REPEAT EVERY 21 DAYS

For a usual total of 8 cycles unless disease progression or unacceptable toxicity occurs

Other Supportive Care:

Doses should be modified according to the protocol by which the patient is being treated.

Hematologic Toxicities

See Appendix 6 for general recommendations.

The dose of ifosfamide should be reduced in the presence of hepatic impairment.

_{* Upon the discretion of the prescriber, less dose reduction may be suggested. See CISPLATIN drug monograph.}

Refer to ifosfamide, mesna, CISplatin drug monograph(s) for additional details of adverse effects

Refer to ifosfamide, mesna, CISplatin drug monograph(s) for additional details

• Aprepitant, CNS depressants and alcohol increase neurotoxicity with ifosfamide; avoid where possible, caution and monitor closely if used
• Ifosfamide is a major substrate of CYP3A4 and susceptible to drug interactions from CYP3A4 inducers and inhibitors. Avoid strong inducers and inihibtiors where possible. Caution and monitor closely if used together.
• Caution and monitor INR closely in patients receiving warfarin
• Avoid nephrotoxic and ototoxic drugs with cisplatin where possible. Caution and monitor renal function closely if used together.
• Caution and monitor phenytoin levels for patients receiving phenytoin

Refer to ifosfamide, mesna, CISplatin drug monograph(s) for additional details

Administration

Ifosfamide:

• May give bolus dose of mesna before ifosfamide infusion, with or without mesna admixed in ifosfamide solution, then followed by 2 doses of mesna by IV bolus or PO.
• Add reconstituted drug to NS or D5W for infusion; the final concentration should be between 0.6 to 20 mg/mL.
• May mix doses ≤2000mg in 100mL bag; Infuse over 30-60 minutes.
• May mix doses >2000mg in 500-1000mL bag; Infuse over 1-4 hours.
• May be admixed with mesna.
• Oral hydration is strongly encouraged; poorly hydrated patients may need more IV hydration.
• Inadequate total hydration may result in dose-related hemorrhagic cystitis.

mesna:

• May be diluted in 50-100mL of diluent (D5W, NS) up to final concentration of 1 mg/mL to 20 mg/mL and given IV over 15-30 minutes.
• May be diluted in larger volumes (1 mg/mL to 20 mg/mL) for continuous infusion over 3-24 hours.
• May be infused concurrently with ifosfamide.  Note:  Benzyl alcohol in multi-dose vials can reduce the stability of ifosfamide and cyclophosphamide.
• Incompatible in solution with cisplatin or carboplatin, nitrogen mustard.  Admixtures with epirubicin lead to inactivation of epirubicin.
• In addition to mesna use, sufficient hydration and urine output should still be maintained.
• IV solution may be given PO; may be mixed with juice, cola or milk to mask unpleasant taste. The manufacturer (for Uromitexan®) reccomends that multi-dose vials should not be used for PO doses.
• Store ampoules and multi-dose vials at 15-25°C.

CISplatin:

• Ensure good urinary output during chemotherapy visit.  Patient should void at least once during chemotherapy visit.  Use locally approved hydration regimens.
• Blood pressure should be taken before and after chemotherapy.
• Additional hydration may be ordered for hypovolemic patients.
• Hydration and diuresis for patients with pre-existing renal, cardiac, or diabetic history at discretion of physician.
• Oral hydration with 8 glasses of fluid per day is strongly encouraged on treatment day and for 1-2 days after cisplatin; if nausea and vomiting prevent oral hydration, the patient may need to return for more IV hydration.
• Cisplatin is physically incompatible with any IV set, needle or syringe containing aluminum.
• Store unopened vials between 15°C to 25°C and protect from light.  Do not refrigerate or freeze since precipitation will occur.

Contraindications:

• Patients with known hypersensitivity to these drugs, other platinum-containing compounds, with severe myelosuppression, severe renal and/or hepatic impairment (unless potential benefit outweighs risk), cystitis, obstructive uropathy, active infections/severe immunosuppression, or cerebral arteriosclerosis.

Other warnings/precautions:

• Use mesna with caution in patients with hypersensitivity to other thiols. Formulations containing benzyl alcohol should not be used in pediatric patients who are 12 years old and younger.
• Use ifosfamide with caution in patients with prior radiotherapy or anticancer therapy, concomitant aprepitant usage, risk factors for cardiotoxicity, hypoalbuminemia, pre-existing cardiac disease, brain or extensive bone marrow metastases, concurrent or prior use of nephrotoxic agents or prior nephrectomy.
• Avoid the use of live vaccines.
• CNS effects may interfere with driving or tasks that require alertness.
• These drugs are not recommended for use in pregnancy. Appropriate contraception should be used during treatment, and for at least 6 months after the last dose (generic recommendation)
• Breastfeeding is not recommended while receiving treatment.
• Fertility effects are probable.

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Suggested Clinical Monitoring

Cisplatin and ifosfamide drug monographs, Cancer Care Ontario.

Sutton G, Brunetto VL, Kilgore L, Soper JT, McGehee R, Olt G, et al. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 2000;79:147-53.

IFOS-CISP: Gynecological Systemic Treatment Summaries, Juravinski Cancer Centre, March 2010.