Endoxan 500 mg powder for solution for injection vial No. 1

Instructions Endoxan 500 mg powder for solution for injection vial No. 1

Composition

active ingredient: cyclophosphamide;

1 bottle contains:

Dosage form

Powder for solution for injection.

Main physicochemical properties: white crystalline substance.

Pharmacotherapeutic group

Antineoplastic agents. Alkylating compounds. Nitrogen mustard analogues. Cyclophosphamide. ATX code L01A A01.

Pharmacological properties

Pharmacodynamics.

Cyclophosphamide is an antineoplastic agent of the oxazaphosphorine class. It is related to nitrogen mustard.

Cyclophosphamide is inactive in vitro. Its activation in vivo occurs mainly by microsomal enzymes in the liver, where it is converted to 4-hydroxycyclophosphamide, which is in equilibrium with its tautomer, aldophosphamide. These tautomers undergo partly spontaneous, partly enzymatic conversion to inactive and active metabolites (especially phosphoramide mustard and acrolein).

The cytotoxic effect of cyclophosphamide is based on the interaction between its alkylating metabolites and DNA. This alkylation leads to the disruption and cross-linking of DNA and DNA-protein cross-links. In the cell cycle, the G2 phase is delayed. The cytotoxic effect is not specific to the cell cycle phase, but specific to the entire cell cycle. Acrolein has no antineoplastic activity, but is responsible for the urotoxic side effect. In addition, the immunosuppressive effect of cyclophosphamide is discussed.

Cross-resistance cannot be excluded, especially with cytostatics of similar structure, such as ifosfamide, as well as with other alkylating agents.

Pharmacokinetics.

Blood levels after intravenous and oral administration are bioequivalent.

Absorption

Cyclophosphamide is almost completely absorbed from the gastrointestinal tract. In humans, after a single intravenous injection of radiolabeled cyclophosphamide, plasma concentrations of cyclophosphamide and its metabolites decline significantly within 24 hours, but detectable plasma levels persist for up to 72 hours.

Biotransformation

Cyclophosphamide is inactive in vitro. Bioactivation occurs only in the body.

In patients with impaired liver function, the biotransformation of cyclophosphamide is slowed. In this regard, in cases of pathologically reduced cholinesterase activity, a prolongation of the drug's serum half-life is observed.

Cyclophosphamide has been detected in cerebrospinal fluid and breast milk. Cyclophosphamide and its metabolites cross the placental barrier.

Breeding

The serum half-life of cyclophosphamide averages 7 hours in adults and 4 hours in children.

Cyclophosphamide itself is almost not protein bound, although its metabolites are approximately 50% bound to plasma proteins.

Cyclophosphamide and its metabolites are excreted primarily by the kidneys. Dosage adjustment is necessary in renal failure. A 50% dose reduction is generally recommended for glomerular filtration rates below 10 mL/min.

It is recommended to reduce the dose by 25% when the serum bilirubin level is 3.1-5 mg/100 ml.

Pharmacokinetic/pharmacodynamic relationship

After intravenous administration of high doses in allogeneic bone marrow transplantation, the plasma concentration of native cyclophosphamide exhibits linear first-order kinetics. An 8-fold increase in dose in one patient did not alter the pharmacokinetic parameters of native cyclophosphamide. Less than 15% of the administered dose is excreted unchanged in the urine. However, compared with conventional cyclophosphamide therapy, this results in an increase in inactive metabolites, indicating saturation of activating enzyme systems rather than metabolic pathways leading to their inactivation. During multi-day therapy at high doses, the area under the plasma concentration/time curve of the parent compound decreases, most likely due to autoinduction of the metabolic activity of microsomal enzymes.

Indication

ENDOXAN® is intended for use in chemotherapy of the following tumors in combination with other antineoplastic agents:

Remission induction and consolidation therapy for acute lymphoblastic leukemia;

induction of remission in Hodgkin's disease;

non-Hodgkin lymphomas (depending on the histological type and stage of the disease also as monotherapy);

chronic lymphocytic leukemia (CLL) after failure of standard therapy (chlorambucil/prednisone);

induction of remission in plasmacytoma (also in combination with prednisone);

adjuvant therapy of breast cancer after tumor resection or mastectomy;

palliative therapy for advanced breast cancer;

advanced ovarian cancer;

small cell lung cancer;

Ewing's sarcoma;

neuroblastoma;

rhabdomyosarcoma in children;

Preparation before allogeneic bone marrow transplantation in:

severe aplastic anemia - as monotherapy or in combination with antiplatelet globulin;

acute myeloid and acute lymphoblastic leukemia - in combination with whole body irradiation or busulfan;

chronic myeloid leukemia - in combination with whole body irradiation or busulfan.

Progressive autoimmune diseases: severe progressive forms of lupus nephritis and Wegener's granulomatosis.

Contraindication

ENDOXAN® is contraindicated in:

hypersensitivity to cyclophosphamide, its metabolites or to other components of the drug;

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

inflammation of the bladder (cystitis);

urinary tract obstruction;

active infections;

pregnancy or breastfeeding.

General contraindications for allogeneic bone marrow transplantation, such as the upper age limit of 50−60 years, contamination of the bone marrow with metastases of malignant (epithelial) tumors, as well as the lack of HLA identity with the planned donor in the case of chronic myeloid leukemia, which must be carefully clarified before starting preparatory therapy with the drug ENDOXAN®.

Special safety precautions

When using the drug ENDOXAN® and preparing the solution, it is necessary to follow the safety rules for working with cytotoxic substances.

Interaction with other medicinal products and other types of interactions

When planning concomitant or sequential use of other substances or therapies that increase the likelihood or severity of toxic effects (due to pharmacodynamic or pharmacokinetic interactions), the expected benefits and risks should be carefully assessed in each individual case.

Patients receiving combination therapy should be closely monitored for signs of toxicity so that timely intervention can be taken. Patients receiving cyclophosphamide and drugs that attenuate its activation should be closely monitored for possible decreased therapeutic efficacy and the need for dose adjustment. In general, patients should be monitored for increased/decreased therapeutic efficacy and/or increased frequency and severity of adverse reactions of the interacting agent. Dose adjustment may be necessary.

Interactions that negatively affect the pharmacokinetics of cyclophosphamide and its metabolites

Reduced activation of cyclophosphamide may reduce the effectiveness of cyclophosphamide therapy. Substances that slow the activation of cyclophosphamide and thus reduce the effectiveness of cyclophosphamide include:

aprepitant;

bupropion;

Busulfan: In addition to reduced cyclophosphamide activation, cyclophosphamide clearance was reduced and the half-life was prolonged in patients receiving high-dose cyclophosphamide less than 24 hours after high-dose busulfan.

Ciprofloxacin: In addition to reducing cyclophosphamide activation, ciprofloxacin has been reported to cause relapse of the underlying disease when administered prior to cyclophosphamide therapy (used to prepare for bone marrow transplantation).

chloramphenicol;

fluconazole;

itraconazole;

prasugrel;

sulfonamides;

Thiotepa: Significant inhibition of bioactivation by thiotepa was observed during high-dose chemotherapy when thiotepa was administered 1 hour before cyclophosphamide administration.

An increase in the concentration of cytotoxic metabolites, leading to an increase in the frequency and severity of side effects, is possible when using the following drugs:

allopurinol;

chloral hydrate;

cimetidine;

disulfiram;

glyceraldehyde;

Inducers of human hepatic and extrahepatic microsomal enzymes (e.g. cytochrome P450 enzymes): may increase the concentration of cytotoxic metabolites. The possibility of stimulation of hepatic and extrahepatic microsomal enzymes should be considered in case of prior or concomitant use of substances that can lead to an increase in the activity of these enzymes, such as rifampin, phenobarbital, carbamazepine, phenytoin, St. John's wort and corticosteroids;

Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Protease inhibitor-based regimens have been shown to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (the “CDE regimen”) compared with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens.

Ondansetron

A pharmacokinetic interaction has been reported between ondansetron and high doses of cyclophosphamide, resulting in a decrease in the AUC of cyclophosphamide.

Pharmacodynamic interactions and interactions with unknown mechanism that negatively affect the use of cyclophosphamide

Increased hemotoxicity and/or immunosuppression may occur in the case of combined action of cyclophosphamide and such drugs as:

Angiotensin-converting enzyme (ACE) inhibitors: ACE inhibitors can cause leukopenia;

natalizumab;

Paclitaxel: increased hemotoxicity has been observed with cyclophosphamide administration after paclitaxel infusion;

thiazide diuretics;

zidovudine.

Increased cardiotoxicity may occur due to the combined effects of cyclophosphamide and, for example, the following drugs:

anthracyclines;

cytarabine;

pentostatin;

radiotherapy of the heart area;

trastuzumab.

Increased pulmonary toxicity may occur with the combined effect of cyclophosphamide and, for example, the following drugs:

amiodarone;

GCSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor): An increased risk of pulmonary toxicity has been reported in patients receiving cytotoxic chemotherapy including cyclophosphamide and GCSF or GM-CSF.

Increased nephrotoxicity may occur as a result of the combined effect of cyclophosphamide and, for example, the following drugs:

amphotericin B;

Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin.

Enhancement of other toxic effects:

azathioprine: increased risk of hepatotoxicity (liver necrosis);

Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported;

Protease inhibitors: increased incidence of mucositis;

Allopurinol and hydrochlorothiazide: increased myelosuppressive effect.

Other interactions

Alcohol

Reduced antitumor activity has been observed in tumor-bearing animals when ethanol (alcohol) is consumed and concomitant oral administration of low doses of cyclophosphamide preparations.

Alcohol may increase cyclophosphamide-induced vomiting and nausea in some patients.

Etanercept

In patients with Wegener's granulomatosis, the addition of etanercept to standard therapy, including cyclophosphamide, was associated with a higher incidence of non-cutaneous solid malignancies.

Metronidazole

Acute encephalopathy has been reported in patients receiving cyclophosphamide and metronidazole. The causal relationship is unclear.

In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity.

Tamoxifen

Concomitant use of tamoxifen and chemotherapy increases the risk of thromboembolic complications.

Interactions affecting the pharmacokinetics and/or action of other drugs

Bupropion

Cyclophosphamide metabolism involving CYP2B6 may inhibit the metabolism of bupropion.

The activation of bupropion may be reduced, leading to reduced effectiveness.

Coumarin preparations

Both potentiation (increased risk of bleeding) and attenuation (decreased anticoagulant activity) of warfarin action have been observed in patients receiving warfarin with cyclophosphamide.

Cyclosporine

Decreased serum concentrations of cyclosporine have been observed in patients receiving the combination of cyclophosphamide and cyclosporine compared to patients receiving cyclosporine alone. This interaction leads to an increased incidence of graft-versus-host disease.

Depolarizing muscle relaxants

Cyclophosphamide treatment results in a marked and persistent inhibition of cholinesterase activity. This may prolong the neuromuscular blockade induced by succinylcholine. With concomitant use of depolarizing muscle relaxants (e.g. succinylcholine), prolonged apnea may occur. If the patient has received cyclophosphamide for 10 days, the anaesthetist should be informed before general anaesthesia.

Digoxin, β-acetyl digoxin

Cytotoxic therapy has been reported to impair the intestinal absorption of digoxin and β-acetyldigoxin in tablet form, resulting in reduced therapeutic efficacy of these drugs.

Vaccines

The immunosuppressive effects of cyclophosphamide may impair the body's response to vaccination. The use of live vaccines may lead to vaccine-induced infections.

Verapamil

The use of cytotoxic drugs has been reported to impair the intestinal absorption of oral verapamil, which may impair the therapeutic efficacy of verapamil.

Sulfonylurea

With simultaneous use, the glucose-lowering effect of sulfonylureas may be enhanced.

Application features

The risk factors for cyclophosphamide toxicity and its late effects, described below and in other sections, may be a contraindication to its use unless ENDOXAN® is used to treat a life-threatening condition. In such situations, an individual assessment of the risk and expected benefit should be made.

Caution should be exercised when treating patients with acute porphyria due to the porphyrogenic effects of cyclophosphamide.

Reservation

Anaphylactic reactions, cross-sensitivity with other alkylating agents

Cases of anaphylactic reactions, including fatal ones, have been reported with the use of cyclophosphamide.

The possibility of cross-sensitivity with other alkylating agents has been reported.

Myelosuppression, immunosuppression, infections

The use of cyclophosphamide can cause myelosuppression and significantly suppress the immune response.

Myelosuppression caused by cyclophosphamide can lead to leukopenia, neutropenia, thrombocytopenia (with an increased risk of bleeding), and anemia.

Severe immunosuppression has resulted in serious, sometimes fatal, infections. Cases of sepsis and septic shock have also been reported. Infections reported with cyclophosphamide include pneumonia, as well as other bacterial, fungal, viral, protozoal, and parasitic infections.

Reactivation of latent infections is possible. Reactivation of a variety of bacterial, fungal, viral, protozoal, and parasitic infections has been reported.

Infections should be treated appropriately.

In certain cases of neutropenia, antimicrobial prophylaxis may be prescribed at the discretion of the physician.

In case of neutropenic fever, antibiotics and/or antifungal agents should be used.

In general, the decline in peripheral blood cell counts and platelet counts may accelerate, and the time required for recovery may increase with increasing doses of cyclophosphamide.

The lowest white blood cell and platelet counts are usually noted within 1-2 weeks of treatment. The bone marrow recovers relatively quickly, and peripheral blood cell levels usually return to normal after about 20 days.

Severe myelosuppression should be expected especially in patients who have previously and/or concomitantly received chemotherapy and/or radiotherapy.

Hematological parameters of all patients should be carefully monitored during the treatment period.

Leukocyte counts should be determined before each administration and regularly during treatment [at intervals of 5 to 7 days at the beginning of treatment and every 2 days if the count falls below 3000 cells/μl (cells/mm3)]. In the case of long-term treatment, monitoring at intervals of approximately 14 days is generally sufficient.

Platelet count and hemoglobin should be determined before each administration of the drug and at appropriate intervals after administration.

Toxic effects on the kidneys and urinary system

Cases of hemorrhagic cystitis, pyelitis and urethritis, as well as hematuria, have been reported with cyclophosphamide. Ulceration/necrosis, as well as fibrosis/contractures and secondary bladder cancer may develop.

In case of urotoxicity, it may be necessary to interrupt therapy.

The need for cystectomy may arise in the case of fibrosis, bleeding, or the appearance of secondary malignancies.

Cases of urotoxicity with fatal outcomes have been reported.

Urotoxic effects are possible with both short-term and long-term use of cyclophosphamide. Hemorrhagic cystitis has been reported after single doses of cyclophosphamide.

Previous or concomitant radiotherapy or busulfan therapy increases the risk of cyclophosphamide-induced hemorrhagic cystitis.

In general, cystitis is initially abacterial. Secondary bacterial colonization is possible.

Any urinary tract obstruction should be ruled out or treated before initiating therapy (see Contraindications).

The urinary sediment should be checked regularly for the presence of red blood cells and other signs of uro-/nephrotoxicity.

Proper use of Mesna and/or the consumption of large amounts of fluid to increase diuresis can significantly reduce the frequency and severity of bladder toxicity. It is important that the patient urinates regularly.

Hematuria usually resolves within a few days after discontinuation of cyclophosphamide, but may be persistent. If cystitis with microscopic or macroscopic hematuria develops during treatment, treatment with the drug should be discontinued until the condition normalizes.

Cases of nephrotoxicity, including renal tubular necrosis, have also been reported with the use of cyclophosphamide.

Hyponatremia, accompanied by an increase in total body fluid, acute water intoxication, and a syndrome similar to the syndrome of inappropriate antidiuretic hormone secretion, has been reported with cyclophosphamide. Fatal cases have been reported.

Cardiotoxicity: Use in patients with heart disease

Myocarditis and myopericarditis have been reported with cyclophosphamide therapy, which may be accompanied by significant pericardial effusion and cardiac tamponade and lead to severe, sometimes fatal, congestive heart failure.

The results of histopathological examinations indicated, first of all, hemorrhagic myocarditis. Hemopericardium occurred against the background of hemorrhagic myocarditis and myocardial necrosis.

Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including marked QT prolongation with ventricular tachyarrhythmia) have been reported in patients with and without other evidence of cardiotoxicity following cyclophosphamide-containing regimens.

The risk of cardiac toxicity from cyclophosphamide may be increased, for example, when high doses are used, in elderly patients and in those who have previously received radiotherapy to the heart and/or previous or concomitant treatment with other cardiotoxic agents (see section 4.5).

Particular caution should be exercised in patients with risk factors for cardiotoxicity and in patients with pre-existing heart disease.

Pulmonary toxicity

Cases of pneumonitis and pulmonary fibrosis have been reported during and after cyclophosphamide therapy. Cases of pulmonary veno-occlusive disease and other forms of pulmonary toxicity have also been reported.

Cases of pulmonary toxicity leading to respiratory failure have been reported.

Although the incidence of cyclophosphamide-induced pulmonary toxicity is low, the prognosis for affected patients is poor.

Late-onset pneumonitis (more than 6 months after initiation of cyclophosphamide therapy) is associated with a very high mortality rate. Pneumonitis can develop even several years after cyclophosphamide treatment.

Acute pulmonary toxicity has been reported after a single dose of cyclophosphamide.

Secondary malignant neoplasms

As with any cytotoxic therapy, the use of cyclophosphamide is associated with the risk of long-term complications such as the formation of secondary tumors and their precursors.

There is an increased risk of urinary tract cancer, as well as myelodysplastic syndromes, some of which progress to acute leukemia. Other malignancies reported after cyclophosphamide use or regimens that include it include lymphomas, thyroid cancer, and sarcomas.

In some cases, secondary malignancies occur several years after discontinuation of cyclophosphamide therapy. Malignancies have also been reported following in utero exposure.

The risk of bladder cancer can be significantly reduced by preventing hemorrhagic cystitis.

Veno-occlusive liver disease

Cases of hepatic veno-occlusive disease (VOD) have been reported in patients receiving cyclophosphamide.

Cytoreductive therapy in preparation for bone marrow transplantation, which involves the use of cyclophosphamide in combination with total body irradiation, busulfan or other drugs, has been shown to be a significant risk factor for the development of VOCP (see section 4.5). Following cytoreductive therapy, the clinical syndrome usually develops 1–2 weeks after transplantation and is characterized by sudden weight gain, painful hepatomegaly, ascites and hyperbilirubinemia/jaundice.

However, cases of gradual development of VOCP have also been reported against the background of long-term use of low immunosuppressive doses of cyclophosphamide.

Complications of VOCP include hepatorenal syndrome and multiorgan failure. Fatal outcomes have been reported for VOCP associated with cyclophosphamide.

Risk factors that predispose a patient to developing VOCP on the background of high-dose cytoreductive therapy include:

already existing liver dysfunction;

previous radiotherapy to the abdominal cavity;

low general condition score.

Genotoxicity

Cyclophosphamide is genotoxic and mutagenic to somatic cells and male and female gametes. For this reason, women should avoid pregnancy and men should avoid fathering children during cyclophosphamide therapy.

Men should wait at least 6 months after stopping cyclophosphamide therapy before attempting to father a child.

Animal data suggest that the drug's effects on oocytes during follicular development may result in reduced implantation rates and viable pregnancies and an increased risk of malformations. This should be considered when planning conception or pregnancy after discontinuation of cyclophosphamide therapy. The exact duration of follicular development in humans is unknown, but may be longer than 12 months.

Sexually active women and men should use effective contraception during this period (see section “Use during pregnancy or breastfeeding”).

Impact on fertility

Cyclophosphamide inhibits oogenesis and spermatogenesis. It can cause sterility in both sexes.

The development of sterility depends on the dose of cyclophosphamide, the duration of therapy, and the state of gonadal function at the time of treatment.

In some patients, sterility caused by cyclophosphamide may be irreversible.

Women

Amenorrhea, temporary or permanent, associated with decreased estrogen secretion and increased gonadotropin secretion, develops in a significant proportion of women treated with cyclophosphamide.

In particular, in older women, amenorrhea may be permanent.

Girls treated with cyclophosphamide during the prepubertal period generally develop secondary sexual characteristics and regular menstruation.

Girls who were treated with cyclophosphamide during prepubertal period became pregnant in the future.

Girls who have retained ovarian function after treatment with cyclophosphamide are at increased risk of developing premature menopause (the cessation of menstruation before the age of 40).

Men

Men undergoing treatment with cyclophosphamide are advised to consult about sperm conservation before starting therapy.

Men treated with cyclophosphamide may develop oligospermia or azoospermia, which is usually associated with increased gonadotropin secretion in the presence of normal testosterone secretion.

Sexual potency and libido are usually not affected in these patients.

In boys treated with cyclophosphamide during the prepubertal period, secondary sexual characteristics may develop normally, but oligospermia or azoospermia may occur.

Some degree of testicular atrophy may develop.

Cyclophosphamide-induced azoospermia is reversible in some patients, although recovery may not occur for several years after completion of therapy.

Men who became temporarily sterile due to cyclophosphamide later fathered children.

Impaired wound healing

Cyclophosphamide may disrupt normal wound healing.

Safety measures

Alopecia

Cases of alopecia have been reported; its frequency may increase with increasing dose.

Alopecia can progress to baldness.

Hair may grow back after therapy is complete or even during the treatment period, but its texture or color may change.

Nausea and vomiting

Cyclophosphamide can cause nausea and vomiting.

Current guidelines for the use of antiemetics to prevent and relieve nausea and vomiting should be considered.

Drinking alcohol may increase vomiting and nausea caused by cyclophosphamide.

Stomatitis

Cyclophosphamide can cause stomatitis (inflammation of the mucous membrane of the mouth).

Modern guidelines for preventing and relieving stomatitis should be taken into account.

Paravenous administration

The cytostatic effect of cyclophosphamide is observed after its activation, which occurs mainly in the liver. Therefore, the risk of tissue damage from accidental paravenous administration is low.

In case of inadvertent paravenous administration of cyclophosphamide, the infusion should be stopped immediately, the extravascular cyclophosphamide solution should be aspirated through the already inserted needle, and other necessary measures should be taken.

Use in patients after adrenalectomy

Patients with adrenal insufficiency may require higher doses of corticoid replacement when stressed by toxicity from cytotoxic drugs, including cyclophosphamide.

For patients with impaired liver or kidney function, the dose of cyclophosphamide should be reduced (see section "Method of administration and dosage").

The use of cyclophosphamide in preparation for bone marrow transplantation should be carried out exclusively in hematology-oncology centers that have specialists with appropriate experience and equipment for performing allogeneic bone marrow transplantation.

Use in patients before allogeneic bone marrow transplantation

Indications for bone marrow transplantation with the use of ENDOXAN® for preparative therapy depend on a complex set of factors and are taken into account individually. Important factors in making a decision in favor of bone marrow transplantation include: stage of the disease, prognosis (risk group), nature and success of previous treatment regimens for the underlying disease, patient's age and general condition, as well as the availability of a suitable bone marrow donor.

Use during pregnancy or breastfeeding

Pregnancy

Cyclophosphamide treatment may damage genetic material in women. Therefore, cyclophosphamide should not be used during pregnancy.

If treatment is indicated during the first trimester of pregnancy to protect the patient's life, medical advice regarding the potential threat to the fetus and termination of pregnancy is mandatory.

After the first trimester of pregnancy, if treatment cannot be postponed and the patient wishes to continue carrying the fetus, chemotherapy should be carried out only after informing the patient about the risk of teratogenic effects, although insignificant. Women should not become pregnant during treatment with ENDOXAN® and for 6 months after its completion. If the patient becomes pregnant during treatment, genetic counseling should be sought.

Breast-feeding

Since cyclophosphamide passes into breast milk, women should discontinue breastfeeding during treatment.

Fertility

Sexually mature male and female patients must use contraception during treatment and for at least 6 months after its completion.

For mutagenic effects and possible effects on fertility, see section "Special warnings and precautions for use".

Ability to influence reaction speed when driving vehicles or other mechanisms

Due to the possible development of side effects such as nausea, vomiting and associated circulatory weakness, the decision as to whether patients treated with ENDOXAN® can drive or operate machinery should be made by the physician on an individual basis. This is especially true in situations where patients consume alcohol.

Method of administration and doses

The dosage should be selected for each patient individually.

The dosage recommendations below apply to both children and adults.

Remission induction and consolidation therapy in acute lymphocytic leukemia

Cyclophosphamide is used in children and adults depending on different risk groups within different polychemotherapy complexes. The typical dosage for the purpose of induction of remission and consolidation therapy in adults is 650 mg/m2 body surface area (BSA) of cyclophosphamide intravenously, for example in combination with cytarabine and mercaptopurine.

Chronic lymphocytic leukemia

600 mg/m2 PPT cyclophosphamide intravenously on day 6 in combination with vincristine and prednisone or 400 mg/m2 PPT cyclophosphamide intravenously on days 1 and 5, also in combination with vincristine and prednisone, repeated every 3 weeks.

Hodgkin's disease

650 mg/m2 PPT cyclophosphamide intravenously on days 1 and 8 in combination with vincristine, procarbazine, and prednisone (“COPP protocol”).

Non-Hodgkin lymphomas

Cyclophosphamide can be used in non-Hodgkin lymphomas (NHL) depending on the histological type and stage of the disease as monotherapy or in combination with other antineoplastic drugs. The following is the standard therapy for low-grade and intermediate/high-grade non-Hodgkin lymphomas:

Low-grade NHL: 600–900 mg/m2 of cyclophosphamide intravenously on day 1 as monotherapy or in combination with corticosteroids; repeat every 3–4 weeks;

Intermediate- or high-grade NHL: 750 mg/m2 IV cyclophosphamide on day 1 in combination with doxorubicin, vincristine, and prednisone (CHOP protocol); repeat every 3–4 weeks.

Plasmacytoma

1000 mg/m2 PPT cyclophosphamide intravenously on day 1 in combination with prednisone; repeat every 3 weeks.

An example of polychemotherapy, the effectiveness of which has been proven for the treatment of plasmacytoma, is the so-called “VBMCP protocol”, which is given below:

400 mg/m2 PPT cyclophosphamide intravenously on day 1 in combination with melphalan, carmustine, vincristine, and prednisone; repeat every 5 weeks.

Breast cancer

Cyclophosphamide should be used for adjuvant and palliative treatment of breast cancer in combination with other cytostatics. The following are two protocols that have been shown to be effective:

“CMF protocol”: 600 mg/m2 PPT cyclophosphamide intravenously on days 1 and 8 in combination with methotrexate and 5-fluorouracil; repeat every 3−4 weeks.

“CAF protocol”: 500 mg/m2 PPT cyclophosphamide intravenously on day 1 in combination with doxorubicin and 5-fluorouracil; repeat every 3−4 weeks.

Advanced ovarian cancer

750 mg/m2 IV cyclophosphamide on day 1 in combination with cisplatin; repeat every 3 weeks.

500-600 mg/m2 PPT cycle