Isophosphamide

Uses

Isophosphamide is used for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. It should be used in combination with Mesna for prophylaxis of hemorrhagic cystitis.

Isophosphamide is also used to associated treatment for these conditions: Cancer, Bladder, Cervical Cancers, Ewing's Sarcoma, Head and Neck Carcinoma, Lymphoma, Hodgkins, Malignant Neoplasm of Pancreas, Non-Hodgkin's Lymphoma (NHL), Ovarian Cancer, Sarcoma, Osteogenic, Small Cell Lung Cancer (SCLC), Soft Tissue Sarcoma (STS), Testicular Germ Cell Cancer, Advanced thymic carcinoma

How Isophosphamide works

The exact mechanism of ifosfamide has not been determined, but appears to be similar to other alkylating agents. Isophosphamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra strand cross-links in the DNA results in cell death.

Dosage

Isophosphamide dosage

Lymphoma, Sarcoma, Solid tumours: Different licensed dosage regimens are available.

• Regimen 1: 8-12 gm/m2 divided over 3-5 days, repeat course every 2-4 wk.
• Regimen 2: 6 gm/m2 divided over 5 days, repeat course every 3 wk.
• Regimen 3: 5-6 gm/m2 (max: 10 gm), give as a single 24-hr infusion, repeat course every 3-4 wkly.

Germ cell testicular carcinoma: 1.2 gm/m2/day for 5 days via slow infusion over at least 30 minutes, repeat treatment every 3 wk or after recovery from haematological toxicity. To be given with mesna and adequate hydration of at least 2 L of oral or IV fluid per day.

Add 20 ml of sterile water for inj or sterile bacteriostatic water for inj containing benzyl alcohol or parabens for each 1 g of the drug to produce solutions of 50 mg/ml.

Side Effects

Confusion, alopoecia, nausea, vomiting, phloebitis, somnolence, depression, hallucinations. Wound healing may be impaired during ifosfamide use.

Potentially Fatal: Severe myelosuppression, haemorrhagic cystitis, nephrotoxicity, cardiotoxicity, coma.

Toxicity

LD₅₀ (mouse) = 390-1005 mg/kg, LD₅₀ (rat) = 150-190 mg/kg. Side effects include nausea, vomiting and myelosuppression. Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine).

Precaution

Hepatic or renal dysfunction, compromised bone marrow reserve. Use with mesna and ensure high oral/IV fluid intake to reduce urotoxic effects.

Interaction

Causes enhanced toxicity with allopurinol, cisplatin. Isophosphamide enhances the anticoagulant effect of warfarin. CYP2A6 inducers (e.g. amobarbital, pentobarbital, phenobarbital, rifampin and secobarbital) may reduce serum levels of ifosfamide while the inhibitors (e.g. isoniazid, methoxsalen and miconazole) may increase its serum levels. CYP3A4 inducers (e.g. aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins) may reduce serum levels of ifosfamide while the inhibitors (e.g. azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid) may increase its serum levels.

Food Interaction

• Avoid alcohol. Ingesting alcohol may worsen nausea and vomiting caused by ifosfamide.
• Exercise caution with grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of ifosfamide to its active metabolite, therefore reducing its efficacy.
• Exercise caution with St. John's Wort. Close monitoring is warranted as this herb induces the CYP3A4 metabolism of ifosfamide to its alkylating active metabolites, including, chloroacetaldehyde, a nephrotoxic and neurotoxic metabolite.

Isophosphamide Alcohol interaction

[Moderate]

Centrally-acting agents such as antiemetics, sedatives, narcotics, or antihistamines may add to the neurotoxic effects of ifosfamide.

Administration of ifosfamide can cause CNS toxicity, which necessitates careful monitoring of the patient.

Neurologic manifestations include somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma.

There have also been reports of peripheral neuropathy.

Isophosphamide neurotoxicity may occur within a few hours to a few days after initial administration and typically resolves within 48 to 72 hours of ifosfamide discontinuation.

However, symptoms may persist for longer periods of time, and recovery has occasionally been incomplete.

Fatal outcomes have been reported.

There have also been reports of recurrence of CNS toxicity after several uneventful treatment courses.

Due to the potential for additive effects, centrally-acting agents should be used with caution in combination with ifosfamide.

Patients should be advised to avoid driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how the medications affect them.

If ifosfamide-induced encephalopathy occurs, both ifosfamide and non-essential concomitant CNS agents should be discontinued.

Supportive therapy should be initiated and maintained until complete resolution of neurotoxicity.

Isophosphamide Drug Interaction

Moderate: doxorubicin, doxorubicin, lorazepam, lorazepam, meperidine, meperidine, pegfilgrastim, pegfilgrastimUnknown: charcoal, charcoal, palonosetron, palonosetron, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, sodium iodide, sodium iodide, cholecalciferol, cholecalciferol, ondansetron, ondansetron

Isophosphamide Disease Interaction

Major: infections, myelosuppressionModerate: CNS toxicity, hepatic dysfunction, renal dysfunction

Volume of Distribution

Isophosphamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. When given to pediatric patients, the volume of distribution was 21±1.6 L/m^2.

Half Life

7-15 hours. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age.

Clearance

• 2.4±0.33 L/h/m^2 [pediatric patients]

Elimination Route

Isophosphamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses. After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6–2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours.

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Hypersensitivity; severe bone-marrow depression. Pregnancy, lactation.

Special Warning

Renal Impairment: CrCl <10: Administer 75% of dose.

Storage Condition

Store at 20-25° C.

Innovators Monograph

You find simplified version here Isophosphamide