5.1 Myelosuppression, Immunosuppression, and Infections

Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections.  Fatal outcomes of ifosfamide-associated myelosuppression have been reported. Ifosfamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding events), and anemia.  The nadir of the leukocyte count tends to be reached approximately during the second week after administration.  When Ifosfamide for Injection is given in combination with other chemotherapeutic/hematotoxic agents and/or radiation therapy, severe myelosuppression is frequently observed.  The risk of myelosuppression is dose-dependent and is increased with administration of a single high dose compared with fractionated administration.  The risk of myelosuppression is also increased in patients with reduced renal function.

Severe immunosuppression has led to serious, sometimes fatal, infections.  Sepsis and septic shock also have been reported.  Infections reported with ifosfamide include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections.  Latent infections can be reactivated.  In patients treated with ifosfamide, reactivation has been reported for various viral infections.  Infections must be treated appropriately.  Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician.  In case of neutropenic fever, antibiotics and/or antimycotics must be given. Close hematologic monitoring is recommended.  White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals after administration. Unless clinically essential, Ifosfamide for Injection should not be given to patients with a WBC count below 2,000/µL and/or a platelet count below 50,000/µL.

Ifosfamide for Injection should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

5.2 Central Nervous System Toxicity, Neurotoxicity

Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects.  The risk of CNS toxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma, have been reported following Ifosfamide for Injection therapy.  There have also been reports of peripheral neuropathy associated with ifosfamide use.

Ifosfamide neurotoxicity may become manifest within a few hours to a few days after first administration and in most cases resolves within 48 to 72 hours of ifosfamide discontinuation.  Symptoms may persist for longer periods of time.  Supportive therapy should be maintained until their complete resolution. Occasionally, recovery has been incomplete.  Fatal outcomes of CNS toxicity have been reported. Recurrence of CNS toxicity after several uneventful treatment courses has been reported.  If encephalopathy develops, administration of ifosfamide should be discontinued.

Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of ifosfamide-induced encephalopathy.

Manifestations of CNS toxicity may impair a patient’s ability to operate an automobile or other heavy machinery.

5.3 Renal and Urothelial Toxicity and Effects

Ifosfamide is both nephrotoxic and urotoxic.  Glomerular and tubular kidney function must be evaluated before commencement of therapy as well as during and after treatment.  Monitor urinary sediment regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity.

Monitor serum and urine chemistries, including phosphorus and potassium regularly.  Administer appropriate replacement therapy as indicated. Renal parenchymal and tubular necrosis have been reported in patients treated with ifosfamide.  Acute tubular necrosis, acute renal failure, and chronic renal failure secondary to ifosfamide therapy have been reported, and fatal outcome from nephrotoxicity has been documented.

Disorders of renal function, (glomerular and tubular) following ifosfamide administration are very common. Manifestations include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glycosuria as well as tubular acidosis.  Fanconi syndrome, renal rickets, and growth retardation in children as well as osteomalacia in adults also have been reported.  Development of a syndrome resembling SIADH (syndrome of inappropriate antidiuretic hormone secretion) has been reported with ifosfamide.

Tubular damage may become apparent during therapy, months or even years after cessation of treatment. Glomerular or tubular dysfunction may resolve with time, remain stable, or progress over a period of months or years, even after completion of ifosfamide treatment.

The risk and expected benefits of ifosfamide therapy should be carefully weighed when considering the use of ifosfamide in patients with preexisting renal impairment or reduced nephron reserve.

Urotoxic side effects, especially hemorrhagic cystitis, have been very commonly associated with the use of Ifosfamide for Injection.  These urotoxic effects can be reduced by prophylactic use of mesna.
 
Hemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide.  The risk of hemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration.  Hemorrhagic cystitis after a single dose of ifosfamide has been reported.  Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for hemorrhagic cystitis.

Before starting treatment, it is necessary to exclude or correct any urinary tract obstructions [see Contraindications (4)].

During or immediately after administration, adequate amounts of fluid should be ingested or infused to force dieresis in order to reduce the risk of urinary tract toxicity.  Obtain a urinalysis prior to each dose of Ifosfamide for Injection.  If microscopic hematuria (greater than 10 RBCs per high power field) is present, then subsequent administration should be withheld until complete resolution.  Further administration of Ifosfamide for Injection should be given with vigorous oral or parenteral hydration.

Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections.

5.4 Cardiotoxicity

Manifestations of cardiotoxicity reported with ifosfamide treatment include:
     - Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia
     - Decreased QRS voltage and ST-segment or T-wave changes
     - Toxic cardiomyopathy leading to heart failure with congestion and hypotension
     - Pericardial effusion, fibrinous pericarditis, and epicardial fibrosis

Fatal outcome of ifosfamide-associated cardiotoxicity has been reported.

The risk of developing cardiotoxic effects is dose-dependent.  It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.

Particular caution should be exercised when ifosfamide is used in patients with risk factors for cardiotoxicity and in patients with preexisting cardiac disease.

5.5 Pulmonary Toxicity

Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity have been reported with ifosfamide treatment.  Pulmonary toxicity leading to respiratory failure as well as fatal outcome has also been reported.  Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated.

5.6 Secondary Malignancies

Treatment with ifosfamide involves the risk of secondary tumors and their precursors as late sequelae.  The risk of myelodysplastic alterations, some progressing to acute leukemias, is increased.  Other malignancies reported after use of ifosfamide or regimens with ifosfamide include lymphoma, thyroid cancer, and sarcomas.

The secondary malignancy may develop several years after chemotherapy has been discontinued.

5.7 Veno-occlusive Liver Disease

Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide.

5.8 Pregnancy

Ifosfamide for Injection can cause fetal harm when administered to a pregnant woman.  Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy. Ifosfamide is genotoxic and mutagenic in male and female germ cells.  Embryotoxic and teratogenic effects have been observed in mice, rats and rabbits at doses 0.05 to 0.075 times the human dose.

Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy.  If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

5.9 Effects on Fertility

Ifosfamide interferes with oogenesis and spermatogenesis.  Amenorrhea, azoospermia, and sterility in both sexes have been reported.  Development of sterility appears to depend on the dose of ifosfamide, duration of therapy, and state of gonadal function at the time of treatment.  Sterility may be irreversible in some patients.

Female Patients
Amenorrhea has been reported in patients treated with ifosfamide.  The risk of permanent chemotherapy-induced amenorrhea increases with age.  Pediatric patients treated with ifosfamide during prepubescence subsequently may not conceive and those who retain ovarian function after completing treatment are at increased risk of developing premature menopause.

Male Patients
Men treated with ifosfamide may develop oligospermia or azoospermia.  Pediatric patients treated with ifosfamide during prepubescence might not develop secondary sexual characteristics normally, but may have oligospermia or azoospermia.  Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.  Sexual function and libido are generally unimpaired in these patients.  Some degree of testicular atrophy may occur.  Patients treated with ifosfamide have subsequently fathered children.

5.10 Anaphylactic/Anaphylactoid Reactions and Cross-sensitivity

Anaphylactic/anaphylactoid reactions have been reported in association with ifosfamide.  Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported.

5.11 Impairment of Wound Healing

Ifosfamide may interfere with normal wound healing.

5.12 Nursing

Ifosfamide is excreted in breast milk. Women must not breastfeed during treatment with ifosfamide [see Use in Specific Populations (8.3)].

6.1 Adverse Reactions from Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse reactions and frequencies below are based on 30 publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m2 per course.

1 The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia. For neutropenic fever, see below.
1a The frequency category of leukopenia is based on the frequency of leukopenia <3 x 103/µL [42.5% (150/353) not shown in table] and <1 x 103/µL; a relevant percentage ratio cannot be calculated for the pooled data and thus the conservative frequency category of “Very common” was included in the table.
2 Thrombocytopenia may also be complicated by bleeding. Bleeding with fatal outcome has been reported.
2a Frequency of thrombocytopenia is based on the frequency of thrombocytopenia <100 x 103/µL [12.2% (24/196) not shown in table] and <50 x 103/µL; a relevant percentage ratio cannot be calculated from the pooled data and thus the conservative frequency of “Very common” was included in the table.
3 Includes cases reported as anemia and decrease in hemoglobin/hematocrit.
4 Encephalopathy with coma and death has been reported.
5 Central nervous system toxicity was reported to be manifested by the following signs and symptoms: Abnormal behavior, Affect lability Aggression, Agitation, Anxiety, Aphasia, Asthenia, Ataxia, Cerebellar syndrome, Cerebral function deficiency,
Cognitive disorder, Coma, Confusional state, Convulsions, Cranial nerve dysfunction, Depressed state of consciousness, Depression, Disorientation, Dizziness, Electroencephalogram abnormal, Encephalopathy, Flat affect. Hallucinations, Headache, Ideation, Lethargy, Memory impairment, Mood change, Motor dysfunction, Muscle spasms, Myoclonus, Progressive loss of brainstem reflexes, Psychotic reaction, Restlessness, Somnolence, Tremor, Urinary incontinence.
6 Cardiotoxicity was reported as congestive heart failure, tachycardia, pulmonary edema. Fatal outcome has been reported.
7 Hypotension leading to shock and fatal outcome has been reported.
8 Hepatotoxicity was reported as increases in liver enzymes, i.e., serum alanine aminotransferase, serum aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase, increased bilirubin, jaundice, hepatorenal syndrome.
9 Frequency of hemorrhagic cystitis is estimated based on the frequency of hematuria. Reported symptoms of hemorrhagic cystitis included dysuria and pollakiuria. See also Post-marketing Adverse Reactions (6.2).
10 Renal dysfunction was reported to be manifested as: Renal failure (including acute renal failure, irreversible renal failure; fatal outcomes have been reported), Serum creatinine increased, BUN increased, Creatinine clearance decreased, Metabolic acidosis, Anuria, Oliguria, Glycosuria, Hyponatremia, Uremia, Creatinine clearance increased. Renal structural damage was reported to be manifested as: Acute tubular necrosis, renal parenchymal damage, Enzymuria, Cylindruria, Proteinuria.
11 Includes cases reported as phlebitis and irritation of the venous walls.
12 Frequency of neutropenic fever: Includes cases reported as granulocytopenic fever.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ifosfamide.  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

INFECTIONS AND INFESTATIONS:
The following manifestations have been associated with myelosuppression and immunosuppression caused by ifosfamide: increased risk for and severity of infections†, pneumonias†, sepsis and septic shock (including fatal outcomes), as well as reactivation of latent infections, including viral hepatitis†, Pneumocystis jiroveci†, herpes zoster, Strongyloides, progressive multifocal leukoencephalopathy†, and other viral and fungal infections.

† Severe immunosuppression has led to serious, sometimes fatal, infections.

NEOPLASMS, BENIGN AND MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS):
 
As treatment-related secondary malignancy*, Acute leukemia* (Acute myeloid leukemia)*, Acute promyelocytic leukemia*, Acute lymphocytic leukemia*, Myelodysplastic syndrome, Lymphoma (Non-Hodgkin’s lymphoma), Sarcomas*, Renal cell carcinoma, Thyroid cancer

BLOOD AND LYMPHATIC SYSTEM DISORDERS:
Hematotoxicity*, Myelosuppression manifested as Bone marrow failure, Agranulocytosis; Febrile bone marrow aplasia; Disseminated intravascular coagulation, Hemolytic uremic syndrome, Hemolytic anemia, Neonatal anemia, Methemoglobinemia

IMMUNE SYSTEM DISORDERS:
Angioedema*, Anaphylactic reaction, Immunosuppression, Urticaria, Hypersensitivity reaction

ENDOCRINE DISORDERS:
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

METABOLISM AND NUTRITION DISORDERS:
Tumor lysis syndrome, Metabolic acidosis, Hypokalemia, Hypocalcemia, Hypophosphatemia, Hyperglycemia, Polydipsia

PSYCHIATRIC DISORDERS:
Panic attack, Catatonia, Mania, Paranoia, Delusion, Delirium, Bradyphrenia, Mutism, Mental status change, Echolalia, Logorrhea, Perseveration, Amnesia

NERVOUS SYSTEM DISORDERS:
Convulsion*, Status epilepticus (convulsive and nonconvulsive), reversible posterior leukoencephalopathy syndrome, Leukoencephalopathy, Extrapyramidal disorder, Asterixis, Movement disorder, Polyneuropathy, Dysesthesia, Hypothesia, Paresthesia, Neuralgia, Gait disturbance, Fecal incontinence, Dysarthria

EYE DISORDERS:
Visual impairment, Vision blurred, Conjunctivitis, Eye irritation

EAR AND LABYRINTH DISORDERS: Deafness, Hypoacusis, Vertigo, Tinnitus

CARDIAC DISORDERS:
Cardiotoxicity*, Cardiac arrest*, Ventricular fibrillation*, Ventricular tachycardia*, Cardiogenic shock*, Myocardial infarction*, Cardiac failure*, Bundle branch block left, Bundle branch block right, Pericardial effusion, Myocardial hemorrhage, Angina pectoris, Left ventricular failure, Cardiomyopathy*, Congestive cardiomyopathy, Myocarditis*, Arrhythmia*, Pericarditis, Atrial fibrillation, Atrial flutter, Bradycardia, Supraventricular extrasystoles, Premature atrial contractions, Ventricular extrasystoles, Myocardial depression, Palpitations, Ejection fraction decreased*, Electrocardiogram ST-segment abnormal, Electrocardiogram T-wave inversion, Electrocardiogram QRS complex abnormal

VASCULAR DISORDERS:
Pulmonary embolism, Deep vein thrombosis, Capillary leak syndrome, Vasculitis, Hypertension, Flushing, Blood pressure decreased

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS:
Respiratory failure*, Acute respiratory distress syndrome*, Pulmonary hypertension*, Interstitial lung disease* as manifested by Pulmonary fibrosis*, Alveolitis allergic, Interstitial pneumonitis, Pneumonitis*, Pulmonary edema*, Pleural effusion, Bronchospasm, Dyspnea, Hypoxia, Cough
 
GASTROINTESTINAL DISORDERS:
Cecitis, Colitis, Enterocolitis, Pancreatitis, Ileus, Gastrointestinal hemorrhage, Mucosal ulceration, Constipation, Abdominal pain, Salivary hypersecretion

HEPATOBILIARY DISORDERS:
Hepatic failure*, Hepatitis fulminant*, Veno-occlusive liver disease, Portal vein thrombosis, Cytolytic hepatitis, Cholestasis

SKIN AND SUBCUTANEOUS TISSUE DISORDERS:
Toxic epidermal necrolysis, Stevens-Johnson syndrome, Palmar-plantar erythrodysesthesia syndrome, Radiation recall dermatitis, Skin necrosis, Facial swelling, Petechiae, Macular rash, Rash, Pruritus, Erythema, Skin hyperpigmentation, Hyperhidrosis, nail disorder

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER:
Rhabdomyolysis, Osteomalacia, Rickets, Growth retardation, Myalgia, Arthralgia, Pain in extremity, Muscle twitching

RENAL AND URINARY DISORDERS:
Fanconi syndrome, Tubulointerstitial nephritis, Nephrogenic diabetes insipidus, Phosphaturia, Aminoaciduria, Polyuria, Enuresis, Feeling of residual urine
Fatal outcomes from acute and chronic renal failure have been documented. REPRODUCTIVE SYSTEM AND BREAST DISORDERS:
Infertility, Ovarian failure, Premature menopause, Amenorrhea, Ovarian disorder, Ovulation disorder, Azoospermia, Oligospermia, Impairment of spermatogenesis, Blood estrogen decreased, Blood gonadotrophin increased

CONGENITAL, FAMILIAL AND GENETIC DISORDERS: Fetal growth retardation

GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS:
Multi-organ failure*, General physical deterioration, Injection/Infusion site reactions including swelling, inflammation, pain, erythema, tenderness, pruritus; Chest pain, Edema, Mucosal inflammation, Pain, Pyrexia, Chills

* Including fatal outcomes

7.1 Inducers of CYP3A4

CYP3A4 inducers (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. John Wort) may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment.

7.2 Inhibitors of CYP3A4

CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, grapefruit juice) may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment.

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.8)].

Ifosfamide for Injection can cause fetal harm when administered to a pregnant woman.  Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy.

Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m2 dose of ifosfamide was administered on day 11 of gestation.  Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m2/day doses from the 6th through the 18th day after mating.  The number of anomalies was also significantly increased over the control group.

Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy.  If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus.

8.3 Nursing Mothers

Ifosfamide is excreted in breast milk.  Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.  Women must not breastfeed during treatment with ifosfamide.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age [see Pharmacokinetics (12.3)].  This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age.  No significant changes in total plasma clearance or renal or non-renal clearance with age were reported.

Ifosfamide and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.  Because elderly patients are
 
more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Use in Patients with Renal Impairment

No formal studies were conducted in patients with renal impairment. Ifosfamide and its metabolites are known to be excreted by the kidneys and may accumulate in plasma with decreased renal function.  Patients with renal impairment should be closely monitored for toxicity and dose reduction may be considered. Ifosfamide and its metabolites are dialyzable.

8.7 Use in Patients with Hepatic Impairment

No formal studies were conducted in patients with hepatic impairment. Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. Ifosfamide for Injection should be given cautiously to patients with impaired hepatic function.

12.1 Mechanism of Action

Ifosfamide is a prodrug that requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert its cytotoxic activity.  Activation occurs by hydroxylation at the ring carbon atom forming the unstable intermediate 4-hydroxyifosfamide and its ring-opened aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound acrolein and an alkylating isophosphoramide mustard as well as multiple other nontoxic products.  The exact mechanism of action of ifosfamide has not been determined, but its cytotoxic action is primarily through DNA crosslinks caused by alkylation by the isophosphoramide mustard at guanine N-7 positions.  The formation of inter- and intra-strand cross-links in the DNA results in cell death.

12.3 Pharmacokinetics

Ifosfamide exhibits dose-dependent pharmacokinetics in humans.  At single doses of 3.8 to 5.0 g/m2, the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours.  At doses of 1.6 to 2.4 g/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about 7 hours.

Ifosfamide exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, a decrease in the median elimination half-life from 7.2 hour on Day 1 to 4.6 hours on Day 5 occurred with a concomitant increase in the median clearance from 66 mL/min on Day 1 to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day 5 compared with Day 1.

Distribution
Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64
L/kg on Day 1 and 0.72 L/kg on Day 5.  Ifosfamide shows little plasma protein binding. Ifosfamide and its active metabolites are extensively bound by red blood cells. Ifosfamide is not a substrate for P-glycoprotein.

Metabolism
Ifosfamide is extensively metabolized in humans through two metabolic pathways: ring oxidation (“activation”) to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma.  Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients.

Excretion
After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in urine as metabolites, with about 61% of the dose excreted as parent compound.  At doses of 1.6 to 2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours. Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4-hydroxyifosfamide and acrolein are present.
 
Pediatrics
Population PK analysis was performed on plasma data from 32 pediatric patients various malignant diseases aged between 1 and 18 years. Patients received a total of 45 courses of ifosfamide at doses of 1.2, 2.0 and 3.0 g/m2 given intravenously over 1 or 3 hours on 1, 2, or 3 days. The mean±standard error population estimates for the initial clearance and volume of distribution of ifosfamide were 2.4±0.33 L/h/m2 and 21±1.6 L/m2 with an interindividual variability of 43% and 32%, respectively.

Effect of Age
A study of 20 patients between 40 to 71 years of age receiving 1.5 g/m2 of ifosfamide daily for 3 or 5 days indicated that elimination half-life appears to increase with age.  The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age.  No significant changes in total plasma clearance or renal clearance with age were reported.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at 6 mg/kg (37 mg/m2, or about 3% of the daily human dose on a mg/m2 basis) 3 times a week for 52 weeks. Female rats had a significantly higher incidence of uterine leiomyosarcomas and mammary fibroadenomas than vehicle controls.

The mutagenic potential of ifosfamide has been documented in bacterial systems in vitro and mammalian cells in vivo.  In vivo, ifosfamide has induced mutagenic effects in mice and Drosophila melanogaster germ cells, and has induced a significant increase in dominant lethal mutations in male mice as well as recessive sex-linked lethal mutations in Drosophila.

Ifosfamide was administered to male and female beagle dogs at doses of 1.00 or 4.64 mg/kg/day (20 or 93 mg/m2) orally 6 days a week for 26 weeks.  Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on a mg/m2 basis) had testicular atrophy with degeneration of the seminiferous tubular epithelium.  In a second study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or 600 mg/m2) ifosfamide intraperitoneally once every 3 weeks for 6 months.  Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about half the daily clinical dose on a mg/m2 basis).