Cyclophosphamide-mili-1000: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYCLOPHOSPHAMIDE-MILI-500 CYCLOPHOSPHAMIDE-MILI-1000 (CYCLOPHOSPHAMIDE-MILI-500 CYCLOPHOSPHAMIDE-MILI-1000)

Composition:

active substance: cyclophosphamide; cyclophosphamide;

1 vial contains cyclophosphamide 500 mg or 1000 mg;

excipients: mannitol (E 421), water for injections.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical characteristics: lyophilisate mass from white to almost white in color.

Pharmacotherapeutic group. Antineoplastic agents. Alkylating compounds. Nitrogen mustard analogues. Cyclophosphamide. ATC code L01A A01.

Pharmacological Properties

Pharmacodynamics

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

Cyclophosphamide is in vitro inactive. Its activation occurs in vivo, primarily via microsomal enzymes in the liver, where it is converted into 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. These tautomers undergo partial spontaneous and partial enzymatic conversion into inactive and active metabolites (particularly phosphoramide mustard and acrolein).

The cytotoxic effect of cyclophosphamide is based on the interaction between its alkylating metabolites and DNA. This alkylation leads to strand breaks and cross-linking of DNA strands as well as DNA-protein cross-links. In the cell cycle, progression through the G2 phase is slowed. The cytotoxic effect is not specific to any particular phase of the cell cycle, but rather is active throughout the entire cell cycle. Acrolein has no antineoplastic activity, but is responsible for urotoxic side effects. In addition, the immunosuppressive effect of cyclophosphamide is also under discussion.

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

Pharmacokinetics

The blood levels following 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, a significant decrease in the concentration of cyclophosphamide and its metabolites in plasma occurs within 24 hours, but measurable levels in plasma persist up to 72 hours.

Biological Transformation

In vitro, cyclophosphamide is inactive. Bioactivation occurs only within the body.

In patients with impaired liver function, the biotransformation of cyclophosphamide is slowed. Consequently, in cases of pathologically reduced cholinesterase activity, an extended elimination half-life of the drug from blood serum is observed.

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

Elimination

The elimination half-life of cyclophosphamide from blood serum 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.

Elimination of cyclophosphamide and its metabolites occurs primarily via the kidneys. Dose adjustment is necessary in renal insufficiency. A general recommendation is to reduce the dose by 50% when the glomerular filtration rate is below 10 mL/min.

A dose reduction by 25% is recommended when serum bilirubin levels are between 3.1 and 5 mg/100 mL.

Pharmacokinetic/pharmacodynamic relationship

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

Clinical Characteristics

Indications

The medicinal product Cyclophosphamide-Mili is indicated for use in chemotherapy of the following tumors in combination with other antineoplastic agents:

induction of remission and consolidation therapy in acute lymphoblastic leukemia;
induction of remission in Hodgkin’s disease;
non-Hodgkin's lymphomas (depending on histological type and disease stage, also as monotherapy);
chronic lymphocytic leukemia (CLL) after lack of response to standard therapy (chlorambucil/prednisone);
induction of remission in multiple myeloma (also in combination with prednisone);
adjuvant therapy of breast cancer after tumor resection or mastectomy;
palliative therapy of advanced breast cancer;
advanced ovarian cancer;
small cell lung cancer;
Ewing's sarcoma;
neuroblastoma;
rhabdomyosarcoma in children;
osteosarcoma.

Preparation prior to allogeneic bone marrow transplantation in:

severe aplastic anemia – as monotherapy or in combination with antithymocyte globulin;
acute myeloid leukemia and acute lymphoblastic leukemia – in combination with total body irradiation or busulfan;
chronic myeloid leukemia – in combination with total body irradiation or busulfan.

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

Contraindications

The medicinal product Cyclophosphamide-Mili is contraindicated in:

hypersensitivity to cyclophosphamide, its metabolites, or any of the excipients;
severe impairment of bone marrow function (myelosuppression, particularly in patients previously treated with cytotoxic agents and/or radiotherapy);
bladder inflammation (cystitis);
urinary tract obstruction;
active infections;
pregnancy or breastfeeding.

General contraindications for allogeneic bone marrow transplantation, such as upper age limit of 50–60 years, contamination of bone marrow with metastases from malignant (epithelial) tumors, and lack of HLA identity with the intended donor in cases of chronic myeloid leukemia, must be carefully evaluated before initiating preparative therapy with Cyclophosphamide-Mili.

Special Safety Precautions

When handling Cyclophosphamide-Mili and preparing the solution, safety procedures for working with cytotoxic substances must be strictly observed.

Interaction with Other Medicinal Products and Other Forms of Interaction

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

Patients undergoing combination therapy must be closely monitored for signs of toxicity to allow timely intervention. Patients receiving cyclophosphamide and agents that may reduce its activation should be carefully observed for possible reduction in therapeutic efficacy and need for dose adjustment. In general, patients should be monitored for enhanced or reduced therapeutic efficacy and/or increased frequency and severity of adverse reactions of the interacting substance. Dose adjustments may be required.

Interactions negatively affecting the pharmacokinetics of cyclophosphamide and its metabolites

Reduced activation of cyclophosphamide may decrease the efficacy of cyclophosphamide therapy. Substances that slow down cyclophosphamide activation and thus reduce its efficacy include:

aprepitant;
bupropion;
busulfan: it has been observed that in addition to reduced cyclophosphamide activation, cyclophosphamide clearance was decreased and elimination half-life prolonged in patients receiving high-dose cyclophosphamide less than 24 hours after high-dose busulfan;
ciprofloxacin: it has been reported that in addition to reduced cyclophosphamide activation when administered prior to cyclophosphamide therapy (used for bone marrow transplantation preparation), ciprofloxacin led to recurrence of the underlying disease;
chloramphenicol;
fluconazole;
itraconazole;
prasugrel;
sulfonamides;
thiotepa: significant inhibition of bioactivation by thiotepa has been observed in high-dose chemotherapy when thiotepa was administered 1 hour before cyclophosphamide.

Increased concentrations of cytotoxic metabolites, leading to increased frequency and severity of adverse reactions, may occur with the use of the following agents:

allopurinol;
chloral hydrate;
cimetidine;
disulfiram;
glyceraldehyde;
inducers of hepatic and extrahepatic microsomal enzymes in humans (e.g., cytochrome P450 enzymes): may increase concentrations of cytotoxic metabolites. The possibility of stimulation of hepatic and extrahepatic microsomal enzymes should be considered in cases of prior or concomitant use of substances capable of increasing the activity of these enzymes, such as rifampicin, phenobarbital, carbamazepine, phenytoin, St. John's wort, and corticosteroids;
protease inhibitors: concomitant use of protease inhibitors may increase concentrations of cytotoxic metabolites. Treatment regimens based on protease inhibitors have been shown to be associated with higher rates of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (the "CDE regimen") compared to regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Ondansetron

A pharmacokinetic interaction between ondansetron and high-dose cyclophosphamide has been reported, resulting in decreased AUC of cyclophosphamide.

Pharmacodynamic interactions and interactions with unknown mechanism negatively affecting cyclophosphamide use

Combined or sequential use of cyclophosphamide with other agents having similar toxic effects may lead to additive or synergistic toxic effects.

Increased hematotoxicity and/or immunosuppression may occur with combined action of cyclophosphamide and the following agents:

angiotensin-converting enzyme (ACE) inhibitors: ACE inhibitors may cause leukopenia;
natalizumab;
paclitaxel: enhanced hematotoxicity was observed when cyclophosphamide was administered after paclitaxel infusion;
thiazide diuretics;
zidovudine.

Increased cardiotoxicity may occur due to combined action of cyclophosphamide and, for example:

anthracyclines;
cytarabine;
pentostatin;
radiation therapy to the heart area;
trastuzumab.

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

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

Increased nephrotoxicity may occur due to combined effect of cyclophosphamide and, for example:

amphotericin B;
indomethacin: acute water intoxication was observed 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 frequency of mucositis;
allopurinol and hydrochlorothiazide: enhanced myelosuppressive effect.

Other interactions

Alcohol

Reduced antitumor activity was observed in tumor-bearing animals consuming ethanol (alcohol) concomitantly with oral administration of low doses of cyclophosphamide.

In some patients, alcohol may exacerbate cyclophosphamide-induced nausea and vomiting.

Etanercept

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

Metronidazole

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

In animal studies, administration of cyclophosphamide in combination 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 medicinal products

Bupropion

Metabolism of cyclophosphamide via CYP2B6 may inhibit bupropion metabolism.

Activation of bupropion may be reduced, leading to decreased efficacy.

Coumarin derivatives

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

Cyclosporine

Decreased serum concentrations of cyclosporine were observed in patients receiving cyclophosphamide in combination with cyclosporine compared to those receiving cyclosporine alone. This interaction leads to increased incidence of graft-versus-host reaction.

Depolarizing muscle relaxants

Cyclophosphamide treatment leads to pronounced and prolonged inhibition of cholinesterase activity. This may prolong neuromuscular blockade caused by succinylcholine. Concomitant use of depolarizing muscle relaxants (e.g., succinylcholine) may result in prolonged apnea. If a patient has received cyclophosphamide within 10 days, the anesthesiologist must be informed prior to general anesthesia.

Digoxin, β-acetyldigoxin

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

Vaccines

The immunosuppressive effect of cyclophosphamide may weaken the body's response to vaccination. Administration of live vaccines may lead to vaccine-induced infections.

Verapamil

Cytotoxic therapy has been reported to impair intestinal absorption of oral verapamil, potentially compromising its therapeutic efficacy.

Sulfonylureas

Concomitant use may enhance the glucose-lowering effect of sulfonylureas.

Special precautions for use

Risk factors for the toxic effects of cyclophosphamide and their late consequences, described below and in other sections, may be contraindications to its use unless the medicinal product Cyclophosphamide-Mili is used to treat a life-threatening condition. In such cases, an individual assessment of risk versus expected benefit is required.

As with all antineoplastic agents, Cyclophosphamide-Mili should be used cautiously in debilitated patients, elderly patients, and patients previously treated with radiotherapy. Close monitoring is required for patients with compromised immune systems, diabetes mellitus, chronic liver or kidney disease, and pre-existing heart disease. In diabetic patients, careful monitoring of glucose metabolism should also be performed during cyclophosphamide therapy.

Caution is required when treating patients with acute porphyria due to the porphyrinogenic effect of cyclophosphamide.

Warnings

Anaphylactic reactions, cross-sensitivity with other alkylating agents

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

Cross-sensitivity with other alkylating agents has been reported.

Myelosuppression, immunosuppression, infections

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

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

Severe immunosuppression has led to serious, sometimes fatal, infections. Cases of sepsis and septic shock have also been reported. Infections observed during cyclophosphamide therapy include 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 physician's discretion.

In cases of febrile neutropenia, antibiotics and/or antifungal agents should be used.

In general, the reduction in peripheral blood cell counts and platelet counts may be accelerated, and the time required for their recovery may be prolonged with increasing doses of cyclophosphamide.

The lowest leukocyte and platelet counts are usually observed during the 1st–2nd week of treatment. The bone marrow recovers relatively quickly, and peripheral blood cell levels usually normalize approximately 20 days after treatment.

Severe myelosuppression should be particularly expected in patients who have previously and/or concurrently undergone chemotherapy and/or radiotherapy.

Hematological parameters in all patients should be carefully monitored throughout the treatment period.

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 drops below 3,000 cells/µL (cells/mm³)]. For long-term treatment, monitoring at intervals of approximately 14 days is generally sufficient.
Platelet count and hemoglobin level must be determined before each administration of the drug and at appropriate intervals after administration.

Renal and urinary tract toxicity

Cases of hemorrhagic cystitis, pyelitis, urethritis, and hematuria have been reported during cyclophosphamide therapy. Development of ulcers/necrosis, fibrosis/contractures, and secondary bladder cancer is possible.

In cases of urotoxicity, interruption of therapy may be necessary.

Cystectomy may be required in cases of fibrosis, bleeding, or development of secondary malignant neoplasms.

Cases of urotoxicity with fatal outcomes have been reported.

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

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

Cystitis is initially usually acellular (non-bacterial). Secondary bacterial colonization is possible.

Before initiating therapy, any obstruction of the urinary tract should be excluded or treated (see section "Contraindications").

Urine sediment should be regularly examined for the presence of erythrocytes and other signs of uro-/nephrotoxicity.

Appropriate use of "Mesna" and/or high fluid intake to enhance diuresis can significantly reduce the frequency and severity of bladder toxicity. It is important that the patient regularly empties the bladder.

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

Cases of nephrotoxicity, including renal tubular necrosis, have also been reported during cyclophosphamide therapy.

Hyponatremia associated with increased total body fluid, acute water intoxication, and a syndrome resembling the syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been observed with cyclophosphamide use. Fatal cases have been reported.

Cardiotoxicity: use in patients with heart disease

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

Histopathological findings primarily indicate hemorrhagic myocarditis. Hemopericardium occurs on the background of hemorrhagic myocarditis and myocardial necrosis.

Acute cardiotoxicity has been observed after single doses of cyclophosphamide less than 20 mg/kg.

After treatment regimens including cyclophosphamide, supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including marked QT interval prolongation associated with ventricular tachyarrhythmia) have been observed in patients with and without other signs of cardiotoxicity.

The risk of cardiotoxic effects of cyclophosphamide may increase, for example, with high-dose therapy, in elderly patients, and in patients previously treated with radiotherapy to the heart area and/or previous or concomitant therapy with other cardiotoxic agents (see section "Interaction with other medicinal products and other forms of interaction").

Particular caution is required 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 veno-occlusive lung disease and other forms of pulmonary toxicity have also been reported.

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

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

Late-onset pneumonitis (more than 6 months after starting cyclophosphamide therapy) is associated with very high mortality. Pneumonitis may develop even several years after cyclophosphamide treatment.

Acute pulmonary toxicity has been observed after single doses of cyclophosphamide.

Secondary malignant neoplasms

As with any cytotoxic therapy, cyclophosphamide use is associated with the risk of delayed complications such as the development of secondary tumors and their precursors.

The risk of urinary tract cancer increases, as well as the risk of myelodysplastic changes, some of which progress to acute leukemia. Other malignancies reported after cyclophosphamide use or treatment regimens including cyclophosphamide include lymphomas, thyroid cancer, and sarcomas.

In some cases, secondary malignant neoplasms occur several years after discontinuation of cyclophosphamide therapy. Malignant neoplasms have also been reported after in utero exposure.

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

Hepatic veno-occlusive disease

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

Cytoreductive therapy used in preparation for bone marrow transplantation, which includes cyclophosphamide in combination with total body irradiation, busulfan, or other agents, has been identified as a significant risk factor for VOD (see section "Interaction with other medicinal products and other forms of interaction"). After cytoreductive therapy, the clinical syndrome typically 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 VOD during long-term use of low-dose immunosuppressive cyclophosphamide have also been reported.

Complications of VOD may include hepatorenal syndrome and multi-organ failure. Fatal outcomes of VOD caused by cyclophosphamide have been reported.

Risk factors predisposing a patient to VOD following high-dose cytoreductive therapy include:

Pre-existing hepatic function impairment;
Previous radiotherapy to the abdominal cavity;
Poor general condition score.

Genotoxicity

Cyclophosphamide exerts genotoxic and mutagenic effects on somatic cells and male and female gametes. Therefore, women should avoid pregnancy and men should avoid conception during cyclophosphamide therapy.

Men should wait at least 6 months after discontinuation of cyclophosphamide therapy before attempting conception.

Animal studies indicate that the drug's effect on oocytes during follicular development may lead to reduced implantation rates and viable pregnancies and an increased risk of developmental abnormalities. 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 exceed 12 months.

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

Effects on fertility

Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes.

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

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

Embryo and fetotoxicity

Based on the mechanism of action and published reports on effects in pregnant women or animals, cyclophosphamide may harm the fetus when administered to a pregnant woman. Exposure to cyclophosphamide during pregnancy may cause congenital malformations, miscarriage, fetal growth retardation, and fetotoxic effects in newborns. Cyclophosphamide is teratogenic and embryo-fetotoxic in mice, rats, rabbits, and monkeys.

Pregnant women and women of reproductive age should be informed of the potential risk to the fetus. Women of reproductive age are advised to use effective contraception during cyclophosphamide therapy and for one month after completion of therapy. Male patients with female partners of reproductive age are advised to use effective contraception during cyclophosphamide therapy and for 4 months after completion of therapy.

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, amenorrhea may be permanent in older women.

Oligomenorrhea has also been reported in association with cyclophosphamide therapy.

In girls treated with cyclophosphamide during the prepubertal period, secondary sexual characteristics and regular menstruation generally develop normally.

Girls treated with cyclophosphamide during the prepubertal period have become pregnant in the future.

Girls in whom ovarian function was preserved after completion of cyclophosphamide therapy belong to a group at increased risk of premature menopause (cessation of menstruation before age 40).

Men

Men undergoing cyclophosphamide therapy are advised to consult regarding sperm cryopreservation before starting therapy.

Oligospermia or azoospermia may develop in men treated with cyclophosphamide, usually associated with increased gonadotropin secretion despite normal testosterone secretion.

Sexual potency and libido are generally unaffected 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 may be reversible in some patients, although recovery may not occur for several years after completion of therapy.

Men who became temporarily sterile due to cyclophosphamide have subsequently fathered children.

Impaired wound healing

Cyclophosphamide may impair normal wound healing.

Safety measures

Alopecia

Cases of alopecia have been reported; its frequency may increase with higher doses.

Alopecia may progress to complete hair loss.

Hair may regrow after completion of therapy or even during treatment, although its texture or color may change.

Nausea and vomiting

Cyclophosphamide may cause nausea and vomiting.

Current guidelines for the use of antiemetic agents to prevent and alleviate nausea and vomiting should be considered.

Alcohol consumption may exacerbate nausea and vomiting caused by cyclophosphamide.

Stomatitis

Cyclophosphamide may cause stomatitis (inflammation of the oral mucosa).

Current guidelines for the prevention and alleviation of stomatitis should be considered.

Paravenous administration

The cytostatic effect of cyclophosphamide occurs after its activation, which primarily takes place 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 immediately stopped, the extravascular cyclophosphamide solution aspirated through the already inserted needle, and other necessary measures taken.

Use in patients after adrenalectomy

Patients with adrenal insufficiency may require higher doses of corticosteroid replacement during stress due to toxicity induced by cytostatic agents, including cyclophosphamide.

Dosage reduction of cyclophosphamide is required in patients with impaired liver or kidney function (see section "Method of administration and dosage").

The use of cyclophosphamide as part of preparation for bone marrow transplantation should be performed exclusively in hemato-oncological centers with specialists experienced in allogeneic bone marrow transplantation and appropriate equipment.

Use in patients prior to allogeneic bone marrow transplantation

Indications for bone marrow transplantation using Cyclophosphamide-Mili as part of preparative therapy depend on a comprehensive set of factors and are considered on an individual basis. Important factors in deciding in favor of bone marrow transplantation include: disease stage, prognosis (risk group), nature and success of previous treatment regimens for the underlying disease, patient age and general condition, and availability of a suitable bone marrow donor.

Use during pregnancy or breastfeeding

Pregnancy

Cyclophosphamide therapy 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 consultation regarding the potential risk 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 the pregnancy, chemotherapy may be administered only after informing the patient of the risk of teratogenic effects, although minimal. Women must not become pregnant during treatment with Cyclophosphamide-Mili and for 6 months after its completion. If a patient becomes pregnant during treatment, genetic counseling should be obtained.

Breastfeeding

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

Fertility

Contraceptive measures must be used by sexually mature male and female patients during treatment and for at least 6 months after its completion.

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

Ability to affect reaction speed when driving or operating machinery

Due to the possible development of adverse effects such as nausea, vomiting, and associated circulatory weakness, the decision on whether patients treated with Cyclophosphamide-Mili can drive or operate machinery should be made by the physician on an individual basis. This is particularly relevant in situations where patients consume alcohol.

Method of Administration and Dosage

Dosage should be individually adjusted for each patient.

The dosage recommendations below apply to both children and adults.

Induction of remission and consolidation therapy in acute lymphoblastic leukemia

Cyclophosphamide is administered to children and adults depending on different risk groups within various polychemotherapy regimens. The typical dosage for 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 BSA of cyclophosphamide intravenously on day 6 in combination with vincristine and prednisone, or 400 mg/m² BSA of cyclophosphamide intravenously on days 1 and 5, also in combination with vincristine and prednisone, repeated every 3 weeks.

Hodgkin's disease

650 mg/m² BSA of cyclophosphamide intravenously on days 1 and 8 in combination with vincristine, procarbazine, and prednisone ("COPP regimen").

Non-Hodgkin's lymphomas

Cyclophosphamide may be used in non-Hodgkin's lymphomas (NHL) either as monotherapy or in combination with other antineoplastic agents, depending on histological type and disease stage. The following are standard therapies for NHL with low-grade and intermediate/high-grade malignancy:

Low-grade NHL: 600–900 mg/m² BSA 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 BSA of cyclophosphamide IV on day 1 in combination with doxorubicin, vincristine, and prednisone ("CHOP regimen"); repeat every 3–4 weeks.

Plasma cell myeloma

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

An example of a proven polychemotherapy regimen for plasma cell myeloma is the so-called "VBMCP regimen," listed below:

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

Breast cancer

Cyclophosphamide should be used in adjuvant and palliative therapy of breast cancer in combination with other cytostatic agents. Two proven regimens are provided below as examples:

"CMF regimen": 600 mg/m² BSA of cyclophosphamide intravenously on days 1 and 8 in combination with methotrexate and 5-fluorouracil; repeat every 3–4 weeks.

"CAF regimen": 500 mg/m² BSA of cyclophosphamide intravenously on day 1 in combination with doxorubicin and 5-fluorouracil; repeat every 3–4 weeks.

Advanced ovarian cancer

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

500–600 mg/m² BSA of cyclophosphamide intravenously on day 1 in combination with carboplatin; repeat every 4 weeks.

Small cell lung cancer

Cyclophosphamide should be used in combination with other antineoplastic agents. An example of an effective polychemotherapy regimen is the so-called "CAV regimen" listed below:

1000 mg/m² BSA of cyclophosphamide intravenously on day 1 in combination with doxorubicin and vincristine; repeat every 3 weeks.

Ewing's sarcoma

An example of a proven polychemotherapy regimen in Ewing's sarcoma is the "VACA regimen" listed below:

500 mg/m² BSA of cyclophosphamide intravenously once weekly in combination with vincristine, doxorubicin, and actinomycin D.

Osteosarcoma

Cyclophosphamide should be used as part of comprehensive polychemotherapy for neoadjuvant (preoperative) and adjuvant (postoperative) therapy. The following is the Multinational Osteosarcoma Study (MOS) protocol as an example of adjuvant therapy: 600 mg/m² BSA of cyclophosphamide intravenously daily on days 2, 13, 26, 39, and 42 of treatment in combination with bleomycin, actinomycin D, doxorubicin, cisplatin, and methotrexate.

Neuroblastoma

Depending on disease stage and patient age, cyclophosphamide should be used within various chemotherapy regimens. An example of combination therapy for advanced neuroblastoma is the "OPEC regimen" listed below:

600 mg/m² BSA of cyclophosphamide intravenously on day 1 in combination with vincristine, cisplatin, and teniposide; repeat every 3 weeks.

Rhabdomyosarcoma in children

Cyclophosphamide should be used depending on disease stage and histological type within various comprehensive polychemotherapy regimens. The typical dosage for patients at stage III (macroscopic residual tumor after surgery) and stage IV (distant metastases) is 10 mg/kg body weight of cyclophosphamide intravenously for 3 consecutive days, repeated multiple times in combination with vincristine and actinomycin D ("VAC regimen").

Preparation for allogeneic bone marrow transplantation in acute myeloid and acute lymphoblastic leukemia

60 mg/kg body weight of cyclophosphamide intravenously daily for 2 consecutive days in combination with total body irradiation or busulfan.

Note: Appropriate selection of therapy components to be combined with cyclophosphamide requires specialized knowledge, as treatment outcomes may differ significantly depending on the underlying disease and its stage.

Preparation for allogeneic bone marrow transplantation in chronic myeloid leukemia

60 mg/kg body weight of cyclophosphamide intravenously daily for 2 consecutive days in combination with total body irradiation or busulfan.

Note: In chronic myeloid leukemia, both possible combinations of cyclophosphamide components lead to similar treatment outcomes.

Preparation for allogeneic bone marrow transplantation in severe aplastic anemia

The following dosage recommendations apply to conditioning without total body irradiation, which is usually omitted in severe aplastic anemia:

50 mg/kg body weight of cyclophosphamide intravenously daily for 4 consecutive days as monotherapy or in combination with antithymocyte globulin.

In patients with Fanconi anemia, the daily dose should be reduced from 50 to 35 mg/kg body weight of cyclophosphamide intravenously daily for 4 consecutive days.

Severe progressive forms of lupus nephritis and Wegener's granulomatosis

Initial dose is 500–1000 mg/m² BSA intravenously.

Renal function impairment

In patients with impaired renal function, especially those with severe renal dysfunction, reduced renal excretion may lead to elevated plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity, which should be considered when determining dosage for such patients. In renal impairment, a dose reduction of approximately 50% is recommended when 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. For patients requiring dialysis, the interval between administration of Cyclophosphamide-Mili and dialysis session should be coordinated (see section "Special precautions").

Hepatic function impairment

Severe hepatic dysfunction may be associated with reduced activation of cyclophosphamide. This may affect the efficacy of Cyclophosphamide-Mili treatment and should be considered when selecting dosage and interpreting response to the chosen dose. In hepatic impairment, a dose reduction of approximately 25% is recommended when serum bilirubin levels are between 3.1 and 5 mg/100 mL.

Dose reduction recommendations for patients with bone marrow suppression

White blood cell count (per µL)	Platelet count (per µL)	Dosage
> 4000	> 100000	100 % of planned dose
4000−2500	100000−50000	50 % of planned dose
< 2500	< 50000	Dose adjustment until normalization of parameters or individual decision

Elderly patients

Cyclophosphamide-Mili should be used with special caution in elderly patients due to the higher incidence of impaired hepatic, renal, cardiac, or other organ functions, as well as the presence of concomitant diseases and use of other medicinal products in this patient group. Therefore, enhanced monitoring for the development of toxic effects is required, and dose adjustment may also be necessary.

Administration method

Administration of Cyclophosphamide-Mili should be performed only by physicians experienced in oncology/rheumatology or under their supervision.

Doses, duration of therapy, and intervals between treatment cycles depend on the respective therapeutic indications, the applied combination therapy regimen, the patient's general health status, organ functions, and laboratory parameters (particularly blood counts).

When Cyclophosphamide-Mili is used in combination with other cytotoxic agents of similar toxicity levels, dose reduction or prolonged intervals between administrations may be necessary.

Consideration may be given to the use of hematopoietic growth factors (colony-stimulating factors and erythropoiesis-stimulating agents) to reduce the risk of myelosuppressive complications and/or to facilitate the administration of required doses.

Urinary tract obstruction, cystitis, infections, and electrolyte imbalances must be excluded and/or treated prior to initiating therapy (see section "Special precautions").

During and immediately after administration of Cyclophosphamide-Mili, patients must consume or receive adequate fluid intake or infusions to induce diuresis and thereby reduce the risk of toxic effects on the urinary tract. Therefore, the drug should be administered in the morning (see section "Special precautions").

During treatment with Cyclophosphamide-Mili, patients should avoid eating grapefruit or drinking grapefruit juice, as this may reduce the efficacy of cyclophosphamide.

Regular blood and urine sediment analyses should be performed throughout the treatment period (see section "Special precautions").

Cyclophosphamide-Mili is administered intravenously either as a bolus injection or short infusion. Intravenous administration is preferably performed as an infusion.

To reduce the risk of adverse reactions considered to be infusion-rate-dependent (e.g., facial swelling, headache, nasal congestion, burning sensation on the scalp), Cyclophosphamide-Mili should be administered slowly, either as an injection or infusion.

The duration of infusion should also be compatible with the volume and type of infusion fluid to be administered. Infusion duration may range from 30 minutes to 2 hours.

For parenteral administration as a direct bolus injection, Cyclophosphamide-Mili should be reconstituted with physiological saline (0.9% sodium chloride). Reconstitution with water produces a hypotonic solution, which must not be administered directly.

For infusion use, Cyclophosphamide-Mili is reconstituted in sterile water or physiological saline and then added to the recommended infusion solution.

Prior to administration, the medicinal product should be inspected visually for particulate matter and discoloration, if the solution and container permit. The substance must be completely dissolved before intravenous administration.

Solution preparation

To prepare a 2% isotonic solution, add the appropriate volume of physiological saline to the dry substance (25 mL of physiological saline to Cyclophosphamide-Mili-500 and 50 mL to Cyclophosphamide-Mili-1000).

The substance dissolves readily upon vigorous shaking after addition of the solvent. If the substance does not dissolve immediately and completely, it is recommended to let the vial stand for several minutes.

For short-term intravenous infusion, the Cyclophosphamide-Mili solution is added to Ringer's solution, physiological saline, or glucose solution to a total volume of approximately 500 mL.

Stability of prepared solution

After reconstitution and dilution, chemical and physical stability has been demonstrated (in aqueous solutions, sodium chloride solutions, and glucose solutions) for 48 hours at 2–8°C.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage time and conditions are the responsibility of the user and should generally not exceed 24 hours at 2–8°C, unless reconstitution/dilution was performed under controlled and validated aseptic conditions.

Children

Dosage recommendations and administration guidelines for children and adolescents are the same as for adult patients.

Overdose

Severe consequences of overdose include dose-dependent toxic effects such as myelosuppression, urotoxicity, cardiotoxicity (including heart failure), hepatic veno-occlusive disease, and stomatitis (see section "Special precautions").

Patients who have received an excessive dose should be closely monitored for the development of toxic effects, particularly hematotoxicity.

There is no specific antidote for cyclophosphamide.

Cyclophosphamide and its metabolites are eliminated by dialysis. Therefore, prompt hemodialysis is indicated in the treatment of overdose, whether due to suicide attempt or accidental overdose.

In case of overdose, administration of Cyclophosphamide-Mili should be discontinued, and supportive measures should be implemented, including appropriate treatment of any concomitant infections, myelosuppression, or other toxic effects.

Prophylaxis of cystitis with "Mesna" may prevent or limit urotoxic effects of cyclophosphamide overdose (see section "Special precautions"). "Mesna" should be administered immediately after Cyclophosphamide-Mili overdose. To prevent hemorrhagic cystitis, "Mesna" may be administered intravenously over 24–48 hours.

Note: Paravenous administration of properly diluted cyclophosphamide usually does not pose a risk of cytotoxic tissue damage, as cytotoxic activity primarily occurs after bioactivation, which mainly takes place in the liver.

However, if extravasation occurs, the infusion should be stopped immediately, the administered drug aspirated using the needle, the area flushed with physiological saline, and the limb immobilized.

Adverse reactions

The adverse reactions listed below were observed during post-marketing surveillance. Reactions are presented by system organ classes according to MedDRA and by frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

System organ class

Adverse reaction

Frequency

Infections and infestations

Infections¹

Pneumonia²

Sepsis¹

Septic shock

Common

Uncommon

Very rare

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Secondary tumors⁴

Acute leukemia

Myelodysplastic syndrome

Bladder cancer

Ureter cancer

Tumor lysis syndrome

Lymphomas

Progression of underlying malignancies

Sarcoma

Renal cell carcinoma

Transitional cell carcinoma of renal pelvis

Thyroid cancer

Carcinogenic effects in offspring

Uncommon

Very rare

Frequency not known

Blood and lymphatic system

Myelosuppression

Leukopenia

Neutropenia

Thrombocytopenia

Agranulocytosis

Anemia

Pancytopenia

Decreased hemoglobin levels

Febrile neutropenia

Neutropenic fever

Disseminated intravascular coagulation syndrome

Hemolytic uremic syndrome

Granulocytopenia

Lymphopenia

Very common

Common

Very rare

Frequency not known

Immune system

Immunosuppression

Hypersensitivity reactions

Anaphylactic shock

Anaphylactic/anaphylactoid reactions²

Very common

Uncommon

Very rare

Endocrine system

Inappropriate antidiuretic hormone secretion syndrome

Water intoxication

Very rare

Frequency not known

Metabolism and nutrition

Anorexia

Dehydration

Hyponatremia

Fluid retention

Changes in blood glucose levels (increase or decrease)

Common

Uncommon

Very rare

Frequency not known

Psychiatric disorders

Confusion

Very rare

Nervous system

Peripheral neuropathy

Polyneuropathy

Neuralgia

Dizziness

Seizures

Encephalopathy

Paresthesia

Taste alteration

Neurotoxicity

Dysgeusia

Hypogeusia

Hepatic encephalopathy

Posterior reversible leukoencephalopathy syndrome

Myelopathy

Dysesthesia

Hypoesthesia

Tremor

Parosmia

Uncommon

Rare

Very rare

Frequency not known

Eye

Blurred vision

Visual disturbance

Conjunctivitis

Eye swelling

Increased lacrimation

Rare

Very rare

Frequency not known

Ear and labyrinth

Deafness

Tinnitus

Uncommon

Frequency not known

Cardiac

Cardiomyopathy

Myocarditis

Heart failure (including individual cases with fatal outcome)

Tachycardia

Arrhythmia

Ventricular arrhythmia (including ventricular tachycardia and ventricular fibrillation)

Supraventricular arrhythmia

Atrial fibrillation

Cardiac arrest

Myocardial infarction

Pericarditis

Cardiogenic shock

Pericardial effusion/tamponade

Myocardial hemorrhage

Left ventricular dysfunction

Bradycardia

Cardiac arrhythmias

QT interval prolongation on electrocardiogram

Reduced ejection fraction

Uncommon

Rare

Very rare

Frequency not known

Vascular

Feeling of warmth

Low blood pressure

Thromboembolism

Arterial hypertension

Arterial hypotension

Pulmonary embolism

Venous thrombosis

Vasculitis

Peripheral ischemia

Uncommon

Very rare

Frequency not known

Respiratory, thoracic and mediastinal

Pneumonitis⁴

Acute respiratory distress syndrome

Chronic interstitial pulmonary fibrosis

Lung edema

Pulmonary hypertension

Bronchospasm

Dyspnea

Hypoxia

Cough

Unspecified lung function disorders

Nasal congestion

Nasal discomfort

Oropharyngeal pain

Rhinorrhea

Sneezing

Veno-occlusive lung disease

Obliterative bronchiolitis

Organizing pneumonia

Allergic alveolitis

Pleural effusion

Rare

Frequency not known

Gastrointestinal

Stomatitis

Diarrhea

Vomiting

Constipation

Nausea

Hemorrhagic enterocolitis

Acute pancreatitis

Ascites

Ulceration of mucous membrane

Gastrointestinal hemorrhage

Abdominal pain

Parotitis

Colitis

Enteritis

Appendicitis

Common

Very rare

Frequency not known

Hepatobiliary system

Liver function disorders

Hepatic veno-occlusive disease⁴

Elevated blood bilirubin levels

Elevated liver enzymes (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase)

Viral hepatitis reactivation

Hepatomegaly

Jaundice

Hepatitis

Cholestatic hepatitis

Cytolytic hepatitis

Cholestasis

Hepatic encephalopathy

Hepatotoxicity with liver failure

Common

Uncommon

Very rare

Frequency not known

Skin and subcutaneous tissue

Alopecia

Exanthema

Dermatitis

Change in pigmentation of palms, nails and soles

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Multiform erythema

Radiation-induced skin injury

Radiation burn

Pruritus (including inflammatory pruritus)

Redness of skin

Toxic rash

Palmar-plantar erythrodysesthesia syndrome

Urticaria

Bullae formation

Redness of skin

Facial swelling

Hyperhidrosis

Very common

Rare

Very rare

Frequency not known

Musculoskeletal and connective tissue

Rhabdomyolysis

Scleroderma

Muscle spasms

Myalgia

Arthralgia

Frequency not known

Renal and urinary

Cystitis

Microhematuria

Hemorrhagic cystitis (including individual fatal cases)

Macrohematuria

Suburothelial hemorrhage

Bladder wall edema

Interstitial inflammation with fibrosis and sclerosis of the bladder

Renal failure

Elevated blood creatinine levels

Tubular necrosis

Renal tubular injury

Toxic nephropathy

Hemorrhagic ureteritis

Ulcerative cystitis

Bladder contracture

Nephrogenic diabetes insipidus

Atypical urothelial cells in bladder

Elevated blood urea levels

Very common

Common

Very rare

Frequency not known

Pregnancy, puerperium and perinatal conditions

Preterm labor

Frequency not known

Reproductive system and breast

Spermatogenesis disorders

Ovulation disorders

Amenorrhea⁵

Azoospermia⁵

Oligospermia⁵

Infertility

Ovarian function insufficiency

Ovulation discomfort

Oligomenorrhea

Testicular atrophy

Decreased blood estrogen levels

Elevated blood gonadotropin levels

Common

Uncommon

Rare

Frequency not known

Congenital, familial and genetic disorders

Fetal death in utero

Fetal deformity

Fetal growth retardation

Toxic effect on fetus (including myelosuppression/gastroenteritis)

Frequency not known

General and administration site

Fever

Chills

Asthenia

Increased fatigue

Discomfort

Mucosal inflammation

Chest pain

Headache

Pain

Multiple organ failure

Phlebitis

Injection/infusion site reactions (thrombosis, necrosis, inflammation, pain, swelling, skin redness)

Edema

Influenza-like illness

General physical instability

Delayed wound healing

Very common

Common

Rare

Very rare

Frequency not known

Investigations

Hyperuricemia due to tumor lysis syndrome

Elevated blood lactate dehydrogenase levels

Elevated C-reactive protein levels

Very rare

Frequency not known

1Including reactivation of other latent bacterial, fungal, viral, protozoal, and parasitic infections, including viral hepatitis, tuberculosis, John Cunningham virus with progressive multifocal leukoencephalopathy (including cases with fatal outcome), Pneumocystis jiroveci, herpes zoster, strongyloidiasis, sepsis, and septic shock (including cases with fatal outcome).

2Including fatal cases.

3Including acute myeloid leukemia and acute promyelocytic leukemia.

4With high-dose therapy: very common.

5Persistent phenomenon.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after registration of the medicinal product is of great importance. It allows ongoing monitoring of the benefit/risk balance of the use of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at 2–8 °C, in a place inaccessible to children.

Incompatibility.

Solutions containing benzyl alcohol may reduce the stability of cyclophosphamide.

Packaging.

500 mg or 1000 mg of lyophilisate for solution for injection in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Venus Remedies Limited.

Manufacturer’s address and location of operations.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India.

Marketing Authorization Holder.

Mili Healthcare Limited.

Address of the Marketing Authorization Holder.

2nd Floor, Office Premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.