Ifosfamide for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Ifosfamide for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Arteriosclerosis (Atherosclerosis), Renal Dysfunction, Serum Sickness, Thrombocytopenia
Class: Antineoplastic detoxifying agents
Form: Intravenous (IV), Powder
Ingredients: Ifosfamide

Pharmaceutical Information

Drug Substance

Common Name: Ifosfamide
Chemical Name: 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide
Structural Formula:
Molecular Formula: C7H15Cl2N2O2P
Molecular Weight: 261.09
Description: Ifosfamide belongs to the family of oxazaphosphorine nitrogen mustards. It is a white crystalline powder, soluble in water or saline.
pH of 10% solution (w/v) is 4.5 - 7.0.
Melting Range: 48.0 °C − 51.0 °C.

Composition

Ifosfamide for Injection vials contain ifosfamide sterile powder. The pH of freshly reconstituted 5% w/v solutions usually range from 4 to 7.

Stability and Storage Recommendations

Store Ifosfamide for Injection vials at room temperature between 15 °C and 25 °C. Protect from temperatures above 30 °C.

Preparation for Intravenous Use

Reconstitute with Sterile Water for Injection as follows:

Vial Size Volume to be Added Approximate Available Volume Approximate Average Concentration
1 gram 20 mL 20 mL 50 mg/mL
3 gram 60 mL 60 mL 50 mg/mL

Shake well until dissolved. The prepared solution may be further diluted to achieve concentrations of 0.6 to 20 mg/mL with any of the solutions for i.v. infusion listed below in PVC bags.

Solutions for IV Infusion

5% Dextrose Injection, USP

0.9% Sodium Chloride, USP

Lactated Ringer's Injection, USP

Stability of Solutions

Reconstituted solutions should be used within 24 hours if stored at room temperature, or within 72 hours if refrigerated. Use further diluted solutions immediately.

NOTE: As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solution showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

Availability of Dosage Forms

Ifosfamide for Injection is available as sterile lyophilized powder supplied in 1 g and 3 g vials. Vial stoppers do not contain natural rubber latex.

C104210 1 g single-dose vial in 30 mL vial, packaged individually
C104300 3 g single-dose vial in 100 mL vial, packaged individually

Handling and Disposal

Preparation of Ifosfamide for Injection should be done in a vertical laminar flow hood (Biological Safety Cabinet - Class II). Personnel preparing ifosfamide should wear PVC gloves, safety glasses, disposable gowns and masks.

All needles, syringes, vials and other materials which have come in contact with Ifosfamide for Injection should be segregated and incinerated at 1,000°C or more. Sealed containers may explode while still sealed. Intact vials should be returned to the Manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport. Personnel regularly involved in the preparation and handling of ifosfamide should have bi-annual blood examinations.

Pharmacology

Pharmacology (in humans)

The terminal plasma half-lives have been shown to be dose dependent. At lower doses, the terminal plasma half lives ranged from 4 - 7 hours. At higher doses (3.8 - 5.0 gm/m2), a bi-phasic decrease in plasma levels of unchanged drug was observed with a terminal half-life of about 15 hours. Clearance of unchanged drug was 21 ml/min. Maximal plasma concentrations of alkylating ifosfamide metabolites occurred at 3 hours after dosage. Approximately one-half of the dose was recovered in the urine unchanged while 20 - 36% was excreted in the urine as metabolites. At doses of 5 g/m2 and above, it appears that the processes responsible for metabolism of ifosfamide are saturated. Two monodechloroethylated derivatives as well as carboxyifosfamide have been identified in urine as major metabolites.

A multicompartment pharmacokinetic model has been used to describe the disposition of the drug, and it was calculated that the apparent volume of distribution for the central and peripheral tissue compartments was about 32 and 15 litres, respectively. Volume of distribution for ifosfamide metabolites was observed to approximate plasma volume, which may be due to very high plasma protein binding. Although ifosfamide was found in cerebrospinal fluid, its concentration there was much less than in plasma and negligible amounts of ifosfamide metabolites were found in cerebrospinal fluid.

Differences were evident in the pharmacokinetics of ifosfamide when drug was administered singly (3.8 - 5 g/m2) or in smaller multiple daily doses (1.6 - 2.4 g/m2/day). In the latter case with equal intravenous doses on three consecutive days, a monoexponential plasma level decay curve with a much shorter half-life than that found after single high dosage was observed. The half-life decreased from 8.3 hours, on Day 1 to 6.3 hours on Day 3 of the multiple dose study. Urinary excretion was mainly in the form of ifosfamide metabolites rather than unchanged drug. These observations suggest that ifosfamide induces its own hepatic microsomal metabolism. The pharmacokinetic profiles of a three-day course of ifosfamide therapy and a second course of therapy 21 days later were similar.

Ifosfamide labelled with 14C given intravenously to dogs shows a half-life of less than 30 minutes and in one hour the serum isotope level is less than l0% of the peak level. Total urinary recovery is about 84% of which only a small fraction is unaltered drug.

Toxicology

Acute Toxicity

Acute Toxicity of Ifosfamide in Various Species
Species Route LD50 (mg/kg)
Mouse IP 520
Mouse IV 741
Rat IV 160
Rat IP 150 - 190
Rabbit IV 200
Dog IV 20 - 40

Abnormalities noted for the mice in the lethal range were ataxia, labored respiration, hypoactivity and exophthalmos. In rats, the following morphological effects were noted: necrosis in the germinal centers of the cervical and mesenteric lymph nodes and spleen, atrophy of the spleen, irritation of the urinary bladder, congestion, hemorrhage, bone marrow depression and focal necrosis in the cortex of the thymus. A study made of the acute intravenous toxicities of ifosfamide showed adverse reactions of hypoactivity and emesis.

Subacute Toxicity

Subacute studies on 10 male and 10 female mice (5 daily doses i.p., 36 day observation period) gave an LD50 value of 145 mg/kg (delayed deaths). Lesions were frequently seen in the liver and occasionally in the spleen and urinary bladder in the two highest dose groups (238 and 173 mg/kg). Liver abnormalities consisted of necrosis of the hepatic parenchyma, inflammatory hepatitis, focal fatty metamorphosis, and mineralization.

Studies on 10 male and 10 female rats (4 weeks, oral) revealed no mortality, no gross pathology and only slight fatty infiltrations of the liver in the high dose treated group (l0 mg/kg). The highest non-toxic-intravenous dose of ifosfamide in pairs of male and female young beagle dogs (5 consecutive daily doses) was 4.12 mg/kg. Clinical signs of toxicity were tachycardia, anorexia and dehydration. A value of 2.06 mg/kg for the highest non-toxic intravenous dose was obtained in beagle dogs who received a series of 5 consecutive daily doses of ifosfamide followed by 9 days of rest and another set of 5 consecutive daily doses of ifosfamide. Clinical signs of toxicity were tachycardia, anorexia and dehydration.

The highest non-toxic dose of ifosfamide given on 14 consecutive days to rhesus monkeys by intravenous injection was about 1.03 mg/kg. Histopathologic signs of kidney damage were seen in only the monkey that died. Marked leukopenia occurred in the high dose female only.

Chronic Toxicity

Chronic studies on 15 male and 15 female rats dosed intraperitoneally (25, 50 or 100 mg/kg once every 3 weeks for 6 months) showed myelosuppressive effects on testes, cystitis, enteritis or lung congestion. It is believed that the latter two pathologies may be related to the immunosuppressive properties of ifosfamide and infection. Clinical signs of toxicity were rough haircoats, ataxia and substantial weight losses prior to death. Treatment related microscopic changes included cystitis, lymphoid atrophy in the lymph nodes and spleen, thymus involution, decreased bone marrow cellularity and decreased spermatogenesis. The major contributory causes of death during the study were cystitis; enteritis and pneumonia.

Relative to the chronic toxicity studies in rats, studies in 3 male and 3 female beagle dogs (oral 6 days/week x 26 weeks) demonstrated that the high dose group tolerated the drug well. One female dog of the high dose group died of "distemper-pneumonia". Testicular atrophy was noted in male dogs and most of the treated dogs showed signs of kidney pathology, mainly fatty infiltration of the medullary cortex.

Groups of 3 male and 3 female beagle dogs treated with ifosfamide intravenously (5, 10, 20 mg/kg once every 3 weeks for 6 months) showed hematologic changes, lung pathology, cystitis and renal pathology. The most consistent alterations observed clinically, and at necropsy involved the lungs. Several treated dogs developed rales and necropsy revealed dark or consolidated areas on the lungs of dogs in all groups. The lung lobes of the one high dose male that died were dark, firm and congested.

Reproductive Toxicology

Fetal toxicity in rats was noted with ifosfamide (10 and 20 mg/kg doses, i.p. on day 11 of gestation). Ifosfamide (45 mg/kg s.c. as a single dose) decreased the rate of body growth and development in one day old drug-treated mice.

Embryotoxicity and teratogenic effects in rabbits were observed with ifosfamide (7.5, 15 or 30 mg/kg i.v, on days 6 - 18 after breeding).

Embryolethal effects and maternal toxicity were evident in pregnant female rats with ifosfamide administration at 9 mg/kg i.p. No teratogenic effects were observed in fetuses from dams given 1.0 or 3.0 mg/kg of ifosfamide.

Special Studies

Injections of ifosfamide into veins of the rat tail, the rabbit ear and the dog forepaw were well tolerated.

Carcinogenicity

Carcinogenicity studies with ifosfamide conducted on 35 male and 35 female mice (10 to 20 mg/kg per dose i.p. 3 times a week x 52 weeks) showed a significant dose-related increase in the incidence of malignant lymphomas in female mice.

Similar studies done on 35 male and 35 female rats (6 or 12 mg/kg per dose i.p. 3 times a week x 52 weeks) revealed the drug to be carcinogenic. There was a greater incidence of malignant lymphomas and granulocytic leukemias in males. These differences were not statistically significant. On the other hand, in females, there was a greater incidence of leiomyosarcomas and mammary fibroadenomas. These differences were statistically significant.