Usual Adult Dose for Multiple Myeloma

ORAL:
A typical oral dosage regimen is:
6 mg orally once daily; after 2 to 3 weeks therapy should be discontinued for up to 4 weeks and the blood count followed; when white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be instituted

Alternate Oral Regimens:

• Osserman and Takatsuki have used an initial course of 10 mg/day for 7 to 10 days. They report that maximal suppression of the leukocyte and platelet counts occurs within 3 to 5 weeks and recovery within 4 to 8 weeks. Continuous orally maintenance therapy with 2 mg/day is instituted when the white blood cell count is greater than 4000 cells/mcL and the platelet count is greater than 100,000 cells/mcL. Dosage is adjusted to between 1 and 3 mg/day depending on the hematological response. It is desirable to try to maintain a significant degree of bone marrow depression to keep the leukocyte count in the range of 3000 to 3500 cells/mcL.
• Hoogstraten et al have started therapy with 0.15 mg/kg/day for 7 days followed by a rest period of at least 14 days, but it may be up to 5 to 6 weeks. Maintenance therapy is started when the white blood cell and platelet counts are rising. The maintenance dose is 0.05 mg/kg/day or less and is adjusted according to the blood count.
• One study by Alexanian et al has shown that using this drug in combination with prednisone significantly improves the percentage of patients with multiple myeloma who achieve palliation. One regimen has been to administer courses of this drug at 0.25 mg/kg/day for 4 consecutive days (or, 0.2 mg/kg/day for 5 consecutive days) for a total dose of 1 mg/kg/course. These 4- to 5-day courses are then repeated every 4 to 6 weeks if the granulocyte and platelet count have returned to normal levels.

Comments:

• The entire oral dose may be given at one time.
• Numerous oral regimes have been used. Scientific literature and/or institutional protocol should be consulted for further information.
• Oral administration of this drug results in variable absorption; dosage may need to be cautiously increased until myelosuppression is seen to ensure that therapeutic levels have been reached.
• The administration of this drug with prednisone is more effective than this drug as monotherapy. The combination is usually given on an intermittent basis, although the superiority of this technique over continuous therapy has not been established.
• Evidence suggests that one-third to one-half of the patients with multiple myeloma show a favorable response to administration of this drug.
• Experience with oral administration suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if therapy is abandoned prematurely.
• There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.

IV (when oral therapy is not appropriate):
16 mg/m2 as a single IV infusion over 15 to 20 minutes every 2 weeks for 4 doses; then, after adequate recovery from toxicity, at 4-week intervals

Comments:

• Evidence suggests that one-third to one-half of the patients with multiple myeloma show a favorable response to administration of this drug.
• Dose adjustment based on blood cell counts at the nadir and day of therapy should be considered.
• There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.
• Consult local institutional guidelines for alternate dosing options.

Uses:

• Oral: For the palliative treatment multiple myeloma.
• IV: For the palliative treatment multiple myeloma when oral therapy is not appropriate.

Usual Adult Dose for Ovarian Cancer

Common regimen: 0.2 mg/kg orally daily for 5 days as a single course; courses are repeated every 4 to 5 weeks depending upon hematologic tolerance

Comments:

• There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.
• Consult local institutional guidelines for alternate dosing options.

Use: For the palliation of nonresectable epithelial carcinoma of the ovary.

Renal Dose Adjustments

• In patients with moderate to severe renal impairment, currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction to those patients, but it may be prudent to use a reduced dose initially.
• Patients with azotemia should be closely observed to make dosage reductions, if required, as soon as possible.

IV:
A reduction of up to 50% should be considered in patients with renal insufficiency (BUN greater than or equal to 30 mg/dL).

ORAL:
A recommendation as to whether dosage reduction should be made routinely in patients with renal insufficiency cannot be made because:

• There is considerable inherent patient-to-patient variability in the systemic availability of this drug in patients with normal renal function.
• Only a small amount of the administered dose appears as parent drug in the urine of patients with normal renal function.

Liver Dose Adjustments

Data not available

Dose Adjustments

Consult institutional protocol.

Precautions

US BOXED WARNINGS:

• This drug should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.
• Severe bone marrow suppression with resulting infection or bleeding may occur and is more pronounced with the IV formulation
• This drug is leukemogenic in humans
• This drug produces chromosomal aberrations; therefore, it should be considered potentially mutagenic in humans

CONTRAINDICATIONS:

• Hypersensitivity to the active component or any of the ingredients
• In patients whose disease has demonstrated prior resistance to this drug

This drug is not recommended for use in children.

Consult WARNINGS section for additional precautions.

Dialysis

This drug is not removed from plasma to any significant degree by hemodialysis.

Other Comments

Administration advice:

• The IV formulation of this drug is for IV use and regional arterial perfusion only.
• This drug should not be given without hematopoietic stem cell rescue at doses of above 140 mg/m2.

Storage requirements:

• Store at room temperature 25C (77F).
• Temperature excursions permitted between 15C- 30C (59F-86F).
• Keep product in original container and protect from light.

• For IV administration, it is recommended that the solution is injected slowly into a fast-running infusion solution via a swabbed injection port.
• If direct injection into a fast-running infusion is not appropriate, the solution may be administered diluted in an infusion bag.
• Discard any solution with visible turbidity or crystallization.
• Care should be taken to avoid possible extravasation of the IV formulation and in cases of poor peripheral venous access, consideration should be given to use of a central venous line.
• If high dose IV solution is administered with or without autologous bone marrow transplantation, administration via a central venous line is recommended.
• For regional arterial perfusion, the literature should be consulted for detailed methodology.

IV compatibility:

• The IV formulation of this drug is not compatible with infusion solutions containing dextrose and it is recommended that only sodium chloride IV infusion 0.9% w/v is used.

Monitoring:

• Hematologic: Complete blood counts.
• Hepatic: Liver function.
• Oncologic: Secondary malignancies.

Patient advice:

• Read the US FDA-approved patient labeling (Patient Information and Instructions for Use).
• Women of childbearing potential should be advised to avoid becoming pregnant.
• Women of child-bearing potential should be advised to use effective contraception during therapy and for at least 6 months after the last dose.
• Nursing women should be advised not to breastfeed during treatment with this drug and for at least one week after the last dose.
• Males with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose.
• Patients should be informed that the major toxicities of this drug are related to bone marrow suppression, hypersensitivity reactions, GI toxicity, and pulmonary toxicity.
• The major long-term toxicities are related to infertility and secondary malignancies.
• Patients should only receive this drug under medical supervision and should be advised to consult their physician if they experience skin rash, vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses.