombocytopenia were reported in 14% of patients.

Neutropenia

Neutropenia was reported in 72% of patients, Grade ¾ neutropenia was reported in 66% of patients treated with Pepaxti. 38% of patients experienced Grade ¾ neutropenia during the first treatment cycle. Median time to onset of Grade 3 or 4 neutropenia was 22 days from first dose.

Grade ¾ neutropenia resulted in dose delay, dose reduction and dose discontinuation of Pepaxti in 26%, 9% and 4%, respectively.

Infections occurred in cycle concomitant with Grade ¾ neutropenia in 21% of patients. Clinically significant infections (Grade 3 or higher) were reported in 8% of patients with concomitant Grade 3-4 neutropenia. Febrile neutropenia was reported in 4% of patients.

Infections

All patients in the target population are at risk of infections due to their immunodeficient status. Myelosuppression and immunosuppressive effects induced by melphalan flufenamide may facilitate the development of infections which may have fatal outcome in the most severe manifestations. Adoption of prophylactic measures such as the administration of antimicrobials can be useful (see section 4.2).

In patients receiving Pepaxti, 52% of patients experienced any type of infection. Pneumonia and other respiratory tract infection are the most common types of infections.

Anaemia

Anaemia was reported in 66% of patients, and Grade 3 anaemia was reported in 41% of patients and Grade 4 anaemia was reported in 1% of patients treated with Pepaxti.

Second primary malignancies

Alkylating agents have been associated with development of MDS, AML and other second primary malignancies. Development of MDS and AML in patients receiving Pepaxti in clinical studies was uncommon. Also a low number of other second primary malignancies have been reported, the most common being basal cell carcinoma and squamous cell carcinoma.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.