IFEX (Page 3 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of IFEX. 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

Ifosfamide has been reintroduced after neurotoxicity. While some patients did not experience neurotoxicity, others had recurrent, including fatal, events.

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 DRUG INTERACTIONS

Ifosfamide is a substrate for both CYP3A4 and CYP2B6.

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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

IFEX 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.

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