45 Vogell Road, Suite 200 Date of Preparation: Richmond Hill, ON L4B 3P6 January 17, 2008 Control Number : 119281

g/vial and 3 g/vial

CAUTION:

IFOSFAMIDE FOR INJECTION, USP IS A POTENT DRUG AND SHOULD BE USED ONLY BY PHYSICIANS EXPERIENCED WITH CANCER CHEMOTHERAPEUTIC DRUGS (SEE

). 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, USP 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 tumors. An accumulation of cells in the G-1 phase is found in tumors that respond well.

CONTRAINDICATIONS

Ifosfamide for Injection, USP 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.

WARNINGS

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, USP 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).

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.

PRECAUTIONS

IFOSFAMIDE FOR INJECTION, USP SHOULD BE GIVEN CAUTIOUSLY TO PATIENTS WITH ANY OF THE FOLLOWING CONDITIONS:

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.

ADVERSE REACTIONS

Urinary System

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 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.

Hematopoietic System

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.

Gastrointestinal System

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.

Integumentary System

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. Non-specific 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, pre-treatment with nephrotoxic drugs, and post-renal obstructions (e.g., pelvic tumors). Other possible risk factors may include decreased levels of serum albumin or hydrogen carbonate, or concurrent high-dose treatment with antiemetic drugs.

Cardiotoxicity

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.

Respiratory System

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.

Other

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 of antidiuretic hormone (SIADH) has been reported. Pancreatitis has been reported in isolated cases.

Drug Interactions

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, USP 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, USP 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 2000- 2400 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.

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 liters. If urinary excretion appears insufficient, a fast-acting diuretic such as furosemide may be administered.

PHARMACEUTICAL INFORMATION

Common Name: Ifosfamide Chemical Name: 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2- oxazaphosphorine-2-oxide Structural Formula: Molecular Formula: C7 H15Cl2N2O2P Molecular Weight: 261.09 Description: Ifosfamide belongs to the family of oxazaphosphorine nitrogen mustards. It is white crystalline powder, soluble in water or saline. pH of 10% solution (w/v) is 4.5 - 7.0. Melting Range: 48.0 - 51.0 C.

: Ifosfamide for Injection, USP 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, USP vials at room temperature (15 to 25C). Protect from temperatures above 30C.

Preparation for Intravenous Use:

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.

Solution for IV Infusion

Reconstituted 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, USP 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, USP 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 1000degC 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

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 hrs. Clearance of unchanged drug was 21 ml/min. Maximal plasma concentrations of alkylating ifosfamide metabolites occurred at 3 hrs. 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 liters, 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 hrs, on Day 1 to 6.3 hrs. 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

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 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 week, 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 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.

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.

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

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.

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

Species Mouse	Route IP	LD 50 (mg/kg) 520
Mouse	IV	741
Rat	IV	160
Rat	IP	150 - 190
Rabbit	IV	200
Dog	IV	20 - 40

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