Alkeran

Alkeran (melphalan) is a potent alkylating chemotherapeutic agent specifically indicated for the treatment of multiple myeloma and palliative management of advanced ovarian carcinoma. As a nitrogen mustard derivative, it exerts its cytotoxic effects by cross-linking DNA strands, thereby inhibiting tumor cell replication and proliferation. Its targeted mechanism and established efficacy profile make it a cornerstone in specific oncologic treatment protocols, particularly within hematologic malignancies. This product card provides a comprehensive, expert-level overview of its clinical application, safety profile, and pharmacologic characteristics for healthcare professionals.

Features

• Active Pharmaceutical Ingredient: Melphalan hydrochloride
• Available Formulations: Oral tablets (2 mg) and lyophilized powder for intravenous infusion (50 mg per vial)
• Pharmacologic Class: Nitrogen mustard alkylating agent
• Mechanism of Action: Forms covalent interstrand and intrastrand cross-links in DNA, leading to cell cycle arrest and apoptosis
• Bioavailability: Oral bioavailability is variable and incomplete (approximately 25-90%), significantly influenced by food intake
• Metabolism: Undergoes rapid spontaneous hydrolysis in aqueous media; minimal hepatic metabolism via non-enzymatic processes
• Elimination Half-life: Approximately 1.5 hours
• Excretion: Primarily renal (up to 50% of IV dose within 24 hours); <15% excreted unchanged in feces

Benefits

• Provides a targeted chemotherapeutic option with a well-documented history of efficacy in the management of multiple myeloma, both as a monotherapy and in combination regimens.
• Offers flexible administration routes (oral and IV) to accommodate different treatment phases and patient-specific factors, including outpatient management.
• Serves as a critical component in high-dose conditioning regimens prior to autologous hematopoietic stem cell transplantation, facilitating successful engraftment.
• Demonstrates a predictable and generally manageable toxicity profile when administered with appropriate monitoring and supportive care.
• Enables long-term disease control and palliation in selected patient populations, improving progression-free survival metrics.

Common use

Alkeran is primarily employed in the systemic treatment of multiple myeloma. It is used as a first-line induction therapy, often in combination with prednisone (MP regimen) or as part of more modern triplet therapies incorporating proteasome inhibitors or immunomodulatory drugs. Its second major application is in the high-dose conditioning setting for autologous stem cell transplantation, where it is administered intravenously at myeloablative doses. Off-label, it may be used in the palliative treatment of other hematologic malignancies like Waldenström’s macroglobulinemia or advanced, refractory ovarian carcinoma, though this is less common. Treatment decisions are always based on comprehensive patient assessment, disease staging, and institutional protocols.

Dosage and direction

Dosing is highly individualized based on treatment intent, regimen, renal function, and prior hematologic tolerance.

For Multiple Myeloma (Oral):

• Common regimen: 0.15 mg/kg body weight daily for 7 days, every 4-6 weeks, in combination with prednisone. Alternatively, 0.25 mg/kg daily for 4 days, repeated at 4-6 week intervals.
• Dosing must be rounded to the nearest whole tablet. Administration should be on an empty stomach (1 hour before or 2 hours after food) to maximize and standardize absorption.

For High-Dose Conditioning (Intravenous):

• Dosing is based on ideal body weight or adjusted body weight and is typically administered at 140-200 mg/m² as a single agent, usually split over two days (e.g., 70-100 mg/m²/day).
• IV administration is via a slow intravenous infusion over 15-30 minutes, following reconstitution as per manufacturer guidelines. Pre- and post-hydration with intravenous fluids is standard to mitigate nephrotoxicity.

Dosage adjustments are mandatory in patients with renal impairment. A 50% dose reduction is recommended for patients with a BUN level ≥30 mg/dL. Complete blood counts must be monitored weekly during therapy, and dosing intervals should be prolonged until evidence of hematologic recovery is observed.

Precautions

• Hematologic Toxicity: Alkeran is profoundly myelosuppressive. Severe bone marrow suppression with resulting leukopenia, thrombocytopenia, and anemia is common and expected. Blood counts nadir typically occurs 2-3 weeks after dosing, with recovery in 4-5 weeks. Frequent monitoring is essential.
• Extravasation Risk: Intravenous formulation is a potent vesicant. It must be administered with extreme care to avoid extravasation, which can cause severe tissue damage, necrosis, and thrombophlebitis.
• Hypersensitivity Reactions: Although rare, anaphylaxis and other hypersensitivity reactions have been reported, particularly with the IV formulation. Resuscitation facilities should be available during infusion.
• Secondary Malignancies: Treatment with alkylating agents, including Alkeran, is associated with a significantly increased risk of developing secondary malignancies, such as myelodysplastic syndrome (MDS) and acute leukemia.
• Impaired Fertility: Alkeran is mutagenic and may cause irreversible infertility in both male and female patients. Sperm banking or egg/embryo cryopreservation should be discussed prior to initiation of therapy, especially with high-dose regimens.
• Pulmonary Toxicity: Interstitial pneumonitis and pulmonary fibrosis have been reported, which can be fatal. Patients presenting with dry cough, dyspnea, or radiographic abnormalities should be evaluated promptly.

Contraindications

Alkeran is contraindicated in patients who have demonstrated a history of severe hypersensitivity reaction to melphalan or any component of the formulation. Its use is also contraindicated if the disease has proven resistant to prior melphalan therapy. The drug must not be administered to patients with severely compromised bone marrow function prior to treatment initiation, as evidenced by a platelet count <75,000/µL or a neutrophil count <1,500/µL, unless the treatment intent is myeloablation for transplant.

Possible side effect

The frequency and severity of adverse reactions are dose- and route-dependent.

• Very Common (>10%): Nausea, vomiting, diarrhea, stomatitis, universal myelosuppression (leukopenia, neutropenia, thrombocytopenia, anemia), alopecia (less common with oral dosing).
• Common (1-10%): Rash, pruritus, vasculitis, hepatic enzyme elevations, amenorrhea, azoospermia, hypersensitivity reactions (including anaphylaxis with IV form).
• Uncommon (0.1-1%): Interstitial pneumonitis, pulmonary fibrosis, hemolytic anemia, jaundice, sinusoidal obstruction syndrome (veno-occlusive disease) of the liver.
• Rare (<0.1%): Secondary malignancies (MDS, acute leukemia), cardiac arrest (with high-dose IV), skin ulceration at injection site (if extravasation occurs).

Drug interaction

Alkeran has several clinically significant interactions:

• Nalidixic Acid: Concomitant use may increase the incidence of severe hemorrhagic necrotic enterocolitis in children; avoid combination.
• Other Myelosuppressive Agents/Cytotoxics: Additive myelosuppression occurs with other chemotherapy drugs or radiotherapy. Blood counts must be monitored closely.
• Carmustine (BCNU): Concurrent use may enhance pulmonary toxicity.
• Ciclosporin: High-dose IV melphalan with ciclosporin can lead to severe renal impairment; monitor renal function closely.
• Live Vaccines: Vaccination with live vaccines is not recommended during treatment due to diminished immune response and potential for infection.

Missed dose

If a dose of oral Alkeran is missed, the patient should not take a double dose to make up for the forgotten one. They should contact their treating oncologist or clinical team immediately for specific instructions, which will depend on the timing of the missed dose and the overall treatment schedule. The management of a missed dose in a high-dose IV transplant regimen is a critical medical decision that must be handled by the specialist medical team.

Overdose

Overdose is expected to manifest as severe, prolonged bone marrow suppression, leading to life-threatening infections and hemorrhage. Symptoms include fever, chills, profound weakness, and bleeding. Gastrointestinal toxicity (severe mucositis, ulceration, diarrhea) may also be exacerbated. There is no specific antidote for melphalan overdose. Management consists of immediate hospitalization for intensive supportive care, including reverse isolation, broad-spectrum antibiotics, granulocyte colony-stimulating factors (G-CSF), and transfusions of platelets and red blood cells. Hemodialysis is not expected to enhance elimination due to melphalan’s rapid hydrolysis.

Storage

• Tablets: Store in the original packaging at room temperature (15-30°C or 59-86°F). Protect from light and moisture. Keep tightly closed.
• Lyophilized Powder for Injection: Store the unopened vials in a refrigerator between 2-8°C (36-46°F). Protect from light.
• Reconstituted Solution: The reconstituted solution for IV infusion is unstable and must be used immediately. The manufacturer states it should be administered within 60 minutes of preparation. Solutions should be clear and colorless to pale yellow; any discoloration or particulate matter indicates degradation, and the solution must be discarded.
• Keep out of reach of children and pets.

Disclaimer

This information is intended for educational and informational purposes for qualified healthcare professionals only. It is not a substitute for professional medical advice, diagnosis, or treatment. The content provided is based on the manufacturer’s prescribing information and clinical literature but may not encompass all possible uses, directions, precautions, or interactions. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition or before starting any new treatment. Never disregard professional medical advice or delay in seeking it because of something you have read here. Dosing and administration must be determined by a qualified oncologist based on the individual patient’s condition.

Reviews

• “A foundational agent in our multiple myeloma arsenal. Its role in the transplant conditioning regimen is irreplaceable. Requires meticulous handling and monitoring, but its efficacy is well-established.” – Director, Hematologic Malignancies Program
• “The oral formulation allows for manageable outpatient treatment cycles. The variable bioavailability is a challenge, but emphasizing consistent fasting administration helps mitigate this.” – Oncology Pharmacist, BCOP
• “While newer agents have emerged, melphalan remains a workhorse, particularly in combination therapies. Its toxicity profile is predictable, which allows for proactive management.” – Medical Oncologist
• “The IV high-dose protocol is highly effective but demands an expert team for administration and subsequent supportive care during the inevitable pancytopenia period.” – BMT Unit Head Nurse