Alkeran 2 mg

Drug Interactions

Drug-Food Interactions

ALKERAN

Established or Potential Drug-Drug Interactions

Information for the Patient

Alkeran

Special Handling Instructions

As with other toxic compounds, caution should be exercised when handling and preparing the solution of ALKERAN. Skin reactions associated with accidental exposure may occur. The use of gloves is recommended. If the solution of ALKERAN contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Dosage and Administration

Preparation for Administration/Stability

Epithelial Ovarian Cancer

Recommended Dose and Dosage Adjustment

Multiple Myeloma

ALKERAN

Reconstitution

Administration

Malignant Melanoma

Perfusion Method

Parenteral Products

Intravenous

Oral

Adverse Reactions

Renal

Gastrointestinal

Hypersensitivity

Hyperthermic Isolated Limb Perfusion

Hematologic

Local Reactions

Adverse Drug Reaction Overview

Miscellaneous

Hepatic

Indications and Clinical Use

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.

  Overdosage

  For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.

  
  

  Overdose as high as 290 mg/m² resulting in death has been reported. It has also been reported that a pediatric patient survived a 254 mg/m² overdose treated with standard supportive care. The immediate effects are severe nausea and vomiting. Decreased consciousness, convulsions, muscular paralysis and cholinomimetic effects are less frequently seen. Severe mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract occur at high doses (>100 mg/m²). Elevations in liver enzymes and veno-occlusive disease occur infrequently. Nephrotoxicity and adult respiratory distress syndrome have been reported rarely. The principal toxic effect is bone marrow suppression leading to leukopenia, thrombocytopenia and anemia. Hematologic parameters should be closely followed for 3 to 6 weeks. Administration of autologous bone marrow or hematopoietic growth factors (i.e., sargramostim, filgrastim) may shorten the period of pancytopenia. General supportive measures together with appropriate blood transfusions and antibiotics should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by hemodialysis or hemoperfusion.

  Dosage Forms, Composition and Packaging

  Tablets

  Each white to off-white, round, biconvex, film-coated tablet, imprinted with “A” on one side and on the other side “GX EH3”, contains: melphalan 2 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400 and titanium dioxide. Bottles of 50.

  Injection

  Each vial of sterile, white to cream-colored, freeze-dried powder contains: melphalan HCl equivalent to melphalan 50 mg and povidone 20 mg. Each vial of solvent-diluent provides 10 mL of buffer solution containing sodium citrate 0.20 g, ethanol 0.52 mL, propylene glycol 6 mL and water for injection, q.s. Component packs of 2 comprising a vial containing a freeze-dried powder and a vial of solvent-diluent.

  
  
  

  Warnings and Precautions

  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.

  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 ≥30 mg/dL) and these patients should be closely monitored for toxicity.

  Special Populations

  
  
  

  Hematologic

  As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow suppression. Bone marrow suppression is the most significant toxicity associated with ALKERAN for injection in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent dose of ALKERAN: platelet count, hemoglobin, white blood cell count and differential. The occurrence of a platelet count below 50×10⁹/L or an absolute neutrophil count below 0.5×10⁹/L is an indication to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity.

  
  

  If the leukocyte count falls below 3×10⁹/L, or the platelet count below 100×10⁹/L, the drug should be discontinued until the blood picture has had a chance to recover.

  
  

  Blood counts may continue to fall for 6-8 weeks after initiation of treatment. So, at the first sign of abnormally large fall in leukocyte or platelet counts, treatment should be temporarily interrupted.

  
  

  In one trial by Cornwell et al. (1982), melphalan administered intravenously without adjustment for renal failure increased incidence rates for severe leukopenia and thrombocytopenia by 35% in patients with renal insufficiency (BUN ≥30 mg/dL).

  Immune

  Acute hypersensitivity reactions, including anaphylaxis, have occurred infrequently (see Adverse Reactions). 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.

  Carcinogenesis and Mutagenesis

  Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukemia, myeloproliferative syndrome or carcinoma is not possible. Published reports of leukemia in patients who have received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis increases with chronicity of treatment and with cumulative dose. In one study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was 19.5% for cumulative doses ranging from 730 mg to 9652 mg. In this same study, as well as in an additional study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was less than 2% for cumulative doses under 600 mg. This does not mean that there is a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy.

  
  

  Melphalan has been shown to cause chromatid or chromosome damage in man.

  General

  ALKERAN should be administered in carefully adjusted dosages by or under the supervision of experienced physicians who are familiar with the drug's actions and the possible complications of its use. The drug should not be administered by hyperthermic isolated limb perfusion unless the clinician is experienced and well-trained in this technique.

  
  

  In all instances where the use of ALKERAN for injection is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events. Melphalan should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from previous cytotoxic therapy. Dose reduction should be considered in patients with renal insufficiency receiving IV melphalan (see Hematologic and Renal).

  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.

  Respiratory

  Rare reports of pulmonary fibrosis or interstitial pneumonitis (including fatal reports) have been seen in patients treated with ALKERAN.

  Pediatrics

  The safety and effectiveness in children have not been established.

  Sexual Function/Reproduction

  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.

  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.

  Nursing Women

  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.

  
  
  

  Storage and Stability

  Tablets: Store in a refrigerator, 2-8°C.

  
  

  Injection: Store at controlled room temperature (15-30°C). Protect from light.

  Action and Clinical Pharmacology

  Distribution

  The steady-state volume of distribution of melphalan is 0.5 L/kg and approximates total body water. Penetration into cerebrospinal fluid (CSF) is low. The extent of melphalan binding to plasma proteins is ranging from 69% to 78%. There is evidence that the protein binding is linear in the range of plasma concentrations usually achieved at standard dose therapy, but that the binding may become concentration-dependent at the concentrations observed at high dose therapy. Serum albumin is the major binding protein, accounting for about 55% to 60% of the plasma protein binding, and 20% is bound to α₁-acid glycoprotein. In addition, melphalan binding studies have revealed the existence of an irreversible component attributable to the alkylation reaction with plasma proteins. Interactions with immunoglobulins have been found to be negligible.

  
  

  Melphalan displays limited penetration of the blood-brain barrier. Melphalan was found at concentrations of approximately 10% of the corresponding plasma concentration in the cerebrospinal fluid samples following high-dose intravenous melphalan in two studies.

  Pharmacokinetics

  
  
  

  Absorption

  The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the drug in plasma and peak plasma concentration. In studies of the absolute bioavailability of melphalan the mean absolute bioavailability ranged from 56 to 85%.

  
  

  Mean (±SD) peak melphalan plasma concentrations in myeloma patients given melphalan intravenously at doses of 10 or 20 mg/m² were 1.2±0.4 and 2.8±1.9 µg/mL, respectively. Studies in children as young as 1 year showed results similar to adults.

  
  

  The oral administration of melphalan tablets immediately after food delayed the time to achieving peak plasma concentrations and reduced the area under the plasma concentration-time curves by between 39 and 45% (see Drug Interactions).

  Mechanism of Action

  ALKERAN (melphalan) is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N⁷ position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.

  Elimination

  Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 and 70 minutes, respectively. Estimates of average total body clearance varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m²) were observed.

  
  

  Melphalan clearance may be decreased in renal impairment. An increase in AUC (i.e. melphalan systemic exposure) was observed in patients with renal impairment when melphalan was administered by either route. One study noted an increase in the occurrence of severe leukopenia in patients with elevated BUN after 10 weeks of therapy (see Warnings and Precautions, Hematologic).

  
  

  The pharmacokinetics of melphalan administered by closed circuit limb perfusion have been studied by several investigators. Melphalan concentrations declined rapidly and biexponentially from circulating perfusate with average terminal half-lives reported from 26 min (n=4) to 53 min (n=48). Systemic exposure to melphalan during limb perfusion is generally very low. Peak melphalan concentrations in the closed circuit perfusate are typically 10 to 100 times greater than peak concentrations in plasma observed following standard dose systemic intravenous therapy for multiple myeloma.

  Metabolism

  Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxy- and dihydroxy-melphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in man.

  
  
  

  Contraindications

  Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

• ALKERAN (melphalan) should not be used in patients whose disease has demonstrated a prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug. There may be cross-sensitivity (skin rash) between melphalan and chlorambucil (LEUKERAN).

  
  

• Melphalan should not be given if other similar chemotherapeutic agents or radiotherapy have been administered to the patient recently, or if neutrophil and/or platelet counts are depressed.

  
  

• Melphalan should not be administered concurrently with radiotherapy.