Cyclophosphamide - instructions for use, dose, side effects, contraindications

Antitumor agent of alkylating action. Has a cytostatic and immunosuppressive effect. The antitumor effect is realized directly in the tumor cells, where cyclophosphamide biotransformiruetsya under the influence of phosphatases with the formation of an active metabolite, which has an alkylating effect.

Pharmacokinetics:

Well absorbed after oral administration (75% bioavailability). It binds little to proteins (12-14%), but for some active derivatives, binding is 60% or more. Biotransformiruetsya in the liver (including the initial activation and subsequent transformation) with the formation of active metabolites. Passes through the placental barrier, penetrates into breast milk. The half-life of cyclophosphamide is 3-12 hours.After intravenous administration, the time to reach the maximum concentrationin plasma (for metabolites) is 2-3 hours Excreted mainly with urine in the form of metabolites (chloroacetic acid, acrolein, etc.) and unchanged (5-25%); is removed during dialysis. Against the background of renal failure, an increase in the severity of toxic effects was not observed.

Indications:

Small cell lung cancer, ovarian cancer, cervical and uterine bodies, breast, bladder, prostate gland, testis seminaloma; neuroblastoma, retinoblastoma, angiosarcoma, reticulosarcoma, lymphosarcoma, chronic lymphoblastic, myeloblastic, monoblast leukemia, lymphogranulomatosis, non-Hodgkin's lymphoma, myeloma, Wilms tumor, Ewing tumor, soft tissue sarcoma, osteogenic sarcoma, germ cell tumors, fungal mycosis ; autoimmune diseases, including systemic connective tissue diseases, including rheumatoid arthritis, psoriatic arthritis, autoimmune hemolytic anemia, nephrotic syndrome, suppression of graft rejection reaction.

ICD-10

II.C64-C68.C67 Malignant neoplasm of bladder

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

II.C60-C63.C62 Malignant neoplasm of testis

II.C60-C63.C61 Malignant neoplasm of prostate

II.C51-C58.C53 Malignant neoplasm of cervix

II.C50.C50 Malignant neoplasm of breast

II.C40-C41 Malignant neoplasms of bones and articular cartilages

II.C30-C39.C34 Malignant neoplasm of bronchi and lungs

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

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

II.C81-C96.C84.0 Mushroom mycosis

II.C81-C96.C85.0 Lymphosarcoma

II.C81-C96.C95 Leukemia of unspecified cell type

II.C81-C96.C92.1 Chronic myeloid leukemia

II.C81-C96.C92.0 Acute myeloid leukemia

II.C81-C96.C92 Myeloid leukemia [myeloid leukemia]

II.C81-C96.C91.1 Chronic lymphocytic leukemia

II.C81-C96.C91.0 Acute lymphoblastic leukemia

II.C81-C96.C91 Lymphoid leukemia [lymphocytic leukemia]

XIII.M05-M14.M06.9 Rheumatoid arthritis, unspecified

XIV.N00-N08.N04 Nephrotic syndrome

Contraindications:

Hypersensitivity, severe renal dysfunction, bone marrow hypoplasia, leukopenia (the number of leukocytes is less than 3.5 · 10⁹/ l) and / or thrombocytopenia (the number of platelets is less than 120 · 10⁹/ l), severe anemia, severe cachexia, terminal stages of cancer, pregnancy, breast-feeding.

Carefully:

Assessment of the risk-benefit ratio is necessary if necessary in the following cases: chickenpox, herpes zoster and other systemic infections, renal dysfunction (urolithiasis, gout, etc.), liver, severe heart disease, bone marrow depression, bone marrow infiltration tumor cells, hyperuricemia, cystitis, adrenalectomy, previous cytotoxic or radiation therapy, elderly and children's age.

Pregnancy and lactation:

Action category for the fetus by FDA - D.

Contraindicated in pregnancy. For the duration of treatment, breastfeeding should be discontinued.

Dosing and Administration:

Inside, intravenously, intramuscularly, in the cavity (intraperitoneal or intrapleural). The choice of the route of administration, the dosage regimen is carried out in accordance with the indications and scheme of chemotherapy. The dose is selected individually, adjusted based on the clinical effect, the severity of the toxic effect.The course dose is 8-14 g, then go on supporting treatment - 0.1-0.2 g 2 times a week. As an immunosuppressive agent is appointed at the rate of 0.05-0.1 g per day (1-1.5 mg / kg / day), with good tolerability - 3-4 mg / kg.

Side effects:

From the side organs of the digestive tract: anorexia, stomatitis, dry mouth, nausea, vomiting, diarrhea, stomach pain, gastrointestinal bleeding, hemorrhagic colitis, toxic hepatitis, jaundice.

From the side nervous system and sense organs: asthenia, dizziness, headache, confusion, visual impairment.

From the side cardiovascular system and blood (hematopoiesis, hemostasis): myelodepression, leukopenia, agranulocytosis, thrombocytopenia, anemia, bleeding and hemorrhages, blood flush to the face, cardiotoxicity, heart failure, palpitations, hemorrhagic myopericarditis, pericarditis.

From the side respiratory system: shortness of breath, pneumonitis, interstitial pneumosclerosis.

From the side genitourinary system: hemorrhagic cystitis, urethritis, bladder fibrosis, atypia of bladder cells, hematuria, rapid,painful or difficult urination, hyperuricemia, nephropathy, edema of the lower extremities, hyperuricosuria, necrosis of the renal tubules, amenorrhea, suppression of ovarian function, azoospermia.

From the side skin integument: alopecia, hyperpigmentation (nails on fingers, palms), intradermal hemorrhages, facial flushing, rash, urticaria, pruritus, congestion, swelling, pain at the injection site.

Other: anaphylactoid reactions, pain syndrome (pain in the back, side, bones, joints), febrile syndrome, chills, development of infections, ADH syndrome, myxedema (edema of the lips), hyperglycemia, increased transaminase activity in the blood.

Overdose:

Symptoms: nausea, vomiting, severe bone marrow depression, fever, dilated cardiomyopathy syndrome, multiple organ dysfunction, hemorrhagic cystitis, etc.

Treatment: hospitalization, monitoring of vital functions; symptomatic therapy, including the appointment of antiemetics; if necessary, transfusion of blood components; introduction of hemopoietic stimulants, broad-spectrum antibiotics, vitamin therapy (pyridoxine intramuscularly 0.05 g, etc.).

Interaction:

With simultaneous application cyclophosphamide can enhance the effect of hypoglycemic drugs.

Combined use with allopurinol may lead to increased myelotoxicity.

With simultaneous use with indirect anticoagulants, it is possible to change anticoagulant activity (as a rule, cyclophosphamide reduces the synthesis of clotting factors in the liver and disrupts the formation of platelets).

When combined with cytarabine, daunorubicin or doxorubicin, cardiotoxic effect may be increased.

When combined with immunosuppressants, the risk of infections and secondary tumors increases.

With the simultaneous use of cyclophosphamide with lovastatin, the risk of developing acute necrosis of skeletal muscles and acute renal failure is increased.

Medicines, which are inducers of microsomal enzymes, cause increased formation of active metabolites of cyclophosphamide, which leads to an increase in its action.

Special instructions:

The application is possible only under the supervision of a physician with experience of chemotherapy.You should strictly follow the dosing regimen, including at certain times of the day (especially with combination therapy) and do not double the subsequent dose if the previous one is missed. For the preparation of drugs for use in newborns, diluents containing benzyl alcohol are not recommended, since it is possible to develop a lethal toxic syndrome: metabolic acidosis, CNS depression, respiratory failure, renal failure, hypotension, convulsions, intracranial hemorrhage.

Prior to and during treatment (at short intervals), it is necessary to determine the level of hemoglobin or hematocrit, the number of leukocytes (total, differential), platelets, urea nitrogen, bilirubin, creatinine, uric acid concentration, ALT activity, AST, LDH, diuresis, specific the density of urine, the detection of microhematuria. Severe leukopenia with the lowest number of leukocytes develops 7-12 days after the administration of the drug. The level of the formed elements is restored after 17-21 days. With a decrease in the number of leukocytes less than 2.5 · 10⁹/ l and / or platelets - less than 100 · 10⁹/ l treatment should be discontinued until symptoms of hematotoxicity are eliminated. Cardiotoxic effect is most pronounced (at doses of 180-270 mg / kg) for 4-6 days.

During the whole course of treatment it is recommended to transfuse blood (100-125 ml once a week). In order to prevent hyperuricemia and nephropathy due to increased uric acid formation (often occur during the initial treatment period), adequate fluid intake (up to 3 liters per day) is recommended before cyclophosphamide therapy and within 72 hours after administration, allopurinol administration (in some cases ) and the use of alkalinizing urine. For the prevention of hemorrhagic cystitis (can develop within a few hours or several weeks after the administration) should be taken in the morning (most of the metabolites are excreted before sleep), as often as possible to empty the bladder and apply preventive drugs. When the first signs of hemorrhagic cystitis appear, treatment stops until the symptoms of the disease are eliminated.

In order to reduce the dyspeptic phenomena, cyclophosphamide can be taken in small doses for 1 day.Partial or complete alopecia observed during treatment is reversible and after normal treatment the normal hair growth is restored (structure and color can be changed). If the following symptoms appear: chills, fever, cough or hoarseness, pain in the lower back or in the side, painful or difficult urination, bleeding or hemorrhage, black stools, blood in urine or feces should consult your doctor immediately.

The emergence of thrombocytopenia requires extreme caution in performing invasive procedures and dental interventions, regular examination of intravenous sites, skin and mucous membranes (to detect signs of bleeding), limiting the frequency of venous punctures and refusing intramuscular injections, monitoring blood urine, vomit, feces . Such patients need to shave carefully, do a manicure, brush their teeth, use dental floss and toothpicks, prevent constipation, avoid falls and other injuries, and take alcohol and acetylsalicylic acid, which increase the risk of gastrointestinal bleeding.It is necessary to delay the vaccination schedule (to be carried out after 3-12 months after completion of the last course of chemotherapy) to the patient and his family members living with him (immunization with oral polio vaccine should be discarded). It is recommended to exclude contact with infectious patients or use non-specific measures for the prevention of infections (protective mask, etc.). Adequate contraceptive measures should be used during treatment. In case of contact with the skin or mucous membranes, thorough rinsing with water (mucous membranes) or water with soap (skin) is necessary. Dissolution, dilution and administration of the drug are carried out by trained medical personnel with observance of protective measures (gloves, masks, clothing, etc.).

When performing diagnostic tests (skin test for candidiasis, epidemic parotitis, trichophytosis, tuberculin test), it is possible: suppression of a positive reaction, and when performing the method of Pap test - obtaining false positive results. The injection solution using a non-lyophilized or lyophilized powder is prepared by adding water for injection (sterile or bacteriostatic,using only paraben as a preservative) in vials (cyclophosphamide concentration is 20 mg / ml). The prepared solution is stable at room temperature for 24 hours, in the refrigerator for 6 days. For administration by intravenous infusion, add to solutions for parenteral administration. If the solution is not prepared on bacteriostatic water, it should be used within 6 hours. Chemotherapy in newborn children as a diluent eliminates the use of benzyl alcohol.

Instructions

Cyclophosphamide (Cyclophosphamidum)