Antitumor drug cyclophosphamide and the effectiveness of its use. Cyclophosphamide Cyclophosphamide 50 mg

Gross formula

Pharmacological group of the substance Cyclophosphamide

Nosological classification (ICD-10)

CAS code

Characteristics of the substance Cyclophosphamide

White crystalline powder. Soluble in water: 40 g/l, slightly soluble in alcohol, benzene, ethylene glycol, carbon tetrachloride, dioxane; sparingly soluble in ether and acetone. Molecular weight - 279.10.

Pharmacology

It is biotransformed in the liver with the formation of active metabolites that have an alkylating effect. Alkylating metabolites attack the nucleophilic centers of protein molecules, form cross-links between DNA strands, and block the mitosis of tumor cells. Possesses a wide range antitumor activity. The immunosuppressive effect is manifested in the suppression of the proliferation of lymphocytic clones (mainly B-lymphocytes) involved in the immune response. With prolonged use (for several years), the development of secondary malignant tumors (long-term effect) is possible: myelo- and lymphoproliferative diseases, cancer Bladder(especially in patients with hemorrhagic cystitis), cancer of the renal pelvis (noted in a patient who was treated for cerebral vasculitis).

There are numerous reports of depression of the function of the gonads in patients using cyclophosphamide (depending on the dose, duration of administration and combination with other antitumor agents); in some patients, infertility may be irreversible. When prescribed in prepubertal age, secondary sexual characteristics in girls and boys usually develop normally, menstrual cycles in girls they pass regularly and subsequently pregnancy occurs, but in boys oligospermia or azoospermia, increased secretion of gonadotropin, testicular atrophy are possible. There are reports that girls developed ovarian fibrosis and the complete disappearance of germ cells after long-term treatment in late prepubertal age. Introduction to men before the conception of a child led to the appearance of malformations of the heart and limbs in children. Use during pregnancy in women has resulted in both healthy and malformed babies (missing fingers and/or toes, heart malformations, hernias) and weight loss in newborns.

Shows carcinogenic properties when administered to experimental animals. The use of cyclophosphamide during pregnancy in animals (mice, rats, rabbits, monkeys) at doses corresponding to 0.02; 0.08; 0.5 and 0.07 doses recommended for humans revealed the presence of teratogenic properties.

Well absorbed after oral administration (bioavailability 75%). Little binds to proteins (12-14%), but for some active derivatives the binding is 60% or more. It is biotransformed in the liver (including initial activation and subsequent transformation) with the formation of active metabolites. Passes through the placental barrier, penetrates into breast milk. T 1/2 cyclophosphamide - 3-12 hours. After intravenous administration, the time to reach Cmax in plasma (for metabolites) is 2-3 hours. It is excreted mainly in the urine as metabolites (chloroacetic acid, acrolein, etc.) and unchanged (5-25%); removed during dialysis. On the background kidney failure no increase in the severity of toxic effects was observed.

There is evidence of the use of cyclophosphamide in glomerulonephritis, systemic lupus erythematosus, nonspecific aortoarteritis, dermatomyositis, multiple sclerosis, Wegener's granulomatosis.

Application of the substance Cyclophosphamide

Small cell lung cancer, cancer of the ovaries, cervix and body of the uterus, breast, bladder, prostate, testicular seminoma; neuroblastoma, retinoblastoma, angiosarcoma, reticulosarcoma, lymphosarcoma, chronic lymphocytic and myeloid leukemia, acute lymphoblastic, myeloblastic, monoblastic leukemia, lymphogranulomatosis, non-Hodgkin's lymphomas, multiple myeloma, Wilms' tumor, Ewing's tumor, soft tissue sarcoma, osteogenic sarcoma, germ cell tumors, mycosis fungoides; autoimmune diseases, including systemic diseases connective tissue, incl. rheumatoid arthritis, psoriatic arthritis, autoimmune hemolytic anemia, nephrotic syndrome, suppression of transplant rejection.

Contraindications

Hypersensitivity, severe renal dysfunction, bone marrow hypoplasia, leukopenia (leukocyte count less than 3.5 10 9 /l) and / or thrombocytopenia (platelet count less than 120 10 9 /l), severe anemia, severe cachexia, terminal stages oncological diseases, pregnancy, breastfeeding.

Application restrictions

An assessment of the risk-benefit ratio is necessary if it is necessary to prescribe in the following cases: chickenpox, herpes zoster and other systemic infections, impaired renal function ( urolithiasis disease, gout, etc.), liver, severe heart disease, bone marrow suppression, bone marrow infiltration with tumor cells, hyperuricemia, cystitis, adrenalectomy, previous cytotoxic or radiation therapy, elderly and childhood.

Use during pregnancy and lactation

Contraindicated in pregnancy.

Stop during treatment breast-feeding.

Side effects of the substance Cyclophosphamide

From 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, blurred vision.

From the side of cardio-vascular system and blood (hematopoiesis, hemostasis): myelodepression, leukopenia, agranulocytosis, thrombocytopenia, anemia, bleeding and hemorrhage, flushing, cardiotoxicity, heart failure, palpitations, hemorrhagic myopericarditis, pericarditis.

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

From the side genitourinary system: hemorrhagic cystitis, urethritis, bladder fibrosis, bladder cell atypia, hematuria, frequent, painful or difficult urination, hyperuricemia, nephropathy, edema lower extremities, hyperuricosuria, renal tubular necrosis, amenorrhea, ovarian depression, azoospermia.

From the side skin: alopecia, hyperpigmentation (nails on the fingers, palms), intravenous hemorrhage, redness of the face, rash, urticaria, itching, hyperemia, swelling, pain at the injection site.

Others: anaphylactoid reactions, pain syndrome (pain in the back, side, bones, joints), febrile syndrome, chills, development of infections, syndrome of inadequate ADH secretion, myxedema (swelling of the lips), hyperglycemia, increased activity of transaminases in the blood.

Interaction

The effect is enhanced by chlorpromazine, tricyclic antidepressants, barbiturates, theophylline, hormones thyroid gland, inducers of microsomal liver enzymes (increase the formation of alkylating metabolites), weaken (incl. toxic effect) - glucocorticoids and chloramphenicol. Other myelotoxic drugs, radiation therapy, allopurinol can potentiate bone marrow suppression. Weakens the effectiveness of immunization inactivated vaccines; when using vaccines containing live viruses, it increases the replication of the virus and the side effects of vaccination. May increase (as a result of inhibition of the synthesis of blood coagulation factors in the liver and impaired platelet formation) or decrease the activity of anticoagulants indirect action. Weakens the effect (increases the concentration of uric acid) of anti-gout drugs (allopurinol, colchicine, probenecid or sulfinpyrazone) in the treatment of hyperuricemia and gout (adjustment of doses of the latter is necessary). Increases the cardiotoxicity of cytarabine, doxorubicin, enhances the blockade of neuromuscular transmission caused by succinylcholine. Uricosuric agents increase the risk of nephropathy, immunosuppressants (azathioprine, chlorambucil, glucocorticoids, cyclosporine, mercaptopurine) increase the risk of developing secondary tumors and infections. Against the background of lovastatin in patients after heart transplantation, the risk of acute necrosis of skeletal muscles and acute renal failure increases.

Overdose

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

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

Routes of administration

Inside, in / in, in / m, in the cavity (intraperitoneally or intrapleurally).

Substance Precautions Cyclophosphamide

Use is possible only under the supervision of a doctor with experience in chemotherapy. The dosing regimen should be strictly observed, incl. at certain times of the day (especially with combination therapy) and do not double the next dose if the previous one is missed. For the preparation of drugs for use in newborns, it is not recommended to use diluents containing benzyl alcohol, because. possible development of a fatal toxic syndrome: metabolic acidosis, CNS depression, respiratory failure, renal failure, hypotension, convulsions, intracranial hemorrhage.

Before and during treatment (at short intervals), it is necessary to determine the level of hemoglobin or hematocrit, the number of leukocytes (general, differential), platelets, urea nitrogen, bilirubin, creatinine, uric acid concentration, activity of ALT, AST, LDH, measurement of diuresis, specific urine density, detection of microhematuria. Severe leukopenia with the lowest number of leukocytes develops 7-12 days after the administration of the drug. The level of formed elements is restored after 17-21 days. With a decrease in the number of leukocytes less than 2.5 10 9 /l and / or platelets - less than 100 10 9 /l, treatment should be stopped until the symptoms of hematotoxicity are eliminated. The cardiotoxic effect is most pronounced (at doses of 180-270 mg/kg) within 4-6 days.

During the entire 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 formation of uric acid (often occur during the initial period of treatment), before therapy with cyclophosphamide and within 72 hours after its use, adequate fluid intake (up to 3 liters per day), the appointment of allopurinol (in some cases ) and the use of alkalinizing urine. For the prevention of hemorrhagic cystitis (may develop within a few hours or a few weeks after administration), it should be taken in the morning (the main part of the metabolites is excreted before sleep), empty the bladder as often as possible and apply Uromitexan. When the first signs of hemorrhagic cystitis appear, treatment is stopped until the symptoms of the disease are eliminated.

In order to reduce dyspeptic symptoms, it is possible to take cyclophosphamide in small doses for 1 day. Partial or complete alopecia observed during treatment is reversible and after completion of the course of treatment, normal hair growth is restored (structure and color may be changed). If you experience the following symptoms: chills, fever, cough or hoarseness, pain in the lower back or side, painful or difficult urination, bleeding or bruising, black stools, blood in the urine or stool, you should immediately consult a doctor.

The occurrence of thrombocytopenia necessitates extreme caution when performing invasive procedures and dental interventions, regular examination of places of intravenous injections, skin and mucous membranes (to detect signs of bleeding), limiting the frequency of venipuncture and refusing intramuscular injections, monitoring blood levels in urine, vomit, feces. Such patients should be careful to shave, manicure, brush their teeth, use dental floss and toothpicks, prevent constipation, avoid falls and other injuries, and avoid alcohol and acetylsalicylic acid that increase the risk gastrointestinal bleeding. The vaccination schedule should be postponed (to be carried out after 3-12 months after the completion of the last course of chemotherapy) for the patient and family members living with him (immunization should be abandoned oral vaccine against poliomyelitis). It is recommended to exclude contact with infectious patients or use non-specific measures to prevent infections (protective mask, etc.). During treatment, adequate contraceptive measures should be used. In case of contact of the drug with the skin or mucous membranes, thorough washing with water (mucous membranes) or soap and water (skin) is necessary. Dissolution, dilution and administration of the drug is carried out by trained medical personnel in compliance with protective measures (gloves, masks, clothing, etc.).

special instructions

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

The active substance of the drug Cyclophosphamide belongs to the clinical and pharmacological classification of cytostatic drugs, anticancer drugs, alkaline compounds.

Cyclophosphamide
Instructions for use

Tradename
Cyclophosphamide (may be called Cyclophosphamide or Endoxan depending on the manufacturer)

international name
Cyclophosphamide

Latin
Cyclophosphamideum

Full chemical formula of the substance
С7Н15Cl2N2О2Р

BUT active active substance

Active ingredient medicinal product is Cyclophosphamide, the drug is a white or yellowish powder of crystalline type with an available molecular weight of 279.1. The powder is practically insoluble in acetone or ether; it is difficult to dilute in solutions of dioxane, tetravalent carbon chloride, ethylene glycol, alcohol, or pure benzene. It dissolves well in water, including water for injection.

Pharmacological classification
The active substance of the drug Cyclophosphamide belongs to the clinical and pharmacological classification of cytostatic drugs, anticancer drugs, alkaline compounds

Pharmacology
The active substance of the drug Cyclophosphamide has a strong cytostatic effect aimed at inhibiting or completely stopping the division of tumor cells, while simultaneously providing immunosuppressive assistance to the body by alkalizing structural elements DNA. Cells malignant neoplasms divide and develop faster than the cells of ordinary tissues, in connection with this, the former react much more strongly to various DNA damages, especially to alkylation. Thus, the active substance has a strongly pronounced antitumor effect.
Chemical transformation of the active active substance in the liver is expressed in the production of two main metabolites, they are the main organizers of alkaline processes. The action of alkalizing metabolites is directed to protein molecules. in particular, on their nucleophilic nuclei, which connect DNA strands with transverse membranes along their entire length and prevent the reproduction of the mitotic nature of tumor cells.
The properties of the active substance are aimed at suppressing the growth of cancer cells. Moreover, antitumor activity has a wide spectrum of action.
Immunosuppressive activity is expressed in the selective inhibition of beta-lymphocytes, without affecting the proliferation of other lymphocytic clones involved in the immune response. But it should be borne in mind that long-term use of the drug, which is two years or more, can lead to the development of a long-term effect, i.e., to the occurrence of malignant neoplasms of a secondary nature, such as lympho- and myeloproliferative cancers, renal pelvis carcinomas or bladder carcinomas. In particular, such phenomena were observed in patients with signs of hemorrhagic cystitis. And cancer of the renal pelvis was observed in a single case in a patient with cerebral-type vasculitis. The described cases of oppression of the normal functioning of the gonads, mostly reversible, are more often noted, but there were isolated precedents of recorded infertility. It mainly depends on the dose of the drug taken and the duration of its use.
In the case of therapy with the drug Cyclophosphamide in children at the age preceding puberty (prepubertal period), later in female patients puberty passes in the normal mode with cyclic menstruation, without changes and pathologies with the possibility of further pregnancy. Male patients showed signs of azoospermia or oligospermia, an increase in gonadotropin production, and kidney atrophy.

In isolated cases, there are records of the development of ovarian fibrosis in female patients and the absolute destruction of germ cells in the prepubertal period after long-term use of the drug. When conducting cytostatic therapy for men before the time of conception of the fetus, it was reflected in the newborn in the form congenital pathologies such as heart muscle malformation and infant limb malformation. Women in such cases had both healthy children and those with the listed defects, including the absence of toes and / or hands and various hernias. In addition, infants were born with significant weight loss.

Animal experiments have revealed carcinogenic properties during pregnancy. In particular, the administration of the drug to pregnant rabbits, monkeys, rats and mice also gave results of a teratogenic nature when administered in doses, when converted to therapeutic doses in humans.

The active active ingredient when taken orally (orally) is well absorbed, reaching a total bioavailability of up to 77%, but binds little to blood plasma proteins, no more than 15%, although for minor metabolites this figure can be more than 65%. Biotransformation occurs completely in the liver, both at the stage of initial activation and during subsequent metabolic processes, eventually forming active metabolites.

It has the property of overcoming the placental obstruction and getting into breast milk. The half-life in blood plasma lasts from 2.5 to 12.5 hours. when intravenous administration of the drug, the maximum concentration of metabolites of the active substance in the blood plasma is several hours, on average from two to three.
The active active substance is excreted mainly by the kidneys with urine as the main and non-basic metabolites in the form of chloroacetic acid, acrolein and others. It is excreted unchanged by kidney dialysis from 3 to 26%. It is characteristic that with an additional diagnosis of renal failure in an oncological patient, no increase in the toxic properties of the drug is observed.
In recent decades, cases of very effective treatment drug Cyclophosphamide in patients diagnosed with glomerulonephritis, systemic lupus erythematosus, as well as the presence of nonspecific aortoarteritis, dermatomyositis, Wegener's granuloma and even multiple sclerosis.

Cyclophosphamide application

Applies medication Cyclophosphamide in severe oncological diseases in humans: small cell lung cancer, ovarian cancer, carcinoma of the cervix and the body of the uterus itself, breast cancer, bladder carcinoma, prostate cancer in men, with ovarian seminoma.
It is also used for diagnosed retino- and neuroblastomas, angio, reticulo and lymphatic sarcomas, for chronic lymphocytic leukemia and myeloid leukemia, for acute lymphoblastic, myeloblastic or monoblastic leukemias. The cytostatic is also effective in lymphogranulomatosis, non-Hodgkin's lymphomas of various etiologies, in myeloma, Wilms' tumor, malignant Ewing's tumor, in soft tissue sarcomas and osteogenic type. The drug is also effective in nocological germ cell neoplasms, in fungal mycoses.
There is a high efficiency of the drug in various autoimmune diseases, which include all possible systemic diseases of the connective tissue, taking into account joint diseases such as rheumatoid arthritis, psoriatic and gouty arthritis, with autoimmune anemia of the hemolytic type, with nephrotic syndrome (as an immunosuppressor), as well as in the case of the risk of transplant rejection as a preventive and suppressive reaction of this rejection.

Contraindications
Due to the severity of the diseases for the treatment of which the medicinal product Cyclophosphamide is intended for use, there are practically no contraindications, with the exception of individual intolerance to the active active substance or any of excipients Drugs and some severe kidney diseases associated with impaired activity, bone marrow hypoplasia, with leukopenia, if the number of leukocytes is below 3.5 * 109 / l, or with thrombocytopenia, if the platelet count is below 120 * 109 / l, so the medicine is contraindicated in severe anemia, severe cachexia and the terminal stages of any oncological diseases, since the drug can aggravate the condition.
The drug is contraindicated during pregnancy in any trimester and when breastfeeding the baby.

Cyclophosphamide use in pregnant and lactating women
In the paragraph Application of Cyclophosphamide, the instruction warns that the substance is contraindicated for both pregnant and lactating women, in case of a justified risk while feeding the baby, it is necessary to transfer the child to artificial nutrition. During treatment with a cytostatic agent, women must be carefully protected using the most reliable contraceptives. Studies conducted on pregnant animals have shown embryotoxicity and teratogenicity of the active substance to the fetus.

Side effects
Stomach and intestines. On the part of the gastrointestinal tract, the likelihood of stomatitis, dryness of the mucous membranes of the oral cavity, flushes of nausea. urge to vomit, bouts of diarrhea, the occurrence of pain in the stomach, possible bleeding in any of the segments of the stomach or intestines, cases of hemorrhagic colitis, jaundice or toxic hepatitis have rarely been observed. Perhaps a decrease in appetite up to its complete loss and anorexia.
Heart, vessels, blood-forming organs and hemostasis. From these organs, manifestation of myelodepression, myelosuppression, leukopenia or agranulocytosis is possible, anemia may occur, less often - thrombocytopenia. There were also cases of hemorrhages and bleeding, rushes of blood to the head, signs of cardiotoxicity. Possible cases of heart failure, pericarditis, hemorrhagic myopericarditis, palpitations.
Nervous system and sense organs. There may be cases of visual impairment, hearing impairment, asthenia. sudden dizziness and severe headaches. In rare cases, there may be signs of confusion.
Respiratory system. Perhaps the appearance of sudden shortness of breath, pneumonitis, interstitial pneumosclerosis.
Urogenital system. There are diseases of hemorrhagic cystitis, urethritis or fibrosis of the bladder, sometimes there are attacks of hematuria, difficulty urinating, painful attacks. cases of swelling of the extremities, especially the legs, nephropathy, hyperuricosuria or hyperuricemia have been described. Rarely, cases of renal tubular necrosis, amenorrhea, inhibition of normal ovarian function, or azoospermia have been described.
Skin covering. Often the onset of alopecia, less often - hyperpigmentation on the nails and palms, cases of microhemorrhages, allergic reactions rash, hives, itching, or pain at injection sites.
There have also been isolated cases pain syndromes in various parts of the body and joints, swelling of the lips, symptoms of anaphylactic reactions.

Interaction with other drugs
Interaction with Alopurinol complex therapy increases the risk of brain inhibition by both medicines, therefore, taking two of these drugs at once is possible only after agreement with a specialist and taking into account all possible risks.
Joint therapy with the drug Busulfan (Mileran buy) can lead to mutual reinforcement of already manifested side effects, or to the emergence of new ones, including veno-occlusive disease or even tamponade of the heart muscle.
Interaction with the drug Colchicine (Buy Colchicine) can lead to a serious risk of the onset or development of nephropathy on the part of the former and to an increase in the concentration of uric acid salts in the patient's blood as an effect of the drug Cyclophosphamide.
Mercaptopurine (Puri-Netol buy) leads to an increased risk of secondary tumors, as a result of increased immunosuppressive effects. It is also likely to increase the risk of occurrence or development of infections of a different nature.
Recommended concomitant use of the drug Mesna (Uromitexan buy) with the current active substance Cyclophosphamide, since their interaction significantly reduces the risk of dysfunction of the patient's urinary system.
Interaction with the drug Methotrexate (buy methotrexate) is twofold. On the one hand, the concentration of the free active substance in the blood plasma increases, positive effect from cytostatic therapy, and on the other hand, the toxic effect is also enhanced.
Complex therapy with the drug Metformin (Metformin buy) leads to an increase in the hypoglycemic effect of metformin, which has a positive effect on the treatment of articular rheumatoid diseases and similar ones.
The drug, when interacting with which there may be risks of secondary infections or tumors - Chlorambucil (Leukeran buy), complex application with which is possible only in case of justified reasons.

Dosage and application
It is used strictly for the intended purpose and under the supervision of the attending physician, who is a specialist in the treatment of cytotoxic drugs. The dose per course is from 7 to 14 mg / kg, and the method of application depends on the entire treatment regimen.

Storage
Store the drug in a hermetically sealed container at positive temperatures up to 30 degrees Celsius in a place strictly protected from children.

• Instructions for use Cyclophosphamide
• Ingredients of Cyclophosphamide
• Indications for Cyclophosphamide
• Storage conditions of the drug Cyclophosphamide
• Shelf life of the drug Cyclophosphamide

ATC code: Antineoplastic and immunomodulatory drugs (L) > Antineoplastic drugs (L01) > Alkylating drugs (L01A) > Nitrogen mustard analogs (L01AA) > Cyclophosphamide (L01AA01)

Release form, composition and packaging

Powder for solution for intravenous administration white or almost white, crystalline.

200 mg - bottles (1) - packs.
200 mg - bottles (40) - group boxes.

Description medicinal product CYCLOPHOSPHANE was created in 2013 on the basis of instructions posted on the official website of the Ministry of Health of the Republic of Belarus. Date of update: 07/16/2014

pharmachologic effect

Antitumor agent alkylating action, chemical structure close to the nitrogen analogues of mustard gas. It has a cytostatic and immunosuppressive effect. It is an inactive transport form that decomposes under the action of phosphatases with the formation of an active component directly in tumor cells, "attacks" the nucleophilic centers of protein molecules, disrupts the synthesis of DNA and RNA, and blocks mitotic division.

Pharmacokinetics

After the / in the introduction of C max metabolites in the blood plasma is reached after 2-3 hours, the concentration of cyclophosphamide in the blood decreases rapidly in the first 24 hours (in the blood plasma, cyclophosphamide is determined within 72 hours). Bioavailability - 90%. V d - 0.6 l / kg. Communication of cyclophosphamide with plasma proteins is insignificant (12-14%), however, some active metabolites bind more than 60%. It is metabolized in the liver with the participation of the CYP2C19 isoenzyme. T 1/2 is up to 7 hours in adults and 4 hours in children. 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 unchanged. Several cytotoxic and non-cytotoxic metabolites have been identified in urine and plasma. A small part of cyclophosphamide is also excreted in the bile. It is possible to remove the drug by dialysis.

Indications for use

• leukemias: acute or chronic lymphoblastic/lymphocytic and myeloid/myelogenous leukemias;
• malignant lymphomas, Hodgkin's disease (lymphogranulomatosis), non-Hodgkin's lymphomas, plasmacytoma;
• large malignant tumors with or without metastases: ovarian cancer, testicular cancer, breast cancer, small cell carcinoma lungs, neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma in children, osteosarcoma;
• progressively "autoimmune diseases": rheumatoid arthritis, psoriatic arthropathy, systemic lupus erythematosus, scleroderma, systemic vasculitis (eg, with nephrotic syndrome), certain types of glomerulonephritis (eg, with nephrotic syndrome), myasthenia gravis, autoimmune hemolytic anemia, cold agglutinin disease, granulomatosis Wegener.

Cyclophosphamide is also used as an immune suppressant during organ transplantation and for conditioning before bone marrow transplantation in severe aplastic anemia, acute myeloid and acute lymphoblastic leukemia, and chronic myeloid leukemia.

Dosing regimen

Use is possible only under the supervision of a doctor with experience in chemotherapy.

Cyclophosphamide is administered intravenously by bolus or as an infusion, intramuscularly. Cyclophosphamide is part of many chemotherapy regimens, and therefore, when choosing a specific route of administration, regimen and doses in each individual case, one should be guided by the data of special literature.

The dosage should be selected individually for each patient. The following dosage recommendations can be used for cyclophosphamide monotherapy. With the joint appointment of other cytostatics of similar toxicity, it may be necessary to reduce the dose or increase the pauses in the treatment with the drug.

• For continuous treatment of adults and children - from 3 to 6 mg / kg body weight, daily (equivalent to 120 to 240 mg / m 2 body surface area);
• For intermittent treatment of adults and children - from 10 to 15 mg / kg body weight (equivalent to 400 to 600 mg / m 2 body surface area), at intervals of 2 to 5 days;
• For intermittent treatment of adults and children at a high dose of 20 to 40 mg/kg body weight (equivalent to 800 to 1600 mg/m 2 body surface area), or at an even higher dose (for example, when conditioning before bone marrow transplantation), with intervals from 21 to 28 days.

Solution preparation

Immediately before use, 10 ml of 0.9% sodium chloride solution is added to the contents of the 200 mg vial. The substance readily dissolves with vigorous shaking after addition of the solvent. If the substance does not dissolve immediately and completely, it is recommended to let the vial stand for a few minutes. The solution is suitable for intravenous use, while it is better to make the introduction in the form intravenous infusion. For short-term administration, Cyclophosphamide solution is added to Ringer's solution, 0.9% sodium chloride solution or 5% dextrose solution to a total volume of approximately 500 ml. Duration of infusion - from 30 minutes to 2 hours, depending on the volume.

Treatment cycles for intermittent therapy may be repeated every 3-4 weeks. The duration of therapy and the intervals between courses depend on the indications, the combination of chemotherapy drugs used, the general health of the patient, laboratory parameters and the restoration of the number of blood cells.

• Leukocytes> 4000 µl, and platelets> 100000 µl - 100% of the planned dose
• Leukocytes 4000-2500 µl, and platelets 100000-50000 µl - 50% of the dose
• Leukocytes<2500 мкл, а тромбоцитов <50000 мкл - подбор дозы до нормализации показателей или принятия отдельного решения.

The use in combination with other substances that inhibit hematopoiesis requires dose adjustment. You should use the appropriate tables for regulating the dose of cytotoxic drugs according to the quantitative composition of blood cells at the beginning of the cycle and adjusting the dose for a low level of cytostatic substances.

Severe liver failure requires dose reduction. The general recommendation is to reduce the dose by 25% when serum bilirubin levels are between 3.1 and 5 mg/100 ml.

Children and teenagers

Dosage - according to the accepted treatment plan; recommendations for dose selection and use of the drug in children and adolescents are the same as for adult patients.

Elderly and physically debilitated patients

Given the increased frequency of cases of decreased hepatic, renal or cardiac function, as well as the presence of concomitant diseases and the use of other drug therapy, dose selection for this group of patients should be done with caution.

Side effects

In patients receiving Cyclophosphamide, depending on the dosage, the following adverse reactions may occur, in most cases they are reversible.

Infections and infestations:

• usually severe bone marrow suppression can lead to agranulocytic fever and secondary infections such as pneumonia, which can progress to sepsis (life-threatening infections), which in some cases can be fatal.

From the immune system: Rarely, hypersensitivity reactions may occur, accompanied by rashes, chills, fever, tachycardia, bronchospasm, shortness of breath, edema, blood flow and a decrease in blood pressure. In rare cases, anaphylactoid reactions may progress to anaphylactic shock.

From the blood and lymphatic system: depending on the dosage, various forms of bone marrow suppression may occur, such as leukopenia, neutropenia, thrombocytopenia with an increased risk of bleeding, and anemia. It should be borne in mind that severe bone marrow suppression can lead to agranulocytic fever and the development of secondary (sometimes life-threatening) infections. The minimum number of leukocytes and platelets is usually noted during the 1st and 2nd weeks of treatment. The bone marrow recovers relatively quickly, and the blood picture returns to normal, usually 20 days after the start of treatment. Anemia usually can only develop after several cycles of treatment. The most severe bone marrow suppression should be expected in patients previously treated with chemotherapy and/or radiation therapy, as well as in patients with renal insufficiency.

Simultaneous treatment with other substances that inhibit hematopoiesis requires dose adjustment. Appropriate dosage adjustment charts should be used for drug cytotoxicity based on blood counts at the start of the treatment cycle and dosage adjustments for low levels of cytostatics.

From the nervous system: in rare cases, neurotoxic reactions such as paresthesia, peripheral neuropathy, polyneuropathy, as well as neuropathic pain, taste disturbance and convulsions have been reported.

From the digestive tract: adverse reactions such as nausea and vomiting are very common and dose dependent. Moderate and severe forms of their manifestations are observed in approximately 50% of patients. Anorexia, diarrhea, constipation, and inflammation of the mucous membranes from stomatitis to ulceration are less common. In some cases, hemorrhagic colitis, acute pancreatitis have been reported. In some cases, gastrointestinal bleeding has been reported. In case of nausea and vomiting, dehydration can sometimes develop. Isolated cases of abdominal pain due to gastrointestinal disorders have been reported.

From the digestive system: rarely reported violations of liver function (increased levels of serum transaminases, gamma-glutamyl transpeptidase transpeptidase, alkaline phosphatase, bilirubin).

Hepatic venous endophlebitis obliterans has been reported in approximately 15-50% of patients receiving high doses of cyclophosphamide in combination with busulfan or whole body irradiation in allogeneic bone marrow transplantation. On the contrary, this complication was noted in patients with aplastic anemia who received only high doses of Cyclophosphamide. The syndrome usually develops 1-3 weeks after transplantation and presents with dramatic weight gain, hepatomegaly, ascites and hyperbilirubinemia, and portal hypertension. Very rarely, hepatic encephalopathy can develop. Known risk factors that contribute to the development of obliterating endophlebitis of the hepatic veins in a patient are the presence of impaired liver function, therapy with hepatotoxic drugs in combination with high-dose chemotherapy, and especially if the alkylating compound busulfan is an element of co-induced therapy.

From the side of the kidneys and urinary system: after excretion into the urine, the metabolites of cyclophosphamide cause changes in the urinary system, namely in the bladder. Hemorrhagic cystitis, microhematuria and macrohematuria are the most common dose-dependent complications in the treatment with Cyclophosphamide and require discontinuation of therapy. Cystitis develops very often, at first they are sterile, but secondary infection can occur. Also, swelling of the walls of the bladder, bleeding from the cell layer, interstitial inflammation with fibrosis, and sometimes sclerosis of the bladder were noted. Renal dysfunction (especially in cases of impaired renal function in history) is an infrequent adverse reaction when used in high doses. Treatment with uromitexane or drinking plenty of fluids may reduce the frequency and severity of urotoxic adverse reactions. In some cases, fatal hemorrhagic cystitis has been reported. There may be acute or chronic renal failure, toxic nephropathy, especially in patients with a history of reduced renal function.

From the reproductive system: through an ankylling action, cyclophosphamide can rarely cause impairment of spermatogenesis (sometimes irreversible) and lead to azoospermia and/or persistent oligospermia. Rarely, ovulation disorders have been reported. In some cases, amenorrhea and a decrease in the level of female sex hormones have been reported.

From the side of the cardiovascular system: cardiotoxicity from minor changes in blood pressure, ECG changes, arrhythmias, to secondary cardiomyopathy with reduced left ventricular function and heart failure, which in some cases can cause death. Clinical symptoms of cardiotoxicity may manifest, for example, as chest pain and angina attacks. Ventricular supraventricular arrhythmias have occasionally been reported. Very rarely, atrial or ventricular fibrillation, as well as cardiac arrest, may develop during cyclophosphamide therapy. In very rare cases, myocarditis, pericarditis and myocardial infarction have been reported. Cardiotoxicity is especially enhanced after the use of the drug in high doses (120-240 mg / kg body weight) and / or when it is combined with other cardiotoxic drugs, for example, anthracyclines or pentostatin. Increased cardiotoxicity may also occur after prior radiotherapy to the cardiac region.

From the side of the respiratory system: bronchospasm, shortness of breath or cough, leading to hypoxia. Very rarely, obliterating endophlebitis of the lungs can develop, sometimes as a complication of pulmonary fibrosis. Very rarely, toxic pulmonary edema, pulmonary hypertension, pulmonary embolism, and pleural effusion have been reported. In some cases, pneumonitis and interstitial pneumonia may develop, turning into chronic interstitial pulmonary fibrosis, respiratory distress syndrome and respiratory failure with a fatal outcome have also been reported.

Benign and malignant neoplasms (including cysts and polyps): as always with cytostatic treatment, the use of Cyclophosphamide is accompanied by the risk of developing secondary tumors and their precursors as late complications. There is an increased risk of developing urinary tract cancer, as well as myelodysplastic changes, which can partially progress to acute leukemia. Animal studies have shown that the threat of bladder cancer can be significantly reduced by appropriate administration of uromitexane. In rare cases, tumor disintegration syndrome has been reported due to the rapid response of large, chemotherapy-responsive tumors.

From the skin and its derivatives / allergic reactions: alopecia areata, which is a common adverse reaction (may progress to complete baldness), is usually reversible. There have been reports of changes in pigmentation of the skin of the palms, nails and fingers, as well as soles;

From the musculoskeletal system and connective tissue: muscle weakness, rhabdomyolysis.

From the endocrine system and metabolism: very rarely - SNSAH (syndrome of inappropriate secretion of ADH), Schwartz-Bartter syndrome with hyponatremia and fluid retention, as well as the corresponding symptoms (confusion, convulsions). Anorexia, rarely dehydration, and very rarely fluid retention and hyponatremia have been reported in isolated cases.

From the side of the organs of vision: deterioration of vision. Very rarely, symptoms such as conjunctivitis and swelling of the eyelids have been reported due to hypersensitivity reactions.

Vascular disorders: the underlying disease may cause certain very rare complications, such as thromboembolism and peripheral ischemia, DIC, or hemolytic uremic syndrome, the incidence of these complications may increase with cyclophosphamide chemotherapy.

General disorders: fever during treatment with cyclophosphamide is a very common adverse reaction in conditions of hypersensitivity and neutropenia (associated with infection). Asthenic conditions, malaise are frequent complications in cancer patients. Very rarely, as a result of extravasation, reactions at the injection site in the form of erythema, inflammation or phlebitis may occur.

Contraindications for use

• known hypersensitivity to cyclophosphamide;
• severe bone marrow dysfunction (especially in patients who have previously been treated with cytotoxic drugs and / or radiotherapy);
• inflammation of the bladder (cystitis);
• urinary retention;
• active infections.

Use during pregnancy and lactation

Cyclophosphamide is contraindicated during pregnancy. With vital indications for the use of Cyclophosphamide in the first 3 months of pregnancy, it is necessary to resolve the issue of termination of pregnancy. In the future, if treatment cannot be delayed and the patient wishes to continue bearing the fetus, chemotherapy can be given only after the patient has been informed of the possible risk of teratogenic effects.

Since cyclophosphamide passes into breast milk, breast-feeding should be discontinued during treatment with the drug.

Use in elderly patients

Elderly patients: given the increased incidence of decreased hepatic, renal or cardiac function, as well as the presence of concomitant diseases and the use of other drug therapy, dose selection for this group of patients should be done with caution.

special instructions

During the period of treatment, it is necessary to carefully monitor the patient's condition due to the possibility of toxic effects in any of the following conditions: leukopenia, thrombocytopenia, bone marrow infiltration with tumor cells, previous radiation or chemotherapy, renal/liver failure.

During the main course of treatment, it is necessary to monitor the overall blood picture (especially the number of neutrophils and platelets) 2 times a week to assess the degree of myelosuppression), with maintenance therapy 1 time per week, as well as a urine test for the presence of erythrocyturia, which may precede the development of hemorrhagic cystitis. If symptoms of cystitis appear with micro- or macrohematuria, as well as a decrease in the number of leukocytes to 2500 / μl and / or platelets to 100 thousand / μl, treatment with the drug should be discontinued.

In the event of infections, treatment should be interrupted or the dose of the drug should be reduced.

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

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

When prescribing cyclophosphamide during the first 10 days after surgery using general anesthesia, it is necessary to inform the anesthesiologist. After adrenalectomy, it is necessary to adjust the doses of both glucocorticosteroids (as replacement therapy) and cyclophosphamide. May increase anticoagulant activity as a result of reduced hepatic synthesis of coagulation factors and impaired platelet formation, as well as as a result of an unknown mechanism.

For the prevention of hemorrhagic cystitis, it is recommended to prescribe an adequate amount of fluid and uroprotectors (mesna). Hematuria usually resolves within a few days after the end of cyclophosphamide treatment. In severe forms of hemorrhagic cystitis, it is necessary to cancel cyclophosphamide.

According to ECG and ECHO-KG data, patients who underwent episodes of cardiotoxic effects of high doses of cyclophosphamide did not show any 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 and menstruation was normal; subsequently they were. capable of conception. Sexual desire and potency in men is 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 may be noted.

After previous treatment with the drug, secondary malignant tumors may occur, most often bladder tumors (usually in patients with a history of hemorrhagic cystitis), myelo- or lymphoproliferative diseases. Secondary tumors most often developed in patients as a result of treatment of primary myeloproliferative malignant or non-malignant diseases in violation of immune processes. In some cases, secondary tumors develop several years after discontinuation of drug treatment.

With extreme caution, cyclophosphamide is used in patients with decompensated diseases of the heart, liver and kidneys; after adrenalectomy, with gout (in history), nephrourolithiasis, bone marrow suppression, bone marrow infiltration with tumor cells, after previous chemotherapy or radiation therapy.

Special Security Measures

When using Cyclophosphamide and preparing the solution, it is necessary to follow the safety rules when working with cytotoxic substances.

Application features

Use only as directed and under medical supervision.

Before starting treatment, it is necessary to eliminate possible obstacles to the removal of urine from the urinary tract, electrolyte imbalance, sanitize possible infections (cystitis).

From the blood and lymphatic systems. Severe bone marrow suppression should be expected, especially in patients previously treated with chemotherapy and/or radiotherapy, as well as in patients with impaired renal function. Therefore, for all patients during treatment, constant hematological monitoring with regular counting of blood cells is indicated. The count of leukocytes and platelets and the determination of hemoglobin content should be carried out before each administration of the drug, as well as at certain intervals. During treatment, it is necessary to systematically monitor the number of leukocytes:

• at initial treatment - with an interval of 5-7 days, if their number decreases to<3000 в мм 3 , то раз в два дня или ежедневно. При длительном лечении обычно достаточно проводить анализ крови раз в две недели. Без крайней необходимости Циклофосфан нельзя назначать пациентам при количестве лейкоцитов менее 2500/мкл и/или числа тромбоцитов менее 50000/мкл. В случае агранулоцитарной лихорадки и/или лейкопении необходимо профилактически назначать антибиотики и/или противогрибковые препараты. Следует регулярно анализировать мочевой остаток на содержание эритроцитов.

From the immune system. Patients with a weakened immune system, such as those with diabetes, chronic kidney or liver failure, also require special care. Cyclophosphamide, like other cytostatics, should be used with caution in the treatment of debilitated and elderly patients, as well as after radiotherapy.

From the side of the kidneys and urinary system. Before starting treatment, you should pay attention to the condition of the urinary system.

Appropriate treatment with the uroprotector uromitexane, as well as adequate fluid intake, can markedly reduce the frequency and severity of drug effects. Regular emptying of the bladder is important.

If during treatment with Cyclophosphamide, the appearance of cystitis with micro- or macrohematuria is observed, therapy with the drug should be discontinued until the condition returns to normal.

Patients with kidney disease in the treatment of Cyclophosphamide require careful care.

Cardiac disorders. There is evidence of an increased cardiotoxic effect of cyclophosphamide in patients after prior cardiac radiotherapy and/or concomitant treatment with anthracyclines or pentostatin. It should be remembered about the need for regular checks of the electrolyte composition of the blood, pay special attention to patients with a history of heart disease.

GIT. To reduce the frequency and severity of effects such as nausea and vomiting, it is necessary to prescribe antiemetic drugs for the purpose of prophylaxis. Alcohol may exacerbate these side effects, so patients treated with Cyclophosphamide should be advised not to drink alcohol.

To reduce the incidence of stomatitis, attention should be paid to oral hygiene.

From the digestive system. Use the drug for the treatment of patients with impaired liver function should only be after careful evaluation in each case. Such patients need careful care. Alcohol abuse can increase the risk of liver dysfunction.

Reproductive System Disorders/Genetic Disorders. Cyclophosphamide treatment can cause genetic abnormalities in men and women. Therefore, during treatment and for six months after its completion, pregnancy should be avoided. During this time, sexually active men and women must use effective methods of contraception.

In men, treatment may increase the risk of irreversible infertility, so they should be advised of the need to conserve sperm prior to treatment.

General Disorders/Disturbances at the injection site. Since the cytostatic effect of Cyclophosphamide appears after its bioactivation, which occurs in the liver, the risk of tissue damage in case of inadvertent paravenous administration of the drug solution is negligible.

In patients with diabetes, it is necessary to regularly check the level of sugar in the blood in order to adjust antidiabetic therapy in time.

Influence on the ability to drive vehicles and other potentially dangerous mechanisms

During treatment with the drug, it is necessary to refrain from engaging in activities that require increased concentration of attention.

Overdose

Since no specific antidote for cyclophosphamide is known, special care should be taken when using it. Cyclophosphamide can be excreted from the body by dialysis, therefore, in case of overdose, rapid hemodialysis is indicated. A dialysis clearance of 78 ml/min was calculated from the concentration of cyclophosphamide, not metabolized in dialysates (normal renal clearance is approximately 5-11 ml/min). Other sources report a value of 194 ml / min. After 6:

• 00 dialysis 72% of the administered dose of cyclophosphamide was found in the dialysate. In case of overdose, among other reactions, suppression of bone marrow function, more often leukopenia, should be assumed. The severity and duration of bone marrow suppression depends on the degree of overdose. Careful monitoring of blood counts and the patient's condition is necessary. If neutropenia develops, infection prevention measures should be taken and infections should be treated with appropriate antibiotics. If thrombocytopenia occurs, platelet replenishment should be provided. In order to prevent urotoxic events, it is necessary to take measures to prevent cystitis with the help of uromitexan.

drug interaction

Enhances the action of suxamethonium (long-term suppression of cholinesterase activity), reduces or slows down the metabolism of cocaine, increasing and / or increasing the duration of its action, increasing the risk of toxicity. Cyclophosphamide inhibits the activity of cholinesterase, which potentiates the action of acetylcholine. Enhances the cardiotoxic effect of doxorubicin and daunorubicin. Inducers of liver microsomal oxidation increase the formation of alkylating metabolites of cyclophosphamide, reduce its half-life and enhance its activity. Myelotoxic drugs, incl. allopurinol, radiation therapy cause an increase in the myelotoxic effect of cyclophosphamide. Uricosuric drugs increase the risk of developing nephropathy (dose adjustment of uricosuric drugs may be required). Grapefruit juice disrupts the activation and thus the action of cyclophosphamide. Other immunosuppressants (including azathioprine, chlorambucil, glucocorticosteroids, cyclosporine, mercaptopurine) increase the risk of infections and secondary tumors. Co-administration of lovastatin in heart transplant patients increases the risk of acute skeletal muscle necrosis and acute renal failure. Simultaneous administration of cytarabine in high doses in preparation for bone marrow transplantation leads to an increased incidence of cardiomyopathy with subsequent death.

Cyclophosphamide is an alkylating compound. Anticancer drug.

Release form and composition

Powder for solution for intravenous and intramuscular administration is crystalline, from almost white to white.

Composition of 1 vial: cyclophosphamide - 200 mg.

Indications for use

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

As part of complex therapy for the following diseases:

• lung cancer;
• germ cell tumors;
• cervical cancer;
• bladder cancer;
• soft tissue sarcoma;
• reticulosarcoma;
• Ewing's sarcoma;
• Wilms tumor;
• prostate cancer.

Cyclophosphamide is also used as an immunosuppressive agent in progressive autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, collagenosis, autoimmune hemolytic anemia, nephrotic syndrome, as well as to suppress transplant rejection.

Contraindications

Absolute contraindications:

• increased sensitivity to the components of the drug;
• severe dysfunction of the bone marrow;
• cystitis;
• urinary retention;
• active infections;
• pregnancy and lactation.

Relative contraindications:

• severe diseases of the heart, kidneys, liver;
• adrenalectomy;
• history of gout;
• nephrourolithiasis;
• oppression of bone marrow function;
• bone marrow infiltration with tumor cells;
• undergone radiation or chemotherapy.

Method of application and dosage

Cyclophosphamide is an ingredient in many chemotherapy regimens. When choosing doses, routes and modes of administration in each individual case, one should be guided by the data of special literature.

The most common regimens and doses for adults and children are:

• 50-100 mg / m 2 every day for 2-3 weeks;
• 100-200 mg/m 2 2-3 times a week for 3-4 weeks;
• 600-750 mg / m 2 1 time in 2 weeks;
• 1500-2000 mg/m 2 once every 3-4 weeks up to a total dose of 6000-14000 mg.

When taking Cyclophosphamide with other anticancer drugs, it may be necessary to reduce the dose of both Cyclophosphamide and other drugs.

Solution preparation

Add 0.9% sodium chloride solution to the powder vial according to the following recommendations:

• for 100 mg of Cyclophosphamide - 5 ml of solvent;
• for 200 mg of Cyclophosphamide - 10 ml of solvent;
• for 500 mg of Cyclophosphamide - 25 ml of solvent;
• for 1000 mg of Cyclophosphamide - 50 ml of solvent;
• for 2000 mg of Cyclophosphamide - 100 ml of solvent.

To prepare a solution for infusion, add Ringer's solution, 0.9% sodium chloride solution or glucose solution to the contents of the vial to a total volume of about 500 ml.

Side effects

• hematopoietic system: neutropenia, leukopenia, anemia, thrombocytopenia (the greatest decrease in the number of platelets and leukocytes is usually observed on the 7-14th day of taking the drug. With leukopenia, after stopping therapy on the 7-10th day, recovery usually begins);
• digestive system: anorexia, nausea, vomiting, stomatitis, pain or discomfort in the abdominal region, diarrhea, constipation. There are separate reports of the development of hemorrhagic colitis, jaundice, violations of liver function with an increase in the activity of alkaline phosphatase, transaminases and serum bilirubin. Hepatic vein obliterans endophlebitis develops in 15–50% of patients receiving high doses of cyclophosphamide with busulfan and total irradiation during allogeneic bone marrow transplantation. It also occurs in very rare cases in patients with aplastic anemia using high doses of cyclophosphamide alone. This syndrome develops 1-3 weeks after bone marrow transplantation (symptoms: a sharp increase in body weight, hepatomegaly, ascites, hyperbilirubinemia). There is also a risk of hepatic encephalopathy;
• skin and skin appendages: alopecia (after completion of the course of treatment or during prolonged treatment, hair regrowth occurs, there may be a difference in the structure and color of the hair), rash, skin pigmentation, nail changes;
• urinary system: hemorrhagic urethritis / cystitis, renal tubular necrosis (up to death), bladder fibrosis (including common) with and without cystitis. Atypical bladder epithelial cells may be found in the urine. When using the drug in high doses, renal dysfunction, hyperuricemia, nephropathy (due to increased formation of uric acid) may occur;
• cardiovascular system: with the introduction of high doses of Cyclophosphamide (120-270 mg / kg) for several days, cardiotoxicity was noted with episodes of congestive heart failure caused by hemorrhagic myocarditis, sometimes leading to death;
• respiratory system: interstitial pulmonary fibrosis (noted when using the drug for a long time in high doses);
• reproductive system: impaired spermatogenesis and oogenesis. Both men and women may develop sterility (including irreversible). Amenorrhea often develops in women, and after discontinuation of the drug, regular menstruation is usually restored. In girls undergoing treatment with Cyclophosphamide in the prepubertal period, the normal development of secondary sexual characteristics and normal menstruation were noted, the drug did not affect the further ability to conceive. The use of the drug in men can cause oligospermia or azoospermia (without a violation of sexual desire), associated with an increase in the level of gonadotropins with normal testosterone secretion. In boys undergoing treatment with Cyclophosphamide in the prepubertal period, the normal development of secondary sexual characteristics was noted, but oligospermia, azoospermia, and increased secretion of gonadotropins may be noted. Testicular atrophy of varying degrees is possible. Azoospermia is in some cases reversible, but it may take several years to restore impaired function.

When using Cyclophosphamide, allergic reactions are possible, such as urticaria, skin rash, itching, anaphylactic reactions. There is a risk of cross sensitivity with other alkylating compounds.

Serious infections may develop in patients with severe immunosuppression.

The following undesirable effects are also possible: a syndrome similar to the syndrome of inappropriate secretion of antidiuretic hormone (ADH), flushing of the face or flushing of the skin of the face, increased sweating, headache, development of secondary malignant tumors.

Due to the fact that grapefruit contains a compound that can disrupt the activation of cyclophosphamide, it is not recommended to use it, as well as its juice during the treatment period.

special instructions

During the period of use of the drug, a regular blood test should be carried out (especially the content of neutrophils and platelets should be monitored) to assess the degree of myelosuppression. It is also necessary to regularly analyze urine for the presence of red blood cells, the presence of which may indicate the development of hemorrhagic cystitis.

Treatment with the drug should be interrupted:

• with the appearance of symptoms of cystitis with micro- or macrohematuria;
• with a decrease in the number of leukocytes< 2500/мкл и/или тромбоцитов < 100 000/мкл;
• when an infection occurs, if the dose reduction of the drug is not enough.

During treatment with Cyclophosphamide, it is required to use reliable methods of contraception, as well as to refrain from drinking alcohol.

The anesthesiologist should be informed if Cyclophosphamide is prescribed to the patient under general anesthesia within 10 days after surgery.

drug interaction

The following drugs affect Cyclophosphamide:

• inducers of microsomal oxidation: reduce the half-life of cyclophosphamide and increase its activity;
• allopurinol: enhances the toxic effect on the bone marrow;
• colchicine, probenecid, allopurinol, sulfinpyrazone: there may be an increased risk of nephropathy caused by increased production of uric acid (these drugs may need to be adjusted);
• immunosuppressants (azathioprine, chlorambucil, glucocorticosteroids, cyclosporine, mercaptopurine, etc.): increase the risk of developing secondary tumors and infections;
• lovastatin (for heart transplant): possible increased risk of acute renal failure and acute skeletal muscle necrosis;
• myelosuppressive drugs, radiation therapy: risk of additive bone marrow suppression;
• High-dose cytarabine in preparation for bone marrow transplantation: increased risk of fatal cardiomyopathy.

Cyclophosphamide affects the following drugs:

• suxamethonium: enhances its action due to a noticeable and prolonged suppression of cholinesterase activity;
• cocaine: reduces and slows down its metabolism, enhancing and prolonging its effect, as well as increasing the risk of toxic effects;
• anticoagulants: it is able to increase their activity due to a decrease in the synthesis of blood coagulation factors in the liver and impaired platelet formation. However, the ability to also reduce anticoagulant activity through an unknown mechanism has been noted;
• doxorubicin, daunorubicin: enhances their cardiotoxic effect.

Analogues

An analogue of Cyclophosphamide is Endoxan.

Terms and conditions of storage

Store in a dry place, away from light, at a temperature not exceeding 10 °C. Keep away from children.

Shelf life - 3 years.

Terms of dispensing from pharmacies

Released by prescription.

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Cyclophosphamide is classified as an "alkylating agent".

• Active substance: cyclophosphamide.
• Pharmacotherapeutic group:antineoplastic agents. alkylating compounds.
• Drug synonyms:cyclophosphamide, mitoxan, cytoxan.
• Release form:tablets, powder for solution for injection.
• Storage conditions:store at a temperature not exceeding 25 ° C away from moisture and heat.
• Terms of sale: on prescription.
• Manufacturer:PAT "Kyivmedpreparat", Ukraine.

Indications for use

Cyclophosphamide is used in the treatment of such:

• chronic lymphocytic;
• chronic myelocytic;
• neuroblastoma;

Cyclophosphamide is also used in bone marrow transplantation regimens and for the treatment of diseases that are not oncological (rheumatoid arthritis, vasculitis, Wegener's granulomatosis, scleroderma, lupus erythematosus, nephrotic syndrome). Cyclophosphamide is more often used simultaneously or sequentially with other anticancer drugs.

Contraindications

Cyclophosphamide is contraindicated in patients with:

• active or recent infection;
• cystitis;
• hypersensitivity to cyclophosphamide;
• a weak immune system (caused by a disease or by using certain medications);
• heart, kidney or liver disease;
• myelosuppression.

You should tell your doctor if you are taking other chemotherapy drugs or if you have ever had radiation therapy. In such cases, Cyclophosphamide should be taken with caution.

In connection with the listed contraindications, before starting treatment, the patient's urinary system and hematopoietic system, kidneys, and liver are carefully checked.

Use during pregnancy and lactation

It is dangerous for pregnant women to use Cyclophosphamide, as its toxicity to the developing child has been proven. During chemotherapy, it is important to carefully protect yourself from pregnancy, and if you do become pregnant, then consult your doctor for advice.

Cyclophosphamide passes into breast milk and may harm a nursing baby.

Children

The drug is used in pediatric practice. Doses are calculated according to the relevant instructions.

pharmachologic effect

Cyclophosphamide has a cytostatic, antitumor, immunosuppressive effect. In vitro, it is inactive, and it is activated only in the liver, where cyclophosphamide is converted to 4-hydroxyn-cyclophosphamide. It interacts with the DNA of cells and leads to their apoptosis. Alkylating agents, to which this drug belongs, are most active in the resting phase of the cell. This drug is nonspecific with respect to cell cycles.

Pharmacokinetics

Approximately 20% of cyclophosphamide binds to proteins. After intravenous administration, the half-life is from 3 to 12 hours with a total clearance of 4-5.6 l / h. After oral administration, the drug is almost completely absorbed in the digestive tract and reaches its highest concentration after 1 hour.

24 hours after the last injection, the concentration of the drug in the blood plasma decreases significantly, and is completely eliminated within 72 hours.

Cyclofosan is biotransformed to active alkylating metabolites mainly in the liver (75% of the substance). These metabolites interfere with the growth of susceptible, rapidly proliferating malignant cells. From 10 to 20% of Cyclophosphamide is excreted unchanged in the urine, and 4% is excreted in the bile.

Instructions for use

Cyclophosphamide is usually administered in several ways: orally and intravenously by injection or infusion. In addition, the drug is approved for intramuscular, intraperitoneal and intrapleural administration. The route of administration of Cyclophosphamide is chosen based on the dose, the type of disease and the condition of the patient.

Tablets should be taken with or after food. They should not be cut, chewed or crushed. During treatment, you need to drink more fluids and go to the toilet more often to avoid side effects from the kidneys and bladder.

The dosage and schedule of administration depends on a number of individual factors, so they are selected by an oncologist. The standard initial course of cyclophosphamide when used as monotherapy in patients without hematological deficiency is 40-50 mg/kg given intravenously in divided doses over 2-5 days.

Other intravenous regimens include 10-15 mg/kg every 7-10 days or 3-5 mg/kg twice a week. The oral dose of cyclophosphamide is usually 1 to 5 mg/kg per day. The course of admission can be repeated several times, between each course there is a break of 3-4 weeks. The regimen may be adjusted according to evidence of antitumor activity and the development of myelosuppression.

Before intravenous administration, cyclophosphamide powder is diluted with 0.9% sodium chloride solution in the following ratio: 50 ml of sodium chloride per 1 g of the drug. The concentration of cyclophosphamide should be 20 mg/ml. The diluted preparation can be stored at room temperature for another 24 hours.

Dosage for the treatment of nephrotic syndrome in children: an oral dose of 2 mg/kg body weight per day for 8-12 weeks is recommended (maximum cumulative dose 168 mg/kg).

Precautionary measures

When using cyclophosphamide, it is necessary to observe safety regulations when working with cytotoxic substances.

You can use the drug only under the supervision of a specialist!

Side effects

Common side effects of Cyclophosphamide, which can often be controlled, are:

• nausea;
• loss of appetite;
• stomach pain or upset, diarrhea;
• temporary hair loss;
• increased sweating;
• violation of the menstrual cycle;
• discoloration of the skin and nails.

Also, chemotherapy drugs of this group have a depressing effect on the bone marrow, in connection with which a person’s blood formation is disturbed. This entails a lack of platelets (thrombocytopenia), erythrocytes (erythropenia), leukocytes (leukopenia). Most of all, Cyclophosphamide affects leukocytes, the lack of which increases the risk of infection of the patient.

Some unwanted effects (including, for example, dizziness and blurred vision) may affect a person's ability to operate machinery and mechanisms.

Symptoms of serious side effects may include:

• blood in urine or stool;
• pain or burning when urinating;
• pale skin, rapid heartbeat;
• increased sweating;
• skin rash, hives, or itching;
• sudden chest pain;
• wheezing, dry cough;
• elevated temperature;
• ulcers in the oral mucosa;
• bleeding from the nose, mouth, vagina, or rectum;
• purple or red pinpoint spots under the skin;
• jaundice;
• severe allergic reaction.

These violations are the reason for going to the doctor. The use of cyclophosphamide may increase the risk of developing other types of cancer, such as bladder cancer. Also, this medicine can affect the ability to have children in men or women.

Overdose

Overdose symptoms may include severe forms of some of the side effects listed in this leaflet.

Serious signs of an overdose are:

• blood in the urine;
• dizziness, confusion, or agitation;
• joint pain;
• intermittent breathing;
• swelling of the legs or arms;
• severe weakness.

There are no antidotes for Cyclophosphamide, so it must be taken with caution, not exceeding the prescribed dose. To remove the substance from the body, hemodialysis is performed.

special instructions

Avoid contact with sick people while you are being treated with Cyclophosphamide. Tell your doctor right away if you notice signs of infection. Do not receive a "live" vaccine during chemotherapy and avoid contact with anyone who has recently received a live vaccine. There is a possibility that the virus could be passed on to you.

It is important to check with your doctor regularly while you are taking Cyclophosphamide to monitor side effects and check your response to therapy. You will have periodic blood draws to monitor your blood cell count and the function of other organs (particularly your kidneys and liver).

To reduce the chance of side effects, pay sufficient attention to oral hygiene. It is advisable to refuse alcohol during chemotherapy.

Interaction

Before starting treatment with Cyclophosphamide, be sure to tell your doctor about any other medicines you are taking. Do not take aspirin, products containing aspirin, unless your doctor tells you to do so.

Combined or sequential use of cyclophosphamide and other agents with similar toxicity may increase the negative effect on the body. For example, increased hematotoxicity and immunosuppression may result from the interaction of Cyclophosphamide with:

• ACE inhibitor drugs;
• Natalizumab;
• Paclitaxel;
• thiazide diuretics;
• Zidovudine.

Cardiotoxicity is increased when cyclophosphamide is combined with:

• anthracyclines;
• Pentostatin;
• Trastuzumab.

Other drugs that can increase the toxicity of Cyclophosphamide:

• Amphotericin B;
• Indomethacin;
• Azathioprine (increased risk of liver necrosis);
• Busulfan;
• protease inhibitors;
• Metronidazole;
• Tamoxifen (increases the risk of thromboembolic complications);
• Coumarins;
• Cyclosporine;
• depolarizing muscle relaxants.