Pepaxti 20 mg powder for concentrate for solution for infusion – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Pepaxti 20 mg powder for concentrate for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of powder contains 20 mg melphalan flufenamide (as hydrochloride).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion (powder for concentrate).

Lyophilised white to off-white powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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).

4.2 Posology and method of administration

Treatment with Pepaxti must be initiated and supervised by physicians experienced in the treatment of multiple myeloma.

Posology

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.

Dose modification for adverse reactions

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

*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)

Recommended concomitant medicinal products

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).

Special populations

Elderly

No dose adjustment is recommended for elderly patients.

Renal impairment

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).

Hepatic impairment

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.

Paediatric population

The safety and efficacy of Pepaxti in children below 18 years of age have not been established. No data are available.

Method of administration

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.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

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.

4.5 Interaction with other medicinal products and other forms of interaction

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).

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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 3/4 thrombocytopenia was reported in 74% of patients treated with Pepaxti. 33% of patients experienced Grade 3/4 thrombocytopenia during the first treatment cycle. Median time to onset of Grade 3 or 4 thrombocytopenia was 43 days from first dose. Grade 3/4 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 3/4 thrombocytopenia were reported in 14% of patients.

Neutropenia

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

Grade 3/4 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 3/4 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: Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, nitrogen mustard analogues, ATC code: L01AA10

Mechanism of action

Melphalan flufenamide is a peptide conjugated alkylating drug. The drug is composed of a di-peptide and an alkylating moiety of the nitrogen mustard analogues group. The lipophilic intact peptide conjugate is rapidly distributed via passive transport into cells where it is bound to and catalysed by esterases and peptidases to the metabolite melphalan. Similar to other nitrogen mustard drugs, cross-linking of DNA is involved in the antitumor activity of melphalan flufenamide. In cellular assays, melphalan flufenamide inhibited proliferation and induced apoptosis of haematopoietic tumour cells. Retained cytotoxic activity was demonstrated in multiple myeloma cells with absent or impaired p53 functionality. Melphalan flufenamide showed synergistic cytotoxicity with dexamethasone in melphalan resistant and non-resistant multiple myeloma cell lines.

Pharmacodynamic effects

Cardiac electrophysiology

At the approved dose, melphalan flufenamide does not affect the ECG parameters PR interval, QRS interval, or QTc interval to any clinically relevant extent.

Clinical efficacy and safety

The efficacy and safety of melphalan flufenamide in combination with dexamethasone were evaluated in HORIZON, a multicentre, single-arm study in 157 patients with relapsed-refractory multiple myeloma (RRMM). A total of 157 patients received melphalan flufenamide 40 mg on Day 1 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Day 1, 8, 15 and 22 of each 28 day cycle. Patients were treated until disease progression or unacceptable toxicity. 110 of the patients had multiple myeloma that was refractory to at least one proteasome inhibitor, at least one immunomodulatory agent and an anti-CD38 monoclonal antibody, i.e. were triple-class refractory (TCR) and had received at least 3 prior lines of therapies. Primary refractory patients were excluded from the study.

The median duration of melphalan flufenamide treatment in the TCR patient population (n=110) was 3.0 months (range 1.0 to 28.0 months).

Out of the 110 ≥3^rd line TCR patients in the HORIZON study, 52 patients had no ASCT or progressed more than 36 months after an ASCT and 58 patients had progressed within 36 months from an ASCT. The disease characteristics and efficacy results in TCR patients who have received at least 3 prior lines of therapies and who had no ASCT or progressed more than 36 months after an ASCT are summarised in Table 4 and Table 5.

The major efficacy outcome measure was overall response rate (ORR) assessed according to the IMWG criteria by investigators.

Table 4: Disease characteristics in triple-class refractory patients who have received at least 3 prior lines of therapies and who had no ASCT or progressed more than 36 months after an ASCT in HORIZON study

Parameter

HORIZON study (n=52)

^a del(17p), t(4;14), t(14;16), gain (1q) and t(14;20)

Table 5: Efficacy results for triple-class refractory patients who have received at least 3 prior lines of therapies and who had no ASCT or progressed more than 36 months after an ASCT in HORIZON study

^a Includes sCR + CR + VGPR + PR.

Paediatric population

The Medicines and Healthcare products Regulatory Agency has waived the obligation to submit the results of studies with Pepaxti in all subsets of the paediatric population in the treatment of multiple myeloma (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following Pepaxti 40 mg, melphalan flufenamide peak plasma concentrations of an average 159 ng/mL (CV% 39) were reached during the 30-minute infusion. Peak plasma concentrations of the active metabolite melphalan were reached 4 to 15 minutes after the end of infusion of Pepaxti 40 mg. Following Pepaxti 40 mg, the mean (CV%) C_max was 432 ng/mL (30%) and AUC_0-INF was 873 ng/mL·hr (28%) for the metabolite melphalan after a single dose. The mean (CV%) C_max was 419 ng/mL (33%) and AUC_0-INF was 815 ng/mL·hr (29%) for the metabolite melphalan at steady-state. Comparison of PK parameters of the metabolite melphalan showed that the 90% CI for the adjusted geometric mean ratio for peripheral and central intravenous infusion was within 0.8 and 1.25 for C_max, AUC(0-t), and AUC(0-∞), which concludes bioequivalence for peripheral and central venous infusion of melphalan flufenamide.

Melphalan flufenamide and the metabolite melphalan AUC increases in an approximately dose proportional manner over the dose range 25 to 130 mg.

Distribution

In vivo the disappearance of melphalan flufenamide from plasma is rapid and is attributed to distribution to peripheral tissues.

The mean (CV%) volume of distribution was 35 L (71%) for melphalan flufenamide and the mean apparent volume of distribution is 76 L (32%) for the metabolite melphalan after a single dose of melphalan flufenamide.

Biotransformation

Melphalan flufenamide is metabolised in tissues into the metabolite desethyl-melphalan flufenamide and into the metabolite melphalan. There is no appreciable metabolism of melphalan flufenamide to the metabolite melphalan in plasma. Melphalan is metabolised primarily by spontaneous hydrolysis to monohydroxy-melphalan and dihydroxy-melphalan.

Elimination

After the end of infusion of Pepaxti 40 mg, the mean (CV%) elimination half-life of melphalan flufenamide is 2.1 minutes (34%). The mean (CV%) elimination half-life of the metabolite melphalan is 70 minutes (21%). The mean (CV%) clearance of melphalan flufenamide and the metabolite melphalan is 692 L/hr (49%) and 23 L/hr (23%), respectively, at the recommended dose of Pepaxti 40 mg.

Renal and hepatic excretion of unchanged melphalan flufenamide is assessed to be negligible as total plasma clearance of melphalan flufenamide greatly exceeds renal glomerular filtration rate (GFR) and hepatic blood flow.

Specific populations

Elderly patients (> 65 years old)

Based on population PK analysis, no differences in the pharmacokinetics of the metabolite melphalan were observed based on age or gender.

Renal impairment

The melphalan flufenamide metabolite melphalan is partially cleared through renal excretion. In melphalan flufenamide treated patients in study OP-103 72 patients had normal renal function, 112 patients had mild renal impairment and 43 patients had moderate renal impairment.

Based on population PK analysis melphalan AUC was on average 6% higher in mild impairment, 18% higher in patients with moderate renal impairment with eGFR 45-60 mL/min/1.73 m² and 32% higher in patients with moderate renal impairment with eGFR 30-45 mL/min/1.73 m² compared to patients with normal renal function. A larger effect of Pepaxti on thrombocyte levels was observed in patients with a lower eGFR. A Pepaxti 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.

Hepatic impairment

No differences in the PK of the metabolite melphalan were observed in patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST). The effect of moderate to severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST) on PK is not known.

Body weight

Higher exposures of the metabolite melphalan were observed in patients with lower body weight. At a body weight of 60 kg C_max was on average 36% higher and AUC on average 31% higher compared to a body weight of 95 kg. Higher incidence of thrombocytopenia and neutropenia was observed in patients with lower body weight. A Pepaxti dose of 30 mg is recommended in patients with a body weight of 60 kg or less.

5.3 Preclinical safety data

Carcinogenicity and mutagenicity

Pepaxti is genotoxic. Mechanistic in vitro studies showed that melphalan flufenamide caused irreversible DNA damage.

No carcinogenicity or mutagenicity studies have been conducted with melphalan flufenamide.

Reproductive toxicology

In repeated dose toxicology studies, melphalan flufenamide was administered intravenously to rats at 20, 40, or 55 mg/m², and to dogs at 0.45 or 0.90 mg/kg (9 or 18 mg/m²) every 21 days for two or three doses. Decreased testes weights and depletion of germ cells were observed in both species, and epididymal oligospermia was observed in dogs. Adverse effects on male reproductive organs were observed in dogs at exposures below the recommended clinical dose of 40 mg. The reversibility of adverse effects on male reproductive organs was not assessed.

Reproduction toxicity studies have not been conducted with melphalan flufenamide. The melphalan flufenamide metabolite melphalan was teratogenic in rats after single dose exposure. In repeated dose reproductive toxicity studies, melphalan exposure resulted in maternal toxicity and induced congenital malformations. In a study in mice, a reduction in number of pups per litter was observed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sucrose

6.2 Incompatibilities

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

6.3 Shelf life

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).

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal

Additional solvents required for preparation

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

Preparation steps

Read the complete instructions prior to starting preparation. Steps 3 to 5 must be completed within 30 minutes.

Reconstitution and dilution steps

Step 1

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.

Step 2

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.

Step 3

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.

Step 4

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.

Step 5

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.

Storage timelines

Pepaxti degrades in solution, especially at room temperature, and the storage timelines for diluted solution should not be exceeded.

For immediate administration

Infusion of the diluted solution must begin within 60 minutes of start of reconstitution (step 3).

For delayed administration

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.

Administration

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.

Administration steps

Step 6

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.

Step 7

Upon completion of Pepaxti infusion, flush the catheter with sodium chloride 9 mg/mL (0.9%) solution for injection.

Disposal

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.

7. MARKETING AUTHORISATION HOLDER

Oncopeptides AB (publ)

Luntmakargatan 46

111 37 Stockholm

Sweden

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 46117/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

11/11/2022

10 DATE OF REVISION OF THE TEXT

30/01/2025