VA Class:AN100
Ifosfamide, an alkylating agent structurally related to cyclophosphamide, is an antineoplastic agent.1, 2, 3, 96, 103, 111, 112
Ifosfamide is used in conjunction with other antineoplastic agents for salvage therapy in the treatment of germ cell testicular neoplasms,1, 2, 3, 4, 6, 7, 9, 52 and has been designated an orphan drug by the US Food and Drug Administration (FDA) for this use.5 The drug also has been designated an orphan drug by FDA for use in the treatment of various bone and soft tissue sarcomas,5 and usually is included as a component of various regimens for initial chemotherapy in these sarcomas.2, 3, 9, 33, 34, 37, 38, 39, 40, 41, 44, 45, 47, 49, 50, 51, 111 In addition, ifosfamide is used for initial or second- or third-line therapy in the treatment of various other malignancies including lung cancer†, 2, 3, 8, 9, 10, 11, 12, 13, 54, 132 cervical cancer†, 2, 3, 9, 20, 21, 22, 23, 24, 25, 152, 153, 154, 155, 156, 157, 158 and ovarian cancer†.2, 3, 9, 26, 27, 28, 29 Mesna, a uroprotective sulfhydryl (thiol) compound, is administered concomitantly with ifosfamide to minimize urotoxicity.1, 2, 3, 4, 58, 59, 95
Ifosfamide is used as a component of various chemotherapeutic regimens for salvage therapy in patients with recurrent or refractory germ cell testicular cancer.1, 2, 3, 4, 6, 7, 9, 52 Although the manufacturer states that such therapy is considered third-line,1 a regimen of ifosfamide, cisplatin, and either vinblastine sulfate or etoposide has induced complete responses in 20-45% of patients who previously received other cisplatin-based chemotherapy regimens,3, 4, 6, 7, 52 and is considered by most clinicians to be the standard initial salvage (i.e., second-line) regimen in patients with recurrent testicular cancer.52, 141 Patients with minimal or moderate disease have a more favorable outcome with this salvage regimen than those with extensive disease.4, 52 In a clinical study in patients with recurrent germ cell tumors (who had previously received at least 2 cisplatin-based chemotherapy regimens and were considered to have cisplatin-responsive disease), a regimen of ifosfamide, cisplatin, and either vinblastine sulfate or etoposide resulted in disease-free status in 36% of patients (with or without surgery) and median duration of disease control ranged from 3 to more than 42 weeks, median survival was 53 weeks, and 20% of patients had survival of 2 years or longer.1, 4 In patients with refractory disease, high-dose chemotherapy (e.g., carboplatin and etoposide with or without ifosfamide) with autologous bone marrow transplant (ABMT) or peripheral stem cell rescue may produce durable complete remissions in some patients.52, 141, 142 Patients with progressive tumors during initial or salvage therapy and those with refractory mediastinal germ cell tumors generally appear to benefit less from high-dose chemotherapy and ABMT or peripheral stem cell rescue than those whose disease relapses after a response.52 Salvage surgery also may be considered for certain highly selected patients (e.g., those with chemorefractory disease confined to a single site).52
The role of ifosfamide in the initial management of patients with advanced testicular cancer remains to be more fully elucidated.4, 111, 116, 141 However, there is some evidence that response rate and survival in patients with previously untreated, advanced germ cell testicular cancer are similar and hematologic toxicity less pronounced with a regimen of ifosfamide, cisplatin, and etoposide compared with a regimen of cisplatin, etoposide, and bleomycin.141
Ifosfamide is used as a component of various chemotherapeutic regimens in conjunction with surgery and/or radiation therapy in the treatment of various bone and soft tissue sarcomas† in adults and children†.2, 3, 9, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 111 Regimens that include ifosfamide have been used for initial or second-line chemotherapy in these sarcomas.2, 3, 9, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, 50, 51, 111
Ifosfamide has been used in conjunction with other drugs (e.g., etoposide)9, 35, 36, 40, 41 and occasionally alone37, 40, 42 in the treatment of localized, metastatic, and recurrent osteosarcoma† in adults and children†. When used for initial therapy ofosteosarcoma†, ifosfamide has been included as a component of various chemotherapeutic regimens both preoperatively (as a neoadjunct) and postoperatively (as an adjunct) in conjunction with surgical resection of the tumor.9, 40, 41 Although ifosfamide is considered one of the more active drugs that can be used in the management of osteosarcoma,37 various regimens have been used in combination therapy for the disease and comparative efficacy is continually being evaluated.37, 40 In addition, although chemotherapy is being used preoperatively in an attempt to increase the likelihood of a limb-sparing procedure (rather than amputation) as well as to evaluate the potential response to specific chemotherapy regimens, the role of preoperative therapy in affecting the extent of surgery required for complete ablation of the primary tumor and the prognostic value of response to such chemotherapy regarding possible disease recurrence remain to be more fully elucidated.40, 141
Ifosfamide also is used as a component of intensive combination chemotherapy for the management of metastatic and unresectable osteosarcoma.40 For metastatic disease, chemotherapy usually is used after, or where possible, before and after, surgical ablation of the primary tumor and, where possible, metastases; multiple thoracotomies may be required to remove recurrent pulmonary metastases.40 Even if the primary tumor and metastases are not resectable, intensive chemotherapy is indicated.40 For patients with recurrent or progressive metastatic disease confined to the lungs, combination chemotherapy may be used as an adjunct to aggressive surgical resection.40 The choice of further therapy depends on many factors including the site of recurrence and prior treatment (e.g., chemotherapy used for primary therapy) as well as patient-specific considerations.40 Ifosfamide used alone37, 40, 42 or in conjunction with etoposide35, 36, 40 has shown activity in up to one-third of patients with recurrent osteosarcoma.
Ifosfamide has been used alone43, 46, 111 or as a component of various chemotherapeutic regimens9, 43, 44, 45, 111 in the palliative treatment of advanced or recurrent adult soft tissue sarcomas†. In adults with advanced or metastatic soft tissue sarcoma, regimens that include doxorubicin with or without other agents (e.g., ifosfamide or cyclophosphamide, dacarbazine, vincristine) have been associated with response rates of 15-30% but with little or no impact on survival.3, 44, 45, 117, 118 Results from clinical studies in patients with advanced soft tissue sarcomas indicate that treatment with doxorubicin as a single agent is as effective as and has a more favorable adverse effect profile than combination regimens;117, 118 however, a regimen of ifosfamide and doxorubicin may be useful in patients in whom substantial tumor-volume reduction is an important therapeutic end point.117 Additional studies, including studies using high-dose ifosfamide, are under way in an attempt to improve the prognosis in patients with advanced soft tissue sarcoma.115, 117
Although the manufacturer states that safe use of ifosfamide in children has not been definitely established,1 ifosfamide is used in conjunction with other antineoplastic agents for the treatment of Ewing's sarcoma†.9, 33, 34, 35, 36, 37, 38, 39, 41 Use of multiple-drug chemotherapy regimens in addition to radiation therapy and/or surgery has been shown to improve the rate of local control and the duration of survival in children with Ewing's sarcoma.33, 37 While a regimen of vincristine, doxorubicin, and cyclophosphamide (with or without dactinomycin) has been widely used in the treatment of children with Ewing's sarcoma, the combination of ifosfamide and etoposide also has shown activity in the disease,33, 34, 37 and results from a large randomized study indicate that outcome may be improved in these children when ifosfamide and etoposide are given in alternating courses with vincristine, doxorubicin (or dactinomycin), and cyclophosphamide.33 A regimen employing alternating courses of chemotherapy that include ifosfamide and etoposide is considered by some clinicians to be the standard initial regimen in children with Ewing's sarcoma.33 Alternating courses of vincristine, doxorubicin, and cyclophosphamide with ifosfamide and etoposide may be used in patients with metastatic Ewing's sarcoma.33 There is some evidence that a regimen of ifosfamide and etoposide also may be effective for the treatment of recurrent Ewing's sarcoma in children who previously received other regimens.33, 35, 36
Ifosfamide also has been used in various combination regimens for the treatment of rhabdomyosarcoma† in children.9, 35, 37, 47, 49, 50, 51 Although not considered standard initial therapy for the treatment of rhabdomyosarcoma by some clinicians,47 ifosfamide in conjunction with vincristine and etoposide or dactinomycin has been used successfully in a limited number of children with rhabdomyosarcoma and is considered by other clinicians as one of several alternative regimens that can be used initially (i.e., as first-line therapy).9, 47, 50, 141 Regimens that have been most extensively evaluated to date include vincristine and dactinomycin for group I tumors and vincristine, dactinomycin, and cyclophosphamide for group II tumors; the addition of doxorubicin to this latter regimen does not appear to improve response.47 Substitution of ifosfamide for cyclophosphamide in this 3-drug regimen and combined therapy with vincristine, ifosfamide, and etoposide also have shown significant activity in this cancer.9, 47, 50 Rhabdomyosarcoma is curable in most children when optimal therapy is used, with more than 60% surviving 5 years after diagnosis.47 Ifosfamide also has been used in conjunction with etoposide in the treatment of recurrent rhabdomyosarcoma in children who have not previously received these drugs.35, 47 Although such patients occasionally achieve a complete remission with second-line therapy, long-term prognosis generally is poor.47, 141
Ifosfamide also has shown activity in the management of Wilms' tumor,35, 36, 60, 61, 133 and has been used in conjunction with etoposide for second-line or salvage therapy in a limited number of children with recurrent Wilms' tumor†.9, 36, 60, 133 Initial chemotherapy for Wilms' tumor usually includes vincristine and dactinomycin (with the addition of doxorubicin for more advanced stages), with regimens that include various combinations with drugs such as ifosfamide, etoposide, carboplatin, and cisplatin generally reserved for patients with relatively poor prognosis such as those with recurrent tumors of unfavorable histology, abdominal recurrence after radiation therapy, or recurrence within 6 months of nephrectomy or after initial 3-drug combination chemotherapy (e.g., vincristine, dactinomycin, and doxorubicin).9, 36, 60, 133, 141 Although Wilms' tumor is curable in most children, with more than 90% surviving 4 years after diagnosis, prognosis in patients with recurrence is variable, with the above patients having a relatively poor prognosis,60 and it remains to be established whether such second-line or salvage therapy (including regimens with autologous bone marrow transplant) can improve prognosis substantially in patients in whom it is relatively poor.60
Ifosfamide is an active agent in the treatment of advanced or metastatic bladder cancer†.143 Concomitant mesna is used to prevent the urotoxicity associated with ifosfamide therapy.9, 95, 143 Ifosfamide has been used alone9, 143 and in combination with other antineoplastic agents144, 145, 146, 147 for the treatment of advanced urothelial carcinoma. Objective responses to ifosfamide have been observed in patients with advanced bladder cancer that did not respond to previous treatment with cisplatin-based regimens.143 However, the use of ifosfamide has been associated with substantial toxicity, including myelosuppression, nephrotoxicity, and encephalopathy, particularly in geriatric patients and patients who have received previous treatment with cisplatin-based regimens.143
In a phase II trial of ifosfamide in 56 patients with advanced urothelial cancer who had received one prior chemotherapy regimen, typically consisting of cisplatin, methotrexate, and vinblastine with or without doxorubicin (abbreviated as M-VAC or CMV, respectively), objective responses occurred in 20% (9% complete responses, 11% partial responses) of patients.143 Dosage reduction was required for all patients because of excessive renal and CNS toxicity associated with the planned treatment schedule.143
Combination therapy with ifosfamide, vinblastine, and gallium nitrate (abbreviated as VIG) produces response rates that appear to be comparable to those observed with M-VAC in patients with advanced or metastatic bladder cancer;145, 146 however, because of the excessive toxicity (particularly hematologic and cardiac toxicity), sometimes fatal, associated with this regimen, no further clinical trials are planned for VIG in patients with transitional cell bladder carcinoma.145, 146, 148, 149
The role of ifosfamide in the treatment of advanced or metastatic bladder cancer has not been established.145, 149 The use of ifosfamide in combination therapy with other antineoplastic agents (e.g., paclitaxel, cisplatin) as first-line or salvage therapy for advanced urothelial carcinoma is being investigated.147, 149
Ifosfamide is used as a component of combination chemotherapy for the treatment of small cell lung cancer†.2, 3, 8, 9, 10, 11, 12, 13, 54, 132 Combination chemotherapy regimens are superior to single-agent therapy for the treatment of small cell lung cancer and moderately intensive drug doses are superior to doses that produce minimal toxicity.3, 8, 12, 54 Various regimens have been used in combination therapy and many 2- to 4-drug combination regimens have produced similar response rates.8, 12, 54 Ifosfamide is used in conjunction with etoposide and either carboplatin or cisplatin for the treatment of small cell lung cancer.3, 9, 10, 11, 12, 13, 54, 132, 150 In clinical studies that used regimens that included ifosfamide, an objective response occurred in 75-95% of patients who had limited disease and in 44-100% of patients who had extensive disease.3, 10, 11, 12, 13, 54, 150 The median duration of disease control with these ifosfamide regimens ranged from 5-45 weeks,3, 12 and median duration of survival was 9-14 months.3, 11, 12, 13, 150 In at least one study, the addition of ifosfamide to a regimen of cisplatin and etoposide improved progression-free and overall survival but was associated with an increased incidence of myelosuppression.150
Although optimum duration of chemotherapy has not been clearly defined, improvement in survival has not been observed when the duration of drug administration exceeds 3-6 or 6 months in patients with limited-stage or extensive-stage small cell lung cancer, respectively.54 While efficacy of the various available regimens is continually being evaluated, a combination chemotherapy regimen containing ifosfamide, a platinum-containing agent (carboplatin or cisplatin), and etoposide is one of several preferred or alternative regimens for the treatment of extensive-stage small cell lung carcinoma.9, 54 Because the current prognosis for small cell lung carcinoma is unsatisfactory regardless of stage and despite considerable diagnostic and therapeutic advances, all patients with this cancer are candidates for inclusion in clinical trials at the time of diagnosis.54
Ifosfamide has been used as a component of combination regimens with cisplatin (e.g., ifosfamide with mesna, cisplatin, and mitomycin) in the treatment of non-small cell lung carcinoma†;2, 3, 9, 14, 15, 16, 17 however, other platinum-containing regimens currently are preferred for the treatment of advanced non-small cell lung cancer.53 The addition of ifosfamide to cisplatin or carboplatin was associated with higher response rates but had no effect on survival and increased the frequency and severity of toxicity (e.g., leukopenia, thrombocytopenia, alopecia, vomiting) in patients with advanced non-small cell lung cancer.151
Ifosfamide is an active agent in the treatment of metastatic or recurrent cervical cancer†.3, 9, 20, 21, 23, 156, 157, 158 Response rates of 16-33% have been reported with use of ifosfamide as a single agent in advanced squamous cell carcinoma of the cervix.20, 21, 23, 24, 157 An overall response rate of 15% was observed in a small uncontrolled phase II study of patients receiving ifosfamide and mesna for recurrent or advanced adenocarcinoma, adenosquamous, or other nonsquamous carcinoma of the cervix.158
Ifosfamide has been used in various combination regimens (e.g., cisplatin and ifosfamide with or without bleomycin) for the treatment of metastatic or recurrent cervical cancer.9, 22, 23, 25, 152, 153, 154, 155 In a large randomized trial, higher response rates and increased duration of progression-free survival but greater toxicity and no difference in overall survival were observed for the combination of ifosfamide (with mesna) and cisplatin compared with cisplatin alone in patients with metastatic or recurrent squamous cell carcinoma of the cervix.152 Although high objective response rates have been observed with the combination regimen of ifosfamide, bleomycin, and cisplatin in women with metastatic or recurrent cervical cancer,153, 154 toxicity is greater and survival is not improved in women receiving the combination regimen rather than cisplatin alone.153 The benefit of combination cisplatin-based chemotherapy regimens, such as cisplatin and ifosfamide, versus cisplatin alone has not been fully established,152, 153, 155, 156, 159 and further study is needed to define the role of ifosfamide in the treatment of advanced cervical cancer.152, 153, 156, 159 (See Uses: Cervical Cancer in Cisplatin 10:00 for overview of treatment for cervical cancer.)
Ifosfamide has been used alone or in conjunction with other antineoplastic agents for second-line (salvage) therapy in patients with advanced or recurrent ovarian carcinoma†.9, 26, 28, 29, 135 In patients with platinum-responsive disease (no disease progression within 5-12 months of discontinuing a platinum-based combination regimen), an objective response has been produced in 25-56% of patients treated with a salvage regimen of ifosfamide and carboplatin.27 In patients with platinum-refractory advanced ovarian carcinoma (i.e., disease that has progressed while treated with a platinum-based regimen or that has recurred shortly after completion of a platinum-based regimen), other drugs (e.g., paclitaxel) generally are preferred for initial second-line therapy.26 However, ifosfamide is one of several drugs that can be considered for salvage therapy in platinum-resistant disease, and partial or complete response has been observed in 12-20% of patients receiving salvage therapy with ifosfamide alone.26, 27, 28
Although ifosfamide has shown some activity when used in conjunction with other antineoplastic agents in the treatment of recurrent or advanced lymphomas†2, 3, 55 and is recommended by some clinicians as one of several alternatives that can be used for the treatment of advanced small noncleaved cell lymphoma (Burkitt's and non-Burkitt's) in children,9, 119 regimens containing other antineoplastic agents generally are preferred for first-line treatment of lymphomas.9, 56, 57, 119, 141
Ifosfamide has shown some activity when used as single-agent therapy in a limited number of patients for the management of advanced or recurrent uterine sarcoma†.30, 31, 32 Ifosfamide therapy has resulted in partial or complete responses in 32% of patients with mixed mesodermal sarcomas and partial responses in 17% of patients with leiomyosarcomas. 30, 31, 32 There currently is no established standard therapy for recurrent uterine sarcoma, and further study is needed to determine the role of ifosfamide when used alone or in combination (e.g., with cisplatin) regimens for the treatment of these tumors.30, 31, 32, 141
Reconstitution and Administration
Ifosfamide is administered by IV infusion.1 IV infusions of ifosfamide should be administered over a period of at least 30 minutes;1, 2 the drug also has been administered by continuous IV infusion.2, 3, 111
To minimize urotoxicity, patients should be adequately hydrated prior to and during ifosfamide therapy (e.g., 2 liters of oral or IV fluid daily).1, 2, 58, 59, 141 In addition, a uroprotective agent such mesna should be administered during ifosfamide therapy to decrease the incidence of ifosfamide-induced bladder toxicity (e.g., hemorrhagic cystitis, hematuria); adequate uroprotection is particularly important at relatively high dosages.1, 2, 58, 59, 95, 141
Because of the carcinogenic potential of ifosfamide (see Cautions: Mutagenicity and Carcinogenicity), the usual precautions for handling and preparing solutions of cytotoxic drugs should be observed.1 The manufacturer recommends use of protective gloves when handling ifosfamide since accidental exposure may be associated with skin reactions.1 If ifosfamide solution comes in contact with skin or mucosa, affected skin areas should be washed immediately and thoroughly with soap and water and affected mucosa should be thoroughly rinsed with copious amounts of water.1
Ifosfamide sterile powder is reconstituted by adding 20 or 60 mL of sterile water for injection or of sterile bacteriostatic water for injection containing benzyl alcohol or parabens to a vial labeled as containing 1 or 3 g of the drug, respectively, to provide solutions containing 50 mg/mL.1 These reconstituted solutions may be infused directly or further diluted to a concentration of 0.6-20 mg/mL with a compatible IV solution (see Chemistry and Stability: Stability).1
Alternatively, commercially available aqueous isosfamide injection labeled as containing 100 mg/mL may be infused directly or diluted to 20 mg/mL in a compatible IV solution.160 (See Chemistry and Stability: Stability.) Dilution of each mL of the commercially available injection in 4 mL of IV solution will yield a final concentration of 20 mg/mL.160
Ifosfamide solutions should be inspected visually for discoloration and particulate matter prior to administration.1
Dosage of ifosfamide must be based on the clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic response with minimal adverse effects.1 Although higher total doses of ifosfamide can be given by continuous infusion compared with short IV infusion with similar toxicity, the most effective dosage schedule has not been established.58, 59, 62, 82 In patients who experience myelosuppression following a dose of ifosfamide, a subsequent course of the drug should not be administered until the patient's hematologic functions are within acceptable limits.1 (See Cautions: Precautions and Contraindications)
To minimize the risk of urotoxic effects, each dose of isosfamide must be accompanied by a mesna regimen.160 (See Dosage and Administration: Dosage, in Mesna 92:56)
For the treatment of recurrent germ cell testicular cancer in adults, the usual dosage of ifosfamide in combination chemotherapy regimens is 1.2 g/m2 IV daily for 5 consecutive days every 3 weeks.1 In the study used to establish efficacy for this indication, ifosfamide-containing combination chemotherapy was given for a total of 4 courses.4
For the treatment of other malignant neoplasms†, various dosage schedules and regimens of ifosfamide, alone or in conjunction with other antineoplastic agents, have been used.2, 12, 13, 14, 20, 21, 24, 25, 27, 28, 29, 31, 32, 35, 36, 37, 38, 42, 44, 45, 46, 48, 49, 50, 51, 61 Clinicians should consult published protocols for dosages and the method and sequence of administration. While the dosage of ifosfamide used in the treatment of other malignant neoplasms generally has been similar to that used in the treatment of germ cell testicular cancer, dosage has varied.2 For the management of malignant neoplasms (i.e., sarcomas†, small cell lung cancer†, cervical cancer†, ovarian cancer†, uterine cancer†), ifosfamide has been given IV in a dosage of 1.2-2.5 g/m2 daily for 3-5 days, with cycles of therapy repeated as necessary depending on the patient's response and dosage reduced as necessary depending on the patient's tolerance.2, 12, 13, 14, 20, 21, 24, 25, 27, 28, 29, 31, 32, 35, 36, 37, 38, 42, 44, 45, 46, 48, 49, 50, 51, 61 Although higher doses have been used, they may be associated with substantially increased risk of toxicity (e.g., myelosuppression, neurotoxicity, nephrotoxicity).2, 58, 59
Dosage in Renal and Hepatic Impairment
Although ifosfamide has been used in a limited number of patients with renal and/or hepatic impairment, the manufacturer states that studies to determine the optimum dosage in such patients have not been conducted.1
The major adverse effects of ifosfamide are myelosuppression (leukopenia, thrombocytopenia), urinary tract and renal toxicity (bladder toxicity, nephrotoxicity, electrolyte effects), and neurotoxicity.1, 2, 3, 58, 59, 110 The incidence and severity of bladder toxicity (e.g., hemorrhagic cystitis, hematuria) is reduced substantially when ifosfamide is administered in fractionated dosage schedules and given in conjunction with conventional uroprophylaxis (e.g., high fluid intake, frequent urination) and when mesna is used prophylactically as a uroprotective agent.1, 2, 3, 59, 110
Hematologic toxicity is a major and dose-limiting adverse effect of ifosfamide.1, 2, 3, 58, 59 Myelosuppression, which is dose related, is manifested mainly by leukopenia and, to a lesser extent, thrombocytopenia. 1, 2, 3, 58, 59 Leukopenia (leukocyte count less than 3000/mm3) has been reported in 50% and thrombocytopenia (platelet count less than 100,000/mm3) in 20% of patients receiving the usual dosage of ifosfamide (i.e., 1.2 g/m2 IV daily for 5 days).1, 2, 3, 59 At higher dosages, leukopenia occurs in almost all patients, and severe leukopenia (leukocyte count less than 1000/mm3) occurs in 50% and platelet counts less than 50,000/mm3 in 8% of patients receiving IV ifosfamide regimens totaling 10-12 g/m2 per cycle.1, 2, 3 Severe myelosuppression occurs frequently when ifosfamide is used in conjunction with other antineoplastic agents.1 (See Drug Interactions: Myelosuppressive Therapy.)
Ifosfamide-induced myelosuppression generally is reversible.1 Leukocyte nadirs usually occur within 7-14 days after administration of ifosfamide, and leukocyte recovery generally occurs by the third week after administration of the drug.1, 2, 3, 58, 59
Anemia has been reported in patients receiving ifosfamide.1
Genitourinary, Renal, and Electrolyte Effects
Ifosfamide is toxic to the urothelium, producing effects that range in severity from microscopic to gross urinary bleeding.1, 2, 3, 36, 59 Prior to the introduction of the uroprotective agent, mesna, urotoxicity was a major dose-limiting adverse effect of ifosfamide despite vigorous hydration.1, 2, 3, 59, 96 Urotoxic effects attributed to ifosfamide include hemorrhagic cystitis, hematuria, dysuria, urinary frequency, and other manifestations of bladder irritation.1, 2, 3, 36, 59 Hematuria has been reported in 6-92% of patients receiving ifosfamide.1 When ifosfamide is administered in a dosage of 1.2 g/m2 IV daily for 5 days without uroprotection (i.e., mesna), microscopic hematuria occurs in about 50% and gross hematuria in about 8% of patients.1
Ifosfamide-induced bladder toxicity is attributed to chemical irritation of the epithelium of the bladder resulting from ifosfamide metabolites (e.g., acrolein) that accumulate in concentrated urine, and the incidence and severity of bladder toxicity can be reduced by conventional uroprophylaxis (e.g., high fluid intake, frequent urination), use of a fractionated ifosfamide dosage schedule, and concurrent administration of mesna. 1, 2, 3, 38, 59, 111 While most cells contain naturally occurring sulfhydryl (thiol) compounds (e.g., glutathione) and are able to inactivate such toxic metabolites, the concentration of thiols in urine is low.111 Studies in animals indicate that the initial urotoxic effect is disruption of the cell plasma membrane and cytoplasmic matrix.111 Various sulfhydryl (thiol) compounds (e.g., acetylcysteine, mesna) that can react with the toxic metabolites of ifosfamide have been studied for uroprotective activity.2, 3 Oral acetylcysteine was one of the first agents tested for uroprotection, but acceptance was limited because of undesirable pharmacokinetic characteristics and resultant need for high dosages, and the poor patient tolerance (e.g., nausea, vomiting, bad taste) of such dosages.2 Mesna, 2-mercaptoethanesulfonate, acts specifically as a regional urologic detoxificant, and currently is preferred because of favorable pharmacodynamic properties (e.g., poor lipid solubility and distribution, extensive renal clearance) and documented lack of effect on the antitumor activity of concomitantly administered antineoplastic agents.2, 3, 95, 108, 139, 140 Mesna substantially decreases the incidence and severity of ifosfamide-induced bladder toxicity.2, 3, 62, 63, 71, 95, 108, 141 (See Drug Interactions: Mesna.)
Nephrotoxicity and Electrolyte Effects
Potentially serious nephrotoxicity may occur in patients receiving ifosfamide.1, 3, 18, 19, 59, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 96, 121, 122 In clinical studies employing ifosfamide as single-agent therapy at the usual recommended dosage, nephrotoxicity was reported in 6% of patients.1, 59 In a limited number of patients receiving high ifosfamide dosage (2-2.5 g/m2 daily for 4 days), metabolic acidosis occurred in 31% of patients.1, 58 Ifosfamide-induced nephrotoxicity may be evidenced by biochemical signs of renal dysfunction (e.g., aminoaciduria, glycosuria, proteinuria, cells or casts in the urine, increase in serum creatinine or BUN, decrease in creatinine clearance), glomerular impairment (e.g., acute or chronic renal failure), and/or renal tubular impairment (e.g., Fanconi's syndrome, renal tubular acidosis, nephrogenic diabetes insipidus).1, 3, 19, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 96, 124 Although ifosfamide-induced renal toxicity may involve each of the 3 segments of the nephron, toxicity generally has been associated with proximal tubule dysfunction.1, 62, 64, 69, 70, 71, 77, 124 Rarely, renal tubular acidosis has progressed to chronic renal failure.1, 72
Potentially irreversible Fanconi's syndrome, characterized by aminoaciduria, glycosuria, phosphaturia, bicarbonaturia, and kaliuresis, has been reported in children and adults and usually occurs after several courses of ifosfamide.1, 19, 59, 62, 66, 68, 69, 70, 74, 75, 76, 96, 121, 122, 124 Rarely, ifosfamide-induced phosphaturia may lead to hypophosphatemia and rickets.1, 59, 62, 68, 69, 75, 121, 122, 124 (See Cautions: Pediatric Precautions.) If electrolyte abnormalities develop in patients receiving ifosfamide, appropriate therapy to correct any electrolyte imbalance(s) should be instituted.1, 62, 65, 68, 121
Nephrotoxicity may develop during ifosfamide therapy or following discontinuance of the drug.62, 64, 67, 68, 69, 70, 72, 74, 76, 77, 122 While the exact mechanism(s) is not known, renal toxicity may be caused by depletion of renal tubular glutathione by ifosfamide metabolites (e.g., acrolein, chloroacetaldehyde)59, 62 or by alteration in amino acid, glucose, and/or phosphate renal cell transport by ifosfamide metabolites (e.g., 4-hydroxyifosfamide, chloroacetaldehyde).124 Ifosfamide-induced nephrotoxicity can be reversible; however, the long-term effects of the drug on renal function are not fully known.62, 64, 67, 68, 74, 76, 77 Although not clearly established, the risk of ifosfamide-induced nephrotoxicity appears to be increased in patients who have received previous or concurrent cisplatin therapy and in patients with preexisting renal impairment, infiltrating renal tumor, or prior nephrectomy.3, 19, 59, 62, 64, 67, 68, 73, 74, 76, 110, 124, 125 In addition, patients who are 5 years of age or younger or have received high cumulative doses of ifosfamide (e.g., 50 g/m2) appear to be at increased risk for renal toxicity.19, 59, 62, 64, 67, 68, 73, 76, 121, 124, 125 (See Cautions: Pediatric Precautions.)Various ifosfamide regimens including direct IV injection, short infusion, or continuous infusion have been used in an attempt to decrease the incidence of nephrotoxicity; however, there are reports of serious renal toxicity with all schedules and a relative therapeutic advantage has not been established.62 While concomitant administration of mesna decreases the incidence of ifosfamide-induced bladder toxicity (e.g., hemorrhagic cystitis, hematuria), mesna does not prevent ifosfamide-induced nephrotoxicity.3, 62, 63, 71, 72, 78, 96
Adverse nervous system effects occur in about 10-20% of patients receiving ifosfamide,1, 2, 3, 59, 84 and range in severity from mild somnolence and confusion to severe encephalopathy and coma. 1, 2, 3, 36, 58, 59, 82, 84, 86, 87, 126, 128 Ifosfamide-induced neurotoxicity usually is characterized by confusion,1, 2, 36, 58, 59, 79, 80, 82, 83, 84, 86, 127 mutism,79, 82, 87 auditory and/or visual84 hallucinations,1, 2, 79, 81, 82, 84 stupor,1, 2, 79, 82 and coma.1, 2, 58, 79, 80, 86 In addition, seizures,1, 79, 80, 85 dizziness,1, 2 disorientation,1, 2, 58, 82, 86 agitation,84 and cranial nerve dysfunction1, 2, 86 occur less frequently. Fatigue,1 malaise,1 polyneuropathy,1 extrapyramidal manifestations,87, 88, 89 and peripheral neuropathy89 have been reported in less than 1% of patients receiving ifosfamide.
If one or more signs of serious neurotoxicity (i.e., somnolence, confusion, hallucinations, and/or coma) occur during ifosfamide therapy, the drug should be discontinued and appropriate measures for supportive therapy instituted.1, 82, 142 If neurotoxicity is promptly detected and the drug discontinued, the effects generally are reversible and resolve within 2-4 days.1, 2, 3, 36, 58, 59, 80, 82, 83, 84, 85, 128 Manifestations of emotional instability, impairment of short-term memory, and flattened affect may persist for 4-10 weeks in some patients.2, 82, 129 Rarely, neurotoxicity is irreversible,2, 3, 59, 80, 82, 83, 84, 85, 128 and fatal encephalopathy has been reported.80 Methylene blue has been used in the management of ifosfamide-induced encephalopathy and has been beneficial in some patients.126, 127, 161 (See Methylene Blue 92:12.)
While the exact mechanism(s) is not known, CNS toxicity may be caused by ifosfamide metabolites (e.g., chloroacetaldehyde), and it has been suggested that differences in the neurotoxic potentials of ifosfamide and cyclophosphamide may result from metabolic difference of the drugs.2, 3, 82, 96, 128, 141 Patients with renal impairment,1, 2, 3, 36, 58, 59, 82, 86 poor performance status,3, 36, 46, 58, 59 or previous exposure to cisplatin82, 110 appear to be at increased risk of ifosfamide-related neurotoxicity. It is unclear whether neurotoxicity is dose related.2, 58, 59, 82, 128
Nausea and/or vomiting,1, 2, 3, 36 which generally are moderate in severity, have been reported in 56-81% of patients receiving ifosfamide.1, 3, 59 The incidence and severity of nausea and vomiting are dose related, occurring in virtually all patients receiving high-dose ifosfamide.2, 3 These GI effects generally begin within a few hours after administration of ifosfamide,2, 3 last an average of 3 days,2 and respond to treatment with antiemetics.1, 3 Anorexia,1, 2, 3 increased salivation,1 diarrhea,1, 2, 3 constipation,1 and stomatitis1 have been reported in less than 1% of patients receiving the drug.1
Dermatologic and Local Effects
Alopecia occurs in 74-83% of patients who receive ifosfamide alone,1, 59 but may occur in up to 100% of patients who receive the drug in conjunction with other antineoplastic agents.1 Patients should be forewarned of the possibility of alopecia.1 Nonspecific dermatitis1 and hyperpigmentation90, 91 have been reported in a limited number of patients receiving ifosfamide. Although ifosfamide-induced skin pigmentation generally is localized on dorsal and plantar surfaces of the hands and feet, genitalia, or areas occluded by bandages, it may cover large areas of the trunk.90, 91 Hyperpigmentation appears more rapidly in dark- than in light-skinned individuals and may fade despite continued ifosfamide therapy or persist for several months after therapy with the drug has been completed.91
Extravasation of ifosfamide can produce local pain, inflammation, and induration.131 Phlebitis has been reported in 1% of patients receiving the drug.1
Pulmonary symptoms have been reported in less than 1% of patients receiving ifosfamide.1 Rarely, potentially fatal interstitial pneumonitis has been reported in patients who received high ifosfamide dosage (2-4.5 g/m2 IV daily for 4 days).3, 58, 59, 92
Cardiotoxicity has occurred in less than 1% of patients receiving ifosfamide.1, 59 Rarely, severe, reversible cardiac dysfunction has occurred in patients who received high ifosfamide dosage (2.5-4.5 g/m2 IV daily for 4 days) in conjunction with other antineoplastic agents.94 Myocardial depression occurred 6-23 days after initiation of ifosfamide therapy and resulted in a rapidly progressive syndrome of congestive heart failure and cardiopulmonary decompensation which, in most patients, was responsive to cardiac support therapy.94
Abnormalities in liver function test results (e.g., increases in serum concentration of liver enzymes and/or serum bilirubin) have occurred in 3% of patients receiving ifosfamide.1 Infection has occurred in 8% and fever of unknown origin in 1% of patients receiving the drug.1, 59 Other adverse effects reported in less than 1% of patients include allergic reactions, coagulation disorders, hypertension, and hypotension.1 Acute pancreatitis has been reported rarely.130
Although the clinical importance is unclear, the manufacturer states that ifosfamide therapy may interfere with normal wound healing.1
Precautions and Contraindications
Ifosfamide is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity.1, 2, 3 The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents.1
To decrease the incidence and severity of bladder toxicity (e.g., hemorrhagic cystitis, hematuria) in patients receiving ifosfamide, most experts recommend use of conventional uroprophylaxis (e.g., adequate hydration, frequent urination) and administration of mesna, a uroprotective agent. 1, 2, 3, 58, 59, 95 These measures do not prevent hemorrhagic cystitis in all patients receiving ifosfamide and the urine of patients receiving the drug should be examined regularly for the presence of erythrocytes, which may precede hemorrhagic cystitis.1, 95 A morning urine specimen should be examined for the presence of erythrocytes before each scheduled dose of ifosfamide.1, 95 In patients who develop microscopic hematuria (more than 10 erythrocytes per high power field [HPF]), ifosfamide therapy should be discontinued until the hematuria resolves, and vigorous oral or parenteral hydration as well as mesna should be used in these patients for subsequent courses of ifosfamide.1, 141 Because hemorrhagic cystitis can be severe and may be fatal, ifosfamide therapy should be discontinued or dosage of the drug reduced in patients who develop hematuria (more than 50 erythrocytes/HPF) while receiving usual dosages of ifosfamide in conjunction with mesna.95
Ifosfamide should be used with caution in patients with impaired renal function.1 Because electrolyte abnormalities and/or acidosis, which rarely have been fatal,65 may occur in patients receiving ifosfamide, serum and urine chemistries, including phosphorus, potassium, alkaline phosphatase, and other appropriate laboratory studies should be monitored closely.1, 62, 65, 68, 77, 141 If electrolyte abnormalities develop in patients receiving the drug, appropriate therapy to correct any imbalance(s) should be instituted.1, 62, 65, 68, 77
Because patients who receive myelosuppressive drugs experience an increased frequency of infection and/or bleeding, hematologic status must be monitored carefully during ifosfamide therapy to determine the degree of hematopoietic suppression.1, 2, 3, 58, 59 The manufacturer states that ifosfamide is contraindicated in patients with severely depressed bone marrow function.1 Ifosfamide should be used with caution in patients with compromised bone marrow reserve as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.1 The manufacturer recommends that leukocyte counts, platelet counts, and hemoglobin concentrations be assessed prior to and at appropriate intervals during ifosfamide therapy.1 In patients who experience myelosuppression following a course of ifosfamide, subsequent courses generally should be withheld until leukocyte counts have recovered to greater than 4000/mm3 and platelet counts exceed 100,000/mm3.1 Unless ifosfamide therapy is considered clinically essential, the manufacturer states that the drug should not be administered to patients with leukocyte counts less than 2000/mm3 and/or platelet counts less than 50,000/mm3.1
If serious neurotoxicity manifested as somnolence, confusion, hallucinations, and/or coma occurs during ifosfamide therapy, the drug should be discontinued and appropriate measures instituted.1, 2, 3, 59, 80, 82, 83, 84, 85 Most neurotoxic manifestations of ifosfamide are reversible if detected promptly.1, 2, 3, 58, 59, 80, 82, 83, 84, 85
Ifosfamide is contraindicated in patients with known hypersensitivity to the drug.1
Safety and efficacy of ifosfamide in children have not been established.1 Ifosfamide has been used in children 15 days to 17 years of age for the treatment of certain malignancies (e.g., Ewing's sarcoma, rhabdomyosarcoma, Wilms' tumor), and adverse effects of the drug reported in these children appear to be similar to those reported in adults.34, 61, 62, 75, 121, 122, 133 However, further study is needed to evaluate the safety of ifosfamide in children,62, 64, 69, 73, 75, 123, 125 especially those 5 years of age or younger who may be more susceptible to ifosfamide-induced renal toxicity than older children or adults.3, 62, 64 Severe nephrotoxicity leading to Fanconi's syndrome, which may be irreversible, has been reported in young children who received ifosfamide alone or in conjunction with other antineoplastic agents.64, 66, 67, 69, 73, 75, 121 Progressive tubular damage resulting in potentially debilitating hypophosphatemia and rickets has been reported rarely.62, 68, 69, 75, 77, 121 Follow-up assessment of bone mineralization in a limited number of children who had received ifosfamide revealed essentially normal bone marrow density.15 Neurotoxicity and conjunctivitis and blurring of vision have been reported rarely in children receiving ifosfamide.80, 85, 93, 121 A 4-year old child who received ifosfamide in conjunction with mesna developed severe, irreversible, encephalopathy that was fatal.80 In addition, encephalopathy, loss of developmental milestones, progressive brain atrophy, and cessation of brain growth was reported in one infant who received ifosfamide.128
Although small differences in pharmacokinetic values have been reported in children, changes in these parameters are unlikely to be clinically relevant given the extensive interindividual variation in ifosfamide metabolism.96, 107 If ifosfamide is used in children, the potential benefits of the drug should be weighed carefully against the drug's potentially serious adverse effects.62, 73, 123, 125, 128, 141 Appropriate laboratory tests should be performed during, as well as after, ifosfamide therapy to monitor renal and bone biochemistries (e.g., urine glucose, urine protein, serum electrolytes)3, 66, 69, 73, 75, 77, 121, 122, 125, 141 and appropriate supplementation initiated if renal tubular abnormalities are detected.68, 73, 121 Some clinicians recommend that the drug not be used in children with infiltrating renal tumors, prior nephrectomy, or any evidence of renal impairment.3, 62, 64, 67
Ifosfamide has not been evaluated systematically in geriatric patients to date.1, 2, 3 In general, dosage of ifosfamide must be based on the clinical, renal, hematologic response and tolerance of the patient; the greater frequency of reduced drug clearance as well as decreased hepatic, renal, and hematopoietic function observed in the elderly should be considered.1 Although small differences in pharmacokinetic values have been reported in older individuals, changes in these parameters are unlikely to be clinically relevant given the extensive interindividual variation in ifosfamide metabolism.96, 101
Mutagenicity and Carcinogenicity
Ifosfamide has been shown to be mutagenic in vitro in bacterial systems.1 In vivo, the drug increased dominant lethal mutations in male mice and recessive sex-linked lethal mutations in Drosophila melanogaster germ cells.1
Ifosfamide has been shown to be carcinogenic in rats, and has been associated with an increased incidence of leiomyosarcomas and mammary fibroadenomas in female rats.1 Cyclophosphamide has been shown to cause urinary bladder tumors in mice, and acrolein, a toxic metabolite of both cyclophosphamide and ifosfamide, is the carcinogenic compound implicated in the development of these tumors.2, 3, 147 It has been suggested that concomitant use of mesna, by neutralizing the toxic effects of acrolein, may reduce the risk of bladder carcinoma induced by these oxazaphosphorine agents.2, 3, 136, 147
Pregnancy, Fertility, and Lactation
Ifosfamide can cause fetal harm when administered to a pregnant woman,1 but potential benefits from use of the drug may be acceptable in certain conditions despite possible risk to the fetus.1, 137, 138 Ifosfamide has been shown to be teratogenic and embryotoxic in mice, rats, and rabbits in doses 0.05-0.075 times the human dose.1 There are no adequate or controlled studies to date using ifosfamide in pregnant women.1 Ifosfamide should be used during pregnancy only in life-threatening situations or for disease for which safer drugs cannot be used or are ineffective.1, 137, 138 If the drug is administered during pregnancy or if the patient becomes pregnant while receiving ifosfamide, the patient should be informed of the potential hazard to the fetus.1 Women of childbearing potential should be advised to avoid becoming pregnant during ifosfamide therapy.1
The effects of ifosfamide on fertility have not been fully determined.1
Ifosfamide is distributed into milk.1 Because of the potential for serious adverse reactions to ifosfamide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Although ifosfamide has been used concurrently with other drugs, including other cytotoxic agents, without unusual adverse effects, the possibility of adverse drug interactions cannot be excluded.1, 59
Concomitant administration of mesna substantially decreases the incidence and severity of ifosfamide-induced bladder toxicity (e.g., hemorrhagic cystitis, hematuria).2, 3, 62, 63, 71, 95, 108, 141 Mesna is a synthetic sulfhydryl (thiol) compound.2, 3, 95, 108 In urine, mesna interacts chemically with urotoxic ifosfamide metabolites (e.g., binding with double-bonds of acrolein) and precursors (e.g., binding with 4-hydroxyifosfamide to form 4-sulfethylthioifosfamide) resulting in detoxification of these metabolites.2, 3, 95, 108 Although the incidence of ifosfamide-induced bladder toxicity (e.g., hemorrhagic cystitis, hematuria) is substantially lower in patients receiving concomitant mesna compared with that reported in patients receiving ifosfamide alone, mesna does not prevent ifosfamide-induced nephrotoxicity2, 3, 62, 63, 71, 72, 78, 96, 141 and does not prevent or decrease the incidence of nonrenal toxicities associated with the drug (i.e., myelosuppression, neurotoxicity, alopecia).3, 95, 108 Although mesna can undergo alkylation and presumably could reduce the cytotoxic effectiveness of ifosfamide by interfering with the mechanism of action, mesna and dimesna are hydrophilic and do not enter most cells, including tumor cells.2, 3, 139, 140, 141 There is no evidence from in vitro and in vivo tumor models that concomitant mesna interferes with the antitumor activity of ifosfamide.2, 3, 95, 108, 139, 140
Concomitant administration of mesna dosages up to 60 mg/kg reportedly does not exacerbate adverse GI effects associated with ifosfamide.108
Concomitant use of ifosfamide and other myelosuppressive agents or radiation therapy may potentiate the hematologic toxicity of the other agents and vice versa.3, 7, 10, 11 Severe myelosuppression occurs frequently when ifosfamide is used in conjunction with other antineoplastic agents.1, 7, 10, 11 Patients receiving ifosfamide concomitantly with other myelosuppressive agents should be monitored carefully and dosage of the drugs and time of administration should be managed to minimize additive effects.1, 3
Drugs Affecting Hepatic Microsomal Enzymes
Although specific studies have not been done and the clinical importance has not been determined, concomitant administration of drugs that affect cytochrome P-450 hepatic microsomal enzymes could alter the metabolism of ifosfamide resulting in increased or decreased conversion to active metabolites and theoretically could increase the toxicity or decrease the activity of the drug, respectively.2, 79, 96, 141 In one study in mice, pretreatment with chlordiazepoxide, diazepam, or oxazepam resulted in increased plasma concentrations of active ifosfamide and potentiated the toxicity of the drug.96, 120
Limited information is available on the acute toxicity of ifosfamide.141 Overdosage of the drug would be expected to produce effects that are mainly extensions of common adverse reactions.1
There is no known specific antidote for ifosfamide overdosage.1 While mesna is effective in preventing urotoxic effects of ifosfamide when administered prophylactically, the drug is not an antidote for systemic toxicity of the drug.2, 3, 62, 63, 71, 72, 78, 95, 96, 108 Management of ifosfamide overdosage consists of discontinuance of the drug and initiation of supportive measures appropriate for the type of toxicity observed.1 Methylene blue has been used in the management of ifosfamide-induced encephalopathy.126, 127, 161 (See Cautions: Nervous System Toxicity.)
The exact mechanism(s) of action of ifosfamide has not been conclusively determined, but it appears to be similar to that of other alkylating agents.3, 143, 144, 145, 146 Ifosfamide, like cyclophosphamide, requires biotransformation in the liver by mixed-function oxidases (cytochrome P-450 system) before it can exert its cytotoxic effects.2, 3, 103, 111 Following conversion to active metabolites, ifosfamide functions as an alkylating agent, interfering with DNA replication and transcription of RNA, and ultimately resulting in disruption of nucleic acid function.1, 2, 3, 143, 144, 145, 146 Like other alkylating agents, ifosfamide is cycle-phase nonspecific.2, 3, 143
Although the clinical importance is unclear, results of several in vitro and in vivo studies indicate that the cytotoxic activity of ifosfamide may be equal to or moderately greater than that of cyclophosphamide against some animal tumor models (e.g., murine leukemia L1210, Yoshida ascites sarcoma in rats, Lewis lung carcinoma in mice, C3H mammary tumor, Ridgeway osteogenic sarcoma, DS-carcinosarcoma, and TA-nephroblastoma in rats).3, 144, 146 Ifosfamide was less active than cyclophosphamide against intraperitoneal B16 melanoma and subcutaneous CD8 fl mammary cancer.3, 144 In human tumor models, the spectrum of activity of ifosfamide resembled that of cyclophosphamide; however, ifosfamide produced higher response rates and less toxicity than cyclophosphamide.3 In vivo on a weight basis, cyclophosphamide may have greater antineoplastic activity than ifosfamide since a greater percentage of the ifosfamide dose is converted irreversibly to inactive metabolites.3, 143, 144, 145
Further study is needed to determine the extent of cross-resistance between ifosfamide, cyclophosphamide, and other alkylating agents.3, 144 Although cross-resistance has been shown in certain cancer cell lines, cross-resistance with other nitrogen mustard alkylating agents does not appear to be complete.3, 144
Like cyclophosphamide and other alkylating agents, ifosfamide is immunosuppressive.112, 144, 146
Ifosfamide is a prodrug and requires biotransformation before it can exert its antineoplastic effects. 1, 2, 3, 96, 98, 99, 103, 104, 105 In vivo, ifosfamide is metabolized to a variety of both active and inactive metabolites and the pharmacokinetics of the drug and its metabolites are complex and have not been fully elucidated.1, 2, 3, 96, 104 Investigation of the pharmacokinetics of ifosfamide has been difficult, partly because many initial studies used assay methods that were not specific and could not reliably differentiate between ifosfamide and its various metabolites.3, 96, 103 In addition, identification and quantitation of some ifosfamide metabolites has been difficult because they are highly unstable and present only in very low concentrations.104, 105 Most recently published pharmacokinetic studies have used improved analytical methods capable of measuring both ifosfamide and its most important metabolites.96, 103, 104, 105
Plasma concentrations of ifosfamide and its metabolites exhibit marked interindividual variation.3, 97, 104, 107 Following IV administration of ifosfamide in a dosage of 1 or 2 g/m2 daily given by continuous IV infusion over 24 hours, plasma drug concentrations after 3 days range from 10-18 or 15-36 mcg/mL, respectively.3, 97 Peak plasma concentrations of ifosfamide mustard (ifosforamide mustard), the principal alkylating metabolite, are reached within 20-30 minutes following IV administration of a single ifosfamide dose104 and average about 1% of concurrent ifosfamide concentrations on a molar basis.104, 105 The area under the plasma concentration-time curve (AUC) of ifosfamide increases linearly over the dosage range of 1-5 g/m2.3
Although ifosfamide usually is given IV, the drug appears to be well absorbed following oral or subcutaneous administration, with reported bioavailabilities of 90-100%.3, 96, 104
Ifosfamide and its metabolites appear to be distributed throughout the body, including the brain and CSF.3, 98, 99 Ifosfamide is distributed into milk.1
The apparent volume of distribution of ifosfamide has been reported to be approximately 33 L,3, 96, 98, 100, 102 with slightly higher values reported in obese individuals3, 100 and individuals older than 60 years of age.101
Ifosfamide is metabolized to both active and inactive metabolites.3, 96, 104, 105 Initial metabolism of ifosfamide occurs by 2 competing pathways, ring oxidation at the 4-carbon position and oxidation of one of the chloroethyl groups.1, 2, 3, 96, 103, 104, 105
Ifosfamide is partially metabolized by mixed-function oxidases (cytochrome P-450 system) in the liver and, to a lesser extent, in the lung to 4-hydroxyifosfamide, which is in equilibrium with aldoifosfamide, the acyclic tautomer.1, 2, 3, 96, 103, 104, 105 Aldoifosfamide spontaneously splits into ifosfamide mustard, the primary alkylating metabolite, and to acrolein.1, 2, 3, 96, 103 Production of ifosfamide mustard appears to be catalyzed by phosphodiesterase I (5'-exonuclease) and/or spleen exonuclease (3'-exonuclease), found in serum, lymphocytes, and lymphatic tissue.96, 103 Because 3',5'-exonucleases linked to DNA-polymerases seem to be more active in catalyzing this reaction than unlinked exonuclease, production of ifosfamide mustard occurs predominately within cells.103 In addition, 4-hydroxyifosfamide may be enzymatically metabolized to 4-ketoifosfamide and aldoifosfamide may be enzymatically metabolized to carboxyifosfamide.1, 2, 3, 96 4-Hydroxyifosfamide also undergoes reversible reactions with sulfhydryl groups of proteins or amino acids to produce 4-thioifosfamide.96 The second metabolic pathway in the initial metabolism of ifosfamide involves side-chain oxidation and results in formation of chloroacetaldehyde, 2-dechloroethylifosfamide, and 3-dechloroethylifosfamide.1, 2, 3, 96, 103, 104, 105
Plasma concentrations of ifosfamide reportedly decline in a linear, dose-independent manner following IV administration of up to about 4-5 g/m2 of the drug.96 Plasma concentrations of ifosfamide mustard and chloroacetaldehyde reportedly decline in a manner similar to that of the parent drug.105 Administration of ifosfamide doses up to 5 g/m2 has not been associated with saturation of the cytochrome P-450 system96, 102 In adults with normal renal and hepatic function who receive a single ifosfamide dose by IV injection or short infusion, the terminal elimination half-life of ifosfamide ranges from 4-8 hours.3, 95, 96, 104 Limited data indicate that the elimination half-life increases with age, averaging 2.1 hours in children 1-17 years of age96, 107 and 6 hours in individuals older than 60 years of a 3, 96, 101 the elimination half-life also may be increased in obese individuals.3, 100 An elimination half-life of 15 hours has been reported in adults with normal renal and hepatic function by one investigator;1, 2, 3, 96, 98 however, the assay method used in the study has been questioned and other investigators consistently have reported shorter half-lives.3, 96 Following administration of ifosfamide over 3-5 days, the terminal elimination half-life decreases in a time-dependent manner, suggesting that ifosfamide induces its own hepatic metabolism.3, 96, 104, 105 Because the ratio of ifosfamide metabolites remains unchanged, increases in metabolism presumably occur in both of the initial metabolic pathways.96 The elimination half-life of ifosfamide mustard is about 5-9 hours.104
Ifosfamide and its metabolites are excreted principally in urine;1, 2, 3, 96 about 14-34%, 10-14%, 4-7%, and 1-3% of a dose is excreted as unchanged drug, 3-dechloroethylifosfamide, 2-dechloroethylifosfamide, and carboxyifosfamide, respectively.96 Other metabolites (e.g., 4-hydroxyifosfamide, 4-ketoifosfamide) also appear to be excreted in the urine in very small amounts (less than 1% of the ifosfamide dose).96
Ifosfamide, an oxazaphosphorine derivative, is an alkylating agent structurally related to cyclophosphamide.1, 2, 3, 96, 103, 111, 112 Ifosfamide differs structurally from cyclophosphamide in that it contains one 2-chloroethyl group attached to the exocyclic nitrogen and a second 2-chloroethyl group attached to the cyclic nitrogen of the oxazaphosphorine ring, whereas both 2-chloroethyl groups contained in cyclophosphamide are attached to the exocyclic nitrogen.2, 3, 96, 111, 112, 143, 144, 145, 146 This structural difference in the spatial separation of the 2-chloroethyl groups results in ifosfamide having greater aqueous solubility, slower rate of activation, different alkylating metabolites, and a more effective DNA cross-linking distance than cyclophosphamide and appears to be responsible for the differences in antineoplastic activity and toxicity profiles associated with the drugs.2, 3, 111, 143, 144, 145, 146
Ifosfamide occurs as an off-white to white, crystalline powder1, 106 and is soluble in water.1 Following reconstitution of the commercially available sterile powder with sterile water for injection, ifosfamide solutions containing 50 mg/mL have a pH of 6.106
Commercially available ifosfamide injection is an aqueous solution containing 100 mg/mL.160
Ifosfamide sterile powder for injection should be stored at 20-25°C.1, 106, 113 The powder should be protected from temperatures higher than 30°C,1 since ifosfamide reportedly liquefies at temperatures exceeding 35°C.106 Commercially available ifosfamide injection (100 mg/mL) should be refrigerated at 2-8°C.
Following reconstitution of ifosfamide sterile powder with sterile water for injection or with sterile bacteriostatic water for injection containing benzyl alcohol or parabens, solutions containing 50 mg of ifosfamide per mL are stable for up to 24 hours when kept refrigerated.1 Reconstituted ifosfamide solutions are compatible with 5% dextrose, 0.9% sodium chloride, lactated Ringer's, and sterile water for injection.1, 114 Reconstituted solutions that have been further diluted to 0.6-20 mg/mL in one of these compatible IV fluids are physically and chemically stable in glass, polyvinyl chloride (PVC), or polyolefin containers for up to 24 hours when kept refrigerated.1 Intermediate concentrations and mixtures of these diluents (e.g., 2.5% dextrose, 0.45% sodium chloride, 5% dextrose and 0.9% sodium chloride) also may be used.1, 114
Following dilution of commercially available ifosfamide injection (100 mg/mL), solutions containing a final concentration of 20 mg/mL are physically and chemically compatible for 24 hours at 25°C in 5% dextrose, 5% dextrose and 0.2% sodium chloride, 5% dextrose and 0.33% sodium chloride, 5% dextrose and 0.45% sodium chloride, 5% dextrose and 0.9% sodium chloride, 0.9% sodium chloride, or lactated Ringer's injection.160
Ifosfamide is physically and chemically compatible with mesna,2, 3, 106, 108, 109 and admixtures of the drugs reportedly are stable for at least 24 hours in 5% dextrose injection or lactated Ringer's injection.108, 114
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Kit | 1 g, For injection, for IV infusion, Ifosfamide (Ifex® Kit) 100 mg/mL (1 g), Injection, Mesna (Mesnex®) (with benzyl alcohol) 100 mg/mL (1 g), Injection, Ifosfamide 100 mg/mL (1 g) Injection, Mesna (with benzyl alcohol) 3 g, For injection, for IV infusion, Ifosfamide (Ifex®) 100 mg/mL (1 g), Injection, Mesna (Mesnex®) (with benzyl alcohol) 100 mg/mL (3 g), Injection, Ifosfamide 100 mg/mL (1 g) Injection, Mesna (with benzyl alcohol) | Ifex®/Mesnex® Kit | |
Ifosfamide Injection/Mesna Injection Kit | ||||
Ifex®/Mesnex® Kit | Bristol-Myers Squibb | |||
Ifosfamide Injection/Mesna Injection Kit |
1. Bristol-Myers Squibb. Ifex® (ifosfamide for injection) prescribing information. Princeton, NJ; 1998 Jun.
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5. Food and Drug Administration. List of orphan product designations & approvals. 1995 Apr.
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12. Loehrer PJ, Rynard S, Ansari R et al. Etoposide, ifosfamide, and cisplatin in extensive small cell lung cancer. Cancer . 1992; 69:669-73. [PubMed 1309677]
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15. de Schepper J, Hachimi-Idrissi S, Louis O et al. Bone metabolism and mineralization after cytotoxic chemotherapy including ifosfamide. Arch Dis Child . 1994; 71:346-8. [PubMedCentral][PubMed 7979531]
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