Ifex

Name: Ifex

Ifex Drug Class

Ifex is part of the drug class:

  • Nitrogen mustard analogues

Ifex and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. You should not become pregnant while you are receiving Ifex. Use a reliable method of birth control to prevent pregnancy while you are receiving Ifex and for 6 months after treatments. If you are male, you and your female partner should continue to use birth control for 6 months after you stop receiving Ifex injection. If you become pregnant while receiving Ifex, call your doctor immediately. Ifex may harm the unborn baby.

Ifex Dosage

This medication is available in an injectable form to be dosed by a healthcare professional.

Ifex injection should be administered into the vein at a dose of 1.2 grams per m2 (body surface area measurement) per day for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from toxicities that may occur.

Ifex Overdose

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

What happens if I miss a dose?

Call your doctor for instructions if you miss a dose of ifosfamide.

Ifex Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common
  • Agitation
  • black, tarry stools
  • blood in the urine
  • chest pain
  • confusion
  • cough or hoarseness
  • fever or chills
  • frequent urination
  • hallucinations (seeing, hearing, or feeling things that are not there)
  • lower back or side pain
  • painful or difficult urination
  • pale skin
  • shortness of breath
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swollen glands
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness
Less common
  • Abdominal or stomach pain or tenderness
  • bleeding gums
  • bluish color
  • changes in skin color
  • clay colored stools
  • dark urine
  • decreased appetite
  • dizziness
  • headache
  • itching
  • loss of appetite
  • nausea and vomiting
  • pain
  • pinpoint red spots on the skin
  • skin rash
  • swelling of the feet or lower legs
  • yellow eyes or skin
Rare
  • Blurred vision
  • burning, numbness, tingling, or painful sensations
  • confusion
  • convulsions (seizures)
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fast or irregular heartbeat
  • sweating
  • troubled breathing
  • unsteadiness or awkwardness
  • weakness in the arms, hands, legs, or feet

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Diarrhea
  • hair loss or thinning of the hair
  • swelling or inflammation of the mouth
Less common
  • Redness, swelling, or pain at place of injection
  • weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Dosage Forms and Strengths

1 gram single-dose vial

3 gram single-dose vial

Adverse Reactions

Adverse Reactions from Clinical Trials

Because clinical trials are conducted from 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.

* The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia. For neutropenic fever, see below. † 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. ‡ Thrombocytopenia may also be complicated by bleeding. Bleeding with fatal outcome has been reported. § 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. ¶ Includes cases reported as anemia and decrease in hemoglobin/hematocrit. # Encephalopathy with coma and death has been reported. Þ 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. ß Cardiotoxicity was reported as congestive heart failure, tachycardia, pulmonary edema. Fatal outcome has been reported. à Hypotension leading to shock and fatal outcome has been reported. è 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. ð 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). ø 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. ý Includes cases reported as phlebitis and irritation of the venous walls. £ Frequency of neutropenic fever: Includes cases reported as granulocytopenic fever.

System Organ Class (SOC)

Adverse Reaction

Percentage (Ratio)

INFECTIONS AND INFESTATIONS

Infection

9.9%

(112/1128)

BLOOD AND LYMPHATIC SYSTEM DISORDERS

Leukopenia* (any)

--†

Leukopenia

<1 x 103/µL

43.5%

(267/614)

Thrombocytopenia‡ (any)

--§

Thrombocytopenia, 

50 x 103/µL

4.8%

(35/729)

Anemia¶

37.9%

(202/533)

METABOLISM AND NUTRITION DISORDERS

Anorexia

1.1%

(15/1317)

NERVOUS SYSTEM DISORDERS

Central nervous system toxicity#,Þ

15.4%

(154/1001)

Peripheral neuropathy

0.4%

(5/1317)

CARDIAC DISORDERS

Cardiotoxicityß

0.5%

(7/1317)

VASCULAR DISORDERS

Hypotentionà

0.3%

(4/1317)

GASTROINTESTINAL DISORDERS

Nausea/Vomiting

46.8%

(443/964)

Diarrhea

0.7%

(9/1317)

Stomatitis

0.3%

(4/1317)

HEPATOBILIARY DISORDERS

Hepatotoxicityè

1.8%

(22/1190)

SKIN AND SUBCUTANEOUS TISSUES DISORDERS

Alopecia

89.6%

(540/603)

Dermatitis

0.08%

(1/1317)

Papular rash

0.08%

(1/1317)

RENAL AND URINARY DISORDERS

Hemorrhagic cystitis

--ð

Hematuria

   - without mesna

44.1%

(282/640)

   - with mesna

21.3%

(33/155)

Macrohematuria

   - without mesna

11.1%

(66/594)

   - with mesna

5.2%

(5/97)

Renal dysfunctionø

--

Renal structural damage

--

GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS

Phlebitisý

2.8%

(37/1317)

Neutropenic fever£

1.0%

(13/1317)

Fatigue

0.3%

(4/1317)

Malaise

Unable to calculate

Postmarketing Experience

The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC), then by Preferred Term in order of severity, where feasible. 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

Use in specific populations

Pregnancy

Pregnancy Category D.

[See Warnings and Precautions (5.8)].

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.

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.

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

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.

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.

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. Ifex should be given cautiously to patients with impaired hepatic function.

Ifex Description

Ifex (ifosfamide for injection, USP) single-dose vials for constitution and administration by intravenous infusion each contain 1 gram or 3 grams of sterile ifosfamide. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. Ifosfamide is 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide. The molecular formula is C7H15Cl2N2O2P and its molecular weight is 261.1. Ifosfamide is a white crystalline powder soluble in water. There are no excipients in the formulation. Each vial contains 1 gram or 3 grams of sterile ifosfamide alone.

Its structural formula is:

In Summary

Common side effects of Ifex include: central nervous system toxicity, confusion, drowsiness, and hallucination. See below for a comprehensive list of adverse effects.

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