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Melphalan

Pronunciation

(MEL fa lan)

Index Terms

  • L-PAM
  • L-Phenylalanine Mustard
  • L-Sarcolysin
  • Melphalan HCl
  • Melphalan Hydrochloride
  • Phenylalanine Mustard

Dosage Forms

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

Solution Reconstituted, Intravenous:

Alkeran: 50 mg (1 ea) [contains alcohol, usp, propylene glycol]

Evomela: 50 mg (1 ea)

Generic: 50 mg (1 ea)

Tablet, Oral:

Alkeran: 2 mg

Brand Names: U.S.

  • Alkeran
  • Evomela

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)

Pharmacology

Alkylating agent which is a derivative of mechlorethamine that inhibits DNA and RNA synthesis via formation of carbonium ions; cross-links strands of DNA; acts on both resting and rapidly dividing tumor cells.

Absorption

Oral: Variable and incomplete

Distribution

Vd: 0.5 L/kg; Evomela: Penetrates CSF; Alkeran: Low penetration into CSF

Metabolism

Hepatic; chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan

Excretion

Oral: Feces (20% to 50%); urine (~10% as unchanged drug)

Time to Peak

Serum: Oral: ~1 to 2 hours

Half-Life Elimination

Terminal: IV: ~75 minutes; Oral: 1.5 ± 0.83 hours

Protein Binding

~50% to 92%; primarily to albumin (~40% to 60%), ~20% to alpha1-acid glycoprotein

Special Populations: Renal Function Impairment

A decrease in estimated creatinine clearance from 100 mL/minute to 30 mL/minute results in 28.2% reduction in clearance for a person with an ideal body weight (IBW) of 70 kg receiving IV melphalan.

Special Populations Note

Body weight: A patient with an IBW of 45 kg receiving IV melphalan has a 28% decrease in clearance relative to a patient with IBW of 70 kg, while a patient with an IBW of 100 kg has a 31% increase in clearance as compared to a patient with an IBW of 70 kg.

Use: Labeled Indications

Multiple myeloma: Palliative treatment of multiple myeloma (injection [Alkeran and Evomela] and tablets); high-dose conditioning treatment prior to hematopoietic stem cell transplantation (HSCT) (Evomela only).

Ovarian cancer: Palliative treatment of nonresectable epithelial ovarian carcinoma (tablets)

Contraindications

Hypersensitivity to melphalan or any component of the formulation; patients whose disease was resistant to prior melphalan therapy (Alkeran only).

Dosing: Adult

Note: Intravenous melphalan is available in different formulations. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations. Melphalan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting. Adjust dose based on patient response and weekly blood counts.

Multiple myeloma (conditioning regimen prior to hematopoietic stem cell transplantation): IV (Evomela only): 100 mg/m2 daily for 2 days on day -3 and day -2 prior to autologous stem cell transplantation on day 0 (Hari 2015). Note: Per the manufacturer, if patients weigh more than 130% of their ideal body weight, body surface area should be calculated using adjusted ideal body weight.

Multiple myeloma conditioning regimen for autologous hematopoietic stem cell transplantation (off-label doses): IV:

200 mg/m2 alone 2 days prior to transplantation (Fermand 2005; Moreau 2002) or

140 mg/m2 2 days prior to transplantation (combined with busulfan) (Fermand 2005) or

140 mg/m2 2 days prior to transplantation (combined with total body irradiation [TBI]) (Moreau 2002) or

140 mg/m2 5 days prior to transplantation (combined with TBI) (Barlogie 2006)

Multiple myeloma (palliative treatment): Note: Response is gradual; may require repeated courses to realize benefit:

Oral: Usual dose (as described in the manufacturer’s labeling):

6 mg once daily for 2 to 3 weeks initially, followed by up to 4 weeks rest, then a maintenance dose of 2 mg daily as hematologic recovery begins or

10 mg daily for 7 to 10 days; institute 2 mg daily maintenance dose after WBC >4,000 cells/mm3 and platelets >100,000 cells/mm3 (~4 to 8 weeks); titrate maintenance dose to hematologic response or

0.15 mg/kg/day for 7 days, with a 2 to 6 week rest, followed by a maintenance dose of ≤0.05 mg/kg/day as hematologic recovery begins or

0.25 mg/kg/day for 4 days (or 0.2 mg/kg/day for 5 days); repeat at 4- to 6-week intervals as ANC and platelet counts return to normal

Other dosing regimens in combination therapy (off-label doses):

4 mg/m2/day for 7 days every 4 weeks (in combination with prednisone or with prednisone and thalidomide) (Palumbo 2006; Palumbo 2008) or

6 mg/m2/day for 7 days every 4 weeks (in combination with prednisone) (Palumbo 2004) or

0.25 mg/kg/day for 4 days every 6 weeks (in combination with prednisone [Facon 2006; Facon 2007] or with prednisone and thalidomide [Facon 2007]) or

9 mg/m2/day for 4 days every 6 weeks (in combination with prednisone or with prednisone and bortezomib) (Dimopoulos 2009; San Miguel 2008)

IV (Alkeran and Evomela): 16 mg/m2 administered at 2-week intervals for 4 doses, then administer at 4-week intervals after adequate hematologic recovery.

Ovarian cancer: Oral: 0.2 mg/kg/day for 5 days, repeat every 4 to 5 weeks or

Off-label dosing: 7 mg/m2/day in 2 divided doses for 5 days, repeat every 28 days (Wadler 1996)

Amyloidosis, light chain (off-label use): Oral: 0.22 mg/kg/day for 4 days every 28 days (in combination with oral dexamethasone) (Palladini 2004) or 10 mg/m2/day for 4 days every month (in combination with oral dexamethasone) for 12 to 18 treatment cycles (Jaccard 2007)

Hodgkin lymphoma, relapsed/refractory (off-label use): IV: 30 mg/m2 over 15 minutes on day 6 (in combination with carmustine, etoposide, and cytarabine [mini-BEAM regimen]); repeat cycle every 4 to 6 weeks (Colwill 1995; Martin 2001)

Dosing: Geriatric

Refer to adult dosing. Use caution and begin at the lower end of dosing range.

Dosing: Pediatric

Note: Intravenous melphalan is available in different formulations. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations. Melphalan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011).

Conditioning regimen for autologous hematopoietic stem cell transplantation (off-label use): IV:

140 mg/m2 2 days prior to transplantation (combined with busulfan) (Canete 2009) or

180 mg/m2 (with pre- and posthydration) 12 to 30 hours prior to transplantation (Pritchard 2005) or

45 mg/m2/day for 4 days starting 8 days prior to transplantation (combined with busulfan or etoposide and carboplatin) (Berthold 2005)

Dosing: Renal Impairment

The manufacturer's labeling contains the following adjustment recommendations (for approved dosing levels) based on route of administration:

Oral: Moderate to severe renal impairment: Consider a reduced dose initially.

IV:

Conditioning regimen for multiple myeloma: No dosage adjustment is necessary.

Palliative treatment of multiple myeloma: BUN ≥30 mg/dL: Reduce dose by up to 50%.

Hemodialysis: Melphalan is not removed (to any significant degree) by hemodialysis.

The following adjustments have also been recommended:

Aronoff 2007: Adults: Oral (based on a 6 mg once-daily dose):

CrCl 10 to 50 mL/minute: Reduce dose to 75% of normal dose.

CrCl <10 mL/minute: Reduce dose to 50% of normal dose.

Hemodialysis: Administer dose after hemodialysis.

Continuous ambulatory peritoneal dialysis (CAPD): Reduce dose to 50% of normal dose.

Continuous renal replacement therapy (CRRT): Reduce dose to 75% of normal dose.

Carlson 2005: Oral (for melphalan-prednisone combination therapy; based on a study evaluating toxicity with melphalan dosed at 0.25 mg/kg/day for 4 days/cycle):

CrCl >10 to <30 mL/minute: Reduce dose to 75% of normal dose

CrCl ≤10 mL/minute: Data is insufficient for a recommendation

Kintzel 1995:

Oral: Adjust dose in the presence of hematologic toxicity

IV:

CrCl 46 to 60 mL/minute: Reduce dose to 85% of normal dose.

CrCl 31 to 45 mL/minute: Reduce dose to 75% of normal dose.

CrCl <30 mL/minute: Reduce dose to 70% of normal dose.

Badros 2001: IV: Autologous stem cell transplant (single-agent conditioning regimen; no busulfan or irradiation): Serum creatinine >2 mg/dL: Reduce dose from 200 mg/m2 over 2 days (as 100 mg/m2/day for 2 days) to 140 mg/m2 given as a single-dose infusion

International Myeloma Working Group (IMWG) Recommendations (Dimopoulos 2016):

The IMWG recommends the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine.

Oral:

CrCl >60 mL/minute: Usual dose: 0.15 to 0.25 mg/kg/day for 4 to 7 days

CrCl 15 to 59 mL/minute: Reduce dose to 75% of usual dose

CrCl <15 mL/minute: Reduce dose to 50% of usual dose

Hemodialysis: Reduce dose to 50% of usual dose

IV (high-dose melphalan for autologous stem cell transplant conditioning regimen):

CrCl >60 mL/minute: Usual dose: 200 mg/m2 per treatment course

CrCl <15 to 59 mL/minute: Reduce dose to 140 mg/m2 per treatment course; 100 mg/m2 (per treatment course) may be appropriate in some patients

Hemodialysis: Reduce dose to 100 to 140 mg/m2 per treatment course

Dosing: Hepatic Impairment

Melphalan is hepatically metabolized; however, dosage adjustment does not appear to be necessary (King, 2001).

Dosing: Adjustment for Toxicity

Oral:

WBC <3000/mm3: Withhold treatment until recovery

Platelets <100,000/mm3: Withhold treatment until recovery

IV: Palliative treatment of multiple myeloma: Adjust dose based on blood cell count at the nadir and day of treatment

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note: Excludes HSCT dosing): Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area in melphalan dosing for hematopoietic stem cell transplant conditioning regimens in adults (Bubalo 2014). Note: The manufacturer of Evomela recommends that if patients weigh more than 130% of their ideal body weight, body surface area should be calculated using adjusted ideal body weight.

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Note: Intravenous melphalan is available in different formulations. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations.

Alkeran injection: Stability is limited; must be prepared fresh. The time between reconstitution/dilution and administration of parenteral melphalan (Alkeran) must be kept to a minimum (manufacturer recommends <60 minutes) because reconstituted and diluted solutions are unstable. Dissolve powder initially with 10 mL of supplied diluent to a concentration of 5 mg/mL; shake immediately and vigorously to dissolve. Immediately dilute dose in NS to a concentration of ≤0.45 mg/mL (manufacturer recommended concentration). Do not refrigerate solution; precipitation occurs if stored at 5°C. The manufacturer recommends administration within 60 minutes of reconstitution.

Evomela injection: Reconstitute each vial with 8.6 mL of NS to a 5 mg/mL concentration. The NS should appear to be “pulled” into the vial by negative pressure due to a partial vacuum present in the vial. If no vacuum is present, discard the vial. Further dilute the appropriate dose in NS to a concentration of 0.45 mg/mL.

Administration

Melphalan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011).

Intravenous melphalan is available in different formulations. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations.

Oral: Administer on an empty stomach (Schmidt 2002)

IV:

Alkeran: Due to limited stability, complete administration of IV dose should occur within 60 minutes of reconstitution. Infuse over 15 to 20 minutes.

Evomela: Infuse over 15 to 20 minutes (palliative treatment for multiple myeloma) or 30 minutes (conditioning regimen for autologous stem cell transplantation).

Melphalan (IV) is an irritant; local reactions may occur (Perez Fidalgo 2012). Extravasation may cause local tissue damage; administration by slow injection into a fast running IV solution into an injection port or via a central line is recommended; do not administer by direct injection into a peripheral vein.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). NIOSH recommends single-gloving for administration of an intact tablet (NIOSH 2014).

Compatibility

Incompatible with D5W, LR.

Y-site administration: Incompatible with amphotericin B, chlorpromazine.

Storage

Alkeran injection: Store intact vials at 15°C to 30°C (59°F to 86°F). Protect from light. The manufacturer recommends administration be completed within 60 minutes of reconstitution; immediately dilute dose in NS. Do not refrigerate reconstituted solution; precipitation occurs.

Evomela injection: Store intact vials at 25°C (77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). Protect from light (store in original container). The reconstituted solution is stable for 1 hour at room temperature or for 24 hours at 5°C (41°F). Solutions diluted in NS for infusion are stable for 4 hours at room temperature (in addition to the 1 hour at room temperature following reconstitution).

Tablet: Store at 2°C to 8°C (36°F to 46°F). Protect from light.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

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

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

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

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

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

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

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

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

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

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

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. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Test Interactions

False-positive Coombs' test [direct]

Adverse Reactions

>10%:

Gastrointestinal: Nausea and vomiting, diarrhea, oral mucosa ulcer

Hematologic & oncologic: Anemia, bone marrow depression, leukopenia (nadir: 14 to 21 days; recovery: 28 to 35 days), metastases (≤20%; cumulative dose and duration dependent; includes acute myeloid leukemia, myeloproliferative syndrome, carcinoma), thrombocytopenia (nadir: 14 to 21 days; recovery: 28 to 35 days)

1% to 10%:

Hypersensitivity: Hypersensitivity reaction (IV: 2%; includes bronchospasm, dyspnea, edema, hypotension, pruritus, skin rash, tachycardia, urticaria)

Frequency not defined:

Cardiovascular: Cardiotoxicity (angina pectoris, cardiac arrhythmia, hypertension, myocardial infarction; with high-dose therapy), hepatic veno-occlusive disease (hepatic sinusoidal obstruction syndrome; SOS; high-dose IV melphalan), vasculitis

Central nervous system: Brain disease, flushing sensation, seizure (with high-dose therapy), tingling sensation

Dermatologic: Allergic skin reaction, alopecia, maculopapular rash, pruritus

Endocrine & metabolic: Amenorrhea, SIADH (syndrome of inappropriate antidiuretic hormone secretion)

Gastrointestinal: Mucositis (with high-dose therapy), paralytic ileus (with high-dose therapy), stomatitis

Genitourinary: Hemorrhagic cystitis, inhibition of testicular function, nephrotoxicity (with high-dose therapy), ovarian function suppression, sterility

Hematologic & oncologic: Agranulocytosis, bone marrow failure (irreversible), hemolytic anemia, hemorrhage (with high-dose therapy)

Hepatic: Hepatitis, increased serum transaminases, jaundice

Hypersensitivity: Anaphylaxis (rare), hypersensitivity reaction

Infection: Infection, sepsis

Local: Injection site reaction (injection site necrosis, ulceration)

Neuromuscular & skeletal: Myelopathy (radiation)

Renal: Increased blood urea nitrogen

Respiratory: Interstitial pneumonitis, pulmonary fibrosis

ALERT: U.S. Boxed Warning

Bone marrow suppression:

Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) to oral melphalan have shown more myelosuppression with the IV formulation. Monitor hematologic laboratory parameters.

Secondary malignancy:

Melphalan produces chromosomal aberrations in vitro and in vivo. Melphalan should be considered potentially leukemogenic in humans.

Hypersensitivity (injection):

Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation of melphalan. Discontinue treatment with melphalan for serious hypersensitivity reactions.

Experienced physician:

Administer melphalan under the supervision of a qualified health care provider experienced in the use of cancer chemotherapeutic agents.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Bone marrow suppression is common; may be severe and result in infection or bleeding; has been demonstrated more with the IV formulation (compared to oral). Myelosuppression is dose-related; myeloablation is expected when used in high doses for conditioning regimens prior to stem cell transplantation. Do not administer melphalan-containing conditioning regimen unless the stem cell product is available for rescue. Monitor blood counts; supportive care for infections, anemia, and thrombocytopenia may be necessary. When used for palliative treatment, may require treatment delay or dose modification for thrombocytopenia or neutropenia. Use with caution in patients with prior bone marrow suppression, impaired renal function (consider dose reduction), or who have received prior (or concurrent) chemotherapy or irradiation. Myelotoxicity is generally reversible, although irreversible bone marrow failure has been reported. In patients who are candidates for autologous transplantation, avoid melphalan-containing induction regimens if future transplant may be necessary (due to the effects on stem cell reserve).

• Extravasation: Melphalan is an irritant; local reactions may occur (Perez Fidalgo 2012). Extravasation may cause local tissue damage. Administration by slow injection into a fast running IV solution into an injection port or via a central line is recommended; do not administer directly into a peripheral vein.

• Fertility effects: Suppresses ovarian function and produces amenorrhea; may also cause reversible or irreversible testicular suppression.

• Gastrointestinal toxicity: Gastrointestinal toxicities, including nausea, vomiting, diarrhea, and mucositis are common, particularly when used in high doses for conditioning regimens (the incidence of grade 3 or 4 mucositis was 13% in clinical trials). When administering high-dose melphalan in autologous transplantation, cryotherapy is recommended to prevent oral mucositis (Lalla 2014). Melphalan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011). Nutritional support and/or analgesics may be necessary in patients with severe mucositis.

• Hepatotoxicity: Abnormal liver function tests may occur; hepatitis and jaundice have also been reported. Hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) has been reported with IV melphalan. Monitor liver function tests.

• Hypersensitivity reactions: [US Boxed Warning]: Hypersensitivity reactions (including anaphylaxis) have occurred in ~2% of patients receiving IV melphalan, usually after multiple treatment cycles. Symptoms may include urticaria, pruritus, edema, skin rashes, tachycardia, bronchospasm, dyspnea, and hypotension. Discontinue infusion and treat symptomatically. Hypersensitivity may also occur (rarely) with oral melphalan. Do not readminister (oral or IV) in patients who experience hypersensitivity to melphalan.

• Pulmonary toxicity: Pulmonary fibrosis (some fatal) and interstitial pneumonitis have been observed with treatment.

• Secondary malignancy: [US Boxed Warning]: Produces chromosomal abnormalities in vitro and in vivo. Melphalan should be considered potentially leukemogenic in humans. Secondary malignancies (including acute myeloid leukemia, myeloproliferative disease, and carcinoma) have been reported (some patients were receiving combination chemotherapy or radiation therapy); the risk is increased with increased treatment duration and cumulative doses.

Disease-related concerns:

• Renal impairment: Dosage reduction is recommended with IV melphalan in patients with renal impairment (when used for palliative treatment); reduced initial doses may also be recommended with oral melphalan. Closely monitor patients with azotemia. High-dose melphalan with autologous stem cell transplant is feasible in patients with multiple myeloma and renal impairment (Dimopoulos 2016). Prolonged mucositis has occurred when standard melphalan doses were administered to patients with chronic kidney disease (Bodge 2014).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Toxicity may be increased in elderly; start with lowest recommended adult doses.

Dosage form specific issues:

• Formulations: Intravenous melphalan is available in different formulations. Evomela (melphalan for injection) is a lyophilized powder which is reconstituted with normal saline to a 5 mg/mL concentration. Alkeran (melphalan hydrochloride for injection) and generic melphalan hydrochloride are also powder formulations which are reconstituted with the supplied diluent (which contains propylene glycol and ethanol) to a 5 mg/mL concentration. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007).

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

• Immunizations: Avoid vaccination with live vaccines during treatment if immunocompromised.

Monitoring Parameters

CBC with differential and platelet count, serum electrolytes, renal/liver function tests, serum uric acid; signs/symptoms of hypersensitivity reaction, pulmonary toxicity, and gastrointestinal toxicity; monitor infusion site.

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects have been observed in animal reproduction studies. May cause fetal harm if administered during pregnancy. Women of reproductive potential should be advised to avoid pregnancy while on and after melphalan therapy. Males with female partners of reproductive potential should use effective contraception during and after melphalan treatment. Therapy may suppress ovarian function leading to amenorrhea. Reversible and irreversible testicular suppression has been reported in male patients after melphalan administration.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, hair loss, or mouth sores. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), severe nausea, vomiting, bruising, bleeding, loss of strength and energy, angina, tachycardia, severe dizziness, passing out, shortness of breath, edema, excessive weight loss, amenorrhea, skin growths, signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), or severe injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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