Holoxan

Ifosfamide.

Ifosfamide is (3-(2-chloroethyl)-2-[(2-chloroethyl)-amino]-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide).

A cytostatic drug from the group of alkylating agents.
Pharmacology: The cytotoxic activity (alkylation of nucleophilic centres in the cell) is linked with the activated oxazaphosphorine ring hydroxylated at the C4-atom and manifests itself in a block in late S- and early G2-phases.
Pharmacokinetics: Holoxan is inactive in vitro but highly active in vivo. Activation mostly takes place in the liver through microsomal mixed-function oxidases. The elimination of the metabolized ifosfamide mostly takes place via the urine. The serum half-life for dosages of 1-2 g/m² and 3 x 1.6-2.4 g/m² is given as lying in the range of 4-7 hrs.

Bronchial carcinoma, testicular tumours of all histological types, soft-tissue sarcomas, osteosarcoma, carcinoma of the breast, ovary, endometrium and cervix, renal cell carcinoma, carcinoma of the pancreas, malignant lymphomas, etc.

Holoxan should only be administered by an experienced oncologist. The dosage must be adapted to each patient individually. In single-drug therapy of adults, the most common treatment is based on fractionated doses. In the absence of individual prescriptions, the following recommendations may serve as a guideline.
In general, Holoxan is given IV in divided doses of 1.2-2.4 g/m² body surface (up to 60 mg/kg body weight) daily for 5 consecutive days (the duration of these infusions is about 30-120 min, depending on the volume). Holoxan may also be given in a single high dose, usually as a 24-hr prolonged infusion. The dosage is generally 5 g/m² body surface (125 mg/kg body weight) and should not exceed >8 g/m² body surface (200 mg/kg body weight)/cycle. A single high dose may cause higher hemato-, uro-, nephro- and CNS toxicity.
Care should be taken to ensure that the ifosfamide concentration of the solution does not exceed 4%.
In combination therapy with other cytostatics, the dose should be adapted to the type of therapeutic scheme.
Because of its urotoxicity, ifosfamide should, as a matter of principle, be used in combination with mesna. Other toxicities and the therapeutic effects of ifosfamide will not be influenced by mesna. Should cystitis with micro- and macrohematuria develop during therapy, the treatment should be discontinued until the patient has recovered.
Because the cytostatic effect of ifosfamide occurs only after activation in the liver, there is no danger of injuring the tissue in the case of paravenous injections.
The therapy cycles may be repeated every 3-4 weeks. The intervals will depend on the blood count and on the recovery from any adverse reactions or side effects.
The administration of uroprotection with uroprotector, Uromitexan (mesna) as directed, should be maintained.
Regular blood counts, regular checks of renal function and regular urinalysis including urinary sediment are necessary.
Timely administration of antiemetics is indicated, and the additional influences on the CNS in connection with Holoxan should be taken into consideration.
Preparation of the Solution: The handling of Holoxan should always be in accordance with the safety precautions used for handling of cytotoxic agents.
To prepare a 4% isotonic solution ready for injection, water for injection is added to the dry substance in the following amounts: Water for injection 13, 25 and 50 mL for Holoxan 500 mg, 1 g and 2 g, respectively.
The substance dissolves readily if the vials are vigorously shaken for 0.5-1 min after the addition of water for injection. If the substance fails to dissolve immediately and completely, it is advisable to allow the solution to stand for a few minutes. The prepared solution can be kept for up to approximately 24 hrs if stored at a temperature not exceeding +8°C (refrigerator). The Holoxan solution for short-term IV infusion (approximately 30-120 min) is prepared by diluting the aforementioned solution with 250 mL Ringer's solution or 5% glucose solution or physiological saline. For longer infusions over 1-2 hrs, dilution is recommended with 500 mL Ringer's solution or 5% glucose solution or physiological saline. For continuous 24-hr infusions of high-dose Holoxan, the prepared Holoxan solution eg, 5 g/m², must be diluted to 3 L with 5% glucose solution and/or physiological saline.
Note: Because of its alkylating action, ifosfamide is a mutagenic and also a potential carcinogenic substance. Contact with the skin and mucous membranes should therefore be avoided.

There is no known specific antidote for Holoxan. Overdosage is likely to result in dose-related side effects (see Side Effects). Management of overdosage would include general supportive measures to sustain the patient through any period of toxicity that might occur eg, dialysis, forced diuresis, monitoring and support of vital functions.

Known hypersensitivity to ifosfamide, severe bone marrow depression, impaired renal function, bilateral outflow obstruction, acute infections, acute hemorrhagic cystitis, pregnancy.

Before starting treatment, it is necessary to exclude or correct any obstruction of the efferent urinary tract, cystitis, infections and electrolyte imbalances. In general, Holoxan, like other cytostatics, should be used with care in weakened or elderly patients and in patients who have had previous radiotherapy. Patients with a weakened immune system eg, those with diabetes mellitus, chronic hepatic and renal impairments, also require special care. Patients with brain metastases, cerebral symptoms and/or deteriorated renal function must be kept under close observation.
Contraceptive Measures: Ifosfamide can cause congenital anomalies. Conception during treatment is not advisable. Men to be treated with Holoxan should be informed about sperm preservation before treatment. Women should not become pregnant during treatment. Should they still conceive during treatment, they should seek genetic consultation. The duration of contraception after the end of chemotherapy depends on the prognosis of the primary disease and on the intensity of the patient's desire for a child. The possibility of a genetic consultation should be used.
Use in pregnancy & lactation: In a vital indication during the 1st trimester of pregnancy, a medical consultation regarding abortion is absolutely necessary.
After the 1st trimester of pregnancy, if therapy cannot be delayed and the patient wishes to continue with her pregnancy, chemotherapy may be undertaken after informing the patient of the minor but possible risk of teratogenic effects.
Mothers must not breastfeed during treatment with Holoxan.

In a vital indication during the 1st trimester of pregnancy, a medical consultation regarding abortion is absolutely necessary.
After the 1st trimester of pregnancy, if therapy cannot be delayed and the patient wishes to continue with her pregnancy, chemotherapy may be undertaken after informing the patient of the minor but possible risk of teratogenic effects.
Mothers must not breastfeed during treatment with Holoxan.

Patients on Holoxan therapy may experience the following side effects:
Myelosuppression: Different degrees of myelosuppression (leucocytopenia, thrombocytopenia and anemia) can occur, depending on the dose. Frequently, leucocytopenia with the risk of life-threatening infections and thrombocytopenia with the risk of bleeding have to be taken into consideration. The lowest leucocyte and thrombocyte counts normally occur 1-2 weeks after start of treatment and recover within 3-4 weeks. Anemia usually occurs after several cycles of treatment. A combination treatment with other myelosuppressive agents may require dose adjustments. Single high-dose treatment leads more frequently to leucocytopenia than fractionated dose-regimen. In pre-treated (chemotherapy and/or radiotherapy) patients or patients with renal function impairment, a more severe myelosuppression can be expected. With ifosfamide as with other cytostatics, blood counts have to be taken before each chemotherapy cycle as well as during the intervals between cycles. Depending on the blood picture, appropriate dose adaptations (see table) should be made.

Click on icon to see table/diagram/image
Urotoxicity and Nephrotoxicity: Hemorrhagic cystitis (macro- and microhematuria) is a frequent, dose-dependent complication of ifosfamide.
Note: Fractionated dosing, adequate hydration, maintenance of fluid balance and particularly concomitant treatment with Uromitexan (mesna) can markedly reduce the frequency and severity of hemorrhagic cystitis.
Disorders of glomerular renal function with an increase in serum creatinine, a decrease in creatinine clearance and proteinuria can occasionally occur, or more frequently, disorders of tubular renal function with hyperaminoaciduria, phosphaturia, acidosis or proteinuria. Severe nephropathies are rare. Possible risk factors for disorders of glomerular renal function are high doses of Holoxan and additional treatment with platinum-containing drugs. Risk factors for disorders of tubular renal function are previous nephrectomy, additional treatment with platinum-containing drugs or concomitant irradiation of the abdomen with inclusion of the kidneys or the remaining kidney. Caution is advisable when potentially nephrotoxic drugs eg, aminoglycosides, acyclovir or amphotericin B are used concomitantly. These drugs do not potentiate the tubular kidney disorder, but may cause further deterioration of glomerular function.
In rare cases, patients with chronic tubular kidney disorder may develop Fanconi's syndrome resulting in rickets or, in adults, osteomalacia. Predisposing factors are high cumulative doses of the drug and young age (particularly <3 years). Glomerular and tubular kidney function must therefore be evaluated and checked before start of therapy, during and after therapy.
During long-term treatment with ifosfamide, sufficient diuresis and regular monitoring of renal function is necessary. This applies especially to children. In case of beginning nephropathy, irreversible kidney damage has to be expected if treatment with ifosfamide is continued. A careful risk-benefit evaluation is required.
Caution is required in unilaterally nephrectomized patients, in patients with impaired renal function and in patients pre-treated with nephrotoxic drugs (eg, cisplatin). In these patients, frequency and intensity of myelotoxicity, nephro- and cerebral toxicity are increased.
Central Nervous System: In 10-20% of cases, encephalopathy occurs and develops within a few hours up to a few days after start of treatment. Risk factors are a poor state of health, impaired renal function (creatinine >1.5 mg/dL), pre-treatment with nephrotoxic drugs (eg, cisplatin) and postrenal obstructions (eg, pelvic tumours). Other possible risk factors are old age, a history of alcohol abuse, decreased levels of serum albumin or hydrogen carbonate, hepatic dysfunction or concurrent high-dose treatment with antiemetic drugs. The most common symptom of encephalopathy is drowsiness which can progress to somnolence and coma. Other symptoms can be weakness, forgetfulness, depressive psychoses, disorientation, restlessness, confusion, hallucinations, cerebellar symptoms, incontinence and convulsions. The encephalopathies are usually reversible and disappear spontaneously within a few days after the last ifosfamide administration. Severe courses are rare, and deaths were only seen in isolated cases and in connection with very high doses of Holoxan. With a fractionated dose regimen, encephalopathies are less frequent and less severe.
Note: Due to the CNS toxicity of ifosfamide, patients must be carefully monitored. In the event of encephalopathy, ifosfamide treatment has to be discontinued and must not be resumed. In case of ifosfamide-induced encephalopathy, drugs acting on the CNS (eg, antiemetics, tranquilizers, narcotics or antihistamines) should be discontinued if possible, or used with special caution.
Other Side Effects: Nausea and vomiting are dose-dependent side effects. Moderate to severe forms can be seen in about 50% of the cases. Another frequent side effect is reversible alopecia which occurs in up to 100% of patients, depending on dosage and duration of treatment. Because of its alkylating mechanism of action, Holoxan can cause partly irreversible impairment of spermatogenesis with resulting azoospermia or persistent oligospermia. Less frequently irreversible ovulation disturbances with resulting amenorrhea and reduced levels of female sex hormones.
Additionally, there can occur, in isolated cases, chronic interstitial pulmonary fibrosis. Toxic-allergic pulmonary edema was reported in a single case.
In isolated cases, SIADH (syndrome of inadequate ADH secretion, Scwartz-Bartter syndrome) with hyponatremia and water retention. Hypokalemia was reported in a single case.
In rare cases, inflammation of the skin and mucous membrane.
In rare cases, hypersensitivity reactions, in isolated cases, progressing to shock.
In rare cases, blurred vision and episodes of dizziness.
An increase in liver enzymes and/or in the bilirubin level can also occur occasionally. Anorexia, diarrhea, constipation, phlebitis or pyrexia may more seldom be seen. Polyneuropathy, pneumonitis, impaired vision or an increased reaction to radiation were seen in isolated cases. There have been isolated reports of supraventricular or ventricular arrhythmias, ST-segment changes and heart failure after very high doses of ifosfamide and/or after pre-treatment or concomitant treatment with anthracyclines. In this context, it is again necessary to stress the need for regular electrolyte monitoring and special caution when treating patients with a history of heart disease. As with cytotoxic therapy in general, especially with alkylating agents, treatment with ifosfamide involves the risk of secondary tumours as a late sequelae.

Myelotoxicity can be increased as a result of interaction with other cytostatics or radiation.
Ifosfamide may intensify skin reactions due to irradiation. The prior or concurrent administration of nephrotoxic agents ie, cisplatin, aminoglycosides, acyclovir or amphotericin B may enhance the nephrotoxic effect of ifosfamide and consequently hematotoxic and neurotoxic (CNS) effects as well.
Because of the immunosuppressive effect of ifosfamide, an impaired response to the respective vaccine may occur. Vaccination injury can be caused by live-virus vaccinations.
The concurrent use of ifosfamide may increase the anticoagulant effect of warfarin and thus raise the risk of hemorrhages.
In analogy with cyclophosphamide, the following interactions seem possible: The myelosuppressive action may be enhanced by the concurrent administration of allopurinol or hydrochlorothiazide. The effect and the toxicity may be enhanced by the concurrent administration of chlorpromazine, triiodothyronine or aldehyde dehydrogenase inhibitors eg, disulfiram. The treatment may increase the hypoglycemic actions of sulfonylureas. Prior or concurrent treatment with phenobarbital, phenytoin or chloral hydrate involves the possibility of microsomal liver enzyme induction and thus a faster metabolism of ifosfamide. The treatment may increase the muscle-relaxant effect of suxamethonium.

Store at a temperature not exceeding +25°C.

Cytotoxic Chemotherapy

L01AA06 - ifosfamide ; Belongs to the class of alkylating agents, nitrogen mustard analogues. Used in the treatment of cancer.

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