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melphalan

( MEL-fa-lan )
Funding:
ODB - General Benefit
  • melphalan - oral tablets
Other Name(s): Alkeran®
Appearance: Oral tablets; Injection - clear liquid mixed into larger bags of fluids
A - Drug Name

melphalan

COMMON TRADE NAME(S):   Alkeran®

 
B - Mechanism of Action and Pharmacokinetics

Melphalan is a phenylalanine derivative of mechlorethamine.  Alkylation of DNA results in breaks in the DNA molecules as well as cross-linking of the twin strands, thus interfering with DNA replication and transcription of RNA.  Like other alkylators, melphalan is cell cycle phase non-specific



Absorption
Oral: Incomplete, variable, 56-85% bioavailable post oral dose; food decreases AUC by 39-45%.
Distribution

Rapid distribution into total body water.  Pharmacokinetics are linear and similar in adults and children.

Cross blood brain barrier? Limited; plasma to CNS ratio 10:1.
PPB 55-60% serum albumin; some irreversible (20% α-acid glycoprotein)
Metabolism

Chemical hydrolysis to mono and dihydroxy products; primary means of elimination.

Active metabolites No
Inactive metabolites Yes
Elimination

Biphasic; mainly feces; renal excretion low.

Feces 20-50% within 6 days (PO).
Urine 20-35% within 24 hours (PO); 10% as intact drug.
Half-life (terminal) : 75 minutes (IV)
 
C - Indications and Status
Health Canada Approvals:

  • Malignant melanoma (hyperthermic isolated limb perfusion, as an adjuvant to surgery)
  • Multiple myeloma
  • Ovarian cancer (palliative)


Other Uses:

  • Hodgkin's lymphoma
  • Non-Hodgkin's lymphomas
 
D - Adverse Effects

Emetogenic Potential:  

Moderate (IV)
Minimal – No routine prophylaxis; PRN recommended (PO)

Extravasation Potential:   Vesicant

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Flushing (high doses) I  E
Dermatological Alopecia (BMT doses) E
Rash E
Gastrointestinal Diarrhea (especially with high-dose regimens) E
Mucositis (with high doses) E
Nausea (or vomiting - PO: up to 30%; IV: up to 50%) I
Vomiting I
General Wound complication (reduced wound healing - limb perfusion) I  E
Hematological Hemolysis
Myelosuppression E
Hepatobiliary Hepatitis E
Jaundice E
↑ LFTs E
Veno-occlusive disease E
Hypersensitivity Anaphylaxis (2%) (Type I anaphylactoid) I
Injection site Injection site reaction (50%) (transient; mild pain, irritation, warmth, tingling) I
Necrosis (rare; or ulceration) I  E
Metabolic / Endocrine Hyperuricemia
Musculoskeletal ↑CPK (with perfusion) I
Rhabdomyolysis (with perfusion) I
Neoplastic Leukemia (secondary) L
MDS L
Secondary malignancy L
Renal ↑ BUN E
Creatinine increased E
Reproductive and breast disorders Infertility L
Irregular menstruation (amenorrhea) D
Respiratory Pneumonitis E
Pulmonary fibrosis (chronic, rare) D
Vascular Vasculitis E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most frequent dose-limiting toxicity is dose-related, cumulative myelosuppression.

Hypersensitivity reactions, including anaphylaxis, have been reported. Cardiac arrest has rarely been associated with such events. If a hypersensitivity reaction occurs, melphalan treatment should be discontinued.

Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g. some leukemias and lymphomas), can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.

The tissue necrosis that occurs with extravasation may happen days to weeks after the treatment. Patients must be observed for delayed reactions and prior injection sites carefully inspected.

Nausea and vomiting occur rarely with chronic low-dose treatment, but may be more severe with single high oral or IV doses. With high dose therapy gastrointestinal toxicity (mucositis, esophagitis, and diarrhea) becomes dose-limiting.

Pulmonary fibrosis and interstitial pneumonitis have been reported. Signs and symptoms are dry cough, dyspnea, tachypnea, fever and cyanosis. Melphalan pulmonary toxicity is not related to dose or to duration of therapy. There are no identifiable risk factors. Patients either recover with complete resolution of all signs and symptoms of pulmonary toxicity or die from progressive pulmonary disease.

Alkylating agents cause gonadal suppression; therefore melphalan may cause amenorrhea or azoospermia, which may be irreversible. Second malignancies may occur in up to 20% of patients with prolonged exposure (over 600mg)

 
E - Dosing

Refer to protocol by which patient is being treated. Numerous dosing schedules exist, depending on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.

Adults:

Oral: 0.15 mg/kg daily x 7 days; 2-6 week break then ≤ 0.05mg/kg/day maintenance

Oral: 0.2 mg/kg Daily for 5 days; every 4-5 weeks

Oral: 6 mg daily x 2-3 weeks; 4 week break then 2 mg/day maintenance

Intravenous: 16 mg/m² (q2w x 4 doses, then q 4-week after recovery from toxicity)

Bone marrow transplant:  Much higher doses are used for tumour ablation prior to marrow transplant than for standard treatment regimens.


Dosage with Toxicity:

  • Discontinue if hypersensitivity or pneumonitis / pulmonary fibrosis occurs.

Dosage with myelosuppression:

  • Do not retreat until platelets > 100 x 109/L and neutrophils > 1.5 x 109/L. Reduce melphalan after grade 4 neutropenia or grade 3 thrombocytopenia.
  • Modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Hematologic and Non-Hematologic Toxicities."


Dosage with Hepatic Impairment:

No adjustment required.

Dosage with Renal Impairment:

Increased incidence of severe myelosuppression has been observed in patients with BUN ≥ 10.7 mmol/L.  Dose reduction should be considered in patients with renal insufficiency receiving melphalan. 

Creatinine clearance (mL/min)  % usual dose
10-50 75% and monitor
<10 50% and monitor


Dosage in the elderly:

No adjustment required, but caution should be exercised.

 



Children:

Safety and efficacy not established. Consult specific protocols for details.

 
F - Administration Guidelines

IV MELPHALAN

  • Slow push through sidearm of free-flowing IV (Normal Saline).
  • For reconstitution, rapid addition of the supplied diluent to the drug vial followed by immediate vigorous shaking is important for proper dissolution.
  • May dilute in Normal Saline to a concentration between 0.1 to 0.45 mg/mL; Infuse over 15-30 minutes.
  • Should be administered within 50 minutes of reconstitution. Reconstituted product is stable for 2 hours at 30°C. Precipitate forms if refrigerated.

ORAL MELPHALAN

  • Oral self-administration; drug available by outpatient prescription.
  • Keep refrigerated.
  • Take on an empty stomach.


 
G - Special Precautions
Other:

Melphalan is contraindicated in patients whose disease has demonstrated a prior resistance to this agent, or have demonstrated hypersensitivity to melphalan or to any of its excipients. There is cross-sensitivity between melphalan and chlorambucil, which is manifested as a rash. Avoid the use of live vaccines.

Melphalan should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior radiation or chemotherapy, or whose marrow function is recovering from previous chemotherapy. Melphalan should not be administered concurrently with radiotherapy.

Melphalan is carcinogenic, mutagenic and teratogenic; it should not be used in pregnancy. Adequate contraception should be used by both sexes during melphalan treatment and for at least 6 months after treatment cessation. Breast feeding is not recommended due to the potential secretion into breast milk.

 
 

 
H - Interactions

AGENT EFFECT MECHANISM MANAGEMENT
Cimetidine (and H2 receptor antagonists) ↓ bioavailability of melphalan Inhibit GI absorption Monitor for ↓ melphalan activity
cyclosporine ↑ nephrotoxicity Unknown Monitor renal function
Nalidixic acid ↑ hemorrhagic enterocolitis Unknown Avoid concurrent treatment
Cisplatin ↑ melphalan levels and toxicity ↓ clearance Caution
BCNU ↑ risk of interstitial pneumonitis Unknown Caution
Interferon ↓ levels of melphalan ↑ melphalan elimination Caution
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency
CBC Baseline and regular

Clinical assessment for bleeding, infection, hematologic, pulmonary, GI, local toxicity.

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

 



Suggested Clinical Monitoring

Monitor Type Monitor Frequency
Uric acid levels Baseline and regular
Liver and renal function tests Baseline and regular
 
J - Supplementary Public Funding

ODB - General Benefit (ODB Formulary )

  • melphalan - oral tablets ()

 
K - References

Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA)

McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1159-62.

Product Monograph: Alkeran® (melphalan). GlaxoSmithKline Inc., October 18, 2007.


June 2019 Updated emetic risk category.

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

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