Ifosfamide

Black Box Warnings

The drug should be administered under the supervision of an experienced cancer chemotherapy physician

Bone marrow suppression may occur

Hemorrhagic cystitis reported

Confusion and coma due to CNS toxicity have been associated with therapy. Discontinue therapy if it occurs.

Dose-related severe myelosuppression reported

Contraindications

Hypersensitivity

Severe myelosuppression

Cautions

Avoid pregnancy

May interfere with wound healing

Use caution in renal impairment

Heart Failure risk

• Acute heart failure, often occurring within 1 to 10 days of treatment, has been reported with induction therapy at doses greater than 12.5 mg/m2
• The onset of HF can be reversible, usually resolving over 3 to 4 weeks

Inform patients of the risks associated with the use of IFEX as well as the plan for regular blood monitoring during therapy.

Specifically inform patients of the following:

• Treatment with ifosfamide may cause myelosuppression which can be severe and lead to fatal outcome. Significant suppression of immune responses can also occur which can lead to severe infections. Latent infections can be reactivated. Patients should report fever or other symptoms of an infection.
• The risk of bleeding and anemia.
• The risk of CNS toxicity and other neurotoxic effects with fatal outcome.
• The risk of bladder and kidney toxicity. Patients should be aware of the need to increase fluid intake and frequent voiding to prevent accumulation in the bladder.
• The risk of cardiotoxicity and fatal outcome. Patients should report preexisting cardiac disease.
• The risk of pulmonary toxicity leading to respiratory failure with fatal outcome.
• The risk of secondary malignancies due to therapy.
• The risk of veno-occlusive liver disease.
• The potential hazard to a fetus if a patient becomes pregnant or fathers a child during therapy and for up to 6 months after therapy. Effective methods of contraception should be used during therapy and for up to 6 months after therapy.
• The potential for serious adverse reactions and tumorigenicity when children are breastfed during therapy.
• The risk of amenorrhea, premature menopause, and sterility.
• The risk of alopecia, wound healing, and other serious skin and subcutaneous tissue disorders.
• Therapy may cause gastrointestinal disorders and alcohol may increase nausea and vomiting.
• The risk of stomatitis and the importance of proper oral hygiene.
• The risk of eye disorders such as visual impairment, blurred vision, and eye irritation.
• The risk of ear and labyrinth disorders such as deafness, vertigo, and tinnitus.

Ifosfamide is a prescription medication used to treat cancer of the testicles that has not improved or that has worsened after previous treatment. Ifosfamide belongs to a class of drugs called alkylating agents. It works by slowing or stopping the growth of cancer cells in your body.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects of ifosfamide include nausea, vomiting, loss of appetite, and sores in the mouth or throat.

Treatment with ifosfamide increase the risk of certain serious side effects including the following:

• Lowered blood count. The number of blood cells in your bone marrow. This may cause certain symptoms and may increase the risk that you will develop a serious or life-threatening infection or bleeding. If you experience any of the following symptoms, call your doctor immediately: fever, chills, sore throat, ongoing cough and congestion, or other signs of infection; unusual bleeding or bruising; bloody or black, tarry stools; bloody vomit; or vomiting blood or brown material that resembles coffee grounds.
• Severe or life-threatening damage to the nervous system. If you experience any of the following symptoms, call your doctor immediately: confusion; drowsiness; blurred vision; seeing things or hearing voices that do not exist (hallucinating); or pain, burning, numbness, tingling in the hands or feet; seizures; or coma (loss of consciousness for a period of time).
• Severe or life-threatening kidney problems. Kidney problems may occur during therapy or months or years after you stop receiving treatment. Tell your doctor if you have or have ever had kidney disease. If you experience any of the following symptoms, call your doctor immediately: decreased urination; swelling of the face, arms, hands, feet, ankles, or lower legs; or unusual tiredness or weakness.
• Toxicity to the heart which could lead to fatal outcome. Patients should report preexisting cardiac disease.
• Toxicity to the lung leading to respiratory failure with fatal outcome.
• The development of other cancers.
• Liver disease
• Harm to an unborn baby if a patient becomes pregnant or fathers a child during therapy and for up to 6 months after therapy. Effective methods of contraception should be used during therapy and for up to 6 months after therapy.
• Harm to a nursing infant if breastfeeding.
• Amenorrhea (absence of a menstrual cycle), premature menopause, and sterility.
• Hair loss, wound healing, and other serious skin and tissue disorders.
• Stomach and intestinal disorders
• Alcohol may increase nausea and vomiting.
• Inflammation of the mouth; it is important to conduct proper oral hygiene.
• Eye disorders such as visual impairment, blurred vision, and eye irritation.
• Hearing disorders such as deafness, vertigo, and tinnitus
• Decreased ability to heal wounds

Do not take ifosfamide if you:

• are allergic to ifosfamide or to any of its ingredients
• have urinary outflow obstruction (not able to urinate)

Before taking ifosfamide, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to ifosfamide, cyclophosphamide (Cytoxan), any other medications, or any of the ingredients in ifosfamide injection
• have liver problems
• have heart problems
• have kidney problems
• have problems urinating
• have previously received treatment with other chemotherapy medications or if you have previously received radiation therapy
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

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 ifosfamide. Use a reliable method of birth control to prevent pregnancy while you are receiving ifosfamide 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 ifosfamide injection. If you become pregnant while receiving ifosfamide, call your doctor immediately. Ifosfamide may harm the unborn baby.

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.

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.

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.

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

Hematotoxicity*, Myelosuppression manifested as Bone marrow failure, Agranulocytosis; Febrile bone marrow aplasia; Disseminated intravascular coagulation, Hemolytic uremic syndrome, Hemolytic anemia, Neonatal anemia, Methemoglobinemia

Angioedema*, Anaphylactic reaction, Immunosuppression, Urticaria, Hypersensitivity reaction

Tumor lysis syndrome, Metabolic acidosis, Hypokalemia, Hypocalcemia, Hypophosphatemia, Hyperglycemia, Polydipsia

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

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

Visual impairment, Vision blurred, Conjunctivitis, Eye irritation

Deafness, Hypoacusis, Vertigo, Tinnitus

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

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

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

Cecitis, Colitis, Enterocolitis, Pancreatitis, Ileus, Gastrointestinal hemorrhage, Mucosal ulceration, Constipation, Abdominal pain, Salivary hypersecretion

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

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

Rhabdomyolysis, Osteomalacia, Rickets, Growth retardation, Myalgia, Arthralgia, Pain in extremity, Muscle twitching

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.

Infertility, Ovarian failure, Premature menopause, Amenorrhea, Ovarian disorder, Ovulation disorder, Azoospermia, Oligospermia, Impairment of spermatogenesis, Blood estrogen decreased, Blood gonadotrophin increased

Fetal growth retardation

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

Read the entire FDA prescribing information for Ifex (Ifosfamide)

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Serious and sometimes fatal infections may occur during treatment with ifosfamide. Stop using this medicine and call your doctor right away if you have signs of infection such as:

• sudden weakness or ill feeling, fever, chills, sore throat, cold or flu symptoms;

• painful mouth sores, pain when swallowing, red or swollen gums;

• pale skin, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum); or

• feeling light-headed or short of breath, chest discomfort, wheezing, dry cough or hack, rapid weight loss.

Call your doctor at once if you have any of these side effects:

• swelling, pain in your side or lower back, little or no urinating, pain or burning when you urinate, blood in your urine;

• upper stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• rapid weight gain, especially in your face and midsection;

• problems with your hearing or vision, ringing in your ears;

• confusion, unusual thoughts or behavior, hallucinations, seizure (convulsions);

• muscle movements you cannot control;

• a wound that will not heal; or

• severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• nausea and vomiting;

• numbness or tingling in your hands or feet;

• drowsiness, dizziness, spinning sensation;

• blurred vision, eye irritation; or

• temporary hair loss.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Testicular Cancer

Component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer1 (designated an orphan drug by FDA for this use).5

Soft Tissue Sarcomas

Component of various chemotherapeutic regimens in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas†2 3 9 33 34 35 36 37 38 39 40 41 42 43 44 45 46 111 (designated an orphan drug by FDA for this use).5

Osteosarcoma

Used alone or in conjunction with other drugs (e.g., etoposide)9 35 36 37 40 41 42 for treatment of localized, metastatic, and recurrent osteosarcoma†9 37 40 41 (designated an orphan drug by FDA for this use).5

Bladder Cancer

Used alone9 143 or in combination with other antineoplastic agents144 145 146 147 for treatment of advanced or metastatic bladder cancer†.143

Small Cell Lung Cancer

Treatment of small cell lung cancer† as part of a combination regimen.2 3 8 9 10 11 12 13 54 132

Cervical Cancer

Component of various combination regimens (e.g., cisplatin and ifosfamide with or without bleomycin) for the treatment of metastatic or recurrent cervical cancer†.3 9 20 21 22 23 25 152 153 154 155 156 157 158

Ovarian Cancer

Used alone or in conjunction with other antineoplastic agents for second-line (salvage) therapy in patients with advanced or recurrent ovarian carcinoma†.9 26 28 29 135

Non-Hodgkin’s Lymphoma

Treatment of advanced small noncleaved cell lymphoma (Burkitt’s and non-Burkitt’s) in children9 119 as part of a combination regimen.c

• It is used to treat testicular cancer.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to ifosfamide or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are not able to pass urine.
• If you are breast-feeding. Do not breast-feed while you take ifosfamide.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take ifosfamide with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Hair loss.
• Upset stomach or throwing up.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Ifosfamide for Injection, USP single dose vials for constitution and administration by intravenous infusion each contain 1 gram or 3 grams of sterile, lyophilized 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.  Its structural formula is:

Ifosfamide is a white crystalline powder that soluble in water.

General

Ifosfamide should be given cautiously to patients with impaired renal function as well as to those with compromised bone marrow reserve, as indicated by: leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

Laboratory Tests

During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression.  Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis.

Drug Interactions

The physician should be alert for possible combined drug actions, desirable or undesirable, involving Ifosfamide even though Ifosfamide has been used successfully concurrently with other drugs, including other cytotoxic drugs.

Wound Healing

Ifosfamide may interfere with normal wound healing.

Pregnancy

Teratogenic Effects: Pregnancy Category D. See WARNINGS.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ifosfamide has been shown to be carcinogenic in rats, with female rats showing a significant incidence of leiomyosarcomas and mammary fibroadenomas.

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.

In pregnant mice, resorptions increased and anomalies were present at day 19 after 30mg/m2 dose of Ifosfamide was administered on day 11 of gestation.  Embryolethal 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Testicular cancer: Treatment (third-line) of germ cell testicular cancer (in combination with other chemotherapy drugs and with concurrent mesna for prophylaxis of hemorrhagic cystitis)

Known hypersensitivity to ifosfamide or any component of the formulation; urinary outflow obstruction

Canadian labeling: Additional contraindications (not in US labeling): Severe leukopenia/thrombocytopenia; severe renal and/or hepatic impairment; cystitis; active infection; advanced cerebral arteriosclerosis

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).