Antitumor drug cyclophosphamide and the effectiveness of its use. Cyclophosphamide powder: instructions for use Method of administration and dosage

Cyclophosphamide is an alkylating compound. Antitumor drug.

Release form and composition

The powder for preparing a solution for intravenous and intramuscular administration is crystalline, from almost white to white.

Composition of 1 bottle: cyclophosphamide – 200 mg.

Indications for use

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

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 for 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 period.

Relative contraindications:

severe diseases of the heart, kidneys, liver;
adrenalectomy;
history of gout;
nephrourolithiasis;
suppression of bone marrow function;
infiltration of bone marrow by tumor cells;
previous radiation or chemotherapy.

Directions for use and dosage

Cyclophosphamide is included in many chemotherapy treatment regimens. When choosing doses, route and mode of administration in each individual case, one should be guided by data from specialized literature.

The most common regimens and doses for adults and children:

50–100 mg/m2 every day for 2-3 weeks;
100–200 mg/m2 2-3 times a week for 3-4 weeks;
600–750 mg/m2 once every 2 weeks;
1500–2000 mg/m2 1 time every 3-4 weeks up to a total dose of 6000–14,000 mg.

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

Preparation of the solution

A 0.9% sodium chloride solution should be added to the bottle with the powder in accordance with 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 bottle 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. For leukopenia, after cessation of therapy, recovery usually begins on the 7–10th day);
digestive system: anorexia, nausea, vomiting, stomatitis, pain or discomfort in the abdominal area, diarrhea, constipation. There are isolated reports of the development of hemorrhagic colitis, jaundice, and liver dysfunction with an increase in the activity of alkaline phosphatase, transaminases and bilirubin content in the blood serum. In 15–50% of patients using high doses of cyclophosphamide in combination with busulfan and total irradiation during allogeneic bone marrow transplantation, obliterating endophlebitis of the hepatic veins develops. It also occurs in very rare cases in patients with aplastic anemia who use cyclophosphamide alone in high doses. This syndrome develops 1–3 weeks after bone marrow transplantation (symptoms: sudden increase in body weight, hepatomegaly, ascites, hyperbilirubinemia). There is also a risk of hepatic encephalopathy;
skin and skin appendages: alopecia (after completion of treatment or during long-term treatment, hair regrowth occurs, differences in hair structure and color are possible), rash, skin pigmentation, nail changes;
urinary system: hemorrhagic urethritis/cystitis, necrosis of the renal tubules (even death), fibrosis of the bladder (including common) with and without cystitis. It is possible to detect atypical bladder epithelial cells in the urine. When using the drug in high doses, renal dysfunction, hyperuricemia, nephropathy (due to increased formation of uric acid) is possible;
cardiovascular system: when high doses of Cyclophosphamide (120–270 mg/kg) were administered for several days, cardiotoxicity was observed 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: disturbance of spermatogenesis and oogenesis. Both men and women can 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, normal development of secondary sexual characteristics and normal menstruation were noted; the drug did not affect further ability to conceive. The use of the drug in men can cause oligospermia or azoospermia (without impaired 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, normal development of secondary sexual characteristics is noted, but oligospermia, azoospermia, and increased secretion of gonadotropins may be noted. Testicular atrophy of varying degrees is possible. Azoospermia is reversible in some cases, but restoration of impaired function may take several years.

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

Patients with severe immunosuppression may develop serious infections.

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

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

special instructions

During the period of use of the drug, regular blood tests should be performed (especially the content of neutrophils and platelets should be monitored) to assess the degree of myelosuppression. Regular urine testing is also necessary 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:

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

During treatment with Cyclophosphamide, it is necessary to use reliable methods of contraception and also refrain from drinking alcohol.

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

Drug interactions

The following medicines 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 formation 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 transplantation): possible increased risk of acute renal failure and acute necrosis of skeletal muscles;
myelosuppressive drugs, radiation therapy: risk of additive suppression of bone marrow function;
Cytarabine in high doses in preparation for bone marrow transplantation: increases the risk of fatal cardiomyopathy.

Cyclophosphamide affects the following drugs:

suxamethonium: enhances its effect due to a noticeable and long-term 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: can increase their activity due to a decrease in the synthesis of blood clotting factors in the liver and impaired platelet formation. However, it has also been noted to reduce anticoagulant activity through an unknown mechanism;
doxorubicin, daunorubicin: enhances their cardiotoxic effect.

Analogs

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.

Conditions for dispensing from pharmacies

Dispensed by prescription.

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

ATX Code: Antineoplastic drugs and immunomodulators (L) > Antineoplastic drugs (L01) > Alkylating drugs (L01A) > Nitrogen mustard analogues (L01AA) > Cyclophosphamide (L01AA01)

Release form, composition and packaging

powder for preparation. solution for intravenous administration 200 mg: vial. 1 or 40 pcs.
Reg. No.: 18/08/608 dated 08/08/2018 - Registration period. beat is not limited

Powder for the preparation of a solution for intravenous administration white or almost white, crystalline.

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

Description of the drug CYCLOPHOSPHANE created in 2013 on the basis of instructions posted on the official website of the Ministry of Health of the Republic of Belarus. Update date: 07/16/2014

pharmachologic effect

Antitumor agent with alkylating action, chemical structure close to nitrogen analogues of mustard gas. It has a cytostatic and immunosuppressive effect. It is an inactive transport form that breaks down under the influence of phosphatases to form 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 intravenous administration, the Cmax of 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 (cyclophosphamide is determined in the blood plasma within 72 hours). Bioavailability - 90%. Vd - 0.6 l/kg. The binding of cyclophosphamide to plasma proteins is insignificant (12-14%), but some active metabolites are bound by more than 60%. Metabolized in the liver with the participation of the CYP2C19 isoenzyme. T1/2 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 5 to 25% of the administered dose is excreted unchanged in the urine. Several cytotoxic and non-cytotoxic metabolites have been identified in urine and blood plasma. A small part of cyclophosphamide is also excreted in bile. The drug can be removed 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 lung cancer, neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma in children, osteosarcoma;
progressive "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.

Dosage regimen

Use is only possible under the supervision of a physician experienced in chemotherapy.

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

The dosage should be selected individually for each patient. The following dosage recommendations may be used for cyclophosphamide monotherapy. When co-prescribing other cytostatics of similar toxicity, it may be necessary to reduce the dose or increase pauses during 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/m2 body surface area);
For intermittent treatment of adults and children - from 10 to 15 mg/kg body weight (equivalent to 400 to 600 mg/m2 body surface area), at intervals of 2 to 5 days;
For intermittent treatment of adults and children with a high dose of 20 to 40 mg/kg body weight (equivalent to 800 to 1600 mg/m2 body surface area), or with an even higher dose (for example, during conditioning before bone marrow transplantation), with at intervals from 21 to 28 days.

Preparation of the solution

Immediately before use, add 10 ml of 0.9% sodium chloride solution to the contents of the bottle with a dosage of 200 mg. The substance dissolves easily with vigorous shaking after adding the solvent. If the substance does not dissolve immediately and completely, it is recommended to let the bottle stand for a few minutes. The solution is suitable for intravenous use, but it is better to administer it as an 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. The duration of the infusion is from 30 minutes to 2 hours, depending on the volume.

Treatment cycles for intermittent therapy can 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 >100,000 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.

Use in combination with other substances that inhibit hematopoiesis requires dose adjustment. You should use the appropriate tables for adjusting the dose of cytotoxic drugs based on the quantitative composition of blood cells at the beginning of the cycle and adjusting the dose based on low levels of cytostatic substances.

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

Children and teenagers

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

Elderly and physically frail 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.

Side effects

In patients receiving Cyclophosphamide, depending on the dosage, the following adverse reactions may occur, which in most cases 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 rash, chills, fever, tachycardia, bronchospasm, shortness of breath, edema, blood flow and decreased blood pressure. In rare cases, anaphylactoid reactions can 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 observed 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 may usually develop only after several cycles of treatment. The most severe suppression of bone marrow function should be expected in patients who have previously been treated with chemotherapy and/or radiation therapy, as well as in patients with renal failure.

Simultaneous treatment with other substances that inhibit hematopoiesis requires dose adjustment. You should use the appropriate dose adjustment tables for cytotoxicity of drugs based on the quantitative composition of the blood at the beginning of the treatment cycle and adjust the dosage with low levels of cytostatic substances.

From the nervous system: in rare cases, neurotoxic reactions such as paresthesia, peripheral neuropathy, polyneuropathy, as well as neuropathic pain, taste disturbances 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 observed with less frequency. In isolated cases, hemorrhagic colitis and acute pancreatitis were reported. Gastrointestinal bleeding has been reported in isolated cases. In cases 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 liver dysfunction (increased levels of serum transaminases, gammaglutamyl transpeptidase transpeptidase, alkaline phosphatase, bilirubin).

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

From the kidneys and urinary system: Once excreted in the urine, cyclophosphamide metabolites cause changes in the urinary system, namely the bladder. Hemorrhagic cystitis, microhematuria and macrohematuria are the most common dose-dependent complications during treatment with Cyclophosphamide and require discontinuation of therapy. Cystitis develops very often, at first they are sterile, but secondary infection can occur. Swelling of the bladder walls, bleeding from the cell layer, interstitial inflammation with fibrosis, and sometimes sclerosis of the bladder were also noted. Renal dysfunction (especially in cases with a history of renal impairment) is an uncommon 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 isolated cases, hemorrhagic cystitis with fatal outcome has been reported. Acute or chronic renal failure and toxic nephropathy may occur, especially in patients with a history of reduced renal function.

From the reproductive system: through its ankylation effect, cyclophosphamide can rarely cause impairment of spermatogenesis (sometimes irreversible) and lead to azoospermia and/or persistent oligospermia. Rarely, ovulation disturbances have been reported. In some cases, amenorrhea and decreased levels of female sex hormones have been reported.

From 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 include, for example, chest pain and angina. Ventricular supraventricular arrhythmia has occasionally been reported. Very rarely, atrial or ventricular fibrillation, as well as cardiac arrest, may occur during cyclophosphamide therapy. In very rare cases, myocarditis, pericarditis and myocardial infarction have been reported. Cardiotoxicity is especially enhanced after use of the drug in high doses (120-240 mg/kg body weight) and/or when combined with other cardiotoxic drugs, for example, anthracyclines or pentostatin. Increased cardiotoxicity may also occur after prior radiotherapy to the cardiac region.

From the respiratory system: bronchospasm, shortness of breath or cough, which leads to hypoxia. Very rarely, obliterating endophlebitis of the lungs can develop, sometimes as a complication of pulmonary fibrosis. Toxic pulmonary edema, pulmonary hypertension, pulmonary embolism and pleural effusion have been reported very rarely. In some cases, pneumonitis and interstitial pneumonia may develop, progressing to chronic interstitial pulmonary fibrosis, and respiratory distress syndrome and respiratory failure with 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. The risk of developing urinary tract cancer, as well as myelodysplastic changes, which can partially progress to acute leukemia, increases. Animal studies have shown that the threat of bladder cancer can be significantly reduced by appropriate use of uromitexane. In rare cases, tumor collapse syndrome has been reported due to the rapid response of large, chemotherapy-sensitive tumors.

Skin and its derivatives/allergic reactions: alopecia areata, which is a common side effect (can progress to complete baldness), is usually reversible. Cases of changes in skin pigmentation of the palms, nails and fingers, as well as soles have been reported;

dermatitis, expressed by inflammation of the skin and mucous membranes. Erythrodysesthia syndrome (tingling sensation in the palms and soles, to the point of severe pain). Very rarely, general irritation and erythema of the irradiated area (radiation dermatitis) have been reported after radiation therapy and subsequent treatment with cyclophosphamide. In isolated cases - Stevens-Johnson syndrome and toxic epidermal necrolysis, fever, shock.

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

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

From the organs of vision: blurred vision. Symptoms such as conjunctivitis and swelling of the eyelids have been reported very rarely as a result of a hypersensitivity reaction.

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

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

Contraindications for use

known hypersensitivity to cyclophosphamide;
severe impairment of bone marrow function (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 breastfeeding

Cyclophosphamide is contraindicated during pregnancy. If there are vital indications for the use of Cyclophosphamide in the first 3 months of pregnancy, it is necessary to decide on termination of pregnancy. In the future, if treatment cannot be postponed and the patient wishes to continue bearing the fetus, chemotherapy can be given only after informing the patient about the possible risk of teratogenic effects.

Since cyclophosphamide passes into breast milk, breastfeeding 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 treatment period, 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 by tumor cells, previous radiation or chemotherapy, renal/liver failure.

During the main course of treatment, it is necessary to monitor the general 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 with micro- or macrohematuria appear, as well as when the number of leukocytes decreases to 2500/μl and/or platelets to 100 thousand/μl, treatment with the drug should be discontinued.

If infections occur, 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 treatment period, 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, the anesthesiologist must be notified. 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 decreased hepatic synthesis of coagulation factors and impaired platelet formation, as well as by an unknown mechanism.

To prevent 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 discontinue cyclophosphamide.

According to ECG and ECHO-CG data, in patients who suffered episodes of cardiotoxic effects of high doses of cyclophosphamide, no residual effects on the state of the myocardium were detected.

In girls, as a result of treatment with cyclophosphamide during the prepubertal period, secondary sexual characteristics developed normally and menstruation was normal; subsequently they were.able to conceive. Sexual desire and potency in men are not impaired. 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 observed.

After previous treatment with the drug, secondary malignant tumors may occur, most often these are 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 with impaired immune processes. In some cases, secondary tumors develop several years after stopping drug treatment.

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

Special Security Measures

When using Cyclophosphamide and preparing the solution, you must follow safety rules when working with cytotoxic substances.

Features of application

Use only as directed and under the supervision of a physician.

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

From the blood and lymphatic systems. Severe suppression of bone marrow function should be expected, especially in patients who have previously been treated with chemotherapy and/or radiotherapy, as well as in patients with impaired renal function. Therefore, constant hematological monitoring with regular counting of blood cells is indicated for all patients during treatment. Counting leukocytes and platelets and determining 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:

during 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 weakened immune systems, such as those with diabetes, chronic renal failure or liver failure, also require special care. Cyclophosphamide, like other cytostatics, should be used with caution when treating debilitated and elderly patients, as well as after radiotherapy.

From 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 significantly reduce the frequency and severity of the drug's effects. Regular bladder emptying is important.

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

Patients with kidney disease when treated with Cyclophosphamide require careful care.

Cardiac disorders. There is evidence of increased cardiotoxic effect of Cyclophosphamide in patients after prior radiotherapy to the cardiac region and/or concomitant treatment with anthracyclines or pentostatin. You should remember the need for regular checks of blood electrolyte composition, paying special attention to patients with a history of heart disease.

Gastrointestinal tract. To reduce the frequency and severity of effects such as nausea and vomiting, it is necessary to prescribe antiemetic drugs for prevention. Alcohol may increase these side effects, so patients receiving treatment with Cyclophosphamide should be advised to avoid drinking alcohol.

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

From the digestive system. The drug should be used to treat patients with impaired liver function only after careful evaluation in each individual case. Such patients require careful care. Alcohol abuse may increase the risk of developing liver dysfunction.

Reproductive system disorders/Genetic disorders. Treatment with Cyclophosphamide can cause genetic abnormalities in men and women. Therefore, pregnancy should be avoided during treatment and for six months after its completion. During this time, sexually active men and women need to use effective contraception.

In men, treatment may increase the risk of developing irreversible infertility, so they should be advised of the need for sperm conservation before starting treatment.

General Disorders/Disorders at the Administration Site. Since the cytostatic effect of Cyclophosphamide occurs after its bioactivation, which occurs in the liver, the risk of tissue damage due to unintentional paravenous administration of the drug solution is negligible.

In patients with diabetes mellitus, It is necessary to regularly check blood sugar levels in order to adjust antidiabetic therapy in a timely manner.

Impact 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.

Overdose

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, most 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 ensured. In order to prevent urotoxic phenomena, it is necessary to take measures to prevent cystitis using uromitexane.

Drug interactions

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

Release form: Liquid dosage forms. Injection.

General characteristics. Compound:

Active ingredient: cyclophosphamide (cyclophosphamide) sterile in terms of 100% substance 200 mg.

Pharmacological properties:

Pharmacodynamics. Cyclophosphamide is a cytostatic drug from the oxazaphosphorine group. Cyclophosphamide is inactive in vitro. Its activation occurs with the help of microsomal enzymes in the liver, where it is converted into 4-hydroxo-cyclophosphamide, which is in equilibrium with its tautomer, aldophosphamide. The cytotoxic action of cyclophosphamide is based on its interaction between its alkylating metabolites and DNA. This alkylation leads to the breaking of the cross-links between the DNA strands and DNA proteins. During the cell cycle, transport through the G2 phase slows down. The cytotoxic effect is not cell cycle phase specific, but it is cell cycle specific. Mutual resistance cannot be ruled out, especially with cytostatics of a similar structure, such as ifosfamide, as well as with other alkylants.

Pharmacokinetics. Cyclophosphamide is almost completely absorbed from the gastrointestinal tract. After a single intravenous injection of cyclophosphamide over 24 hours, there is a significant decrease in plasma concentrations of cyclophosphamide and its metabolites, but detectable plasma levels may be present for up to 72 hours. The half-life of cyclophosphamide from blood serum averages 7 hours for adults and 4 hours for children. Excretion of cyclophosphamide and its metabolites occurs primarily by the kidneys. Blood levels after intravenous and oral dosing are bioequivalent.
Pharmaceutical characteristics.
Basic physical and chemical properties: white or almost white crystalline powder. Incompatibility. Solutions containing benzyl alcohol may reduce the stability of cyclophosphamide.

Indications for use:

Cyclophosphamide® is used for mono- or in the treatment of:
- leukemia: acute or chronic lymphoblastic/lymphocytic and myeloid/myelogenous leukemia;
- malignant lymphomas: Hodgkin's disease (lymphogranulomatosis), non-Hodgkin's lymphomas;
- large with or without metastases: ovarian, testicular cancer, small cell, Ewing's sarcoma, in children, osteosarcoma;
- progressive “autoimmune diseases”, such as rheumatoid, psoriatic, (for example with nephrotic syndrome), certain types (for example with nephrotic syndrome), gravis, autoimmune hemolytic, cold agglutinin disease, Wegener's granulomatosis. Cyclophosphamide® is also used for immune suppression in and for conditioning before bone marrow transplantation in severe, acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia.

Important! Get to know the treatment

Directions for use and dosage:

Intravenous infusion. The drug can only be prescribed by an experienced oncologist. The dosage should be selected individually for each patient. The following dosage recommendations may be used for cyclophosphamide monotherapy. When co-prescribing other cytostatics of similar toxicity, it may be necessary to reduce the dose or extend the pauses during treatment with the drug.
Unless otherwise prescribed, the following dosages are recommended:
- for continuous treatment of adults and children - from 3 to 6 mg/kg body weight, daily (equivalent to 120 to 240 mg/kg2 body surface area);
- for intermittent therapy of adults and children - from 10 to 15 mg/kg body weight (equivalent to 400 to 600 mg/m2 body surface area), at intervals of 2 to 5 days;
- for intermittent therapy of adults and children with a high dose - from 20 to 40 mg/kg (equivalent to 800 to 1600 mg/m2 body surface area), or with an even higher dose
(eg, during conditioning before bone marrow transplantation), at intervals of 21 to 28 days.
Preparation of the solution
Immediately before use, add 10 ml of 0.9% sodium chloride solution to the contents of one bottle with a dosage of 200 mg. The substance dissolves easily with vigorous shaking after adding the solvent. If the substance does not dissolve immediately and completely, it is recommended to let the bottle stand for several minutes. The solution is suitable for intravenous administration, but it is better to administer it as an intravenous infusion. For short-term intravenous administration, Cyclophosphamide® solution is added to Ringer's solution, 0.9% sodium chloride solution or glucose solution to a total volume of about 500 ml. The duration of the infusion is from 30 minutes to 2 hours, depending on the volume.
Treatment cycles for intermittent therapy can be repeated every 3-4 weeks. The duration of therapy and the intervals between courses depend on the indications, the use of a combination of chemotherapy drugs, the general health of the patient, laboratory parameters and the restoration of the number of blood cells.
Special Dosage Recommendations
Dose reduction recommendations for patients with bone marrow suppression:
- leukocytes > 4000 µl, and platelets > 100,000 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 отельного решения.
Use in combination with other substances that depress blood circulation requires dose adjustment. You should use the appropriate dose adjustment tables for the cytotoxicity of drugs based on the quantitative composition of blood cells at the beginning of the cycle and dose adjustment based on the minimum level of cytostatic substances. Recommendations regarding dose selection for patients with hepatic insufficiency Severe hepatic insufficiency requires dose reduction. The general recommendation is to reduce the dose by 25% when the serum bilirubin content is from 3.1 to 5 mg/100 ml.
Recommendations for dose selection in patients with renal failure
A dose reduction of 50% is recommended when the glomerular filtration rate is less than 10 ml/min. Cyclophosphamide can be removed from the body by dialysis.
Children and teenagers
Dosage - in accordance with the accepted treatment plan; recommendations for selecting the dose and use of the drug for the treatment of children and adolescents are the same as for adult patients.
Elderly and physically frail patients
In general, 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.

Features of application:

Use only as directed and under strict medical supervision! Before starting treatment, it is necessary to eliminate possible obstacles to the removal of urine from the urinary tract and to sanitize possible infections (cystitis). From the blood and lymphatic systems. Severe suppression of bone marrow function should be expected, especially in patients who have previously been treated with chemotherapy and/or radiotherapy, as well as in patients with impaired renal function. Therefore, constant hematological monitoring with regular counting of blood cells is indicated for all patients during treatment. Counting leukocytes and platelets, as well as determining 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 the beginning of the course of treatment - with an interval of 5-7 days, if their number decreases to< 3000 в мм3, то раз в два дня или ежедневно. При длительном лечении обычно достаточно проводить анализ
blood once every two weeks. Without urgent need, Cyclophosphamide should not be prescribed to patients with a white blood cell count of less than 2500/µl and/or a platelet count of less than 50,000/µl. In the case of agranulocytorrhea and/or it is necessary to prescribe antibiotics and/or antifungal drugs prophylactically. Urinary residue should be regularly analyzed for red blood cell content. From the immune system. Patients with a weakened immune system, for example patients with chronic renal or liver failure, also require special attention. In general, Cyclophosphamide, like other cytostatics, should be used with caution
in the treatment of weakened patients and the elderly, as well as after radiotherapy. From 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 taking sufficient fluids, can significantly reduce the frequency and severity of the toxic effects of the drug. Emptying your bladder regularly is important.
If micro- or macrohematuria occurs during treatment with Cyclophosphamide®, drug therapy should be discontinued until the condition normalizes. Patients suffering from kidney disease require careful care during treatment with Cyclophosphamide®. Cardiac disorders. There is evidence of an increase in the cardiotoxic effect of Cyclophosphamide in patients after previous radiotherapy of the cardiac region and/or concomitant treatment with anthracyclines or pentostatin. You should remember the need for regular checks of blood electrolyte composition, paying special attention to patients with a history of heart disease. Gastrointestinal disorders. In order to reduce the frequency and severity of such effects, it is necessary to prescribe antiemetic drugs. Alcohol may increase these side effects, therefore patients receiving treatment with Cyclophosphamide should be advised to avoid drinking alcohol. To reduce the frequency of occurrence, attention must be paid to hygiene
oral cavity.
From the hepatobiliary system. The drug should be used to treat patients with impaired liver function only after careful evaluation in each individual case. Such patients require careful monitoring. Alcohol abuse may increase the risk of developing liver dysfunction. Reproductive system disorders/genetic disorders. Treatment with Cyclophosphamide® can cause genetic abnormalities in men and women. Therefore, pregnancy should be avoided during treatment with the drug and for six months after its completion. During this time, sexually active men and women should use effective contraception. In men, treatment may increase the risk of developing irreversible disease, so they should be aware of the need for sperm conservation before starting treatment. General disorders/disturbances at the injection site. Since the cytostatic effect of Cyclophosphamide® is determined after its bioactivation, which occurs in the liver, the risk of tissue damage due to unintentional paravenous administration of the drug solution is negligible. In patients with diabetes, it is necessary to regularly check blood sugar levels in order to promptly adjust antidiabetic therapy. The ability to influence the reaction rate when driving a vehicle or working with other mechanisms. Due to the possibility of side effects when using Cyclophosphamide®, the doctor should warn the patient about the need to be careful when driving a vehicle or engaging in potentially unsafe activities that require increased attention.

Side effects:

In patients receiving Cyclophosphamide, depending on the dosage, the following adverse reactions may occur, which in most cases are reversible. Infections and infestations. Typically, severe bone marrow suppression can lead to agranulocytic fever and secondary infections such as pneumonia progressing to (life-threatening infections), which in isolated cases can be fatal. Immune system disorders. Rarely, hypersensitivity reactions may occur, accompanied by rashes, chills, fever, tachycardia, bronchospasm, shortness of breath, edema, flushing and decreased blood pressure. In isolated cases, anaphylactoid reactions can progress to.
From the blood and lymphatic systems. Depending on the dosage, various forms of bone marrow suppression may occur, such as leukopenia,. with an increased risk of anemia. It should be taken into account 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 observed during the 1st and 2nd weeks of treatment. The bone marrow recovers relatively quickly, and the blood picture
normalizes, as a rule, 20 days after the start of treatment. Anemia may usually develop only after several cycles of treatment. The most severe suppression of bone marrow function should be expected in patients who have previously been treated with chemotherapy and/or chemotherapy, as well as in patients with renal failure. Simultaneous treatment with other substances that inhibit hematopoiesis requires dose adjustment. Appropriate dose adjustment tables for drug cytotoxicity should be used based on blood counts at the beginning of the treatment cycle and dose adjustments based on the lowest levels of cytotoxic substances.
From the nervous system. In isolated cases, neurotoxic reactions such as paresthesia, peripheral neuropathy, polyneuropathy, as well as neuropathic pain, taste disturbances 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. , and inflammation of the mucous membranes from stomatitis to the formation of ulcers are observed with less frequency. In isolated cases, hemorrhagic colitis and acute pancreatitis were reported. In isolated cases, . In case of nausea and
vomiting can sometimes cause dehydration. Isolated cases of abdominal pain due to gastrointestinal disorders have been reported.
From the hepatobiliary system. Rarely, liver dysfunction has been reported (increased levels of serum transaminases, gamma-glutamyl transpeptidase, alkaline phosphatase, bilirubin).
Hepatic vein occlusive endophlebitis has been reported in approximately 15% to 50% of patients who received high-dose cyclophosphamide plus busulfan or whole-body irradiation for allogeneic bone marrow transplantation. Conversely, this complication was observed in patients with aplastic anemia who received only high doses of Cyclophosphamide. The syndrome usually develops 1-3 weeks after transplantation and is characterized by sudden weight gain, hepatomegaly, ascites and hyperbilirubinemia and portal hypertension. Very rarely, liver disease can develop. Known risk factors that contribute to the development of obliterating endophlebitis of the hepatic veins in a patient are impaired liver function, therapy with hepatotoxic drugs in combination with high-dose chemotherapy, and especially if the element of conditioning therapy is the alkylating compound bisulfan.
From the kidneys and urinary system. Once excreted in the urine, cyclophosphamide metabolites cause changes in the urinary system, namely in the bladder. Hemorrhagic cystitis, microhematuria and macrohematuria are the most common dose-dependent complications during treatment with Cyclophosphamide® and require discontinuation of therapy. Cystitis develops very often, at first they are sterile, but secondary infection can occur. Swelling of the walls of the urinary tract was also noted
bladder, bleeding from the cell ball, interstitial inflammation with fibrosis, and sometimes sclerosis of the bladder. Renal dysfunction (especially in cases of impaired renal function in history) is not a common 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 isolated cases, hemorrhagic cystitis with fatal outcomes has been reported. Acute or chronic toxicity may occur, especially in patients with a history of reduced renal function.
From the reproductive system. Due to its ankylation effect, cyclophosphamide can rarely cause (sometimes non-negotiable) and lead to azoospermia and/or persistent azoospermia. Rarely, ovulation disturbances have been observed. In some cases, amenorrhea and decreased levels of female sex hormones have been reported.
From the cardiovascular system. Cardiotoxicity: from minor changes in blood pressure, ECG changes, arrhythmias, to secondary with reduced left ventricular function and heart failure, which in some cases can cause death.
Clinical symptoms of cardiotoxicity may include chest pain and seizures. Ventricular and supraventricular have been reported occasionally. Very rarely, during therapy with cyclophosphamide, atrial or ventricular fibrillation may develop, as well as. In very rare cases, myocarditis, pericarditis and myocardial infarction have been reported.
Cardiotoxicity is especially enhanced after use of the drug in high doses (120-240 mg/kg body weight) and/or when combined with other cardiotoxic drugs, such as anthracyclines or pentostatin. Increased cardiotoxicity may also occur after prior radiotherapy to the cardiac region.
From the respiratory system. , or , which leads to . Very rarely, obliterating endophlebitis of the lungs can develop, sometimes as a complication. Toxic pulmonary edema, pulmonary edema, and pleural effusion have been reported very rarely. In some cases, interstitial inflammation may develop, becoming interstitial, and respiratory distress syndrome and respiratory failure with 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 can be significantly reduced by appropriate use of uromitexane. In isolated cases, tumor collapse syndrome has been reported due to the rapid response of large, chemotherapy-sensitive tumors.
From the skin and its appendages/allergic reactions. Alopecia areata, which is a common side effect (can progress to total baldness), is usually reversible. Cases of changes in skin pigmentation of the palms, nails and fingers, as well as soles have been reported; dermatitis, manifested by inflammation of the skin and mucous membranes. Erythrodysesthesia syndrome (tingling sensation in the palms and soles, up to severe pain). Very rarely, after
radiation therapy and subsequent treatment with cyclophosphamide, general irritation and erythema have been reported in the irradiated area (radiation). In isolated cases - Stevens-Johnson syndrome and toxic epidermal syndrome, fever, shock.
From the musculoskeletal system and connective tissue. Muscle weakness, .
From the endocrine system and metabolism. Very rarely - SIASH (syndrome of inappropriate secretion of antidiuretic hormone), Schwartz-Bartter syndrome with hyponatremia and fluid retention, as well as corresponding symptoms (confusion,). Anorexia has been reported in isolated cases, dehydration has rarely been reported, and fluid retention and hyponatremia have been very rarely reported. Visual disorders. Deterioration of vision. Symptoms such as swelling of the eyelids have been very rarely reported as a result of the hypersensitivity reaction. Vascular disorders. The underlying disease can cause some rare complications, such as peripheral ischemia, disseminated intravascular coagulation or hemolytic-uremic syndrome; frequency
These complications may increase with cyclophosphamide chemotherapy. General disorders. Fever during treatment with cyclophosphamide is a very common adverse reaction in the setting of hypersensitivity or neutropenia (associated with infection). Asthenic conditions and general weakness are frequent complications in cancer patients. Very rarely, due to extravasation, reactions may be observed at the injection site in the form of erythema, inflammation or.

Interaction with other drugs:

With simultaneous use of allopurinol or hydrochlorothiazide, the hypoglycemic effect due to the action of sulfonylurease may be enhanced, as well as the suppression of bone marrow function. Prior or concurrent treatment with phenobarbital, phenytoin, benzodiazepines or hydrochloride may cause microsomal induction of liver enzymes. Fluoroquinolone antibiotics (such as ciprofloxacin) taken before treatment with cyclophosphamide (especially when conditioning before a bone marrow transplant) may reduce the effect of the drug and thereby lead to relapse of the underlying disease.
Because cyclophosphamide is immunosuppressive, a decreased patient response to any vaccination should be expected; injection with activated vaccine may be accompanied by vaccine-induced infection. If depolarizing drugs that relax muscles (for example, succinylcholine halides) are used simultaneously, the result may be prolonged apnea due to a decrease in pseudocholinesterase concentrations. Concomitant use of chloramphenicol leads to an increase in the half-life of cyclophosphamide and a delay in metabolism.
Treatment with anthracyclines, pentostatin and trastuzumab may increase the potential cardiotoxicity of the drug. An intensification of the cardiotoxic effect can also be observed after preliminary radiotherapy of the heart area. Concurrent use of indomethacin should be carried out very carefully, since fluid retention was noted in one case. Because grapefruit contains a compound that can reduce the effects of cyclophosphamide, patients should not eat grapefruits or drink grapefruit juice. In animals with tumors, a decrease in antitumor activity was observed when consuming ethanol (alcohol) and simultaneous treatment with low doses of oral cyclophosphamide.
Anecdotal reports suggest an increased risk of pulmonary toxicity (pneumonia, alveolar fibrosis) in patients who have received cytotoxic chemotherapy containing cyclophosphamide and G-CSF or GM-CSF. A possible interaction with azathioprine, which can lead to liver necrosis, was observed in three patients after administration of cyclophosphamide, which was preceded by treatment with azathioprine.
Azole antifungals (fluconazole, itraconazole) are known to inhibit cytochrome P450 enzymes that metabolize cyclophosphamide. Higher exposure to toxic metabolites of cyclophosphamide has been reported among patients treated with itraconazole. Patients who receive high doses of cyclophosphamide less than 24 hours after treatment with high doses of busulfan may experience lower clearance and a longer half-life of cyclophosphamide. This may lead to an increased incidence of veno-occlusive disease and mucosal (mucosal) inflammation.
Serum concentrations of cyclosporine in patients receiving cyclophosphamide and cyclosporine in combination were lower than in patients receiving cyclosporine alone. This may lead to an increased incidence of graft-versus-host disease. Administration of a high dose of cyclophosphamide and cytarabine on the same day (with a very short time interval) will increase cardiac toxicity, taking into account the cardiac toxicity of each active substance. A pharmacokinetic interaction has been reported between ondansetron and cyclophosphamide (at high doses), resulting in decreased AUCs for cyclophosphamide. Thiotepa has been reported to potently inhibit the bioactivation of cyclophosphamide in a high-dose chemotherapy regimen when thiotepa was administered one hour before cyclophosphamide. Determining the sequence and timing of administration of these two components may be critical.

Contraindications:

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

Use during pregnancy or breastfeeding. Cyclophosphamide® is contraindicated during pregnancy. For vital indications
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 to carry the fetus, chemotherapy can be carried out only after the patient informs about the possible
risk of teratogenic effects. Since cyclophosphamide passes into breast milk, breastfeeding should be discontinued during treatment.
Children. Recommendations for selecting the dose and use of the drug for the treatment of children and adolescents are the same as for adult patients.
Special security measures. When using Cyclophosphamide® and preparing the solution, you must adhere to safety rules when working with cytotoxic substances.

Overdose:

Since no specific antidote is known, extreme caution should be exercised when using it. Cyclophosphamide can be removed from the body by dialysis, so in case of overdose, rapid treatment is indicated. The dialysis clearance of 78 ml/min was calculated from the concentration of cyclophosphamide, which was not metabolized in dialysates (the normal renal clearance is
approximately 5-11 ml/min). Other sources reported a value of 194 ml/min. After 6 hours of 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, most often leukocytopenia, should be expected. 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; infections should be treated with appropriate antibiotics. If thrombocytopenia occurs, platelet replenishment should be ensured. In order to prevent urotoxic phenomena, it is necessary to take measures to prevent cystitis with the help of uromitexan.

Storage conditions:

Shelf life. 3 years. In original packaging at a temperature not exceeding 10 °C. Keep out of the reach of children.

Vacation conditions:

On prescription

Package:

200 mg per bottle, 40 bottles are placed in a box for group packaging.

Cyclophosphamide ® is used for mono- or polychemotherapy in the treatment of:

leukemias: acute or chronic lymphoblastic / lymphocytic and myeloid / myelogenous leukemias;
malignant lymphomas of Hodgkin's disease (lymphogranulomatosis), non-Hodgkin's lymphomas, plasmacytoma;
large malignant tumors with or without metastases: ovarian cancer, testicular cancer, breast cancer, small cell lung cancer, neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma in children, osteosarcoma;
progressive "autoimmune diseases" such as 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, Wegener's granulomatosis.

Cyclophosphamide ® is also used as a means of immunosuppression during organ transplantation and for conditioning before bone marrow transplantation in severe aplastic anemia, acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia.

Contraindications

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

Directions for use and doses

Infusion. The drug can only be prescribed by an experienced oncologist. The dosage should be selected individually for each patient.

The following dosage recommendations may be used for cyclophosphamide monotherapy. When co-prescribing other cytostatics of similar toxicity, it may be necessary to reduce the dose or increase pauses during 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/m2 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 with a high dose of 20 to 40 mg/kg body weight (equivalent to 800 to 1600 mg/m2 body surface area), or with an even higher dose (for example, in conditioning before bone marrow transplantation), at intervals of 21 to 28 days.

preparing the solution

Immediately before use, add 10 ml of 0.9% sodium chloride solution to the contents of one bottle with a dosage of 200 mg. The substance dissolves easily with vigorous shaking after adding the solvent. If the substance does not dissolve immediately and completely, it is recommended to let the bottle sit for a few minutes.

The solution is suitable for intravenous use, and it is best administered as an intravenous infusion. For short-term administration, Cyclophosphamide ® solution is added to Ringer's solution, 0.9% sodium chloride solution or glucose solution to a total volume of approximately 500 ml. The duration of the infusion is from 30 minutes to 2:00, depending on the volume.

Treatment cycles for intermittent therapy can 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 > 100,000 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.

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 regulating the dose according to the lowest 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 - in accordance with 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 frail patients

In general, 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.

Adverse reactions

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

Infections and infestations. Typically, severe bone marrow suppression can lead to agranulocytic fever and secondary infections such as pneumonia, progressing to sepsis (life-threatening infections), which in rare cases can be fatal.

From the immune system. Rarely, hypersensitivity reactions may occur, accompanied by rash, chills, fever, tachycardia, bronchospasm, shortness of breath, edema, flushing and decreased blood pressure. In rare cases, anaphylactoid reactions can progress to anaphylactic shock.

From the blood and lymphatic systems. 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 observed 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 may usually develop only after several cycles of treatment. The most severe suppression of bone marrow function should be expected in patients previously treated with chemotherapy and/or radiation therapy, as well as in patients with renal failure.

Simultaneous treatment with other substances that inhibit hematopoiesis requires dose adjustment. You should use the appropriate dose adjustment tables for the cytotoxicity of drugs based on the quantitative composition of the blood at the beginning of the treatment cycle and adjust the dosage according to the lowest levels of cytostatic substances.

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

From the digestive tract. Adverse reactions such as nausea and vomiting are very common and depend on the dose. 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 occur with less frequency. In isolated cases, hemorrhagic colitis and acute pancreatitis have been reported. Gastrointestinal bleeding has been reported in isolated cases. In cases 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, liver dysfunction has been reported (increased levels of serum transaminases, gamma-glutamyl transpeptidase, alkaline phosphatase, bilirubin).

Hepatic vein occlusive endophlebitis has been reported in approximately 15% to 50% of patients receiving high-dose cyclophosphamide in combination with busulfan or whole-body irradiation for allogeneic bone marrow transplantation. Conversely, this complication was observed in patients with aplastic anemia who received only high doses of Cyclophosphamide ® . The syndrome usually develops 1-3 weeks after transplantation and is characterized by sudden weight gain, hepatomegaly, ascites and hyperbilirubinemia and portal hypertension. Very rarely, hepatic encephalopathy may develop.

Known risk factors that contribute to the development of hepatic vein occlusive endophlebitis in a patient are the presence of impaired liver function, therapy with hepatotoxic drugs in combination with high-dose chemotherapy, and especially if an element of the conditioning therapy is the alkylating compound busulfan.

From the kidneys and urinary system. Once excreted in the urine, cyclophosphamide metabolites cause changes in the urinary system, namely the bladder. Hemorrhagic cystitis, microhematuria and macrohematuria are the most common dose-dependent complications during treatment with Cyclophosphamide ® and require discontinuation of therapy. Cystitis develops very often, at first they are sterile, but secondary infection can occur. Swelling of the bladder walls, bleeding from the cell layer, interstitial inflammation with fibrosis, and sometimes sclerosis of the bladder were also noted. Renal dysfunction (especially in cases with a history of renal impairment) is an uncommon 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 isolated cases, hemorrhagic cystitis with fatal outcome has been reported. Acute or chronic renal failure and toxic nephropathy may occur, especially in patients with a history of impaired renal function.

From the reproductive system. Through its ankylosing action, cyclophosphamide can rarely cause impairment of spermatogenesis (sometimes irreversible) and lead to azoospermia and/or persistent oligospermia. Rarely, ovulation disturbances have been reported. In isolated cases, amenorrhea and decreased levels of female sex hormones have been reported.

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

From the respiratory system. Bronchospasm, shortness of breath or cough, leads to hypoxia. Very rarely, obliterating endophlebitis of the lungs can develop, sometimes as a complication of pulmonary fibrosis. Toxic pulmonary edema, pulmonary hypertension, pulmonary embolism and pleural effusion have been very rarely reported. In some cases, pneumonitis and interstitial pneumonia may develop, progressing to chronic interstitial fibrosis, and respiratory distress syndrome and respiratory failure with 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. The risk of developing urinary tract cancer increases, 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 use of uromitexane. In rare cases, tumor collapse syndrome has been reported due to the rapid response of large, chemotherapy-sensitive tumors.

Skin and its derivatives/allergic reactions. Alopecia areata, which is a common side effect (can progress to complete baldness), is usually reversible. Cases of changes in skin pigmentation of the palms, nails and fingers, as well as soles have been reported; dermatitis, expressed by inflammation of the skin and mucous membranes. Erythrodysesthia syndrome (tingling sensation in the palms and soles, up to severe pain). Very rarely, general irritation and erythema of the irradiated area (radiation dermatitis) have been reported after radiation therapy and subsequent treatment with cyclophosphamide. In isolated cases - Stevens-Johnson syndrome and toxic epidermal necrolysis, fever, shock.

From the musculoskeletal system and connective tissue. Muscle weakness, rhabdomyolysis.

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

From the organs of vision. Deterioration of vision. Symptoms such as conjunctivitis and swelling of the eyelids have been very rarely reported as a result of a hypersensitivity reaction.

Vascular disorders. The underlying disease may cause certain very rare complications, such as thromboembolism and peripheral ischemia, disseminated intravascular coagulation, 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 the setting of hypersensitivity or neutropenia (associated with infection). Asthenic conditions and ailments are frequent complications in cancer patients. Very rarely, due to extravasation, reactions may occur at the injection site in the form of erythema, inflammation or phlebitis.

Overdose

Since no specific antidote is known for cyclophosphamide, extreme caution should be exercised when using it. Cyclophosphamide can be removed from the body by dialysis, so 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, most 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; infections should be treated with appropriate antibiotics. If thrombocytopenia occurs, platelet replenishment should be ensured. In order to prevent urotoxic phenomena, it is necessary to take measures to prevent cystitis with the help of uromitexan.

Use during pregnancy or breastfeeding

Cyclophosphamide ® is contraindicated during pregnancy. If there are vital indications for the use of Cyclophosphamide ® in the first 3 months of pregnancy, it is necessary to decide on termination of pregnancy.

In the future, if treatment cannot be postponed and the patient wishes to continue bearing the fetus, chemotherapy can be given only after informing the patient about the possible risk of teratogenic effects.

Since cyclophosphamide passes into breast milk, breastfeeding should be discontinued during treatment.

Children

Special Security Measures

When using Cyclophosphamide ® and preparing the solution, you must follow safety rules when working with cytotoxic substances.

Features of application

Use only as directed and under the supervision of a physician!

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

From the blood and lymphatic systems. Severe suppression of bone marrow function should be expected, especially in patients previously treated with chemotherapy and/or radiotherapy and in patients with impaired renal function. Therefore, constant hematological monitoring with regular counting of blood cells is indicated for all patients during treatment. Counting leukocytes and platelets and determining 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: during initial treatment - at intervals 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 50 000 / мкл.

In case of agranulocytic fever and/or leukopenia, antibiotics and/or antifungal drugs should be prescribed prophylactically.

Urinary residue should be regularly analyzed for red blood cell content.

From the immune system. Patients with weakened immune systems, such as those with diabetes, chronic renal failure or liver failure, also require special care.

In general, Cyclophosphamide ®, like other cytostatics, should be used with caution when treating debilitated and elderly patients, as well as after radiotherapy.

From 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 toxic effects of the drug. Regular bladder emptying is important.

If during treatment with Cyclophosphamide ® the appearance of cystitis with micro- or macrohematuria is observed, the drug should be discontinued until the condition normalizes.

Patients with kidney disease when treated with Cyclophosphamide ® require careful care.

Cardiac disorders. There is evidence of increased cardiotoxic effects of Cyclophosphamide ® in patients after prior radiotherapy to the cardiac region and/or concomitant treatment with anthracyclines or pentostatin. You should remember the need for regular checks of blood electrolyte composition, paying special attention to patients with a history of heart disease.

Gastrointestinal disorders. To reduce the frequency and severity of effects such as nausea and vomiting, it is necessary to prescribe antiemetic drugs for preventive purposes. Alcohol may increase these side effects, so patients receiving treatment with Cyclophosphamide should be advised to avoid drinking alcohol.

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

From the digestive system. The drug should be used to treat patients with impaired liver function only after careful evaluation in each individual case. Such patients require close care. Alcohol abuse may increase the risk of developing liver dysfunction.

Reproductive system disorders / Genetic disorders. Treatment with Cyclophosphamide ® may cause genetic abnormalities in men and women. Therefore, pregnancy should be avoided during treatment and for six months after its completion. During this time, sexually active men and women need to use effective methods of contraception.

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

General Disorders/Disorders at the Administration Site. Since the cytostatic effect of Cyclophosphamide ® occurs after its bioactivation, which occurs in the liver, the risk of tissue damage due to unintentional paravenous administration of the drug solution is negligible.

In patients with diabetes, it is necessary to regularly check their blood sugar levels in order to adjust antidiabetic therapy in a timely manner.

The ability to influence the reaction rate when driving vehicles or other mechanisms

Due to the possibility of side effects when prescribing Cyclophosphamide ® , the doctor should warn the patient about the need to be careful when driving or engaging in potentially hazardous activities that require increased attention.

Interaction with other drugs and other types of interactions

With simultaneous administration of allopurinol or hydrochlorothiazide, the hypoglycemic effect under the influence of sulfonylurease may be enhanced, as well as the suppression of bone marrow function.

Prior or concurrent treatment with phenobarbital, phenytoin, benzodiazepines or hydrochloride may result in microsomal induction of liver enzymes.

Fluoroquinolone antibiotics (such as ciprofloxacin) taken before treatment with cyclophosphamide (especially when conditioning before a bone marrow transplant) may reduce the effectiveness of the drug and thereby lead to relapse of the underlying disease.

Because cyclophosphamide is immunosuppressive, a decreased patient response to any vaccination should be expected; injection with activated vaccine may be accompanied by vaccine-induced infection.

If depolarizing agents that relax muscles (eg succinylcholine halides) are used simultaneously, prolonged apnea may result due to decreased pseudocholinesterase concentrations.

Concomitant use of chloramphenicol leads to an increase in the half-life of cyclophosphamide and a delay in metabolism.

Treatment with anthracyclines, pentostatin and trastuzumab may increase the potential cardiotoxicity of the drug. Intensification of the cardiotoxic effect can also occur after preliminary radiotherapy of the heart area.

Concomitant use of indomethacin should be done with extreme caution, as acute fluid retention was observed in one case.

Because grapefruit contains a compound that may reduce the effects of cyclophosphamide, patients should not eat grapefruits or drink grapefruit juice.

In animals with tumors, a decrease in antitumor activity was observed when consuming ethanol (alcohol) and concomitant treatment with low doses of oral cyclophosphamide.

Anecdotal reports suggest an increased risk of pulmonary toxicity (pneumonia, alveolar fibrosis) in patients treated with cytotoxic chemotherapy, including cyclophosphamide and G-CSF or GM-CSF.

Possible interaction with azathioprine, leading to liver necrosis, was observed in three patients after administration of cyclophosphamide, which was preceded by treatment with azathioprine.

It is known that azole antifungals (fluconazole, itraconazole) inhibit cytochrome P450 enzymes that are metabolized by cyclophosphamide. Higher exposure to toxic metabolites of cyclophosphamide has been reported among patients treated with itraconazole.

In patients receiving high doses of cyclophosphamide, lower clearance and prolonged half-life of cyclophosphamide may be observed less than 24 hours after treatment with high doses of busulfan. This may lead to an increased incidence of veno-occlusive disease and mucosal inflammation (mucocytes).

Serum concentrations of cyclosporine in patients receiving cyclophosphamide and cyclosporine in combination were lower than in patients receiving cyclosporine alone. This may lead to an increased incidence of graft-versus-host disease.

Administration of a high dose of cyclophosphamide and cytarabine on the same day (with a very short time interval) will increase cardiac toxicity, taking into account the cardiac toxicity of each active substance.

Pharmacokinetic interactions have been reported between ondansetron and cyclophosphamide (at high doses), resulting in decreased AUCs for cyclophosphamide.

Thiotepa has been reported to potently inhibit the bioactivation of cyclophosphamide in a high-dose chemotherapy regimen when thiotepa was administered one hour before cyclophosphamide. Determining the sequence and timing of these two components can be critical.

Pharmacological properties

Pharmacological. Cyclophosphamide is a cytostatic drug from the oxazaphosphorine group. Cyclophosphamide is inactive in vitro. Its activation occurs by microsomnic enzymes in the liver, where it is converted into 4-hydroxy-cyclophosphamide, which is in equilibrium with its tautomer, aldophosphamide. The cytotoxic effect of cyclophosphamide is based on the interaction between its alkylating metabolites and DNA. This alkylation leads to the breaking and cohesion of cross-links of DNA strands and DNA proteins. During the cell cycle, transport through the G2 phase slows down. The cytotoxic effect is not cell cycle phase specific, but it is cell cycle specific.

Mutual resistance cannot be ruled out, especially with cytostatics of a similar structure, such as ifosfamide, as well as with other alkylanthas.

Dosage form: Powder for preparing a solution for intravenous and intramuscular administration. Compound:

Composition for 1 bottle:

active substance: cyclophosphamide monohydrate (in terms of cyclophosphamide) - 200 mg; Excipients- No.

Description: White crystalline powder, odorless. Pharmacotherapeutic group:Antitumor agent, alkylating compound. ATX:

L.01.A.A.01 Cyclophosphamide

Pharmacodynamics:

An antitumor agent with an alkylating effect and also has an immunosuppressive effect. It is an inactive transport form that breaks down under the action of phosphatase to form 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 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 (detected in the blood within 72 hours). Bioavailability - 90%. Volume of distribution - 0.6 l/kg. Communication with plasma proteins is 12-14%, for some active metabolites - more than 60%.

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

Excreted by the kidneys in the form of metabolites - 60%, unchanged - 5-25 % and with bile. The drug can be removed by dialysis.

Indications:

Small cell lung cancer, ovarian cancer, breast cancer, cervical and uterine cancer, bladder cancer, prostate cancer, neuroblastoma, retinoblastoma, lymphogranulomatosis, lymphosarcoma, non-Hodgkin's lymphomas, reticulosarcoma, osteogenic sarcoma, multiple myeloma, chronic lymphocytic leukemia and myeloid leukemia, acute lymphoblastic, myeloblastic and monoblastic leukemia, Wilms tumor, Ewing's sarcoma, mycosis fungoides, testicular seminoma; autoimmune diseases: rheumatoid arthritis, psoriatic arthritis, systemic connective tissue diseases, autoimmune hemolytic anemia, nephrotic syndrome; suppression of transplant rejection reaction.

Contraindications:

Hypersensitivity to the drug, severe dysfunction of the bone marrow (anemia, leukopenia, thrombocytopenia), cystitis, urinary retention, active infections, pregnancy, lactation.

Carefully:

Decompensated diseases of the heart, liver and kidneys, adrenalectomy, gout (history), nephrourolithiasis, suppression of bone marrow function, infiltration of the bone marrow by tumor cells, previous chemotherapy or radiation therapy.

Pregnancy and lactation:

During pregnancy, the use of cyclophosphamide is contraindicated. If it is necessary to use the drug during lactation, breastfeeding should be stopped.

Directions for use and dosage:

Intravenously, intramuscularly. The dosage regimen is set individually depending on the stage of the disease and the state of the hematopoietic system.

Cyclophosphamide is part of many chemotherapy treatment regimens, and therefore, when choosing a specific route of administration, regimen and doses in each individual case, one should be guided by data from special literature.

Various treatment regimens are used:

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 once every 2 weeks;
1500-2000 mg/m2 1 time every 3-4 weeks up to a total dose of 6-14 g.

Injection solutions are prepared immediately before use.

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

Side effects:

From the hematopoietic organs: leukopenia, neutropenia, thrombocytopenia, anemia. The most pronounced leukopenia and thrombocytopenia are observed on days 7-14 of treatment (recovery of indicators occurs 7-10 days after cessation of treatment).

From the digestive system: nausea, vomiting, anorexia, stomatitis, discomfort or pain in the abdominal area, diarrhea or constipation, hemorrhagic colitis, jaundice, liver dysfunction, incl. increased activity of “liver” transaminases, alkaline phosphatase, hyperbilirubinemia; when using high doses of cyclophosphamide in combination with busulfan and total irradiation during allogeneic bone marrow transplantation, as well as when using high doses in patients with aplastic anemia, obliterating endophlebitis of the hepatic veins develops (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 completion of treatment or during long-term treatment, hair may differ in structure and color), skin rash, skin pigmentation, nail changes, impaired regeneration.

From the urinary system: hemorrhagic urethritis/cystitis, necrosis of the renal tubules (even death), fibrosis of the bladder (including common) with or without concomitant cystitis, atypical epithelial cells of the bladder in the urine. When used in high doses - impaired renal function, hyperuricemia, nephropathy (against the background of hyperuricemia).

From the cardiovascular system: cardiotoxicity (with the introduction of doses of 4.5-10 g/m2 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 death) due to hemorrhagic myocarditis.

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

Co aspects of the reproductive system: disturbance 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 the concentration of gonadotropins with normal testosterone secretion, in some cases reversible several years after treatment ), testicular atrophy (various degrees).

Allergic reactions: skin rash, urticaria, skin itching, rarely - anaphylactic reactions; Possible cross-sensitivity with other alkylating compounds.

Others: development of severe infections; a syndrome similar to the syndrome of inappropriate secretion of antidiuretic hormone; flushing of the face or facial hyperemia; headache; increased sweating; development of secondary malignant tumors.

Overdose:

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

Treatment: symptomatic therapy, prescription of antiemetics, if necessary, transfusion of blood components, administration of hematopoietic stimulants, broad-spectrum antibiotics, vitamin therapy (0.05 g intramuscularly).

Interaction:

With simultaneous use, cyclophosphamide may enhance the effect of hypoglycemic drugs.

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

Concomitant use of high doses of cytarabine in preparation for bone marrow transplantation leads to an increased incidence of cardiomyopathy with subsequent death.

When used simultaneously with indirect anticoagulants, a change in anticoagulant activity is possible (as a rule, cyclophosphamide reduces the synthesis of coagulation factors in the liver and disrupts the process of platelet formation).

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

Myelotoxic drugs, including radiation therapy, cause increased myelotoxic effects.

Grapefruit juice disrupts the activation and thereby the effect of cyclophosphamide.

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

Uricosuric drugs increase the risk of developing nephropathy (dose adjustment of uricosuric drugs may be required).

Concomitant use of cyclophosphamide with lovastatin increases the risk of acute skeletal muscle necrosis and acute renal failure.

Special instructions:

During the treatment period, 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 by tumor cells, previous radiation or chemotherapy, renal/liver failure.

Cyclophosphamide may increase anticoagulant activity as a result of decreased hepatic synthesis of coagulation factors and impaired platelet formation, as well as through an unknown mechanism.

During treatment, it is necessary to systematically monitor peripheral blood (during the main course - 2 times/week; during maintenance treatment - 1 time/week). When the number of leukocytes decreases to 2500/μl and platelets to 100,000/μl, treatment should be stopped.

During therapy, it is necessary to monitor the activity of liver transaminases and lactate dehydrogenase, bilirubin content, the concentration of uric acid in the blood plasma, diuresis, specific gravity of urine, and it is also necessary to conduct tests to detect microhematuria.

During treatment, it is necessary to regularly test urine for the presence of erythrocyturia, which may precede the development of hemorrhagic cystitis. If symptoms of cystitis with micro- or macrohematuria appear, treatment with the drug should be discontinued.

In order to prevent hemorrhagic cystitis, it is advisable to drink plenty of fluids and use the drug.

If infections occur during cyclophosphamide therapy, treatment should be interrupted or the dose of the drug should be reduced.

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

When prescribing cyclophosphamide during the first 10 days after surgery using general anesthesia, the anesthesiologist must be notified.

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

According to the electrocardiogram and echocardiogram, in patients who suffered episodes of cardiotoxic effects of high doses of cyclophosphamide, no residual effects on the condition of the myocardium were detected.

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

Sexual desire and potency in men are not impaired. 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 observed.

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

Impact on the ability to drive vehicles. Wed and fur.:

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

Release form/dosage:

Powder for the preparation of a solution for intravenous and intramuscular administration 200 mg.

Package:

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

1 bottle with instructions for use in a cardboard pack.

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

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

When packaging ampoules with a ring or break point, do not insert a scarifier or ampoule knife.

Storage conditions:

In a dry place, protected from light, at a temperature not exceeding 10 °C. Keep out of the reach of children.

Best before date:

Do not use after the expiration date stated on the packaging.

Conditions for dispensing from pharmacies: On prescription Registration number: LS-001048 Registration date: 19.01.2012 Owner of the Registration Certificate:Company DEKO, LLC Russia Manufacturer: Information update date: 12.10.2015 Illustrated instructions