Dosing and uses of Alkeran, Evomela (melphalan)
Adult dosage forms and strengths
injection, lyophilized powder for reconstitution
- 50mg
tablet
- 2mg
Multiple Myeloma
Palliative treatment
- Indicated for the palliative treatment of patients with MM
- Oral
- 6 mg PO qDay for 2-3 weeks, OR
- 10 mg PO qDay for 7-10 days, OR
- 0.15 mg/kg/day PO for 7 days, THEN
- After adequate recovery from toxicity (monitor WBCs and platelets) give 1-3 mg or 0.05 mg/kg PO qDay
- IV
- If unable to take oral, may administer IV 16 mg/m² IV as a single infusion over 15-20 minutes q2wk for 4 doses, THEN
- After adequate recovery from toxicity (monitor WBCs and platelets) administer q4wk
Conditioning treatment
- Indicated for use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation
- 100 mg/m²/day IV administered over 30 min for 2 consecutive days (Day -3 and Day -2) prior to autologous stem cell transplantation (ASCT, Day 0)
- Patients weighing >130% of their ideal body weight, body surface area should be calculated based on adjusted ideal body weight
Ovarian Cancer
0.2 mg/kg/day PO for 5 days; repeat q4-5Weeks
Dosage modifications
Renal impairment (BUN ≥30 mg/dL): Consider dosage reduction of up to 50%
Orphan Designations
Stem cell transplantation
- High dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation
- Orphan sponsor: CyDex Pharmaceuticals, Inc; 10513 W. 84th Terrace; Lenexa, KS 66214
Cutaneous melanoma
- Sponsor: Delcath Systems, Inc; 1301 Avenue of the Americas, 43rd Floor; New York, NY 10019
Hepatocellular cancer
- Sponsor: Delcath Systems, Inc; 1301 Avenue of the Americas, 43rd Floor; New York, NY 10019
Ocular (uveal) melanoma
- Sponsor: Delcath Systems, Inc; 1301 Avenue of the Americas, 43rd Floor; New York, NY 10019
Neuroendocrine tumors
- Sponsor: Delcath Systems, Inc; 1301 Avenue of the Americas, 43rd Floor; New York, NY 10019
Retinoblastoma
- Intraocular injection
- Sponsor: Icon Bioscience, Inc; 1253 Reamwood Ave; Sunnyvale, CA 94089
Multiple myeloma (new dosage form)
- Melphalan flufenamide hydrochloride
- Orphan designation for this salt; results in intracellular trapping of melphalan in malignant cells to increase efficacy
- Sponsor: Oncopeptides AB; Vastra Tradgardsgatan 15; 111 53 Stockholm, Sweden
Cholangiocarcinoma
- Sponsor: Delcath Systems, Inc; 1301 Avenue of the Americas, 43rd Floor; New York, NY 10019
Other Indications & Uses
Off-label: Breast cancer, testicular cancer, melanoma
Pediatric dosage forms and strengths
Safety and efficacy not established
Geriatric dosage forms and strengths
Multiple Myeloma
Induction
6 mg PO qDay for 2-3 weeks, Or
10 mg PO qDay for 7-10 days, Or
0.15 mg/kg/day PO for 7 days, Or
16 mg/m² IV q2Weeks for 4 doses
Maintenance
Wait until WBC and platelet counts rise
1-3 mg PO qDay, Or
0.05 mg/kg/day PO, Or
16 mg/m² IV q4Weeks
Ovarian Cancer
0.2 mg/kg/day PO for 5 days; repeat q4-5Weeks
Alkeran, Evomela (melphalan) adverse (side) effects
>10%
Myelosuppression (30%)
Frequency not defined
Nausea
Vomiting
Interstitial pneumonia
Pulmonary fibrosis
Diarrhea
Stomatitis
Mucositis
Secondary malignancy
Hypersensitivity reaction
Tissue necrosis
Jaundice
Warnings
Black box warnings
The drug should be administered under the supervision of an experienced cancer chemotherapy physician
Severe bone marrow suppression that may result in bleeding and infection may occur. Oral melphalan has been reported to be more myelosuppressive than the IV formulation
Hypersensitivity reactions, including anaphylaxis, reported in patients receiving IV formulation
Melphalan is leukemogenic and potentially mutagenic (carcinogenic) in humans
Contraindications
Hypersensitivity to melphalan or chlorambuciL
Prior resistance to melphalan
Cautions
Renal impairment, leukopenia, thrombocytopenia, anemia, CLL
Possibility of delayed myelosuppression that can last 4-6 wk
Avoid pregnancy
Pregnancy and lactation
Pregnancy category: d
Lactation: not known if excreted in breast milk
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Alkeran, Evomela (melphalan)
Mechanism of action
Mechorethamine derivative that inhibits DNA & RNA synthesis via formation of carbonium ions; cross links DNA strands (interstrand and intrastrand crosslinking) causing miscoding breakage and subsequently DNA replication failure
Pharmacokinetics
Peak plasma time: 2 hr
Concentration: 280 ng/mL
Half-Life: 60-120 min (oral), 75 min (IV)
Bioavailability: 60-90%
Vd: 0.5 L/kg
Clearance: 7-9 mL/min/kg
Excretion: Feces (20-50%); urine (10% as unchanged drug)
Dialyzable: No
Administration
IV Incompatibilities
Solution: D5W, LR, NS (NS can be used in short time period)
Y-site: amphotericin B, chlorpromazine
IV Compatibilities
Y-site (partial list): acyclovir, bleomycin, most cephalosporins, cisplatin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diphenhydramine, doxorubicin, floxuridine, fluconazole, fludarabine, fluorouracil, furosemide, granisetron, heparin, idarubicin, imipenem-cilastatin, lorazepam, methotrexate, metoclopramide, mitomycin, morphine SO4, ondansetron, KCl, prochlorperazine, promethazine, NaHCO3, teniposide, thiotepa, vancomycin, vinblastine, vincristine, vinorelbine, zidovudine
IV Preparation
Use chemotherapy precautions for handling, preparation, administration, and disposaL
Alkeran
- Reconstitute lyophilized powder
- Rapidly inject 10 mL of the supplied diluent directly into the vial containing lyophilized powder using a needle ≥20-gauge
- Immediately shake vial vigorously until a clear solution is obtained
- Dissolve powder initially with 10 mL of provided diluent to 5 mg/mL
- This results in a 5-mg/mL solution
- Rapid addition of the diluent followed by immediate vigorous shaking is important for proper dissolution
- Immediately dilute further
- Immediately dilute solution in 0.9% NaCl to concentration <0.45 mg/mL
- Keep to a minimum (<60 min) time between reconstitution/dilution & administration
- Do not refrigerate solution; precipitation occurs
- Standard dilution: dose/250-500 mL 0.9% NaCl (concentration <0.45 mg/mL); must be prepared fresh
Evomela
- Reconstitute lyophilized powder
- Captisol-enabled; propylene glycol-free product
- Use 8.6 mL 0.9% NaCl to reconstitute vial contents (yields 50 mg/10 mL [5 mg/ mL] solution)
- The normal saline used to reconstitute each vial should appear to be assisted or pulled into the vial by the negative pressure (partial vacuum) present in the vial; discard any vial (and replace with another vial) if there is no vacuum present when reconstituting the vial with normal saline
- Reconstituted solution is stable for 24 hr refrigerated (5°C)without any precipitation due to the high solubility or for 1 hr at room temperature
- Dilute further
- Calculate the required volume of reconstituted solution needed for the dose and withdraw that volume from the vial(s)
- Add the required dosage volume to the appropriate volume of 0.9% NaCl to a final concentration of 0.45 mg/mL
- Admixture solution is stable for 4 hr at room temperature in addition to the 1 hr following reconstitution
IV Administration
Alkeran
- IV infusion
- FDA approved for administration as a single infusion over a minimum of 15-20 min
- Complete administration within 60 min of reconstituting the lyophilized powder
- Avoid skin contact with IV formulation
- IV bolus
- May be administered via central line and via peripheral vein as a rapid IV bolus
- Central line: IV bolus doses of 17-200 mg/² reconstituted and not diluted) have been given over 2-20 min
- Peripheral line: IV bolus doses of 2-23 mg/² reconstituted and not diluted) have been given over 1-4 min
Evomela
- Administer prophylactic antiemetic agents
- Palliative: Infuse IV over 15-20 minutes via an injection port or central venous catheter
- Conditioning: Infuse IV over 30 minutes via an injection port or central venous catheter
Oral Administration
Take on empty stomach; oral administration with a high fat meal may reduce melphalan systemic exposure
Storage
Protect from light
Store at room temp (15-30°C)
