home Diseases Antitumor drug cyclophosphamide and the effectiveness of its use. Cyclophosphamide: instructions for use

Antitumor drug cyclophosphamide and the effectiveness of its use. Cyclophosphamide: instructions for use

Cyclophosphamide is a drug from the group of alkylating compounds. Refers to antitumor drugs.

Composition and release form

The drug is produced in crystalline form white powder, used to prepare a solution for intravenous and intramuscular injections. Packaging is a bottle containing 200 mg of cyclophosphamide, the active component of the medication.

pharmachologic effect

According to the instructions, Cyclophosphamide is an alkylating cytostatic drug, according to chemical composition similar to nitrogen mustard analogues.

The essence of the drug's action is that it forms cross-links between strands of RNA and DNA, and also inhibits protein synthesis.

Indications for use

Chronic lymphocytic leukemia or acute lymphoblastic leukemia;

Non-Hodgkin's lymphomas;

Lymphogranulomatosis;

Ovarian and breast cancer;

Multiple myeloma;

Mycosis fungoides;

Retinoblastoma;

Neuroblastoma.

Cyclophosphamide is used in combination with other antitumor drugs to treat diseases such as:

Germ cell tumors;

Cancer Bladder, lung, prostate, cervix;

Soft tissue sarcoma, Ewing's sarcoma;

Reticulosarcoma;

Wilms tumor.

According to reviews, cyclophosphamide is also effective as an immunosuppressive agent used for the treatment of progressive autoimmune diseases (including psoriatic arthritis, rheumatoid arthritis, autoimmune hemolytic anemia, collagenosis, nephrotic syndrome). In addition, the drug is used as a means of suppressing transplant rejection.

Contraindications

According to the instructions for Cyclophosphamide, the drug is not recommended for use if:

Severe dysfunction bone marrow;

For hypersensitivity;

Urinary retention;

Active infections;

For cystitis.

In addition, the drug should not be prescribed to pregnant and breastfeeding women.

Reviews of Cyclophosphamide indicate that this drug should be prescribed with caution if the patient suffers from:

Nephrourolithiasis;

Severe diseases of the liver, kidneys and heart;

History of gout;

Infiltration of tumor cells in the bone marrow;

Suppression of bone marrow functions;

Adrenalectomy.

Directions for use and dosage

The instructions for Cyclophosphamide recommend using the drug intravenously or intramuscularly. Cyclophosphamide is an integral component of many regimens used to treat oncological diseases. The route of administration and dosage of the drug depend on the patient’s tolerability of the drug and the specific indications.

Typically, the following dosages of Cyclophosphamide are prescribed for adults and children:

From 50 milligrams to 100 per m 2 daily for two or three weeks;

From 100 milligrams to 200 per m 2 two or three times a week for three to four weeks;

From 600 milligrams to 750 per m 2 once every two weeks;

From 1500 milligrams to 2000 per m 2 times a month until a total dose of 6 to 14 grams is achieved.

When cyclophosphamide is combined with other antitumor medications, it is possible to reduce the dosage of both cyclophosphamide and other drugs.

Side effects of Cyclophosphamide

According to reviews, Cyclophosphamide can cause a number of side effects:

From the outside hematopoietic system: neutropenia, thrombocytopenia, anemia, leukopenia. During the period from 7 to 14 days of treatment, a slight decrease in the number of leukocytes and platelets is possible;

From the outside skin– alopecia (baldness). New hair begins to grow after the drug is finished. In addition, during the treatment period, pigmentation and rash may appear on the skin, and nail changes may occur;

From the outside digestive system: anorexia, nausea, vomiting, pain and discomfort in the abdominal area, diarrhea or constipation, stomatitis. In addition, there are reviews of Cyclophosphamide, which note the occurrence of hemorrhagic colitis and jaundice;

From the outside reproductive system: violation of oogenesis and spermatogenesis, sterility (in some cases irreversible). Many women suffer from amenorrhea. After completion of therapy, regular menstrual cycle usually recovers. In men, taking the drug can cause azoospermia or oligospermia, testicular atrophy of varying degrees;

From the outside respiratory system: pulmonary interstitial fibrosis;

From the urinary system: necrosis develops renal tubules(sometimes causing the death of the patient), fibrosis of the bladder, hemorrhagic urethritis or cystitis. Bladder epithelial cells may be present in the urine. According to reviews of Cyclophosphamide in in rare cases use of the drug in high dosages can provoke nephropathy, hyperuricemia and renal dysfunction;

From the blood vessels and heart: introduction long time high doses of cyclophosphamide may cause cardiotoxicity. There is information about the occurrence of complex, sometimes fatal, cases of heart failure resulting from hemorrhagic myocarditis.

In addition, the use of Cyclophosphamide is sometimes accompanied by: manifestations of allergies, including urticaria, itching and skin rash, as well as anaphylactic reactions. Possible side effects in the form of: facial hyperemia, flushing of the facial skin, headache, development of secondary malignant tumors, increased sweating.

special instructions

While using Cyclophosphamide, regular monitoring of the level of neutrophils and platelets in the blood is required, as well as a urine test to determine the number of red blood cells.

According to the instructions for Cyclophosphamide, treatment is stopped if:

Signs of cystitis with micro- or macrohematuria appear;

The platelet level decreases to 100,000/µl or more;

The level of leukocytes decreases to 2500/μl or more;

Severe infections occur.

During the period of use of the drug, drinking alcoholic beverages is prohibited. Reliable methods of contraception are required throughout the entire therapeutic course.

Storage conditions and periods

Store Cyclophosphamide at a temperature not exceeding 10 degrees Celsius. The drug does not lose its properties for three years.

Instructions for use:

Cyclophosphamide is an alkylating compound. Antitumor drug.

Composition and release form of Cyclophosphamide

The drug is produced in the form of a white crystalline powder for the preparation of a solution for intramuscular and intravenous administration. Each bottle contains the active ingredient - 200 mg of cyclophosphamide.

pharmachologic effect

According to the instructions, Cyclophosphamide is an alkylating agent. cytostatic drug, in its chemical composition similar to the nitrogen analogues of mustard gas.

The mechanism of action of the drug is the formation of cross-links between RNA and DNA strands, as well as inhibition of protein synthesis.

Indications for use of Cyclophosphamide

According to the instructions, Cyclophosphamide is indicated in the following cases:

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

Cyclophosphamide is used in combination with other antitumor drugs medicines for treatment:

germ cell tumors;
cancer of the lung, bladder, cervix, prostate;
soft tissue sarcomas, Ewing's sarcomas;
reticulosarcoma;
Wilms tumors.

In addition, Cyclophosphamide is reviewed as effective as an immunosuppressive agent for progressive autoimmune diseases ( psoriatic arthritis, rheumatoid arthritis, autoimmune hemolytic anemia, collagenosis, nephrotic syndrome), as well as to suppress transplant rejection.

Contraindications

The instructions for Cyclophosphamide indicate the following contraindications:

According to reviews, Cyclophosphamide should be prescribed with caution when:

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

Method of use of Cyclophosphamide and dosage regimen

According to the instructions, Cyclophosphamide is used intramuscularly or intravenously. Cyclophosphamide is constituent components many treatment regimens for cancer. Dosage and route of administration depend on the specific indications and patient tolerance.

Average dosages of Cyclophosphamide for children and adults:

from 50 to 100 mg per m2 every day for two to three weeks;
100 to 200 mg per m2 twice or thrice a week for three or four weeks;
from 600 to 750 mg per m2 once every two weeks;
1500 to 2000 mg per m2 once a month for a total dose of 6-14 g.

In the case of a combination of Cyclophosphamide with other anticancer drugs, it may be necessary to reduce the dosage of not only cyclophosphamide, but also other drugs.

Side effects of Cyclophosphamide

According to reviews, Cyclophosphamide causes the following side effects:

Digestive system: anorexia, vomiting, nausea, discomfort and pain in the abdominal area, stomatitis, constipation or diarrhea. There have been isolated reviews of Cyclophosphamide indicating the occurrence of jaundice and hemorrhagic colitis.
Hematopoietic system: neutropenia, anemia, thrombocytopenia, leukopenia. On days 7-14 of treatment, a slight decrease in the number of platelets and leukocytes may be observed.
Skin: alopecia. Hair grows back after you stop taking the drug. In addition, during treatment, a rash may appear on the skin, skin pigmentation and changes in nails.
Cardiovascular system: Cardiotoxicity may occur when high doses of Cyclophosphamide are administered over a long period of time. In addition, complex, sometimes with fatal, cases of heart failure due to hemorrhagic myocarditis.
Urinary system: necrosis of the renal tubules (up to the death of the patient), hemorrhagic cystitis or urethritis, fibrosis of the bladder. Bladder epithelial cells may be observed in the urine. According to rare reviews, cyclophosphamide in high dosages can lead to nephropathy, hyperuricemia and impaired renal function.
Respiratory system: interstitial pulmonary fibrosis.
Reproductive system: impaired spermatogenesis and oogenesis, sterility (in some cases irreversible). Many women develop amenorrhea. After cessation of treatment, regular menstruation is usually restored. Taking the drug by men can lead to azoospermia or oligospermia, testicular atrophy of varying degrees.
Allergies: urticaria, skin rash and itching, anaphylactic reactions.
Other side effects: flushing of the facial skin, facial hyperemia, development of secondary malignant tumors, excessive sweating, headache.

special instructions

During the period of use of Cyclophosphamide, it is necessary to regularly monitor the level of platelets and neutrophils in the blood and take a urine test for the number of red blood cells.

It is necessary to stop treatment with Cyclophosphamide according to the instructions in the following cases:

when signs of cystitis with macro- or microhematuria appear;
when the platelet level decreases to 100,000/μl or more;
when the level of leukocytes decreases to 2500/μl or more;
in the event of severe infections.

It is prohibited to drink alcohol while using the drug. For the entire period of treatment, it is necessary to use reliable methods of contraception.

Storage conditions

Cyclophosphamide is stored at a temperature not exceeding 10 degrees Celsius. Shelf life – 36 months.

Compound

Each bottle contains: active substance: cyclophosphamide - 200 mg.

Description

white or almost white crystalline powder.

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pharmachologic effect

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

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;

Progressively " autoimmune diseases": rheumatoid arthritis, psoriatic arthropathy, systemic lupus erythematosus, scleroderma, systemic vasculitis(for example, 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 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.

Directions for use and doses

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

Cyclophosphamide is administered intravenously as a bolus or as an infusion, intramuscularly. Cyclophosphamide is included in many chemotherapy treatment regimens, and therefore, when choosing a specific route of administration, regimen and dose in each in In individual cases, one should be guided by data from specialized literature.

The dosage should be selected individually for each patient.

The following recommendations according to the dosage, it can be used for monotherapy with cyclophosphamide. 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 high dose- from 20 to 40 mg/kg body weight (equivalent to 800 to 1600 mg/m2 body surface area), or with more higher dose(for example, 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 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, 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, general condition patient health, laboratory parameters and quantity recovery shaped elements blood.

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 of Leukocytes<2500 мкл, а тромбоцитов <50000 мкл - подбор дозы до нормализации

indicators or making a separate decision.

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. Recommendations for dose selection in patients with liver failure 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. ,

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 using dialysis. 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 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.

Side effect

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, 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 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 is restored relatively quickly, and the blood picture is normalized, 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 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 seizures 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, liver dysfunction has been reported (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 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, 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, 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, leading 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 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 - 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 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, and 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 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. 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, you should

take infection prevention measures, 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. Contraindications

Known hypersensitivity to cyclophosphamide;

Severe bone marrow dysfunction (especially in patients who have previously been treated with cytotoxic drugs and/or radiotherapy);

Inflammation of the bladder (cystitis);

Urinary retention;

Active infections.

Interaction with other drugs

require dose adjustment of uricosuric JTCs). 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.

Features of application

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

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. 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 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

should not be prescribed to patients with a white blood cell count less than 2500/μl and/or a platelet count less than 50,000/μl. 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 a weakened immune system, such as those with diabetes, chronic kidney disease or liver disease

insufficiency 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 gross hematuria 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 an 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. the need for sperm conservation should be advised prior to treatment.

General disorders/Disorders at the injection 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.

Precautionary measures

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; 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.

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.

Storage conditions

In a place protected from light at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Instructions for medical use of the drug

Description of pharmacological action

Indications for use

Ovarian cancer, breast cancer, lung cancer, lymphogranulomatosis, non-Hodgkin lymphoma, lymphosarcoma, reticulosarcoma, osteogenic sarcoma, multiple myeloma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, Wilms tumor, Ewing sarcoma, testicular seminoma. Prevention of transplant rejection. Rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome (as an immunosuppressant).

Release form

powder substance; dark glass jar (jar) 0.5 kg plastic bag (sachet) 1;

Powder substance; dark glass jar (jar) 1 kg plastic bag (bag) 1;

Pharmacodynamics

Antitumor agent with alkylating action. It has a cytostatic and immunosuppressive effect. The antitumor effect is realized directly in tumor cells, where cyclophosphamide is biotransformed under the action of phosphatases to form an active metabolite with an alkylating effect.

Pharmacokinetics

After a single intravenous administration, the concentration of cyclophosphamide and its metabolites in plasma decreases rapidly in the first 24 hours, but can be determined within 72 hours. When administered orally, the concentrations of cyclophosphamide and its metabolites are almost the same as with intravenous administration.
T1/2 from plasma after intravenous administration averages 7 hours in adults and about 4 hours in children. Excreted in urine and bile.

Use during pregnancy

Contraindicated during pregnancy.

Breastfeeding should be stopped during treatment.

Contraindications for use

Hypersensitivity, severe renal dysfunction, bone marrow hypoplasia, leukopenia (leukocyte count less than 3.5 109/l) and/or thrombocytopenia (platelet count less than 120 109/l), severe anemia, severe cachexia, end-stage cancer, pregnancy, breastfeeding.

Side effects

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

From the nervous system and sensory organs: asthenia, dizziness, headache, confusion, blurred vision.

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

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

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

From the skin: alopecia, hyperpigmentation (fingernails, palms), intravenous hemorrhage, facial redness, rash, urticaria, itching, hyperemia, swelling, pain at the injection site.

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

Directions for use and doses

They are set individually, depending on the indications and stage of the disease, the state of the hematopoietic system, and the antitumor therapy regimen.

Interactions with other drugs

With simultaneous use, cyclophosphamide may enhance the effect of hypoglycemic drugs.
Concomitant use with allopurinol may lead to increased myelotoxicity.
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).
When combined with cytarabine, daunorubicin or doxorubicin, the cardiotoxic effect may be enhanced.
When combined with immunosuppressants, the risk of infections and secondary tumors increases.
With simultaneous use of cyclophosphamide with lovastatin, the risk of developing acute necrosis of skeletal muscles and acute renal failure increases.
Medicines that are inducers of microsomal enzymes cause increased formation of active metabolites of cyclophosphamide, which leads to increased action.

Precautions for use

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

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

During the entire course of treatment, it is recommended to receive blood transfusions (100–125 ml once a week). In order to prevent hyperuricemia and nephropathy caused by increased formation of uric acid (often occurring during the initial period of treatment), before therapy with cyclophosphamide and within 72 hours after its use, adequate fluid intake (up to 3 liters per day) and the administration of allopurinol (in some cases) are recommended. ) and the use of urine alkalinizers. To prevent hemorrhagic cystitis (which can develop within a few hours or several weeks after administration), it should be taken in the morning (the bulk of the metabolites are eliminated before bed), empty the bladder as often as possible and use Uromitexan. When the first signs of hemorrhagic cystitis appear, treatment is stopped until the symptoms of the disease are eliminated.

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

The occurrence of thrombocytopenia necessitates extreme caution when performing invasive procedures and dental interventions, regular inspection of intravenous injection sites, skin and mucous membranes (to identify signs of bleeding), limiting the frequency of venipuncture and avoiding intramuscular injections, monitoring blood levels in the urine, vomit, feces. Such patients need to be careful when shaving, getting a manicure, brushing their teeth, using dental floss and toothpicks, preventing constipation, avoiding falls and other injuries, as well as taking alcohol and acetylsalicylic acid, which increase the risk of gastrointestinal bleeding. The vaccination schedule should be delayed (carried out 3–12 months after completion of the last course of chemotherapy) for the patient and family members living with him (immunization with oral polio vaccine should be abandoned). It is recommended to exclude contact with infectious patients or use nonspecific measures to prevent infections (protective mask, etc.). During treatment, adequate contraception should be used. In case of contact of the drug with skin or mucous membranes, thoroughly rinse with water (mucous membranes) or water and soap (skin). Dissolution, dilution and administration of the drug is carried out by trained medical personnel in compliance with protective measures (gloves, masks, clothing, etc.).

Special instructions for use

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

Storage conditions

List A.: In a dry place, protected from light, at a temperature not exceeding 10 °C.

Best before date

ATX classification:

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

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. injection solution 200 mg: fl. 1 or 40 pcs.
Reg. No.: 13/07/608 dated 07/25/2013 - Valid

Powder for solution for injection white or almost white, crystalline.

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

Description medicinal product 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.

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.

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.

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).

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.

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).

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.

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.