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ifosfamide
ifosfamide
SYNONYM(S): IFO; Iphosphamide; Isophosphamide; NSC-109724
COMMON TRADE NAME(S): Ifex® (multiple brands available)
Ifosfamide is a structural analogue of cyclophosphamide and its mechanism of action is presumed to be identical. Ifosfamide is cell cycle phase-nonspecific. Cross-resistance has been reported in vitro between ifosfamide, cyclophosphamide and other alkylating agents.
Oral: 90-100% bioavailability, but associated with significant neurotoxicity
IV: Maximal concentration of alkylating metabolites occurred at 3 hours after dosage
Distributed throughout the body. Present in breast milk and in ascites.
Cross blood brain barrier? |
Ifosfamide: yes, low; |
PPB | low |
Activated by hepatic microsomal enzyme oxidation system; pathways saturated at higher doses; autoinduction of hepatic metabolism → time dependent decrease of half-life
Active metabolites | Ifosfamide mustard, acrolein |
Inactive metabolites | yes |
Excreted in kidneys; elimination fits two compartment model for large bolus doses and one compartment model for fractionated doses.
Urine | ± 50% unchanged, 20-36% as metabolites |
Half-life | 7-15 hrs (depending on schedule) |
- Cervical cancer (single agent or combination, advanced or recurrent disease)
- Sarcoma, soft tissue (single agent, 1st or 2nd line)
- Pancreatic cancer (single agent, 2nd line)
Other Uses:
- Genitourinary cancer (penile, testicular)
- Sarcomas (osteogenic, Ewing's, uterine)
- Hodgkin's lymphoma
- Non-Hodgkin's lymphoma
- Germ cell ovarian cancer
Emetogenic Potential:
Extravasation Potential: Irritant
ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
---|---|---|---|---|---|
Auditory | Tinnitus / deafness (rare) | E D | |||
Cardiovascular | Arrhythmia (rare, at high doses) | E | |||
Arterial thromboembolism (rare) | E | ||||
Cardiotoxicity (<1%, at high doses) | E | ||||
Hypotension (<1%) | E | ||||
Venous thromboembolism (rare) | E | ||||
Dermatological | Alopecia (90%) | E | |||
Rash (<1%, may be severe) | E | ||||
Gastrointestinal | Abdominal pain (rare) | E | |||
Anorexia (1%) | E | ||||
Constipation (rare) | E | ||||
Diarrhea (<1%) | E | ||||
Mucositis (<1%) | E | ||||
Nausea, vomiting (47%) | I | ||||
General | Edema (including effusions) | E | |||
Fatigue (<1%) | E | ||||
Hematological | Disseminated intravascular coagulation (rare) | E | |||
Hemolysis (rare) | E | ||||
Hemolytic uremic syndrome (rare) | E | ||||
Immunosuppression | E | ||||
Myelosuppression ± infection, bleeding (grade 3 or 4: 44%) | E | ||||
Hepatobiliary | ↑ LFTs (2%) (may be severe) | E | |||
Pancreatitis (rare) | E | ||||
Hypersensitivity | Hypersensitivity (rare) | I | |||
Injection site | Phlebitis (3%) | I | |||
Metabolic / Endocrine | Abnormal electrolyte(s) | E | |||
Acidosis (rare) | E | ||||
SIADH (rare) | I E | ||||
Musculoskeletal | Arthralgia / myalgia | E | |||
Rhabdomyolysis (rare) | E | ||||
Neoplastic | Secondary malignancy (rare) | D L | |||
Nervous System | Neuropathy (peripheral, <1%) | E | |||
Neurotoxicity (15%) | I E | ||||
Vertigo (rare) | E | ||||
Ophthalmic | Blurred vision (rare) | E | |||
Conjunctivitis | E | ||||
Renal | Nephrotoxicity (>10%) | E | |||
Renal tubular acidosis (>10%, proximal tubular damage, Fanconi syndrome) | E D L | ||||
Reproductive and breast disorders | Infertility (gonadal damage) | L | |||
Respiratory | Pneumonitis (rare) | D | |||
Urinary | Hemorrhagic Cystitis (21%) | I E |
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common reported side effects are alopecia, nausea and vomiting, hemorrhagic cystitis, nephrotoxicity and myelosuppression.
The incidence of urotoxic effects without an uroprotector can be up to 40% and is dose-dependent; coadministration with mesna and adequate hydration are mandatory. Patients may present with hematuria, symptomatic cystitis or bladder fibrosis. Past or concomitant radiation of the bladder or busulfan treatment may increase the risk of hemorrhagic cystitis. Several methods of treatment for established hematuria have been described: Bladder irrigation with water or NS, intravesical instillation of astringents (alum, silver nitrate), systemic administration of antifibrinolytics (aminocaproic acid, tranexamic acid), cystoscopy to evacuate the bladder of clots, continuous bladder irrigation and intravesical prostaglandins. For severe or refractory hematuria, intravesical formalin, phenol or prostaglandin has been used ± surgical intervention (electrocautery, cryosurgery, diversion of urine flow, hypogastric artery ligation or cystectomy).
Glomerular, proximal or distal tubular impairment may all occur, often in combination and may progress even after ifosfamide has been discontinued. Proximal tubular damage often presents as Fanconi syndrome with low serum bicarbonate, proteinuria, glucosuria, aminoaciduria and hypochloremic metabolic acidosis. Risk factors for the development of nephrotoxicity include age less than 5 years; pre-existing renal impairment; prior treatment with cisplatin; concurrent use of nephrotoxic drugs, reduced renal reserve (unilateral nephrectomy, renal radiation); hydronephrosis and total cumulative dose. Renal impairment may increase the risk of myelosuppression and possibly, cardiotoxicity. Mesna does not appear to be protective against the proximal tubular abnormalities induced by ifosfamide.
Central nervous system toxicity appears to be dose-dependent, and is variable in onset, but usually resolve when ifosfamide is discontinued. Incidence is higher with higher doses, concomitant use of aprepitant, electrolyte imbalances, renal/ hepatic impairment or pre-existing CNS disorders. It may manifest as transient mental status changes (somnolence, confusion, hallucination, disorientation, and lethargy), cerebellar dysfunction, extrapyramidal symptoms, transient weakness, cranial nerve dysfunction or seizure activity. Methylene blue, which may act as an electron acceptor or decrease chloracetaldehyde formation, has been suggested as treatment or prophylaxis of ifosfamide-induced encephalopathy.
Myelosuppression is dose and AUC-dependent.
Arrhythmia, ST- and T-wave changes, cardiomyopathy, effusions and pericardial fibrosis have been reported. Cardiac effects are dose dependent and the risk is increased with known cardiac risk factors.
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.
Electrolyte imbalances, urinary obstruction and cystitis must be excluded before treatment and adequate hydration is needed. The use of concurrent mesna is mandatory to prevent severe hematuria from ifosfamide. For ifosfamide short infusions, mesna (at 20% of the ifosfamide dose for each dose of mesna) should be given IV at the start plus at 4 and 8 hours after each ifosfamide dose. See mesna drug monograph.
Prophylactic anti-emetics are required; the risk of neurotoxicity is increased with concomitant use of aprepitant.
Single agent (q3-4 weeks):
- IV short infusion: 2 to 2.4 g/m2 per day on 5 consecutive days
- IV continuous infusion: 5-8 g/m2 total dose over 24 hours with continuous mesna infusion
Dosage in myelosuppression:
Modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Hematologic and Non-Hematologic Toxicities."
(Continued on next page)
Worst Toxicity / Counts (x 109/L) in previous cycle |
|
Worst Toxicity / Counts (x 109/L) in previous cycle |
Ifosfamide (% previous dose)* |
Febrile Neutropenia Or ANC < 0.5 for ≥ 5-7 days |
Or
|
Thrombocytopenic bleeding Or Platelets < 25 |
↓ 20% or consider GCSF for isolated neutropenia |
ANC ≥ 1.5 |
Or
|
Platelets ≥ 100 |
100%
|
Somnolence or other signs of encephalopathy |
|
|
Hold; methylene blue 50mg IV q4h until resolution. Consider prophylactic methylene blue for subsequent cycles. Consider discontinuing or dose reduction for next cycle. |
Grade 3 or 4 neurotoxicity |
|
|
Discontinue
|
Grade 3 related organ / non-hematologic |
|
|
↓ 20%
|
Grade 4 related organ / non-hematologic LVEF ≤ 45% |
|
|
Discontinue
|
* Do not retreat until ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L and toxicity recovered to ≤ grade 2. |
Management of Urotoxicity
Finding
|
Action
|
Microscopic hematuria |
Hold ifosfamide until resolves
|
Macroscopic hematuria |
Discontinue or reduce dose
|
Bilirubin |
|
AST/ALT |
Ifosfamide* (% previous dose)
|
1-2 x ULN |
and/ or |
<2 x ULN |
100% |
2-4 x ULN |
2-5 x ULN |
75% |
|
> 4 x ULN |
> 5 x ULN |
Discontinue |
Ifosfamide
(% previous dose) |
|
> 60 |
100% |
40-60 |
75% |
20-40 |
50% |
< 20 |
Discontinue |
- 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, see mesna monograph.
- 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.
IFOSFAMIDE AND MESNA INFUSION ADMIXTURE
- May be diluted in larger volumes for continuous infusion over 6-24 hours; May be infused using a CADD ambulatory infusion pump over longer periods.
Ifosfamide is contraindicated in patients with known hypersensitivity to the drug, with severe myelosuppression, severe renal and/or hepatic impairment, cystitis, obstructive uropathy, active infections/severe immunosuppression, or cerebral arteriosclerosis.
Mesna must be coadministered. Use with caution in patients with prior radiotherapy or anticancer therapy, concomitant aprepitant usage, hepatic or renal impairment, 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. Do not use within 10 to 14 days of surgery or within 3 months after nephrectomy. Avoid the use of live vaccines. Electrolytes imbalances must be corrected before treatment. CNS effects may interfere with driving or tasks that require alertness.
Ifosfamide has mutagenic, teratogenic, fetotoxic and carcinogenic properties and should not be used in pregnancy. Effective contraception must be used by both sexes during ifosfamide treatment and for at least 12 months after treatment cessation. Fertility is usually affected. In post-pubertal boys ifosfamide may cause irreversible gonadal damage resulting in sterility. Ifosfamide is excreted in breast milk, therefore breastfeeding is not recommended.
Ifosfamide is a major substrate of CYP3A4 and a minor substrate of 2A6, 2B6, 2C8, 2C19 and 2C9. Inhibitors or inducers of these isoenzymes may decrease or increase the metabolism of ifosfamide. Ifosfamide is also a weak inhibitor of CYP3A4 and a weak inducer of CYP2C8 and 2C9. Patients receiving agents that reduce ifosfamide activation should be monitored for a possible reduction in therapeutic effectiveness; dosage adjustment may be required.
AGENT | EFFECT | MECHANISM | MANAGEMENT |
---|---|---|---|
Aprepitant | ↑ neurotoxicity reported; may ↓ effectiveness of ifosfamide | inhibits ifosfamide metabolism and → formation of neuro/nephrotoxic metabolites | Caution and monitor |
Drugs acting on the CNS (e.g. antihistamines, narcotics, some antiemetics, sedatives, SSRIs, neuroleptics, tricyclics) | ↑ CNS toxicity | Additive | Discontinue if possible. Caution and monitor for CNS toxicity if must be used. |
Hepatic-enzyme inducing drugs (e.g. phenytoin, phenobarbital, corticosteroids, St. John’s wort) | May ↑ ifosfamide toxicity | ↑ activation of ifosfamide to its active and toxic metabolite | Caution and monitor |
radiation | May ↑ sensitivity to radiation; ↑ hemorrhagic cystitis (radiation of bladder), ↑ cardiotoxicity (radiation of cardiac region) | Additive | Caution and monitor |
warfarin | ↑ anti-coagulant effect, ↑ INR | possibly inhibition of warfarin metabolism and/or displacement of warfarin from protein binding sites | monitor prothrombin time |
Docetaxel | ↑ GI toxicity when ifosfamide given before docetaxel infusion | Unknown | Avoid; monitor closely if must be used |
CYP3A4 inhibitors (i.e. ketoconazole, voriconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges, starfruit or pomegranate ) | May ↓ ifosfamide effectiveness, or ↑ formation of neurotoxic metabolite through another metabolic pathway | ↓ activation and metabolism of ifosfamide | Caution and monitor |
Cisplatin | ↑ hearing loss, nephrotoxicity | Unknown (hearing loss); additive (nephrotoxicity) | Caution and monitor |
Alcohol | ↑ nausea/vomiting or neurotoxicity | Additive | Avoid |
ACE inhibitors | ↑ risk of leukopenia or agranulocytosis | Additive | Caution and monitor |
Other cardiotoxic drugs (anthracyclines) | ↑ cardiotoxicity risk | Additive | Caution and monitor |
Other nephrotoxic drugs (e.g. cisplatin, aminoglycosides, amphotericin B, acyclovir) | ↑ risk of nephrotoxicity | Additive | Caution and monitor |
Busulfan | ↑ risk of hemorrhagic cystitis | Additive | Caution and monitor |
Immunosuppressants | ↑ immuno-suppression | Additive | Caution and monitor |
Drugs that may cause pulmonary toxicity (e.g. amiodarone, bleomycin) | ↑ risk of lung toxicity | Additive | Caution and monitor |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Monitor Type | Monitor Frequency |
---|---|
CBC | Baseline and regular |
Urinalysis, for RBCs and specific gravity | before each dose and regular |
Liver function tests | Baseline and regular |
Renal function tests, including electrolytes | Baseline and regular |
Clinical assessment of neurotoxicity (especially in patients with increased risk), infection, bleeding and cystitis |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Ajithkumar T, Parkinson C, Shamshad F, et al. Ifosfamide encephalopathy. Clinical Oncology 2006; 19: 108-14.
Chang TKH, Weber GF, Crespi CL, et al. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Research 1993;53:5629-37.
Chang TKH. Cytochrome P450 in cancer therapeutics. In: Ioannides C, ed. Cytochromes P450: role in the metabolism and toxicity of drugs and other xenobiotics. Guildford, UK: Royal Society of Chemistry; 2008, p. 485.
DeVries CR, Freiha FS. Hemorrhagic cystitis: a review. J Urology 1990; 143(1): 1-9.
Ifosfamide: The Merck Manual [Internet]; 2011 [cited 2012 March 12]. Available from: http://www.merckmanuals.com/professional/lexicomp/ifosfamide.html
Jarkowski A 3rd. Possible contribution of aprepitant to ifosfamide-induced neurotoxicity. Am J Health Syst Pharm. 2008 Dec 1;65(23):2229-31.
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Lorigan P, Verweij J, Papai Z, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer soft tissue and bone sarcoma group study. J Clin Oncol 2007;25:3144-50.
McEvoy GK, editor. AHFS Drug Information 2011. Bethesda: American Society of Health-System Pharmacists, p. 1093-8.
Product monograph: Ifex® (ifosfamide). Baxter Corporation, April 5, 2012.
Sarosy G. Ifosfamide – pharmacologic overview. Semin Oncol 1989; 16(1 Suppl 3): 2-8.
October 2017 edited other indications
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