Ifosfamide for Injection - Product Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Arteriosclerosis (Atherosclerosis), Renal Dysfunction, Serum Sickness, Thrombocytopenia|
|Class:||Antineoplastic detoxifying agents|
|Form:||Intravenous (IV), Powder|
IFOSFAMIDE FOR INJECTION IS A POTENT DRUG AND SHOULD BE USED ONLY BY PHYSICIANS EXPERIENCED WITH CANCER CHEMOTHERAPEUTIC DRUGS (SEE WARNINGS AND PRECAUTIONS). IN THOSE PATIENTS WHO DEVELOP BACTERIAL, FUNGAL OR VIRAL INFECTIONS, INTERRUPTION OR MODIFICATION OF DOSAGE SHOULD BE CONSIDERED. BLOOD COUNTS SHOULD BE TAKEN AT REGULAR INTERVALS. DUE TO THE UROTOXIC EFFECT OF OXAZAPHOSPHORINES, IFOSFAMIDE SHOULD NOT BE ADMINISTERED WITHOUT THE USE OF A UROPROTECTIVE AGENT SUCH AS MESNA (SEE MESNA FOR INJECTION PRODUCT MONOGRAPH FOR DOSAGE AND ADMINISTRATION).
Action and Clinical Pharmacology
Ifosfamide for Injection is activated by metabolism in the liver by the mixed function oxidase system of the smooth endoplasmic reticulum. The activation is induced by hydroxylation at the ring carbon atom 4. Opening of the ring results in the formation of aldo-ifosfamide, the tautomer of 4-hydroxyifosfamide. Two stable metabolites, 4-keto-ifosfamide and 4-carboxyifosfamide, appear in the urine. However, they have no cytotoxic activity. N,N'-bis(2-- chloroethyl)-phosphoric acid diamide and acrolein are also found. The enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation may produce further metabolites.
DNA is one of the main target sites of ifosfamide. In vitro, incubation of DNA with activated ifosfamide produces phosphotriesters as the predominant reaction products. The treatment of intact cell nuclei may also result in the formation of DNA-DNA crosslinks. DNA repair occurs in G-1 and G-2 stage cells. Repair capacity is more marked in less sensitive tumours. An accumulation of cells in the G-1 phase is found in tumours that respond well.
Indications and Clinical Use
Ifosfamide for Injection is indicated as follows:
Soft Tissue Sarcoma
- first-line single agent therapy;
- second-line single agent therapy in patients who have failed to respond or who have relapsed on other chemotherapeutic regimens.
- second-line single agent therapy in patients who have failed to respond or who have relapsed on other chemotherapeutic regimens.
- as a single agent or in combination with Cisplatin and Bleomycin in advanced or recurrent disease.
Ifosfamide for Injection is contraindicated in individuals with a known hypersensitivity to it. It is also contraindicated in patients having severe leukopenia, thrombocytopenia and severe renal and/or hepatic impairment, cystitis, obstructions to the urine flow, or active infections. Ifosfamide should not be administered to patients with advanced cerebral arteriosclerosis.
UROTOXIC SIDE EFFECTS, ESPECIALLY HEMORRHAGIC CYSTITIS, HAVE BEEN FREQUENTLY ASSOCIATED WITH THE USE OF IFOSFAMIDE. UNTIL RECENTLY, THESE EFFECTS RESULTED IN CESSATION OF THERAPY. THE THERAPEUTIC BENEFIT OF MESNA AS A UROPROTECTIVE AGENT HAS BEEN DEMONSTRATED IN THAT THE INCIDENCE OF URINARY TRACT COMPLICATIONS WAS REDUCED FROM 40% TO 3.5%. THUS IFOSFAMIDE FOR INJECTION SHOULD ALWAYS BE ACCOMPANIED BY UROPROTECTIVE TREATMENT WITH MESNA (SEE MESNA FOR INJECTION PRODUCT MONOGRAPH FOR DOSAGE AND ADMINISTRATION).
PATIENTS, MALE OR FEMALE, DURING THE REPRODUCTIVE PERIOD OF LIFE, SHOULD BE ADVISED OF THE MUTAGENIC POTENTIAL OF IFOSFAMIDE. ADEQUATE METHODS OF CONTRACEPTION ARE RECOMMENDED FOR SUCH PATIENTS (SEE ADVERSE REACTIONS).
Use in Pregnancy
IFOSFAMIDE FOR INJECTION CAN BE TERATOGENIC OR CAUSE FETAL RESORPTION IN EXPERIMENTAL ANIMALS. IT SHOULD NOT BE USED IN PREGNANCY, PARTICULARLY IN EARLY PREGNANCY, UNLESS IN THE JUDGEMENT OF THE PHYSICIAN, THE POTENTIAL BENEFITS OUTWEIGH THE POSSIBLE RISKS. AS IS THE CASE WITH THE OXAZAPHOSPHORINE CLASS OF ALKYLATING AGENTS, IFOSFAMIDE IS EXCRETED IN BREAST MILK AND BREAST-FEEDING SHOULD BE TERMINATED PRIOR TO INSTITUTION OF IFOSFAMIDE THERAPY.
SINCE THE POSSIBILITY OF INTERFERENCE WITH NORMAL WOUND HEALING HAS BEEN REPORTED WITH OTHER OXAZAPHOSPHORINES, IFOSFAMIDE THERAPY SHOULD NOT BE INITIATED FOR AT LEAST 10 TO 14 DAYS AFTER SURGERY.
IFOSFAMIDE, LIKE OTHER ALKYLATING AGENTS, HAS BEEN REPORTED TO HAVE ONCOGENIC ACTIVITY IN ANIMALS. THUS THE POSSIBILITY THAT IT MAY HAVE ONCOGENIC POTENTIAL IN HUMANS SHOULD BE CONSIDERED.
IFOSFAMIDE FOR INJECTION SHOULD BE GIVEN CAUTIOUSLY TO PATIENTS WITH ANY OF THE FOLLOWING CONDITIONS:
- Tumour-cell infiltration of the bone marrow
- Prior radiotherapy
- Prior treatment with other antineoplastic agents
- Brain metastases and advanced cerebral arteriosclerosis
- Impaired renal function
- Impaired hepatic function
- In the presence of known infections
- Abnormal serum creatinine and serum albumin levels
Because ifosfamide may exert a suppressive action in immune mechanisms, the interruption or modification of dosage should be considered for patients who develop bacterial, fungal or viral infections. This is especially true for patients receiving concomitant steroid therapy, since infections in some of these patients have been fatal.
Ifosfamide may cause significant neurologic, renal and hematologic toxicities which may prove fatal despite careful monitoring prior to and during therapy.
Prior to initiating treatment, it is necessary to exclude or correct any obstruction of the efferent urinary tract, cystitis, infections, and electrolyte imbalances.
Urinary sediment should be examined at regular intervals. Extra care is required in unilaterally nephrectomised patients, in patients with impaired renal function, and in patients pretreated with nephrotoxic drugs (e.g., cisplatin) who obviously tolerate high-doses of ifosfamide less well. Ifosfamide should not be given until three months after the nephrectomy. Additional caution is also advisable in patients treated concomitantly with drugs having nephrotoxic potential (e.g., aminoglycosides and amphotericin B).
Careful monitoring is also required for patients with cerebral metastases, as ifosfamide has been associated with several CNS symptoms.
Leukocyte, erythrocyte and platelet counts should be carried out at regular intervals. There is normally a reduction in the leukocyte count beginning on approximately day 5. The nadir, depending on dosage and baseline count, tends to be reached after 8 - 10 days. Recovery occurs after 10 - 14 days and is usually complete after 2 - 3 weeks.
Neurologic manifestations consisting of somnolence; confusion; hallucinations and, in some instances, coma have been reported following ifosfamide therapy. In the case of ifosfamide-induced CNS symptoms, drugs acting on the CNS (e.g., antiemetics and narcotics) should be discontinued, if possible, or used with caution. The occurrence of these symptoms requires discontinuing ifosfamide therapy. These symptoms have usually been reversible and supporting therapy should be maintained until their resolution.
Hemorrhagic cystitis, manifested by the occurrence of hematuria, dysuria, urinary frequency and occasionally urinary incontinence or retention, develops frequently in patients treated with ifosfamide. The incidence, severity and persistence of ifosfamide-induced hemorrhagic cystitis increase as the dose of the drug increases. In most instances, the hematuria resolves spontaneously upon cessation of ifosfamide therapy.
The urinary tract toxicity of ifosfamide can be minimized by administering a uroprotective agent such as Mesna (See Mesna For Injection Product Monograph for Dosage and Administration), and ensuring adequate hydration and maintenance of fluid balance.
Granular casts in the urinary sediment have occurred mainly after high doses of ifosfamide. The cylinduria generally resolves spontaneously a few days after the last ifosfamide injection.
Renal parenchymal and tubular necrosis, which could lead to death, have been reported. Disorder of glomerular renal function with an increase in serum creatinine, a decrease in creatinine clearance and proteinuria occasionally occur; more frequently, disorders of tubular renal function with hyperaminoaciduria, phosphaturia, acidosis, or proteinuria occur. Severe nephropathies are rare. Predisposing factors for nephrotoxicity include the presence of renal tumors, pre-existing renal impairment, prior treatment with platinum containing drugs, and concomitant treatment with potentially nephrotoxic agents (see Precautions).
Increases and decreases in creatinine clearance are usually reversible.
Metabolic acidosis was reported in 31% of patients in one study when ifosfamide was administered at doses of 2.0 - 2.5 g/m2/d for four days.
Renal tubular acidosis, Fanconi Syndrome and renal rickets have also been reported. Close clinical monitoring of serum and urine chemistries including phosphorus, potassium, alkaline phosphatase and other appropriate laboratory studies is recommended. Appropriate replacement therapy should be administered as indicated.
Leukopenia with the risk of life-threatening infection is an expected effect and ordinarily is used as a guide to therapy. Thrombocytopenia with the risk of hemorrhage and anemia have been known to occur in a few patients. These effects are almost always reversible when therapy is interrupted. Episodes of petechial bleeding due to severe thrombocytopenia have been reported.
When ifosfamide is used in combination with other myelosuppressive agents, adjustments in dosing may be necessary.
Nausea and vomiting are dose-related and also depend on individual sensitivity. Other gastrointestinal adverse events include anorexia, diarrhea, constipation, and stomatitis.
Effects on Gonads
Gonadal suppression, resulting in amenorrhea or azoospermia, has been reported with other oxazaphosphorines and thus may occur with ifosfamide.
It is ordinarily advisable to inform patients in advance of possible alopecia, a frequent complication of ifosfamide therapy. Regrowth of hair can be expected although occasionally the new hair may be of a different colour or texture. Nonspecific dermatitis and inflamation of mucous membranes have been reported to occur with ifosfamide.
Central Nervous System
Cerebral side effects consist mainly of somnolence, confusion, hallucinations and depressive psychosis. Other less frequent symptoms included dizziness, disorientation and cranial nerve dysfunction, and cerebellar symptoms. Seizures of the tonic-clonic type have been reported occasionally. Isolated cases of encephalitis, generalized seizure and seizures resulting in coma have also been observed.
It is possible that the severity and incidence of cerebral effects increase with the administration of high doses, the presence of brain metastases, or advanced cerebral arteriosclerosis. The incidence and extent of cerebral effects due to ifosfamide may also be affected by the age of the patient, and by impaired renal clearance, pretreatment with nephrotoxic drugs, and postrenal obstructions (e.g., pelvic tumours). Other possible risk factors may include decreased levels of serum albumin or hydrogen carbonate, or concurrent high-dose treatment with antiemetic drugs.
Although cardiotoxicity is rarely encountered, there have been reported cases of supraventricular or ventricular arrhythmia, S-T segment changes and heart failure at high doses of ifosfamide, or after pre-treatment or concomitant treatment with anthracyclines. Hypertension and hypotension have been reported rarely.
Interstitial pulmonary fibrosis has been reported in patients treated with large doses of alkylating agents for prolonged periods. Although not reported in patients treated with ifosfamide, physicians should be aware of its possible occurrence. Pulmonary toxicities, including reports of interstitial pneumonitis and pulmonary edema, have been reported from fewer than 1% of patients.
Adverse reactions in addition to those mentioned above have been noted with ifosfamide. They include infection with or without fever, hematemesis, asthenia, thrombophlebitis, increase in liver enzymes and/or bilirubin, allergic reactions, polyneuropathy, impaired or blurred vision, and increased sensitivity to irradiation. In addition, in isolated cases, syndrome of inappropriate antidiuretic hormone (SIADH) has been reported.
Pancreatitis has been reported in isolated cases.
The concurrent use of ifosfamide may enhance the anticoagulant effect of warfarin and thus raise the risk of hemorrages.
Symptoms and Treatment of Overdosage
No specific antidote for Ifosfamide for Injection is known. Management of overdosage would include general supportive measures to sustain the patient through any period of toxicity that might occur.
Dosage and Administration
Chemotherapy with Ifosfamide for Injection as with other drugs used in cancer chemotherapy, is potentially hazardous and fatal complications can occur. It is recommended that it be administered only by physicians aware of the associated risks. Total dosage of 250 - 300 mg/kg per cycle is the usual standard. As a rule, 50 - 60 mg/kg are administered intravenously, over a period of a minimum of 30 minutes, each day for 5 consecutive days. If the calculation of the dosage is based on body surface area, the recommended dosage is 2,000 - 2,400 mg/m2 daily on 5 consecutive days. If a lower daily dosage or the total dosage over a longer period is indicated, ifosfamide can be given every other day (days 1, 3, 5, 7 and 9) or on 10 consecutive days in lower doses.
A treatment series should be repeated after an interval of not less than 3 - 4 weeks. The therapeutic administration of ifosfamide should invariably be accompanied by uroprotective treatment with Mesna for Injection. Alternately, the administration of high single-dose infusions is now feasible up to 5 to 8 g/m2/24 h under protection of continuous mesna infusion. The optimal use of ifosfamide in combination with other myelosuppressive agents requires dosage adjustments according to the regimen and schedule to be adopted.
Prevention of Cystitis
The concomitant administration of Mesna for Injection helps to prevent the urotoxic side effects of Ifosfamide for Injection which had previously limited the drug's therapeutic use. Every ifosfamide regimen should be accompanied by uroprotective treatment with mesna.
Mesna for Injection is usually given by intravenous injection concurrently with Ifosfamide for Injection, and 4 and 8 hours afterwards, each dose being 20% of the Ifosfamide for Injection, dose. (See Mesna for Injection Product Monograph for Dosage and Administration.)
Even with the administration of the uroprotector mesna, the daily fluid intake should be at least 2 litres. If urinary excretion appears insufficient, a fast-acting diuretic such as furosemide may be administered.