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Melphalan flufenamide (United States: Withdrawn from market): Drug information

Melphalan flufenamide (United States: Withdrawn from market): Drug information
(For additional information see "Melphalan flufenamide (United States: Withdrawn from market): Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Pepaxto
Pharmacologic Category
  • Antineoplastic Agent, Alkylating Agent;
  • Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)
Dosing: Adult

Note: Antiemetic prophylaxis was recommended in the clinical study (Richardson 2021); consider a 5-HT3 antagonist or other antiemetic. Consider antimicrobial prophylaxis as clinically appropriate. Melphalan flufenamide (Pepaxto) is a prodrug of melphalan; do not substitute for or with melphalan hydrochloride products. Use caution when selecting product for preparation.

Multiple myeloma

Multiple myeloma (relapsed or refractory): IV: 40 mg on day 1 every 28 days (in combination with dexamethasone) until disease progression or unacceptable toxicity (Richardson 2021).

Note: A confirmatory phase 3 randomized trial in patients with relapsed or refractory multiple myeloma comparing melphalan flufenamide plus dexamethasone to pomalidomide plus dexamethasone demonstrated inferior overall survival outcomes in the melphalan flufenamide arm. Due to the trial results, the manufacturer is withdrawing melphalan flufenamide from the market.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Kidney function estimated using the Cockcroft-Gault equation.

CrCl ≥45 mL/minute: No dosage adjustment necessary.

CrCl 15 to 44 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, there are no clinically meaningful differences in melphalan pharmacokinetics based on mild hepatic impairment.

Moderate to severe impairment (total bilirubin >1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity: Adult
Melphalan Flufenamide Recommended Dose Reduction Levels

Dose level

Dose

Usual (initial) dose

40 mg on day 1 every 28 days.

First dose reduction

30 mg on day 1 every 28 days.

Second dose reduction

20 mg on day 1 every 28 days.

Subsequent dose reduction

Permanently discontinue if unable to tolerate the 20 mg dose.

Melphalan Flufenamide Recommended Dose Modifications

Adverse reaction

Severity

Dosage modification

Hematologic toxicity

Platelets <50,000/mm3 on day 1 of cycle

Withhold melphalan flufenamide and monitor platelets weekly until ≥50,000/mm3. If treatment delay is ≤2 weeks, resume melphalan flufenamide at the same dose. If treatment delay is >2 weeks, resume melphalan flufenamide with the dose reduced 1 dose level.

ANC <1,000/mm3 on day 1 of cycle

Withhold melphalan flufenamide and monitor neutrophils weekly until ≥1,000/mm3. If treatment delay is ≤2 weeks, resume melphalan flufenamide at the same dose. If treatment delay is >2 weeks, resume melphalan flufenamide with the dose reduced 1 dose level. Consider WBC growth factor as clinically appropriate.

Anemia

Manage anemia (per current guidelines) as clinically indicated. May require treatment interruption and/or dose reduction.

Grade 4 hematologic toxicity on day 1 of cycle in 2 consecutive cycles

Upon recovery, resume melphalan flufenamide with the dose reduced 1 dose level.

Nonhematologic adverse reaction

Grade 2

Consider withholding melphalan flufenamide until resolved to at least grade 1 or baseline. Consider resuming melphalan flufenamide with the dose reduced 1 dose level.

Grade 3 or 4

Withhold melphalan flufenamide until resolved to at least grade 1 or baseline. Resume melphalan flufenamide with the dose reduced 1 dose level as clinically appropriate.

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported are in combination with dexamethasone.

>10%:

Cardiovascular: Peripheral edema (14%)

Endocrine & metabolic: Hypokalemia (14%)

Gastrointestinal: Constipation (15%), decreased appetite (14%), diarrhea (27%), nausea (32%), vomiting (13%)

Hematologic & oncologic: Anemia (84%; grade 3: 50%), hemorrhage (28%; grade 3: 3%; grade 4: <1%; grades 3/4: 4%), leukopenia (99%; grades 3/4: 88%), lymphocytopenia (97%; grades 3/4: 95%), neutropenia (95%; grade 3: 41%; grade 4: 40%), thrombocytopenia (99%; grade 3: 26%; grade 4: 54%)

Infection: Infection (58%)

Nervous system: Dizziness (11%), fatigue (55%), headache (13%), insomnia (11%)

Neuromuscular & skeletal: Back pain (12%), limb pain (13%), ostealgia (13%)

Renal: Increased serum creatinine (68%)

Respiratory: Cough (17%), dyspnea (11%), pneumonia (13%), respiratory tract infection (24%)

Miscellaneous: Fever (24%)

1% to 10%:

Endocrine & metabolic: Hypocalcemia (10%)

Hematologic & oncologic: Febrile neutropenia (6%)

Hypersensitivity: Hypersensitivity reaction (7%)

Infection: Sepsis (4%)

Neuromuscular & skeletal: Arthralgia (10%)

Respiratory: Dyspnea on exertion (10%)

Frequency not defined:

Hematologic & oncologic: Second primary malignant neoplasm (acute leukemia, myelodysplastic syndrome)

Respiratory: Respiratory failure

Contraindications

History of serious hypersensitivity to melphalan flufenamide, melphalan, or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Thrombocytopenia commonly occurred with melphalan flufenamide (in combination with dexamethasone), including grades 3 and 4 thrombocytopenia. The median time to initial onset of grade 3 or 4 thrombocytopenia was 15 days (from the first dose). Thrombocytopenia may lead to hemorrhage; hemorrhage of any grade was reported in over one-fourth of patients, with grade 3 and 4 hemorrhage occurring in a small percentage of patients. Neutropenia also commonly occurred with melphalan flufenamide (in combination with dexamethasone), including grades 3 and 4 events and neutropenic fever. The median time to initial onset of grade 3 or 4 neutropenia was 15 days (from the first dose). Neutropenia may lead to infection. Anemia may also occur; grade 3 anemia was reported.

• Infection: Infection (of any grade) occurred in over half of patients who received melphalan flufenamide (in combination with dexamethasone); grade 3 and 4 infections have been reported, and fatal infection occurred rarely. Reported infections included respiratory tract infection, pneumonia, and sepsis.

• Secondary malignancy: Secondary malignancies (myelodysplastic syndromes or acute leukemia) have occurred in patients with multiple myeloma who have received melphalan flufenamide.

Other warnings/precautions:

• Appropriate use: There is limited clinical experience with higher than recommended doses of melphalan flufenamide (animal safety studies at doses exceeding the myeloma dose were associated with mortality). The safety and efficacy of melphalan flufenamide have not been established for use as a conditioning regimen in patients receiving transplant.

• Medication safety: Melphalan is available as different salt forms and different IV formulations. Melphalan flufenamide (Pepaxto) is a prodrug of melphalan. Evomela, Alkeran, and generics are melphalan hydrochloride. Indications for use, product preparation, storage, and dosing differ between salt forms and formulations. Do not substitute melphalan flufenamide for melphalan hydrochloride (or vice versa).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous, as hydrochloride [preservative free]:

Pepaxto: 20 mg (1 ea)

Generic Equivalent Available: US

No

Pricing: US

Solution (reconstituted) (Pepaxto Intravenous)

20 mg (per each): $11,400.00

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Prescribing and Access Restrictions

For patients receiving melphalan flufenamide prior to the market withdrawal, continued access is available for a limited time through the Oncopeptides Patient Assistance Program. Information is available at 1-844-300-6626.

Administration: Adult

IV: Infuse over 30 minutes via a central line (eg, mediport, PICC line, tunneled venous catheter). If administering immediately, infusion must begin within 60 minutes of initiation of reconstitution. If infusion bag was stored in refrigerator, allow to reach room temperature prior to infusion (infusion must begin within 30 minutes of removal from refrigerator). Flush central line/catheter following infusion.

Antiemetic prophylaxis was recommended in the clinical study (Richardson 2021); consider a 5-HT3 antagonist or other antiemetic.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Use: Labeled Indications

Multiple myeloma (relapsed or refractory): Treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone) in adults who have received at least 4 prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.

Limitations of use: Melphalan flufenamide is not indicated and is not recommended for use as a conditioning regimen for transplant outside of controlled clinical trials.

Note: A confirmatory phase 3 randomized trial in patients with relapsed or refractory multiple myeloma comparing melphalan flufenamide plus dexamethasone to pomalidomide plus dexamethasone demonstrated inferior overall survival outcomes in the melphalan flufenamide arm. Due to the trial results, the manufacturer is withdrawing melphalan flufenamide from the market.

Medication Safety Issues
Sound-alike/look-alike issues:

Melphalan flufenamide may be confused with melphalan hydrochloride.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Other safety concerns:

Different formulation issues: Melphalan is available as different salt forms and different IV formulations. Melphalan flufenamide (Pepaxto) is a prodrug of melphalan. Evomela, Alkeran, and generics are melphalan hydrochloride. Indications for use, product preparation, storage, and dosing differ between salt forms and formulations. Do not substitute melphalan flufenamide for melphalan hydrochloride.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Antithymocyte Globulin (Equine): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of cytotoxic chemotherapy is reduced. Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy

Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Carmustine: Melphalan Flufenamide may enhance the adverse/toxic effect of Carmustine. Specifically, melphalan flufenamide may sensitize patients to carmustine lung toxicity. Risk C: Monitor therapy

Chikungunya Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy

CycloSPORINE (Systemic): Melphalan Flufenamide may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk C: Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Nadofaragene Firadenovec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination

Nalidixic Acid: May enhance the adverse/toxic effect of Melphalan Flufenamide. Necrotic enterocolitis has been reported in pediatric patients. Risk C: Monitor therapy

Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification

Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification

Ritlecitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy

Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Ublituximab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy

Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Reproductive Considerations

Verify pregnancy status prior to treatment initiation. Patients who may become pregnant should use effective contraception during therapy and for 6 months after the last melphalan flufenamide dose. Patients with partners who may become pregnant should also use effective contraception during therapy and for 3 months after the last dose of melphalan flufenamide.

Melphalan flufenamide may impair fertility. May cause amenorrhea resulting in infertility in premenopausal patients. Testicular suppression has been reported in patients receiving other alkylating agents.

Pregnancy Considerations

Animal reproduction studies have not been conducted with melphalan flufenamide. Based on the mechanism of action, in utero exposure to melphalan flufenamide may cause fetal harm.

Breastfeeding Considerations

It is not known if melphalan flufenamide is present in breast milk.

Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during therapy or for 1 week after the last melphalan flufenamide dose.

Monitoring Parameters

Monitor CBC with differential at baseline, during treatment (more frequently during the first 2 months of therapy), and as clinically indicated; for platelets <50,000/mm3 or ANC <1,000/mm3, monitor platelets or ANC weekly until recovery. Evaluate pregnancy status prior to use (in patients who may become pregnant). Monitor for signs/symptoms of bleeding, infection, or hypersensitivity. Monitor (life-long) for development of secondary malignancies.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

Melphalan flufenamide is a peptide-drug conjugate that is highly lipophilic and is therefore rapidly and passively distributed into cells and then enzymatically hydrolyzed to the alkylating agent melphalan (Richardson 2021). Melphalan flufenamide's antitumor activity involves crosslinking of DNA; it inhibits proliferation and induces apoptosis of hematopoietic and solid tumor cells and (with dexamethasone) has demonstrated synergistic cytotoxicity in multiple myeloma cell lines, including melphalan-resistant and nonresistant cell lines.

Pharmacokinetics (Adult Data Unless Noted)

Distribution: Vd: Melphalan flufenamide: 35 L; Melphalan (active metabolite): 75 L. Melphalan flufenamide is rapidly distributed into peripheral tissues (with no late redistribution back to plasma).

Metabolism: Metabolized in tissues to desethyl-melphalan flufenamide and melphalan; melphalan is primarily metabolized via spontaneous hydrolysis to monohydroxy-melphalan and dihydroxy-melphalan.

Half-life elimination: Melphalan flufenamide: 2.1 minutes; Melphalan (active metabolite): 70 minutes.

Time to peak: Melphalan flufenamide: Peak concentrations were reached during the 30-minute infusion; Melphalan (active metabolite): 4 to 15 minutes after the end of infusion.

Excretion: Clearance (based on a 40 mg dose): Melphalan flufenamide: 692 L/hour; Melphalan (active metabolite): 23 L/hour.

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Body weight: Higher melphalan exposures were observed in patients with lower BSA.

  1. <800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). United States Pharmacopeia Convention; 2020:74-92.
  2. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
  3. National Institute for Occupational Safety and Health (NIOSH) notice. Centers for Disease Control and Prevention website. https://www.cdc.gov/niosh/docs/2016-161/default.html. Updated May 28, 2021. Accessed June 1, 2021.
  4. Pepaxto (melphalan flufenamide) [prescribing information]. Waltham, MA: Oncopeptides Inc; February 2021.
  5. Pepaxto (melphalan flufenamide): A guide to preparation, administration, and adverse drug reaction management. https://pepaxtohcp.com/docs/PEPAXTO_Prep_Admin_Guide_0221.pdf. Published February 21, 2021. Accessed June 3, 2021.
  6. Richardson PG, Oriol A, Larocca A, et al; HORIZON (OP-106) Investigators. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. 2021;39(7):757-767. doi:10.1200/JCO.20.02259 [PubMed 33296242]
  7. US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. https://www.cdc.gov/niosh/docs/2016-161/default.html. Updated September 2016. Accessed June 1, 2021.
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