Ifosfamide (Ifosfamidum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
Read on
Clinical and pharmacological group: & nbsp

Alkylating agents

Included in the formulation
  • Vero-Ifosfamide
    powder for injections 
    VEROPHARM SA     Russia
  • Ifosfamide
    powder d / infusion 
    Promomed Rus, Open Company     Russia
  • Holoksan
    powder in / in 
    Baxter Oncology GmbH     Germany
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    АТХ:

    L.01.A.A.06   Ifosfamide

    Pharmacodynamics:Antineoplastican alkylating agent, an oxazaphosphorin derivative. The mechanism of action is associated with the alkylation of nucleophilic centers, the formation of cross-links in DNA and RNA molecules, and the blocking of mitotic cell division.
    Pharmacokinetics:

    The active substance is a prodrug (an inactive transport form).

    After intravenous administration, it is metabolized enzymes (phosphoamidases) of the liver (mainly cytochrome P450) and tumor tissue in the pharmacologically active metabolite 4-hydroxyphosphamide.

    Biotransformation of ifosfamide into the active metabolite is inhibited in patients with impaired hepatic function. After a single dose of 3.8-5 g / m2 pharmacokinetics two-phase; half-life (terminal phase) - 15 hours (in small doses or in the fractionation of the dose - 4-8 hours, possibly due to autoinduction of metabolism). After administration in a dose of 1.6-2.4 g / m2 per day pharmacokinetics monophasic; half-life - 7 hours.Elimination of the kidneys - 70-86%, 61% of them - unchanged after a single dose of 5 g / m2, 12-18% - unchanged when administered at a dose of 1.2-2.4 g / m2.

    Indications:Inoperable malignant tumors sensitive to ifosfamide, including lung cancer, ovarian cancer, testicular tumors, soft tissue sarcoma, osteogenic sarcomas, breast cancer, cervical cancer, lymphogranulomah, Wilms tumor, non-Hodgkin's lymphomas, Ewing's sarcoma.
    ICD-10

    II.C15-C26.C25   Malignant neoplasm of pancreas

    XXI.Z80-Z99.Z85.1   In a personal history, a malignant neoplasm of the trachea, bronchi, and lung

    II.C40-C41.C40   Malignant neoplasm of bones and articular cartilages of extremities

    II.C40-C41.C41   Malignant neoplasm of bones and articular cartilages of other and unspecified sites

    II.C45-C49.C49   Malignant neoplasm of other types of connective and soft tissue

    II.C50.C50   Malignant neoplasm of breast

    II.C51-C58.C53   Malignant neoplasm of cervix

    II.C51-C58.C54   Malignant neoplasm of uterine body

    II.C60-C63.C62   Malignant neoplasm of testis

    II.C64-C68.C64   Malignant neoplasm of kidney, except for renal pelvis

    II.C64-C68.C67   Malignant neoplasm of bladder

    II.C69-C72.C71   Malignant neoplasm of brain

    II.C81-C96.C81   Hodgkin's disease [lymphogranulomatosis]

    II.C81-C96.C82.9   Follicular non-Hodgkin's lymphoma, unspecified

    II.C81-C96.C83   Diffuse non-Hodgkin's lymphoma

    II.C81-C96.C84   Peripheral and cutaneous T-cell lymphomas

    II.C81-C96.C85.9   Non-Hodgkin's lymphoma, unspecified

    Contraindications:Pronounced mielodepression, liver or kidney function, urinary tract obstruction, cystitis, hypoproteinemia, pregnancy, lactation, hypersensitivity to ifosfamide.
    Carefully:Oppression of bone marrow function (especially in patients who received radiation or chemotherapy earlier), renal dysfunction, cystitis, urinary tract obstruction, single kidney tumor, electrolyte balance disturbance, immunosuppression, diabetes mellitus, acute infectious diseases (including chicken pox, shingles), hypoproteinemia, impaired liver function, brain metastases, cerebral symptoms, advanced age (age-related renal impairment is more likely), weakened patients.
    Pregnancy and lactation:

    Ifosfamide is contraindicated in pregnancy. If necessary, use during lactation should stop breastfeeding.

    FDA recommendation category D.

    Women of childbearing age need to apply reliable contraceptive methods throughout the course of treatment and for 3 months after it is completed.

    In experimental studies, the teratogenic and embryotoxic effect of ifosfamide was established.

    Dosing and Administration:Intravenously drip for 30 minutes or 24-hour infusion. The choice of the regimen and doses in each case is determined individually depending on the treatment regimen (ifosfamide is part of many chemotherapy regimens).
    Side effects:

    From the digestive system: nausea, vomiting, stomatitis, liver dysfunction.

    From the side of the central nervous system and the peripheral nervous system: agitation, confusion, hallucinations, unusual fatigue, dizziness; rarely - convulsive seizures, coma, peripheral polyneuropathy.

    On the part of the hematopoiesis system: leukopenia, thrombocytopenia.

    From the urinary system: hemorrhagic cystitis, dysuria, frequent urination, nephropathy.

    On the part of the reproductive system: azoospermia, amenorrhea.

    Other: alopecia, cardiotoxic action.

    Overdose:

    Not described; it is expected the development of pronounced side effects.

    There is no specific antidote.

    Treatment symptomatic: mesna, colony-stimulating factors, antibacterial drugs, blood transfusion and transfusion of platelet mass.

    Interaction:

    Allopurinol enhances the myelosuppressive effect.

    When combined with amphotericin In use, the risk of kidney damage increases and the likelihood of developing bronchospasm and hypotension increases.

    Bupropion undergoes metabolism with the formation of the main active metabolite - hydroxybupropion, mainly with the participation of the CYP2B6 isoenzyme. Therefore, care should be taken when bupropion is administered simultaneously with ifosfamide, which affects the activity of the isoenzyme CYP2B6.

    Busulfan increases (mutually) the risk of developing veno-occlusive disease.

    Warfarin. Ifosfamide increases the effect of warfarin and increases the risk of bleeding.

    Doxorubicin. Ifosfamide intensifies (mutually) toxicity.

    Mesna reduces the nephrotoxicity of ifosfamide.

    Nethylmycin. Joint use of netilmicin with ifosfamide, potentially having a neuro- and / or nephrotoxic effect, should be avoided. In the case when it is impossible to avoid joint application, during the treatment, the kidney function of the patient should be closely monitored, conducting the necessary laboratory tests. The risk of developing nephrotoxicity is higher in elderly patients and in dehydration.

    Pegasaspragase. Increases (mutually) the likelihood of complications.

    Phenytoin (an inductor of microsomal liver enzymes) increases the formation of alkylating metabolites.

    Phenobarbital (inducer of microsomal enzymes of the liver) increases the formation of alkylating metabolites.

    Cisplatinum. With simultaneous application of cisplatin and ifosfamide, nephrotoxicity of the latter may be increased. Ifosfamide can enhance the ototoxicity of cisplatin.

    Special instructions:

    Do not recommend applying ifosfamide in patients with chicken pox (including recently transferred or after contact with the diseased), herpes zoster, other acute infectious diseases.

    Before the start of treatment, it is necessary to sanitize foci of chronic infection and correct possible electrolyte imbalance.

    During therapy, the picture of peripheral blood should be monitored regularly, laboratory parameters of liver function, kidney function, and a general urinalysis should be performed.

    Against the background of the use of ifosfamide, it is possible to increase the concentrations of urea and creatinine in the plasma, increase the excretion of glucose, protein, phosphates in the urine.

    Therapy with ifosfamide should be combined with mesna treatment to prevent urotoxic effects.

    It should be borne in mind that ifosfamide increases the healing time of wounds.

    In experimental studies, mutagenic and carcinogenic effects of ifosfamide have been established.

    The duration of infusion of ifosfamide is 0.5-2 h.

    Individual dosage adjustment of ifosfamide is necessary on the basis of clinical response to treatment and the severity of toxic effects.

    Each subsequent administration of ifosfamide should be performed only after regression of the microhematuria, defined as the number of erythrocytes more than 10 in the field of view at high magnification.

    With severe leukopenia, in particular granulocytopenia or thrombocytopenia, ifosfamide should be abolished before the recovery of the number of leukocytes and platelets to an acceptable level. When resuming treatment should consider reducing the dose of ifosfamide.

    Differences in the tolerability of ifosfamide and factors limiting its use in children have not been established.

    Differences in the tolerability of ifosfamide in elderly patients have not been detected, but in this category of patients, liver function disorders are more frequent, which may require a reduction in the dose of the drug and careful monitoring of the patient.

    8% solution of ifosfamide penetrates through latex (faster) and polychlorovinyl (slower) gloves at a rate 4 times lower than the penetration rate through the skin of the corpse. When working with ifosfamidom change gloves are recommended at least every 2 hours.

    Instructions
    Up