Cyclophosphamide (Cyclophosphan)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceCyclophosphamideCyclophosphamide
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    • Dosage form: & nbspPowder for the preparation of solution for intravenous and intramuscular injection.
    Composition:

    Each bottle of powder contains: active substance: cyclophosphamide 200 mg, Excipients: no

    Description:

    White or almost white crystalline powder.

    Pharmacotherapeutic group:An antitumour agent, an alkylating compound.
    ATX: & nbsp

    L.01.A.A.01   Cyclophosphamide

    Pharmacodynamics:

    Cyclophosphamide is an alkylating cytostatic drug that is chemically close to the nitrogen analogues of mustard gas.

    It is assumed that the mechanism of action involves the formation of cross-links between DNA and RNA strands, as well as the inhibition of protein synthesis.

    Pharmacokinetics:

    Cyclophosphamide is metabolized mainly in the liver under the influence of the microsomal oxidase system, forming active alkylating metabolites (4-OH cyclophosphamide and aldophosphamide), some of which undergo further transformation to inactive metabolites, some are transported to cells where, under the influence of phosphatases, they are converted into metabolites that have a cytotoxic effect. The concentration of metabolites reaches a maximum in the plasma 2-3 hours after intravenous administration. The association of the unchanged drug with plasma proteins is negligible (12-14%), but some metabolites bind more than 60%. Through the blood-brain barrier penetrates to a limited extent.

    Cyclophosphamide is excreted from the body by the kidneys mainly in the form of metabolites, but from 5 to 25% of the administered dose is excreted in the urine in unchanged form, as well as with bile. The half-life is 3-12 hours.

    Indications:

    Acute lymphoblastic and chronic lymphocytic leukemia, lymphogranulomatosis, non-Hodgkin's lymphomas, multiple myeloma, breast, ovarian, neuroblastoma, retinoblastoma, fungal mycosis.

    Cyclophosphamide is also used in combination with other antitumor drugs for the treatment of lung cancer, germ cell tumors, cervical cancer, bladder cancer, soft tissue sarcoma, reticulosarcoma, Ewing's sarcoma, Wilms tumor, prostate cancer.

    As an immunosuppressive agent cyclophosphamide is used for progressive autoimmune diseases (rheumatoid arthritis, psoriatic arthritis, collagenoses, autoimmune hemolytic anemia, nephrotic syndrome) and for suppressing the rejection reaction of the graft.

    Contraindications:

    • Hypersensitivity to cyclophosphamide or any other component of the dosage form.
    • Pronounced impairment of bone marrow function.
    • Cystitis.
    • Delayed urination.
    • Pregnancy and lactation.
    • Active infections.

    Carefully:With severe heart, liver and kidney disease, adrenalectomy, gout (in anamnesis), nephrourolythiasis, oppression of bone marrow function, bone marrow infiltration by tumor cells, previous radiation or chemotherapy.
    Dosing and Administration:

    Cyclophosphane is administered intravenously in struino or in the form of infusion, intramuscularly.

    Cyclophosphamide is a part of many chemotherapy regimens, therefore, when choosing a specific route of administration, regimen and dosage in each individual case, reference should be made to the literature.

    The most commonly used doses and regimens for adults and children:

    50-100 mg / m2 daily for 2-3 weeks,

    100-200 mg / m2 2 or 3 times a week for 3-4 weeks,

    600-750 mg / m2 1 time in 2 weeks,

    1500-2000 mg / m2 1 every 3-4 weeks before the total dose - 6-14 g.

    When using cyclophosphamide in combination with other antitumoral drugs, a dose reduction of both Cyclophosphamide and other drugs may be required.

    Preparation of the solution

    To prepare a solution for injection, an appropriate amount of 0.9% sodium chloride solution is added to the dry matter in the vial, as indicated in the table:

    Cyclophosphamide

    100mg

    200mg

    500mg

    1g

    2g

    Solvent

    5 ml

    10ml

    25ml

    50ml

    100ml

    After the addition of the solvent, the vial is vigorously shaken to completely dissolve the preparation. If rapid and complete dissolution is not achieved, leave the vial for a few minutes.

    To prepare the infusion solution, Ringer's solution, 0.9% sodium chloride solution or dextrose solution is added to the resulting solution of the Cyclophosphane preparation so that the total volume of the liquid is about 500 ml.

    Side effects:

    On the part of the hematopoiesis system: leukopenia, neutropenia; rarely, thrombocytopenia, anemia.The greatest decrease in the number of leukocytes and platelets is usually observed on the 7-14 day of treatment. Recovery with leukopenia usually begins 7-10 days after discontinuation of treatment with the drug.

    On the part of the digestive system: nausea, vomiting, anorexia, less common stomatitis, discomfort or pain in the abdominal area, diarrhea or constipation, there are some reports of the development of hemorrhagic colitis, jaundice.

    There have been rare cases of liver dysfunction, manifested by an increase in the activity of transaminases, alkaline phosphatase and bilirubin in serum. In 15-50% of patients receiving high doses of cyclophosphamide in combination with busulfan and. Total irradiation during allogeneic bone marrow transplantation develops endotheliitis obliterans of hepatic veins. A similar reaction in very rare cases is also observed in patients receiving high doses of a single cyclophosphamide in patients with aplastic anemia. This syndrome usually develops 1-3 weeks after bone marrow transplantation and is characterized by a sharp increase in body weight, hepatomegaly, ascites and hyperbilirubinemia.Hepatic encephalopathy can also occur.

    From the skin and skin appendages: often develops alopecia. Hair growth begins after treatment with the drug or even during prolonged treatment; hair can differ in its structure and color. Sometimes during treatment, there is a rash on the skin, skin pigmentation and nail changes.

    From the urinary system: hemorrhagic urethritis / cystitis, renal tubular necrosis (up to a lethal outcome), bladder fibrosis (including common) with or without concomitant cystitis. In the urine, atypical epithelial cells of the bladder can be detected.

    With the appointment of high doses of cyclophosphamide in rare cases, there may be a violation of kidney function, hyperuricemia, nephropathy associated with increased formation of uric acid.

    Infections: Serious infections can develop in patients with severe forms of immunosuppression.

    From the side of the cardiovascular system: cardiotoxicity was observed with the introduction of high doses of 4.5-10 g / m2 (120 to 270 mg / kg) of the drug for several days, usually as part of intensive combined antitumor or drug therapy for organ transplantation.There were severe and sometimes fatal episodes of congestive heart failure caused by hemorrhagic myocarditis.

    From the respiratory system: interstitial pulmonary fibrosis (with the introduction of high doses of the drug for a long time).

    From the side of the reproductive system: violation of oogenesis and spermatogenesis. The drug can cause sterility in both men and women, which in some cases may be irreversible.

    A significant proportion of women develop amenorrhoea, regular menstruation usually recovers within a few months after cessation of treatment. In girls, as a result of treatment with cyclophosphamide during the prepubertal period, secondary sexual characteristics developed normally and menstruation was normal; in the future they were able to conceive. In men, as a result of treatment with the drug, may develop oligospermia or azoospermia associated with an increase in the level of gonadotropins with normal secretion of testosterone. Sexual desire and potency in these patients is not violated.In boys, during treatment with the drug in the prepubertal period, secondary sexual symptoms develop normally, however, oligospermia or azoospermia and increased secretion of gonadotropins can be noted. There may be atrophy of the testes of various degrees. In some patients, the azoospermia caused by the drug is reversible, but the restoration of the impaired function may occur only a few years after discontinuation of treatment.

    Allergic reactions: skin rash, hives, itching of the skin, rarely anaphylactic reactions; Cross-sensitivity with other alkylating compounds is possible.

    Other: a syndrome similar to the syndrome of inadequate secretion of antidiuretic hormone (ADH); flushes of blood to the skin of the face or hyperemia of the face, headache, excessive sweating; development of secondary malignant tumors.

    Overdose:

    Specific antidote for drug overdose is unknown. In cases of overdose, supportive measures should be used, including appropriate treatment for infections, manifestations of myelosuppression and / or cardiotoxicity.

    Interaction:

    Inducers of microsomal oxidation in the liver can induce microsomal metabolism of cyclophosphamide, which leads to increased formation of aliphatic metabolites, thereby reducing the half-life of cyclophosphamide and increasing its activity. The use of cyclophosphamide, which causes a noticeable and prolonged suppression of cholinesterase activity, enhances the action of suxamethonium, and also reduces or slows the metabolism of cocaine, thereby enhancing and / or increasing the duration of its effect and increasing the risk of toxic effects. With simultaneous application with allopurinol, in addition, the toxic effect on the bone marrow can be enhanced. With the simultaneous use of cyclophosphamide and allopurinol, colchicine, probenecid, sulfinpyrazone, dosage adjustments of antidotal drugs may be required in the treatment of hyperuricemia and gout; the use of uricosuric antidotal drugs may increase the risk of nephropathy associated with increased uric acid production with cyclophosphamide.

    Cyclophosphamide can increase anticoagulant activity as a result of a decrease in the liver of the synthesis of coagulation factors and platelet formation disorders,but can also reduce the activity of anticoagulants through an unknown mechanism. Since the grapefruit contains a compound that can disrupt the activation of cyclophosphamide and thereby its effect, patients are not recommended to eat grapefruit or drink grapefruit juice.

    Cyclophosphamide increases the cardiotoxic effect of doxorubicin and daunorubicin. Other immunosuppressants (azathioprine, chlorambucil, glucocorticosteroids, ciclosporin, mercaptopurine and others) increase the risk of infection and secondary tumors.

    With simultaneous application of lovastatin in patients with heart transplantation, an increased risk of acute necrosis of skeletal muscles and acute renal failure is possible.

    In combination with other myelosuppressive drugs or radiotherapy - additive inhibition of bone marrow function is possible.

    Simultaneous use of cytarabine in high doses with cyclophosphamide in preparation for bone marrow transplantation led to an increase in the frequency of cardiomyopathy followed by fatal outcome.

    Special instructions:

    During treatment with the drug, a blood test should be performed regularly (especially paying attention to the content of neutrophils and platelets) to assess the degree of myelosuppression,as well as regular urine analysis for the presence of red blood cells, the appearance of which may precede the development of hemorrhagic cystitis.

    When there are signs of cystitis with micro- or macrogematuria, treatment with cyclophosphamide should be discontinued.

    With a decrease in the number of white blood cells <2500 / μL and / or platelets <100,000 / μl, treatment with cyclophosphamide should be discontinued.

    In the event of infection in the course of therapy with cyclophosphamide, treatment should either be interrupted, or the dose of the drug should be reduced.

    Women and men during treatment with Cyclophosphamide should use reliable methods of contraception.

    During the treatment should refrain from drinking alcohol.

    If during the first ten days after the operation performed under general anesthesia, the patient is prescribed Cyclophosphamide, it is necessary to inform the anesthesiologist about it.

    Patients after adrenalectomy should adjust the dose of both glucocorticosteroids used for substitution therapy and the drug Cyclophosphamide.

    Form release / dosage:

    Powder for the preparation of a solution for intravenous and intramuscular injection in vials of 200 mg.

    Packaging:

    1, 5 or 10 bottles per pack with instructions for medical use.

    50 vials are placed in boxes with an investment of 3 to 5 instructions for medical use (for hospitals).

    Storage conditions:In a dry, dark place at a temperature of no higher than 10 ° C. Keep out of the reach of children.
    Shelf life:

    Shelf life 3 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:P N001579 / 01
    Date of registration:14.08.2008
    The owner of the registration certificate:Promomed Rus, Open CompanyPromomed Rus, Open Company Russia
    Manufacturer: & nbsp
    Information update date: & nbsp12.10.2015
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