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

Antitumor agent of alkylating action, also has an immunosuppressive effect. It is an inactive transport form that decays under the action of phosphatase by the formation of an active component directly in tumor cells, "attacks" the nucleophilic centers of protein molecules, disrupts the synthesis of DNA and RNA, blocks mitotic division.

Pharmacokinetics:

After intravenous administration, the maximum concentration of metabolites is reached after 2-3 hours,the concentration of the drug decreases rapidly in the first 24 hours (in the blood it is determined within 72 hours). Bioavailability is 90%. The volume of distribution is 0.6 l / kg. The connection with plasma proteins is 12-14%, for some active metabolites - more than 60%.

Metabolised in the liver with the participation of the isoenzyme CYP2C19. Half-life is up to 7 hours in adults, 4 hours in children.

It is excreted by the kidneys in the form of metabolites - 60%, unchanged - 5-25 % and with bile. It is possible to remove the drug with dialysis.

Indications:

Small cell lung cancer, ovarian cancer, breast cancer, cervical and endometrial cancer, bladder cancer, prostate cancer, neuroblastoma, retinoblastoma, Hodgkin's disease, lymphosarcoma, Hodgkin's lymphoma, reticulosarcoma, osteogenic sarcoma, multiple myeloma, chronic lymphocytic leukemia, and myeloid leukemia, acute lymphoblastic, myeloblastic and monoblast leukemia, Wilms' tumor, Ewing's sarcoma, fungal mycosis, testicular seminaloma; autoimmune diseases: rheumatoid arthritis, psoriatic arthritis, systemic connective tissue diseases, autoimmune hemolytic anemia, nephrotic syndrome; suppression of graft rejection reaction.

Contraindications:

Hypersensitivity to the drug, pronounced impaired bone marrow function (anemia, leukopenia, thrombocytopenia), cystitis, urinary retention, active infections, pregnancy, lactation.

Carefully:

Decompensated diseases of the heart, liver and kidneys, adrenalectomy, gout (in the anamnesis), nephrourolythiasis, oppression of bone marrow function, bone marrow infiltration by tumor cells, previous chemotherapy or radiation therapy.

Pregnancy and lactation:

In pregnancy, cyclophosphamide is contraindicated. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Intravenous, intramuscular. The dosage regimen is set individually, depending on the stage of the disease, the state of the hematopoiesis system.

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.

Apply different treatment regimens:

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 of 6-14 g.

Injectable solutions are prepared immediately before use.

To prepare the solution, 200 mg is dissolved in 10 ml of water for injection (0.9% sodium chloride solution can not be used). The course dose of the drug is 8-14 g, then pass to maintenance treatment for 100-200 mg 2 times a week.

Side effects:

From the hematopoiesis: leukopenia, neutropenia, thrombocytopenia, anemia. The most pronounced leukopenia and thrombocytopenia is observed on the 7-14th day of treatment (recovery of the indices - 7-10 days after cessation of treatment).

From the digestive system: nausea, vomiting, anorexia, stomatitis, discomfort or pain in the abdominal region, diarrhea or constipation, hemorrhagic colitis, jaundice, impaired hepatic function, incl. increased activity of "hepatic" transaminases, alkaline phosphatase, hyperbilirubinemia; when using high doses of cyclophosphamide in combination with busulfan and total irradiation during allogeneic bone marrow transplantation,and also with the use of high doses in patients with aplastic anemia, endotheliitis of the hepatic veins becomes obliterative (a sharp increase in body weight, hepatomegaly, ascites, hyperbilirubinemia, hepatic encephalopathy) - the syndrome usually develops 1-3 weeks after bone marrow transplantation.

From the skin: alopecia (reversible after the end of treatment or during prolonged treatment, the hair may differ in structure and color), skin rash, skin pigmentation, nail changes, impaired regeneration.

From the urinary system: hemorrhagic urethritis / cystitis, renal tubular necrosis (up to a lethal outcome), bladder fibrosis (including common) with or without concomitant cystitis, atypical epithelial cells of the urinary bladder in the urine. When used in high doses - a violation of kidney function, hyperuricemia, nephropathy (against hyperuricemia).

From the cardiovascular system: cardiotoxicity (with doses of 4.5-10 g / m 2 or 120-270 mg / kg for several days as part of intensive combined cytostatic and other therapy for organ transplantation), incl. severe heart failure (including fatal outcome) against hemorrhagic myocarditis.

From the respiratory system: interstitial pulmonary fibrosis (with prolonged administration of high doses).

Co side of the reproductive system: violation of oogenesis and spermatogenesis, (sterility may be irreversible), amenorrhea (reversible within a few months after cessation of therapy), oligo or azoospermia (associated with an increase in gonadotropin concentrations with normal testosterone secretion, in some cases reversible several years after the course of treatment ), testicular atrophy (varying degrees).

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

Other: development of severe infections; a syndrome similar to the syndrome of inadequate secretion of antidiuretic hormone; blood flow to the skin of the face or hyperemia of the face; headache; increased sweating; development of secondary malignant tumors.

Overdose:

Symptoms: nausea, vomiting, severe bone marrow depression, fever, dilated cardiomyopathy syndromes, multiple organ failure, hemorrhagic cystitis, and other bleeding.

Treatment: symptomatic therapy, the appointment of antiemetics, if necessary - blood transfusion, the introduction of hemopoietic stimulants, broad-spectrum antibiotics, vitamin therapy (pyridoxine intramuscularly 0.05 g).

Interaction:

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

Cyclophosphamide increases the cardiotoxic effect of cytarabine, doxorubicin and daunorubicin.

Simultaneous reception of cytarabine in high doses in preparation for bone marrow transplantation leads to an increased incidence of cardiomyopathy with subsequent fatal outcome.

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

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

Myelotoxic medicines, incl. allopurinol, radiation therapy causes an increase in myelotoxic action.

Grapefruit juice disrupts activation and thereby the action of cyclophosphamide.

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

Urikozuric drugs increase the risk of developing nephropathy (a dose correction of uricosuric medicines may be required).

Simultaneous administration of cyclophosphamide with lovastatin increases the risk of acute necrosis of skeletal muscles and acute renal failure.

Special instructions:

During the treatment period, it is necessary to carefully monitor the patient's condition in connection with the possibility of the appearance of toxic effects in any of the listed conditions: leukopenia, thrombocytopenia, bone marrow infiltration by tumor cells, previously conducted radiation or chemotherapy, renal / hepatic insufficiency.

Cyclophosphamide may increase anticoagulant activity as a result of decreased synthesis in the liver of clotting factors and platelet formation disorders, as well as as a result of an unknown mechanism.

During the treatment, it is necessary to systematically monitor peripheral blood (during the main course - 2 times / week, with maintenance treatment - 1 time / week). With a reduction in the number of white blood cells to 2500 / μL and platelets to 100,000 / μl, treatment should be discontinued.

Against the background of ongoing therapy should monitor the activity of hepatic transaminases and lactate dehydrogenase, the content of bilirubin, the concentration of uric acid in the blood plasma, urine output, specific gravity of urine, and it is necessary to conduct tests to identify microhematuria.

During treatment, urine tests should be performed regularly for erythrocyturia, which may precede the development of hemorrhagic cystitis. When there are symptoms of cystitis with micro- or macrogematuria, treatment with the drug should be discontinued.

In order to prevent hemorrhagic cystitis, it is advisable to drink abundantly and use the drug mesna.

In the event of infection in the process of cyclophosphamide therapy treatment should be interrupted or the dose of the drug should be reduced.

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

When appointing cyclophosphamide within the first 10 days after surgery with general anesthesia, it is necessary to inform the anesthesiologist.

After adrenalectomy it is necessary to correct the doses of both glucocorticosteroids (as replacement therapy) and cyclophosphamide.

According to the electrocardiogram and echocardiogram, in patients who underwent episodes of cardiotoxic effects of high doses of cyclophosphamide, there were no residual effects on the state of the myocardium.

In girls, as a result of treatment with cyclophosphamide in the prepubertal period, secondary sexual characteristics developed normally; menstruation was normal, in the future they were able to conceive.

Sexual desire and potency in men are not violated. In boys, during treatment with the drug in the prepubertal period, secondary sexual characteristics developed normally, however, oligo- or azoospermia and increased secretion of gonadotropins can be noted.

During the treatment it is necessary to refrain from taking ethanol, as well as from eating grapefruit (including juice).

After previous treatment with the drug, the occurrence of secondary malignant tumors, most often these are bladder tumors (usually in patients with hemorrhagic cystitis in the anamnesis), myelo- or lymphoproliferative diseases. Secondary tumors most often developed in patients as a result of the treatment of primary myeloproliferative malignant or non-malignant diseases when immune processes are disturbed. In a number of cases, secondary tumors develop several years after discontinuation of treatment with the drug.

Effect on the ability to drive transp. cf. and fur:

During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

Powder for solution for intravenous and intramuscular injection 200 mg.

Packaging:

For 200 mg in bottles of glass capacity 10 ml, hermetically sealed with rubber stoppers, crimped with aluminum or combined caps.

1 bottle with instructions for use in a pack of cardboard.

For hospitals: 50 bottles with instructions for medical use in the amount of 10 pieces are placed in a box of cardboard.

Complete form: 1 bottle with the preparation (200 mg of active substance) complete with 2 ampoules of the solvent "Water for Injection" 5 ml each with instructions for medical use and a scarifier or a knife ampoule in a pack of cardboard.

When packing ampoules with a ring or break point, the scarifier or ampoule knife is not inserted.

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:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LS-001048

Date of registration:19.01.2012

The owner of the registration certificate:Company DEKO, LLC Company DEKO, LLC Russia

Manufacturer: & nbsp

Company DEKO, LLC Russia

Information update date: & nbsp12.10.2015

Illustrated instructions

Instructions

Cyclophosphamide (Cyclophosphan)