Ifosfamide

IFOSFAMIDE

Complete information including dosage, side effects, interactions and pregnancy & breast feeding warnings for patient and professional use.

Overview and uses

Ifosfamide is an alkylating agent used for the treatment of cancer.

Indication (uses)

  • Third line chemo therapy of germ cell testicular cancer in combination with other approved anti-cancer drugs.
  • Should be used in combination with Mesna for the prophylaxis of hemorrhagic cystitis.

Pharmacological classification

Alkylating agent used for the treatment of cancer.

Brand names

Ifex, Holoxan, Ipamide

Dosage form

  • Available as single dose vials in strengths of 1g and 3g.

Mechanism of action

Alkylating agents produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular macromolecules by forming covalent bonds. These intermediates may react with carboxyl, hydroxyl, amino, sulfhydryl and phosphate groups of biomacromolecules. Alkylation results in cross linking/abnormal base pairing/scission of DNA strand. Cross linking of nucleic acids with proteins can also take place.

Dosage

  • 2 g/m2 per day should be administered as a slow intra venous (IV) infusion lasting a minimum of 30 minutes for 5 consecutive days.
  • Treatment should be repeated every 3 weeks or after the recovery from hematologic toxicity.
  • Ifosfamide should be given with at least 2 liters of fluid per day, either by IV route or by oral route to prevent bladder toxicity.

Further instructions regarding dosage and administration

  • 20 ml of diluent (sterile water for injection, USP or bacteriostatic water for injection, USP) should be added to 1 g vial to get the concentration of 50 mg/ml.
  • 60 ml of diluent (sterile water for injection, USP or bacteriostatic water for injection, USP) should be added to 1 g vial to get the concentration of 50 mg/ml.
  • These solution may further be diluted to achieve the desired concentrations ranging from 0.6 mg/ml to 20 mg/ml in following fluids:
    • 5% dextrose injection USP
    • 9% sodium chloride injection USP
    • Lactated ringer’s injection USP
    • Sterile water for injection USP
  • Do not administer the injection until the substance is completely dissolved.

Pediatric patients

  • Safety and effectiveness is not yet established.

Hepatic dose adjustment

  • Safety and effectiveness is not yet established.
  • Since Ifosfamide is extensively metabolized in liver and it forms both toxic and efficacious metabolites, use of Ifosfamide should be done with caution in patients with impaired hepatic functions.

Renal dose adjustments

  • Safety and effectiveness is not yet established.
  • Ifosfamide and its metabolites are excreted by kidneys. These may accumulate in plasma of patients with impaired renal function.
  • Patients with impaired renal function should be closely monitored for toxicity and dose adjustment should be considered.

Geriatric dose adjustments

  • Elimination half-life of Ifosfamide and its metabolites increases with the advancement of age as reported by a study conducted involving patients with 40 to 71 years of age.
  • Caution should be exercised while administering Ifosfamide in elderly patients since an increase in age is related to reduced hepatic, renal and/or cardiac functions as well as presence of concomitant disease or treatment of concomitant disease.

Overdosage

  • Ifosfamide and its metabolites are dialyzable.
  • No specific antidote is known.
  • General supportive measures should be given.
  • Appropriate treatment for any concurrent infection, Myelosuppression and cardiac toxicity should be considered.
  • Myelosuppression, urotoxicity, nephrotoxicity, CNS toxicity and mucositis are dose dependent.
  • Patient should be monitored for all the toxicities mentioned above as well as for hematologic toxicity.
  • Cystitis prophylaxis with Mensa might be beneficial in limiting or preventing the urotoxicity due to overdose.

Side effects or adverse effects

  • Local side effects
    • Thrombophlebitis and thrombosis at the site of injection.
  • Hypersensitivity reactions
    • Anaphylaxis has been reported with Mechlorethamine use.
    • Pain in chest or abdomen, skin rash, difficulty in breathing, rapid breathing, shortness of breath, dizziness, fainting, low blood pressure are some of the symptoms.
    • Consult your doctor as soon as possible.
  • Other systemic side effects
    • Jaundice
    • Vertigo
    • Tinnitus
    • Diminished hearing
    • Occurrence/precipitation of hemolytic anemia
  • Bone marrow depression
    • Bone marrow depression is the most serious side effect/toxicity. It is also a limiting factor for the dose. Infections and bleeding are the common complications.
    • Bone marrow depression results in granulocytopenia, agranulocytosis, thrombocytopenia and aplastic anemia.
    • Consult your doctor as soon as possible if you observe any of the below mentioned symptoms:
      • Sore throat
      • Chills
      • Sudden fever
      • Weakness in limbs
      • Mouth ulcers
      • Bleeding gums
      • Sore mouth
      • Fast heart rate
      • Low blood pressure
      • Sore gums
      • Skin abscesses
      • Rapid breathing
      • Rapid progression of infection of any organ
      • Rapid progression of Septicemia
    • Gastrointestinal side effects
      • Nausea and vomiting are commonly observed with anti-cancer medicines.
      • Mucositis – painful inflammation and ulceration of mucus membrane lining the digestive tract.
      • Diarrhea, shredding of mucosa and haemorrhage due to decreased rate of renewal of gastrointestinal mucosa lining.
    • Skin
      • Alopecia or hair loss.
      • Dermatitis
      • Pigmentation of the skin and changes in the nail colour.
    • Oral side effects
      • Breaches during chewing.
      • Depression of immunity due to reduction in number of WBCs largely increases the risk of oral infections.
      • Bleeding gums
      • Rapid progression of dental caries.
    • Gonadal side effects
      • Infertility due to Oligozoospermia in males.
      • Impotence in males.
      • Loss or reduces sex drive.
      • Inhibition of ovulation in females
      • Amenorrhea in females.
      • Damage to germinal cells may lead to mutagenesis.
    • Lymphoreticular tissue
      • Lymphocytopenia (reduced number of lymphocytes)
      • Inhibition of lymphocyte function.
      • Suppression of immunity due to bone marrow depression and reduced lymphocyte function highly increases the risk of opportunistic infections like:
        • Candida and other infections causing deep mycosis.
        • Cytomegalo virus
        • Herpes zoster
        • Pneumocystis jiroveci
        • Toxoplasma
      • Pulmonary toxicity
        • Pneumonitis
        • Pulmonary fibrosis
        • Pulmonary veno-occlusive disease
      • Impairment of wound healing
        • Ifosfamide may interfere with normal wound healing.
      • Hyponatremia
        • Hyponatremia associated with increased total body water, acute water intoxication and a syndrome resembling SIADH.
      • Secondary malignancies
        • Urinary tract cancer
        • Myelodysplasia
        • Acute leukemias
        • Lymphomas
        • Thyroid cancer
        • Sarcomas
      • Cardiac side effects
        • Congestive heart failure
        • Myocarditis
        • Myopericarditis
        • Pericardial effusion including cardiac tamponade
        • Supraventricular arrhythmias
        • Ventricular arrythmias
      • Fetal side effects
        • Use of anti-cancer medicines in pregnant women may cause fetal damage leading to:
          • Fetal death
          • Abortion
          • Teratogenesis
        • Hyperuricemia
          • An elevated level of uric acid is common in leukemia and bulky lymphomas.
        • Cardiac side effects
          • Cardiotoxixity
          • Cardiac arrest
          • Ventricular fibrillation
          • Ventricular tachycardia
          • Cardiogenic shock
          • Myocardial infarction
          • Cardiac failure
          • Congestive cardiomyopathy
          • Cardiomyopathy
          • Myocardial hemorrhage
          • Myocarditis
          • Angina pectoris
          • Left ventricular failure
          • Pericarditis
          • Atrial flutter
          • Atrial fibrillation
          • Bradycardia
          • Supraventricular extrasystoles
          • Premature atrial contractions
          • Ventricular extrasystoles
          • Myocardial depression
          • Palpitation
          • Myocardial infarction
          • Bundle branch block left
          • Bundle branch block right
        • Renal side effects
          • Renal failure, Gout and Urate stones may develop in urinary tract.
          • Hemorrhagic cystitis, pyelitis, ureteritis and hematuria.
          • Macrohematuria, renal dysfunction, renal structural damage.
        • CNS side effects
          • Convulsions
          • Status epilepticus
          • Reversible posterior leukoencephalopathy syndrome
          • Leukoencephalopathy
          • Extrapyramidal disorder
          • Asterixis
          • Movement disorder
          • Polyneuropathy
          • Dysesthesia
          • Hypothesia
          • Parethesia
          • Neuralgia
          • Gait disturbances
          • Fecal incontinence
          • Dysarthria

Please note: The side effects mentioned above are from the reported cases. However, side effects are not limited to above mentioned conditions and symptoms. Consult your doctor as soon as possible if you feel or observe any symptoms that you relate to your treatment.

Warnings & Precautions

  • Contra-indicated in patients with known hypersensitivity to Ifosfamide.
  • Contra-indicated in patients with myelosuppression.
  • Contra-indicated in patients with Neurotoxicity.
  • Contra-indicated in patients with Urotoxicity.
  • Contra-indicated in patients with Urinary outflow obstruction.
  • Caution should be exercised in giving Ifosfamide to patients with pre-existing infections.

Pregnancy & breast feeding warnings

  • Pregnancy
  • Category D, which means there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
  • Nursing:
  • Ifosfamide is excreted in human breast milk.
  • Because of the potential for side effects in nursing infants, a decision should be made whether to discontinue drug or to discontinue nursing.

Interactions

Drug – drug interactions

  • Ifosfamide is a substrate for both CYP3A4 and CYP2B6.
  • CYP3A inducers like phenytoin, carnamazepine, fosphenytoin, phenobarbital, rifampin, St. John’s wart may increase the metabolism of Ifosfamide to its active metabolites. Close monitoring of patients is highly recommended in patients taking Ifosfamide with CYP3A inducers for toxicities. Dose adjustments should be considered in such patients.
  • CYP3A4 inhibitors like ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit and grapefruit juice may decrease the metabolism of Ifosfamide to its active metabolites this may lead to a decrease in the efficacy of Ifosfamide.
  • Concomitant use of Ifosfamide with following drugs/medicines should be strictly avoided.
    • ACE inhibitors can cause leukopenia.
    • Thiazide diuretics
    • Zidovudine
    • Paclitaxel causes increased hematotoxicity.
    • Thiotepa may increase the side effects of Ifosfamide.
    • Thalidomide may increase the risk of dangerous blood clots.
    • Leflunomide as it increases the risk of infections.
    • Adalimumab as it increases the risk of infections.
    • Teriflunomide as it increases the risk of infections.
    • Ditrizoate may increase the risk of nephrotoxicity, nephropathy and renal impairment.
    • Certolizumab as it increases the risk of infections.
    • Cidofovir may increase the risk of nephrotoxicity and renal impairment.
    • Iodipamide may increase the risk of nephrotoxicity and renal impairment.
    • Clozapine as it may lower the WBC count.
    • Deferiprone as it may lower the WBC count.
    • Etanercept as it increases the risk of infections.
    • Fingolimod as it increases the risk of infections.
    • Golimumab as it increases the risk of infections.
    • Iothalamate may increase the risk of nephrotoxicity and renal impairment.
    • Ioxagalate may increase the risk of nephrotoxicity and renal impairment.
    • Ioxilan may increase the risk of nephropathy and renal impairment.
    • Ioversol may increase the risk of nephropathy and renal impairment.
    • Iodamide may increase the risk of nephropathy and renal impairment.
    • Iodixanol may increase the risk of nephrotoxicity and renal impairment.
    • Iohexol may increase the risk of nephrotoxicity and renal impairment.
    • Iopamidol may increase the risk of nephropathy and renal impairment.
    • Iopromide may increase the risk of nephropathy and renal impairment.
    • Oprelvekin may cause abnormally low levels of potassium in blood.
    • Infliximab as it increases the risk of infections.
    • Talimogene as it increases the risk of herpes infections.
    • Nalidixic acid as the combination may cause unusual bruising or bleeding, nausea, stomach pain, unusual weakness, low fever and loss of appetite.
    • Natalizumab as it increases the risk of infections.
    • Tofacitinib as it increases the risk of infections.

Click here to go to Ifosfamide forums.

Ifosfamide wikipedia page

Reference

  • “Product information. Ifex (Ifosfamide).” Baxter healthcare corporation, IL, USA.
  • NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
  • OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
  • American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
  • Polovich M, White JM, Kelleher LO, (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. (2nd ed.) Pittsburgh, PA: Oncology Nursing Society.

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About the Author:

B. Pharm (K.L.E. society's S.V.V. Patil College of Pharmacy, Bengaluru) M. Pharm (Maharishi Arvind Institute of Pharmacy, Jaipur)

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