Endoxan sugar-coated tablets 50 mg blister No. 50

Instructions Endoxan sugar-coated tablets 50 mg blister No. 50

Composition

active ingredient: cyclophosphamide;

1 sugar-coated tablet contains: cyclophosphamide monohydrate 53.50 mg equivalent to cyclophosphamide anhydrous 50 mg;

excipients:

core: corn starch; lactose, monohydrate; calcium hydrogen phosphate, dihydrate; talc; magnesium stearate; gelatin; glycerol (85%);

sugar shell: sucrose, talc, titanium dioxide (E 171), calcium carbonate, polyethylene glycols 35000, colloidal anhydrous silica, povidone 25, sodium carboxymethylcellulose, polysorbates 20, montan glycol wax.

Dosage form

Sugar-coated tablets.

Main physicochemical properties: white, round, biconvex tablets, coated with a sugar shell, with a white core.

Pharmacotherapeutic group

Antineoplastic agents. Alkylating compounds. Nitrogen mustard analogues. Cyclophosphamide.

ATX code L01A A01.

Pharmacological properties

Pharmacodynamics.

Cyclophosphamide is a cytostatic agent from the group of oxazaphosphorines, chemically related to nitrogen mustard. Cyclophosphamide is inactive in vitro and is activated in vivo mainly by microsomal enzymes in the liver 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 breaking of DNA strand bonds and DNA-protein cross-linking. In the cell cycle, the G2 phase is delayed. The cytotoxic effect of the drug is not specific to the phase of the cell cycle, but specific to the entire cycle. Acrolein has no antineoplastic activity, but is responsible for the urotoxic side effect. In addition, an immunosuppressive effect of cyclophosphamide is assumed. Cross-resistance cannot be ruled out, especially with structurally related cytostatics such as ifosfamide and other alkylating agents.

Pharmacokinetics.

Blood levels of cyclophosphamide after intravenous administration and oral administration are bioequivalent.

Absorption

Cyclophosphamide is almost completely absorbed from the gastrointestinal tract. In humans, plasma concentrations of cyclophosphamide and its metabolites declined significantly 24 hours after a single intravenous dose of labeled cyclophosphamide, but detectable levels persisted in plasma for up to 72 hours.

Biotransformation

In vitro, cyclophosphamide is inactive. Biotransformation occurs only in the body. In patients with reduced liver function, the biotransformation of cyclophosphamide is slowed down. With pathologically altered cholinesterase activity, this leads to an increase in the serum half-life.

Cyclophosphamide can be detected in cerebrospinal fluid and breast milk. Cyclophosphamide and its metabolites cross the placental barrier.

Breeding

The mean serum half-life of cyclophosphamide is 7 hours for adults and approximately 4 hours for 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 insufficiency. 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.

Pharmacokinetics/pharmacodynamics relationship

After intravenous administration of high doses in allogeneic bone marrow transplantation, the plasma concentration of native cyclophosphamide follows linear 1st order kinetics. Intraindividual dose escalation by 8 times does not change 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 leads to an increase in inactive metabolites, which indicates saturation of activating enzyme systems, rather than metabolic pathways leading to their inactivation. During multi-day therapy with high-dose cyclophosphamide, the area under the plasma concentration-time curve of the parent substance decreases, most likely due to autoinduction of microsomal metabolic activity.

Indication

Endoxan® is used as part of a combination chemotherapy regimen with other antineoplastic drugs to treat the following types of tumors:

adjuvant therapy for breast cancer after tumor resection or mastectomy;

palliative therapy for metastatic breast cancer;

autoimmune diseases with life-threatening progression, namely severe progressive forms of lupus nephritis and Wegener's granulomatosis.

Treatment of lupus nephritis and Wegener's granulomatosis with Endoxan® should be carried out exclusively under the supervision of physicians who have experience in the treatment of these diseases and the use of Endoxan®.

Contraindication

known hypersensitivity to cyclophosphamide, its metabolites or to any of the excipients;

severe bone marrow dysfunction (myelosuppression, especially in patients who have previously received treatment with cytotoxic agents and/or radiotherapy);

inflammation of the bladder (cystitis);

urinary outflow disorders;

active infections.

Interaction with other medicinal products and other types of interactions

The planned simultaneous or sequential administration of other substances or drugs that may increase the likelihood or severity of serious toxic effects (via pharmacodynamic or pharmacokinetic interactions) requires a careful individual approach and assessment of the expected benefits and risks. Patients receiving such combination therapy should be closely monitored for signs of toxicity in order to timely implement the necessary intervention. Patients treated with cyclophosphamide and compounds that reduce its activation should be monitored for potential reduction in 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 side effects of the interacting substance. Dose adjustment may be necessary.

Interactions that negatively affect the pharmacokinetics of cyclophosphamide and its metabolites

Reducing the activation of cyclophosphamide may affect the effectiveness of cyclophosphamide treatment. Agents that delay the activation of cyclophosphamide and thus reduce the effectiveness of cyclophosphamide include:

aprepitant;

bupropion;

Busulfan: In addition to reduced cyclophosphamide activation, reduced cyclophosphamide clearance and prolonged half-life have been reported in patients receiving high doses of cyclophosphamide less than 24 hours after high doses of busulfan.

Ciprofloxacin: In addition to reduced cyclophosphamide activation, relapse of the underlying disease has been reported when ciprofloxacin was used prior to cyclophosphamide treatment (used as part of conditioning therapy prior to bone marrow transplantation);

chloramphenicol;

fluconazole;

itraconazole;

prasugrel;

sulfonamides;

Thiotepa: Marked inhibition of cyclophosphamide bioactivation by thiotepa has been reported in high-dose chemotherapy regimens when thiotepa is administered 1 hour before cyclophosphamide.

An increase in the concentration of cytotoxic metabolites, leading to an increase in the frequency and severity of side effects, may occur when used with

allopurinol;

chloral hydrate;

cimetidine;

disulfiram;

glyceraldehyde;

inducers of human microsomal hepatic and extrahepatic enzymes (e.g. cytochrome P450 enzymes) as they may increase the concentration of cytotoxic metabolites. The potential for induction of microsomal hepatic and extrahepatic enzymes should be considered in the event of prior or concomitant use with substances known to induce increased 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 associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than in combination with non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Ondansetron: There have been reports of a pharmacokinetic interaction 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

Combined or sequential use of cyclophosphamide and other substances with similar toxic effects may cause combined (enhanced) toxic effects.

Increased hemotoxicity and/or immunosuppression may result from the combined effects of cyclophosphamide and, for example:

ACE inhibitors: ACE inhibitors can cause leukopenia;

natalizumab;

Paclitaxel: Increased hemotoxicity has been reported with cyclophosphamide administration following paclitaxel infusions.

thiazide diuretics;

zidovudine.

Increased cardiotoxicity may develop as a result of the combined effects of cyclophosphamide and, for example:

anthracyclines;

cytarabine;

pentostatin;

radiation therapy in the heart area;

trastuzumab.

Increased respiratory toxicity may occur as a result of the combined effects of cyclophosphamide and, for example:

amiodarone;

G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor): There has been an increased risk of respiratory toxicity in patients receiving cytotoxic chemotherapy including cyclophosphamide and G-CSF or GM-CSF.

Increased nephrotoxicity may develop as a result of the combined effects of cyclophosphamide and, for example:

Indomethacin: Acute water intoxication has developed with concomitant use with indomethacin.

Increase in other toxic manifestations:

azathioprine: increased risk of hepatotoxicity (liver necrosis);

Busulfan: increased incidence of hepatic veno-occlusive disease and mucositis is known;

Protease inhibitors: increased incidence of mucositis;

Allopurinol and hydrochlorothiazide: myelosuppressive effect may be enhanced.

Other types of interaction

Alcohol: Reduced antitumor activity was observed when alcohol was administered concomitantly with low oral doses of cyclophosphamide in tumor-bearing animals.

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

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

Metronidazole: Cases of acute encephalopathy have been reported in patients receiving cyclophosphamide and metronidazole. The causal relationship remains unclear. In animal studies, the combination of cyclophosphamide and metronidazole was associated with increased cyclophosphamide toxicity.

Tamoxifen. Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

Interactions affecting the pharmacokinetics and/or action of other drugs

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

Bupropion: Metabolism of cyclophosphamide by cytochrome CYP2B6 may interfere with the metabolism of bupropion. Activation of bupropion may be reduced, resulting in reduced efficacy.

Coumarins: Both augmentation (increased risk of bleeding) and attenuation (decreased anticoagulant activity) of the effect of warfarin have been reported in patients receiving warfarin and cyclophosphamide together.

Cyclosporine: Patients receiving the combination of cyclophosphamide and cyclosporine have been shown to have lower serum concentrations of cyclosporine than patients receiving cyclosporine alone. This interaction may lead to an increased incidence of graft-versus-host disease.

Depolarizing muscle relaxants. Cyclophosphamide treatment causes a pronounced and persistent inhibition of cholinesterase activity. This may prolong the neuromuscular blockade induced by succinylcholine. Prolonged apnea may occur with concomitant use of depolarizing muscle relaxants (e.g. succinylcholine). If the patient has been treated with cyclophosphamide within 10 days prior to planned general anesthesia, the anaesthetist should be aware of this.

Vaccines: Due to the immunosuppressive effect of cyclophosphamide, a reduced response to any vaccination may be expected. Administration of live vaccines may result in vaccine-induced infection.

Sulfonylurea: Concomitant use may enhance the glucose-lowering effect of sulfonylurea.

Verapamil: Cytotoxic treatment has been reported to affect the intestinal absorption of oral verapamil, which may impair the therapeutic efficacy of verapamil.

Application features

The risk factors for cyclophosphamide toxicity and their consequences, described below and in other sections, may constitute a contraindication to its use unless cyclophosphamide is used to treat life-threatening conditions. In such situations, an individual assessment of the risks and expected benefits should be made.

As with all anticancer agents, Endoxan® should be used with caution in frail and elderly patients, as well as in patients who have previously undergone radiotherapy. Patients with a weakened immune system, diabetes mellitus, chronic liver or kidney disease, and pre-existing heart disease should also be carefully monitored. In diabetic patients, glucose metabolism should also be carefully monitored during cyclophosphamide therapy.

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

Reservation

Myelosuppression (suppression of bone marrow function), immunosuppression, infections

Cyclophosphamide treatment can cause myelosuppression and significant suppression of immune responses.

Cyclophosphamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (which is associated with a higher risk of bleeding episodes), 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 therapy have included pneumonia, as well as other bacterial, fungal, viral, protozoal, and parasitic infections.

Reactivation of latent infections is possible. Reactivation of various 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 treating physician.

Cyclophosphamide should be used with caution, if at all, in patients with severe bone marrow dysfunction and in patients with severe immunosuppression.

Cyclophosphamide should not be given unnecessarily to patients with a white blood cell count below 2,500 cells/microliter (cells/mm3) and/or a platelet count below 50,000 cells/microliter (cells/mm3).

Cyclophosphamide treatment should not be given or should be interrupted or the dose reduced in patients who have or develop a serious infection.

In general, increasing the dose of cyclophosphamide may cause the number of peripheral blood cells and platelets to decrease even more rapidly, and the time required for their recovery may increase.

The lowest levels of white blood cells and platelets are usually reached in the 1st and 2nd weeks of treatment. The bone marrow recovers relatively quickly, and peripheral blood cell counts usually return to normal after about 20 days.

Severe bone marrow suppression should be expected, particularly in patients who have previously been treated and/or are currently receiving concomitant chemotherapy and/or radiotherapy.

Careful monitoring of hematological parameters is required for all patients during treatment.

The leukocyte count must be determined before each administration of the drug 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 urinary tract and kidneys

Hemorrhagic cystitis, pyelitis, urethritis, and hematuria have been reported during cyclophosphamide treatment. Ulceration/necrosis, fibrosis/contractures, and secondary bladder cancer may develop.

Urotoxic side effects require treatment interruption.

Cystectomy may be necessary due to fibrosis, bleeding, or secondary malignancies.

Cases of urotoxic events with fatal outcome have been reported.

Urotoxicity can occur with both short-term and long-term use of cyclophosphamide. Cases of hemorrhagic cystitis have been reported after single doses of cyclophosphamide.

Previous and concomitant radiotherapy or busulfan treatment may increase the risk of cyclophosphamide-induced hemorrhagic cystitis.

Cystitis is usually initially abacterial. Secondary bacterial colonization is possible.

Any urinary tract obstruction should be ruled out or treated before starting treatment.

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

Adequate treatment with mesna-containing drugs and/or large volume fluid intake for forced diuresis can markedly reduce the frequency and severity of bladder toxicity. It is important to ensure that patients empty their bladders at regular intervals.

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

Cyclophosphamide has also been associated with nephrotoxicity, including renal tubular necrosis.

Hyponatremia associated with increased total body water content, acute water intoxication, and a syndrome resembling SIDH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in association with cyclophosphamide treatment. Fatal outcomes have been reported.

Cardiotoxicity, use in patients with heart disease

Myocarditis and myopericarditis, sometimes accompanied by significant pericardial effusion and cardiac tamponade, have been reported with cyclophosphamide treatment and have resulted in severe, sometimes fatal, congestive heart failure.

Histopathological examination mainly indicates hemorrhagic myocarditis. Hemopericardium developed secondary to hemorrhagic myocarditis and myocardial necrosis.

Cases of acute cardiotoxicity have been reported after a single dose of cyclophosphamide less than 20 mg/kg.

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

The risk of cyclophosphamide-induced cardiotoxicity may be increased, for example after high doses of cyclophosphamide, in elderly patients and in patients who have previously received radiotherapy to the heart and/or previous or concomitant treatment with other cardiotoxic drugs (see section 4.5). Particular attention should be paid to patients with risk factors for cardiotoxicity and patients with pre-existing cardiac disease.

Pneumonitis and pneumofibrosis have been reported during and after cyclophosphamide treatment. Pulmonary veno-occlusive disease and other forms of pulmonary toxicity have also been reported. Pulmonary toxicity leading to respiratory failure has been reported.

Although the incidence of pulmonary toxicity associated with cyclophosphamide 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 particularly high mortality rate. Pneumonitis can develop even years after cyclophosphamide therapy.

Acute pulmonary toxicity has been observed following administration of a single dose of cyclophosphamide.

Secondary malignant neoplasms

As with cytotoxic treatment in general, treatment with cyclophosphamide is accompanied by the risk of secondary tumors and their precursors as late complications.

There is an increased risk of urinary tract cancer, as well as myelodysplastic disorders, some of which may progress to acute leukemia. Other malignancies, including lymphoma, thyroid cancer, and sarcoma, have also been reported with cyclophosphamide and cyclophosphamide combination regimens.

In some cases, secondary tumors have developed several years after discontinuation of cyclophosphamide treatment. 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

Veno-occlusive hepatic disease (VOLD) has been reported in patients receiving cyclophosphamide.

Cytoreductive regimens in preparation for bone marrow transplantation, involving the use of cyclophosphamide in combination with total body irradiation, busulfan or other agents, are recognized as a major risk factor for the development of VOLD (see section 4.5). Following cytoreductive treatment, the clinical syndrome usually develops 1 to 2 weeks after transplantation and is characterized by a rapid increase in body weight, painful enlargement of the liver, ascites and hyperbilirubinemia/jaundice.

However, there are also reports of gradual development of VOLD in patients receiving long-term immunosuppressive therapy with low doses of cyclophosphamide.

Hepatorenal syndrome and multiple organ failure may develop as complications of VOLD. Fatal cases of VOLD associated with cyclophosphamide have been reported.

Risk factors that may predispose a patient to the development of VOLD receiving high-dose cytoreductive therapy include pre-existing liver dysfunction, prior abdominal radiotherapy, and low general health status index.

Genotoxicity

Cyclophosphamide is a genotoxic and mutagenic drug, exerting this effect in both somatic and male and female germ cells. Therefore, women should not become pregnant and men should not father children during cyclophosphamide treatment.

Men are prohibited from fathering children for 6 months after the end of treatment.

Animal data suggest that exposure of oocytes during follicular development may result in reduced implantation rates and viable pregnancies, as well as an increased risk of malformations. This effect should be considered in cases of planned fertilization or pregnancy after cyclophosphamide withdrawal. 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 these periods (see section “Use during pregnancy or breastfeeding”).

Impact on fertility

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

It has been demonstrated that the development of sterility depends on the dose of cyclophosphamide, the duration of therapy, and the status of gonadal function at the time of treatment.

In some patients, cyclophosphamide-induced sterility may be irreversible.

Women

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

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

The development of oligomenorrhea has also been reported in association with cyclophosphamide treatment.

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 will become 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 treated with cyclophosphamide may develop oligospermia or azoospermia, which is usually associated with increased gonadotropin secretion against a background of normal testosterone secretion.

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 cyclophosphamide treatment.

Men who become temporarily sterile due to cyclophosphamide later father children.

Men being treated with Endoxan® are recommended to undergo sperm cryopreservation before starting treatment.

Anaphylactic reactions, cross-sensitivity with other alkylating agents

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

Cases of cross-sensitivity with other alkylating agents have been reported.

Impaired wound healing

Cyclophosphamide may negatively affect normal wound healing.

Precautions

Alopecia

Alopecia has been reported, which is more common with higher doses.

Alopecia can progress to baldness.

Hair grows back after treatment with the drug and may grow back even during continued treatment, although its structure or color often changes.

Nausea and vomiting

Administration of cyclophosphamide may cause nausea and vomiting.

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

Alcohol consumption may increase the nausea and vomiting caused by cyclophosphamide.

Stomatitis

The use of cyclophosphamide can cause stomatitis (oral mucositis).

It is necessary to take into account current recommendations for measures to prevent and alleviate stomatitis.

Use in patients after adrenalectomy

Patients with adrenal insufficiency may require an increase in the dose of corticosteroid drugs used to alleviate the toxic effects of cytostatics, including cyclophosphamide.

Other precautions

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.

Endoxan® should not be taken by patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase deficiency, galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

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 therapy cannot be postponed and the patient wishes to maintain the pregnancy, chemotherapy may be prescribed after warning the patient about the slight but possible risk of teratogenic effects.

Women should not become pregnant during treatment and for 6 months after the end of treatment with Endoxan®. Genetic counseling is necessary during pregnancy during treatment.

Breast-feeding

Cyclophosphamide passes into breast milk, so women should stop 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 possibility of side effects, such as nausea and vomiting, which can cause circulatory failure, the doctor should individually decide on the patient's ability to drive or operate other mechanisms. This is especially true in situations where patients consume alcohol.

Method of administration and doses

Dosage should be individualized for each patient. The following dosage recommendations apply to both children and adults.

Dosage

Adjuvant therapy for breast cancer, palliative therapy for metastatic breast cancer

“Typical” CMF protocol: 100 mg/m2 body surface area (BSA) cyclophosphamide orally on days 1–14 of the therapy cycle in combination with methotrexate and 5-fluorouracil; repeat cycle every 4 weeks.

Severe progressive forms of lupus nephritis and Wegener's granulomatosis

For daily use – 1−2 mg/kg body weight (BW) (2 mg/kg for Wegener's granulomatosis).

Note: In stable patients, oral pulse therapy with high doses of the drug can be administered in most cases on an outpatient basis. However, high doses of the drug should only be administered to patients at home in the presence of a competent person (including if the dose is taken over a long period of time) or when a doctor or informed representative is available at all times if necessary.

Patients with hepatic impairment

Severe hepatic impairment may be associated with reduced cyclophosphamide clearance. This may affect the efficacy of cyclophosphamide treatment and should be considered when selecting the dose and interpreting the response to the selected dose. In cases of impaired hepatic function, a dose reduction of approximately 25% is recommended when serum bilirubin levels are between 3.1 and 5 mg/100 ml.

Patients with renal impairment

In patients with impaired renal function, especially in patients with severe renal insufficiency, reduced renal excretion may lead to increased plasma levels of cyclophosphamide and its metabolites. This may lead to increased toxicity, which should be taken into account when determining the dosage in such patients. In cases of impaired renal function, a dose reduction of approximately 50% is recommended when the glomerular filtration rate is below 10 ml/min.

Cyclophosphamide and its metabolites are removed by dialysis, although clearance may vary depending on the dialysis system used. In patients on dialysis, appropriate intervals should be observed between cyclophosphamide administration and dialysis (see section 4.4).

Dose reduction recommendations for patients with myelosuppression

Elderly patients

Endoxan® should be used with caution in elderly patients due to the higher frequency of decreased liver, kidney, heart and other organ function, as well as the presence of concomitant diseases and the use of other medications. Elderly patients require increased monitoring for toxicity and dose adjustment.

Method of application

The use of the drug Endoxan® should only be carried out by or under the supervision of physicians with experience in the field of oncology/rheumatology.

Doses, duration of therapy, and intervals between courses depend on the respective therapeutic indications, the combination therapy regimen used, the patient's general health, organ functions, and laboratory parameters (especially blood tests).

When used in combination with other cytotoxic drugs with similar levels of toxicity, it may be necessary to reduce the dose or extend the drug-free intervals.

Hematopoietic stimulants (colony stimulating factors and erythropoiesis stimulants) may be considered to reduce the risk of myelosuppressive complications and/or improve the use of