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ALKERAN is a brand name for Melphalan, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: ALKERAN® (melphalan) is indicated for: • the palliative treatment of multiple myeloma • the palliation of nonresectable epithelial carcinoma of the ovary. • ALKERAN® for injection has been administered by hyperthermic isolated limb perfusion as an adjuvant to surgery in the treatment of malignant melanoma. However,…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations • Due to the risk of thromboembolism, the decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's underlying risk factors (See 7 Hematologic).
• Caution is recommended in patients with renal impairment (See 7 Renal). 2 Recommended Dose and Dosage Adjustment Oral Multiple Myeloma: The usual oral dose is 6 mg (3 tablets) daily. The entire daily dose may be given at one time. It is adjusted, as required, on the basis of blood counts done at approximately weekly intervals.
After 2-3 weeks of treatment, the drug should be discontinued for up to 4 weeks, during which time the blood count should be followed carefully. When the white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be instituted.
Because of the patient-to-patient variation in melphalan plasma levels following oral administration of the drug, several investigators have recommended that melphalan dosage be cautiously escalated until some myelosuppression is observed, in order to assure that potentially therapeutic levels of the drug have been reached.
Other dosage regimens have been used by various investigators. Osserman and Takatsuki have used an initial course of 10 mg/day for 7-10 days. They report that maximal suppression of the leukocyte and platelet counts occurs within 3-5 weeks and recovery within 4-8 weeks.
Continuous maintenance therapy with 2 mg/day is instituted when the white blood cell count is greater than 4 x 109/L and the platelet count is greater than 100 x 109/L. Dosage is adjusted to between 1 and 3 mg/day depending upon the hematological response.
5 x 109/L. Hoogstraten et al. 15 mg/kg/day for 7 days. This is followed by a rest period of at least 14 days, but it may be as long as 5-6 weeks. Maintenance therapy is started when the ALKERAN® 2 mg and 50 mg/vial melphalan Page 6 of 29 white blood cell and platelet counts are rising.
05 mg/kg/day or less and is adjusted according to the blood count. Available evidence suggests that about one-third to one-half of the patients with multiple myeloma show a favorable response to oral administration of the drug. It is to be emphasized that response may be very gradual over many months; it is important that repeated courses or continuous therapy be given since improvement may continue slowly over many months and the maximum benefit may be missed if treatment is abandoned too soon.
). Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of volume expanders, pressor agents, corticosteroids, or antihistamines at the discretion of the physician. Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts.
Therefore, immunisations with live organism vaccines are not recommended. Monitoring and Laboratory Tests Periodic complete blood counts with differentials should be performed during the course of treatment with melphalan. At least one determination should be obtained prior to each dose.
Patients should be observed closely for consequences of bone marrow suppression, which include severe infections, bleeding, and symptomatic anemia. ALKERAN® 2 mg and 50 mg/vial melphalan Page 11 of 29 Renal Systemic exposure of melphalan was positively correlated to the degree of renal insufficiency following either route of administration.
In one trial by Cornwell et al. (1982), increased incidence rate of bone marrow suppression has been associated with impaired renal function in patients with intravenous administration without dose adjustment for renal failure. Dose adjustments should be considered for patients with significant renal dysfunction (BUN ≥ 30mg/dL) and these patients should be closely monitored for toxicity.
The use of high dose melphalan has the potential to cause acute kidney injury in patients, especially those with underlying renal impairment.
Reproductive Health:
Female and Male Potential Due to an increased risk of venous thromboembolism in patients undergoing treatment with melphalan in combination with lenalidomide and prednisone or in combination with thalidomide and prednisone or dexamethasone, combined oral contraceptive pills are not recommended.
07/2024 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. RECENT MAJOR LABEL CHANGES ............................................................................................
2 TABLE OF CONTENTS .............................................................................................................. 2 PART I: HEALTH PROFESSIONAL INFORMATION ......................................................................
4 1 INDICATIONS ............................................................................................................... 4 2 CONTRAINDICATIONS .................................................................................................
4 3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 5 4 DOSAGE AND ADMINISTRATION ................................................................................. 7 5 OVERDOSAGE..............................................................................................................
8 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 8 7 WARNINGS AND PRECAUTIONS .................................................................................. 12 8 ADVERSE REACTIONS ................................................................................................
12 9 DRUG INTERACTIONS ................................................................................................ 14 10 CLINICAL PHARMACOLOGY .......................................................................................
15 11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 16 12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 16 PART II: SCIENTIFIC INFORMATION .......................................................................................
ALKERAN® is contraindicated in: • Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Patients whose disease has demonstrated a prior resistance to this agent. • There may be cross-sensitivity (skin rash) between melphalan and chlorambucil. • Patients who have recently been administered other similar chemotherapeutic agents or radiotherapy, or if neutrophil and/or platelet counts are depressed (see 7 Hematologic).
• Patients who are receiving radiotherapy. 2 Breast-feeding). ALKERAN® 2 mg and 50 mg/vial melphalan Page 5 of 29
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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O. daily for 5 days as a single course. Courses are repeated every 4-5 weeks depending upon hematologic tolerance.
Intravenous Multiple Myeloma:
The usual intravenous dose is 16 mg/m2. 71 mmol/L[30 mg/dL]). The drug is administered in one dose and the length of infusion should be from 15 to 90 minutes. Melphalan is repeated at 2-week intervals initially for 4 doses, then at 4-week intervals after adequate recovery from toxicity.
Available evidence suggests about one-third to one-half of the patients with multiple myeloma show a favorable response to the drug. Experience with oral melphalan suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned prematurely.
Dose adjustment on the basis of blood cell counts at the nadir prior to each dose should be considered.
Intra-arterial/Hyperthermic isolated limb Perfusion Malignant Melanoma:
Only physicians experienced and well-trained in hyperthermic isolated limb perfusion should administer the drug in this fashion. 5 mg/kg in the lower limb added to the perfusate. Perfusion lasts for approximately 60 minutes under mild hyperthermic conditions (final tissue temperatures, 39° to 41° C).
Pediatrics (< 18 years):
Health Canada has not authorized an indication for pediatric use.
Geriatrics (> 65 years):
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
3 Reconstitution ALKERAN® for injection must be reconstituted, at room temperature, by rapidly transferring 10 mL of the supplied solvent-diluent directly into the vial of lyophilized powder using a sterile needle (20 gauge or larger needle diameter) and syringe.
Immediately shake vial vigorously (for at least 50 seconds) until a clear solution is obtained. Rapid addition of the diluent followed by immediate vigorous shaking is important for proper dissolution. 5. Table 1 – Reconstitution Vial Size Volume of Diluent to be Added to Vial Approximate Available Volume Concentration per mL 50 mg 10 mL 10 mL 5 mg/mL ALKERAN® injection solution has limited stability and should be prepared immediately before use.
Any unused solution should be discarded. The reconstituted solution should be used immediately and should not be refrigerated as this will cause precipitation. It is stable for up to 2 hours at 30°C. ALKERAN® injection solution has reduced stability when further diluted in an infusion solution and the rate of degradation increases rapidly with rise in temperature.
9% w/v should be used. Solutions diluted to […]
If a patient is currently using combined oral contraception, her partner should switch to a barrier method like condom. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception. Considering that Melphalan has been shown to cause chromatid or chromosome damage in man, it is recommended that men who are receiving treatment with Melphalan not father a child during treatment and up to 6 months afterwards.
As with all cytotoxic treatments, male and female patients who use melphalan should use effective and reliable contraceptive methods for a period of six months, following the cessation of treatment. The final decision regarding the additional time period on contraception should be taken by the doctor and/or the patient.
• Fertility Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported. There is evidence from some animal studies that melphalan can have an adverse effect on spermatogenesis.
It is recommended that men have a consultation on sperm preservation before treatment due to the possibility of irreversible infertility as a result of Melphalan treatment. Respiratory Rare reports of pulmonary fibrosis or interstitial pneumonitis (including fatal reports) have been seen in patients treated with ALKERAN®.
1 Pregnant Women Safe use of melphalan has not been established with respect to adverse effects on fetal development. Therefore, it should be used in women of childbearing potential and particularly during early pregnancy only when, in the judgment of the physician, the potential benefits outweigh the possible hazards.
2 Breast-feeding It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from melphalan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see 2 CONTRAINDICATIONS).
3 Pediatrics Pediatrics (< 18 years): The safety and effectiveness in children have not been established; therefore, Health Canada has not authorized an indication for pediatric use. 4 Geriatrics Clinical experience with ALKERAN® has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see 7 Renal).
1 Adverse Reaction Overview The following information on adverse reactions is based on data from both oral and intravenous administration of ALKERAN® (melphalan) as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.
For this product, there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the indication and dose received and also when given in combination with other therapeutic agents.
Gastrointestinal:
Gastrointestinal effects such as nausea and vomiting occur in up to 30% of patients receiving conventional oral doses of ALKERAN® and in up to 50% of patients receiving intravenous doses of ALKERAN®. Diarrhea is noted to occur one week post high dose melphalan therapy.
Oral ulceration and hepatic toxicity including veno-occlusive disease have been reported. The incidence of diarrhea, vomiting and stomatitis becomes the dose-limiting toxicity in patients given high intravenous doses of melphalan in association with autologous bone marrow transplantation.
Cyclophosphamide pretreatment appears to reduce the severity of gastrointestinal damage induced by high-dose melphalan and the literature should be consulted for details. Stomatitis at conventional doses […]
17 13 PHARMACEUTICAL INFORMATION ............................................................................ 17 14 CLINICAL TRIALS ........................................................................................................
17 15 MICROBIOLOGY ........................................................................................................ 17 16 NON-CLINICAL TOXICOLOGY .....................................................................................
17 PATIENT MEDICATION INFORMATION .................................................................................. 19 PATIENT MEDICATION INFORMATION ..................................................................................
24 ALKERAN® 2 mg and 50 mg/vial melphalan Page 4 of 29 PART I: HEALTH PROFESSIONAL INFORMATION 1 INDICATIONS ALKERAN® (melphalan) is indicated for: • the palliative treatment of multiple myeloma • the palliation of nonresectable epithelial carcinoma of the ovary.
• ALKERAN® for injection has been administered by hyperthermic isolated limb perfusion as an adjuvant to surgery in the treatment of malignant melanoma. However, there have been no prospective controlled or uncontrolled trials evaluating dose and its relationship to disease response and/or toxicity.
1 Pediatrics Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 2 Geriatrics Geriatrics (> 65 years): ALKERAN is approved for use in the geriatric population.
2 Recommended Dose […]