Endoxan Baxter

Endoxan Baxter Patient Information Leaflet

PATIENT INFORMATION LEAFLET

Endoxan Baxter 50 mg Coated Tablets, 200 mg Powder for Injectable Solution, 500 mg Powder for Injectable Solution, 1 g Powder for Injectable Solution

Cyclophosphamide
THERAPEUTIC PHARMACOLOGICAL CATEGORY
Antineoplastic, nitrogen mustard analogues
THERAPEUTIC INDICATIONS
Cytostatic treatment.
CONTRAINDICATIONS
Endoxan Baxter must not be administered to patients with:

• hypersensitivity to the active substance, its metabolites or any of the excipients
• severely impaired bone marrow function (particularly in patients who have undergone prior therapy with cytotoxic agents and/or radiotherapy),
• bladder inflammation (cystitis),
• urinary outflow obstruction,
• active infections,
• during pregnancy and breastfeeding.

PRECAUTIONS FOR USE
The risk factors for cyclophosphamide toxicity and their consequences described in this and other sections may constitute contraindications if the medicinal product is not used for the treatment of life-threatening conditions. In such situations, an individual assessment of the expected benefit-risk ratio is required.
WARNINGS
Renal and urinary tract

• Hemorrhagic cystitis, pyelitis, urethritis and hematuria have been reported during cyclophosphamide therapy. Bladder ulceration/necrosis, fibrosis/contraction and secondary tumors may also develop.
• Urotoxicity may require discontinuation of treatment.
• Cystectomy may be necessary in cases of fibrosis, hemorrhage or secondary tumors.
• Fatal outcomes due to urotoxicity have been reported.
• Urotoxicity may occur with both short- and long-term cyclophosphamide treatment. Hemorrhagic cystitis has been reported after a single dose of cyclophosphamide.
• Concomitant or subsequent radiotherapy or treatment with busulfan may increase the risk of cyclophosphamide-induced hemorrhagic cystitis.
• Cystitis is generally initially sterile but secondary microbial colonization may occur.
• Before starting therapy, urinary outflow obstructions, cystitis and infections must be eliminated or corrected.

Endoxan Baxter Patient Information Leaflet

• Adequate treatment with Uromitexan (INN: mesna) or intensive hydration can significantly reduce the frequency and severity of bladder toxicity. Ensure that patients empty their bladder at regular intervals.
• If cystitis associated with micro- or macroscopic hematuria occurs during treatment with Endoxan Baxter, discontinue therapy with Endoxan Baxter until normalization. This generally occurs within a few days after discontinuation of the medicinal product, but cystitis may persist.
• Generally, treatment with Endoxan Baxter must be discontinued in case of severe hemorrhagic cystitis.
• Cyclophosphamide has also been associated with nephrotoxicity, including tubular necrosis.
• Hyponatremia associated with increased total body water, acute water intoxication and a syndrome similar to SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in association with cyclophosphamide administration. Fatal outcomes have also been reported.
• Patients with impaired renal function should be closely monitored during treatment with Endoxan Baxter for the presence of erythrocytes and other signs of uro/nephrotoxicity (refer also to "Recommendations for dose adjustment in patients with hepatic or renal impairment" in the section "Dosage, method and duration of administration").

Myelosuppression, Immunosuppression, Infections
In general, Endoxan Baxter, like all other cytostatics, should be used with utmost caution in frail or elderly patients, and in patients who have previously undergone radiotherapy.
Patients with a weakened immune system, for example those with diabetes mellitus, chronic hepatic or renal disorders, should also be closely monitored.

• Treatment with cyclophosphamide may cause myelosuppression and significant suppression of the immune response.
• Severe myelosuppression is expected, especially in patients who have previously undergone chemotherapy and/or radiotherapy or in patients with impaired renal function.
• Cyclophosphamide-induced myelosuppression may cause leukopenia, neutropenia, thrombocytopenia (associated with an increased risk of hemorrhagic events) and anemia.
• Severe immunosuppression has led to serious, sometimes fatal, infections. Septicaemia and septic shock have also been reported. Infections reported with cyclophosphamide include both pneumonias and other infections of bacterial, fungal, viral, protozoal and parasitic origin.
• Latent infections may be reactivated. Reactivation has been reported for various infections of bacterial, fungal, viral, protozoal and parasitic origin.
• Infections must be appropriately treated.
• At the discretion of the treating physician, antimicrobial prophylaxis may be indicated in some cases of neutropenia.
• In case of febrile neutropenia and/or leukopenia, antibiotics and/or antifungals should be administered as prophylaxis.
• If necessary, cyclophosphamide should be used with caution in patients with severe bone marrow function impairment and in patients with severe immunosuppression.
• Treatment with cyclophosphamide may not be indicated or should be discontinued or the dosage reduced in patients who have or develop a severe infection.
• Theoretically, the extent of reduction in peripheral blood cell and platelet counts and the time required for recovery increase with higher dosages.

Endoxan Baxter Patient Information Leaflet

• The lowest white blood cell and platelet counts are usually observed one to two weeks after the start of treatment. Bone marrow recovers relatively rapidly and blood values normally normalize after approximately 20 days.
• Therefore, during treatment, all patients should undergo careful hematological monitoring with regular blood counts. o Before each administration and at appropriate intervals, if necessary daily, white blood cell and platelet counts and hemoglobin values should be checked. o Leukocyte counts should be performed regularly during treatment, every 5-7 days at the beginning of treatment and every 2 days if the count drops below 3,000/mm³ (refer also to the section "Dosage, method and duration of administration").
• If not strictly necessary, Endoxan Baxter should not be administered to patients with a white blood cell count below 2,500/μl and/or a platelet count below 50,000/μl.
• Regular monitoring of urinary sediment is also recommended to detect the possible presence of erythrocytes.

Cardiotoxicity, Use in patients with heart disease

• Myocarditis and myopericarditis have been reported during cyclophosphamide treatment, which may be accompanied by significant pericardial effusion and cardiac tamponade and may lead to severe congestive heart failure, sometimes fatal.
• Histopathological examination has mainly shown hemorrhagic myocarditis. Hemopericardium has occurred as a secondary effect of hemorrhagic myocarditis and myocardial necrosis.
• Acute cardiac toxicity has been observed with a single dose of less than 20 mg/kg of cyclophosphamide.
• Following exposure to treatment regimens including cyclophosphamide, supraventricular arrhythmias (including atrial fibrillation and flutter) as well as ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported in patients with or without other symptoms of cardiotoxicity.
• It has been demonstrated that the use of high doses of cyclophosphamide in elderly patients and in patients who have undergone previous radiotherapy to the cardiac region and/or concomitant treatment with anthracyclines and pentostatin or other cardiotoxic agents (refer to section 4.5) may intensify the cardiotoxic effect of Endoxan Baxter. In this context, regular electrolyte monitoring should be performed and particular attention should be paid to patients with a history of cardiac disorders.

Pulmonary toxicity

• Pneumonitis and pulmonary fibrosis have been reported concomitantly or subsequently to 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.
• While the incidence of cyclophosphamide-associated pulmonary toxicity is low, the prognosis for affected patients is poor.
• Late-onset pneumonitis (more than 6 months after the start of cyclophosphamide treatment) appears to be associated with particularly high mortality. Pneumonitis may also occur years after cyclophosphamide treatment.
• Acute pulmonary toxicity has been reported after a single dose of cyclophosphamide.

Endoxan Baxter Patient Information Leaflet
Secondary tumors

• As with cytostatic therapy in general, treatment with cyclophosphamide entails the risk of secondary tumors and their precursors as late consequences.
• The risk of developing urinary tract carcinoma as well as myelodysplastic alterations, some of which progress to acute leukemia, is increased. Other tumors reported after cyclophosphamide use or cyclophosphamide treatment include lymphoma, thyroid cancer and sarcomas.
• In some cases, secondary tumors have developed several years after cyclophosphamide treatment was discontinued. Tumors have also been reported following in utero exposure.
• The risk of bladder cancer can be significantly reduced by preventing hemorrhagic cystitis.

Hepatic veno-occlusive disease

• Hepatic veno-occlusive disease (VOD) has been reported in patients treated with cyclophosphamide.
• ..Cytoreductive treatment in preparation for bone marrow transplantation, consisting of cyclophosphamide in combination with total body irradiation, busulfan or other agents, has been identified as the major risk factor for the development of VOD (refer to section 4.5). Following cytoreductive therapy, the clinical syndrome develops clinically 1 to 2 weeks after transplantation and is characterized by rapid weight gain, painful hepatomegaly, ascites and hyperbilirubinemia/jaundice.
• However, gradual development of VOD has been reported in patients treated long-term with low-dose immunosuppressive doses of cyclophosphamide.
• As a complication of VOD, hepatorenal syndrome and multiorgan failure may develop. Fatal outcomes due to VOD associated with cyclophosphamide have been reported.
• Risk factors predisposing a patient to develop VOD with high-dose cytoreductive therapies include: o pre-existing liver function disorders or abdominal radiotherapy and o low performance score

Genotoxicity

• Endoxan Baxter is genotoxic and mutagenic in both somatic and male and female germ cells. Therefore, women should avoid pregnancy and men should avoid conceiving children during treatment with Endoxan Baxter.
• Men should avoid conceiving children for up to 6 months after discontinuation of treatment.
• Animal studies indicate that exposure of oocytes during follicular development may result in a lower percentage of implantation and non-risk pregnancies and an increased risk of malformations. This effect should be considered in case of voluntary fertilization or pregnancy after completion of cyclophosphamide treatment. The exact duration of follicular development in humans is not known, but may be longer than 12 months.

Endoxan Baxter Patient Information Leaflet

• Sexually active men and women should use effective contraceptive methods during this period. Refer also to section 4.6.

Effect on fertility

• Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes.
• The development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy and gonadal function status at the time of treatment.
• Cyclophosphamide-induced sterility may be irreversible in some patients.

Female patients

• A significant proportion of women treated with cyclophosphamide develop amenorrhea, transient or permanent, associated with decreased estrogen secretion and increased gonadotropin secretion.
• In particular, amenorrhea may be permanent in older women.
• Oligomenorrhea has also been reported in association with cyclophosphamide treatment.
• Girls treated with cyclophosphamide in prepuberty generally develop normal secondary sexual characteristics and have regular cycles.
• Girls treated with cyclophosphamide in prepuberty have subsequently conceived children.
• Girls treated with cyclophosphamide who maintained ovarian function after discontinuation of treatment have an increased risk of developing premature menopause (cessation of cycles before age 40).

Male patients

• Men treated with cyclophosphamide may develop oligospermia or azoospermia, which are normally associated with increased gonadotropin secretion but normal testosterone secretion.
• Sexual potency and libido are generally not compromised in these patients.
• Boys treated with cyclophosphamide in prepuberty may develop normal secondary sexual characteristics but may have oligospermia or azoospermia.
• Testicular atrophy may occur at various levels.
• Cyclophosphamide-induced azoospermia is reversible in some patients, although reversibility may not occur for several years after discontinuation of therapy.
• Men rendered temporarily sterile by cyclophosphamide have subsequently conceived children.
• Since treatment with Endoxan Baxter may increase the risk of permanent infertility in men, they should be informed about sperm preservation before treatment.

Anaphylactic reactions, cross-sensitivity with other alkylating agents

• Anaphylactic reactions, including those with fatal outcomes, have been reported in association with cyclophosphamide.

Endoxan Baxter Patient Information Leaflet

• Cross-sensitivity with other alkylating agents has been reported.

Impairment of wound healing

• Cyclophosphamide may interfere with the normal wound healing process.

PRECAUTIONS
Alopecia

• Alopecia has been reported and may occur more commonly with increasing dosage.
• Alopecia may progress to baldness.
• Hair should regrow after treatment with the medicinal product or even during treatment, although it may differ in texture and color.

Nausea and Vomiting

• Administration of cyclophosphamide may cause nausea and vomiting. Current guidelines on the use of antiemetics for the prevention and management of nausea and vomiting should be considered.
• Alcohol may increase the emetic effects and nausea induced by cyclophosphamide; therefore, alcohol consumption should be avoided in patients treated with cyclophosphamide.

Stomatitis

• Administration of cyclophosphamide may cause stomatitis (oral mucositis).
• Current guidelines for the prevention and management of stomatitis should be considered.
• Particular attention should be paid to oral hygiene to reduce the incidence of stomatitis.

Paravenous administration

• Since the cytostatic effect of Endoxan Baxter occurs after its activation, which takes place mainly in the liver, there is only a minimal risk of tissue damage in case of accidental paravenous administration. Note: In case of accidental paravenous injection, immediately stop the infusion, aspirate the extravasated liquid with the applied cannula and take other appropriate measures, e.g., irrigate the area with saline solution and immobilize the limb.

Use in patients with renal impairment
In patients with renal impairment, especially if severe, reduced renal elimination may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be taken into account when determining the dosage for these patients. Refer also to section 4.2.
Use in patients with hepatic impairment
Severe hepatic impairment may be associated with reduced activation of cyclophosphamide.
This may alter the efficacy of cyclophosphamide therapy and should be taken into account
Endoxan Baxter Patient Information Leaflet
when determining the dosage and interpreting the response to the selected dosage. Alcohol abuse may increase the risk of developing hepatic dysfunction.
Use in adrenalectomized patients
Patients with adrenal insufficiency may require an increased dosage of corticosteroid replacement if exposed to the stress caused by cytotoxic toxicity, including cyclophosphamide.
Diagnostic tests
Blood glucose levels should be monitored regularly in diabetic patients to allow timely adjustment of antidiabetic therapy (refer also to the section "Interactions")
INTERACTIONS
Inform your doctor or pharmacist if you have recently taken any other medicinal products, including those without prescription.
Planned concomitant or subsequent administration of other substances or treatments that could increase the likelihood or severity of toxic effects (through pharmacodynamic or pharmacokinetic interactions) requires careful individual assessment of expected benefits and risks. Patients receiving such combinations should be closely monitored for symptoms of toxicity to allow timely intervention. Patients treated with cyclophosphamide and agents that reduce its activation should be monitored for potential reduction in therapeutic efficacy and the need for dosage adjustment.
Interactions affecting the pharmacokinetics of cyclophosphamide and its metabolites

• The hypoglycemic effect of sulfonylureas may be intensified, as well as the myelosuppressive action, when allopurinol or hydrochlorothiazide is administered simultaneously.
• Reduced activation of cyclophosphamide may alter the efficacy of cyclophosphamide treatment. Substances that delay the activation of cyclophosphamide include: o Aprepitant o Bupropion o Busulfan: Administration of Endoxan Baxter at high doses within 24 hours of high-dose busulfan treatment may cause reduced clearance and prolonged elimination half-life of cyclophosphamide. o Ciprofloxacin: Administration of fluorquinolone-based antibiotics (e.g., ciprofloxacin) before the start of Endoxan Baxter treatment (especially in conditioning prior to bone marrow transplantation) may reduce the efficacy of Endoxan Baxter and thus lead to worsening of the primary disease. o Chloramphenicol: Concomitant administration of chloramphenicol leads to prolonged halving of cyclophosphamide and delayed metabolism. o Fluconazole, Itraconazole: Azole antifungals (fluconazole, itraconazole) are known to inhibit the metabolism of cyclophosphamide by cytochrome P450. Increased exposure to toxic metabolites of Endoxan Baxter has been observed in patients treated with itraconazole. o Prasugrel o Sulfonamides o Thiotepa: In high-dose chemotherapy regimens, strong inhibition of the bioactivation of cyclophosphamide by thiotepa has been observed when administered one hour

Endoxan Baxter Patient Information Leaflet
before Endoxan Baxter. The sequence and timing of administration of these two agents may be of fundamental importance.

• Increased concentration of cytotoxic metabolites may occur with: o Allopurinol o Chloral hydrate o Cimetidine o Disulfiram o Glyceraldehyde o Inducers of human hepatic and extrahepatic microsomal enzymes (e.g., cytochrome P450 enzymes): Potential induction of hepatic and extrahepatic microsomal enzymes should be considered in case of previous or concomitant treatment with substances known to induce increased activity of such enzymes, such as rifampicin, phenobarbital, carbamazepine, benzodiazepines, phenytoin, St. John's wort and corticosteroids. o Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. In patients receiving cyclophosphamide, doxorubicin and etoposide (CDE), the use of protease inhibitor-based treatments was associated with a higher incidence of infections and neutropenia compared to NNRTI-based treatments. o Ondansetron: Pharmacokinetic interactions between ondansetron and Endoxan Baxter (at high doses) have been observed, resulting in decreased AUC (area under the curve) for cyclophosphamide.
• Since grapefruit contains a compound capable of inhibiting the activation of cyclophosphamide and consequently its efficacy, patients should not consume grapefruit or grapefruit juice.

Pharmacodynamic interactions and interactions with unknown mechanism affecting the use of cyclophosphamide
Combination or subsequent use of cyclophosphamide and other agents with similar toxicity may cause combined toxic effects (increased).

• Increased hematotoxicity and/or immunosuppression may result from the combination of effects of cyclophosphamide and, for example: o ACE inhibitors: ACE inhibitors may cause leukopenia. o Natalizumab o Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after a paclitaxel infusion o Thiazide diuretics o Zidovudine
• Increased cardiotoxicity may result from the combination of effects of cyclophosphamide and, for example: o Anthracyclines o Pentostatin o Cytarabine - Administration of high doses of Endoxan Baxter and cytarabine on the same day, i.e., within a very short time interval, may lead to potentiation

Endoxan Baxter Patient Information Leaflet
of the cardiotoxic effect, considering that each substance is already cardiotoxic per se.
o Radiotherapy to the cardiac region.
o Trastuzumab

• Increased pulmonary toxicity may result from the combination of effects of cyclophosphamide and, for example: o Amiodarone o G-CSF o GM-CSF (granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor): Reports suggest an increased risk of pulmonary toxicity (pneumonitis, alveolar fibrosis) in patients undergoing chemotherapy with cytotoxic agents including Endoxan Baxter and G-CSF or GM-CSF.
• Increased nephrotoxicity may result from the combination of effects of cyclophosphamide and, for example: o Amphotericin B o Indomethacin: Simultaneous administration of indomethacin should be performed with utmost caution, as acute water intoxication has been observed in a single case.
• Increase in other toxicities: o Azathioprine: Increased risk of hepatotoxicity (liver necrosis) Busulfan: higher incidence of veno-occlusive disease and mucositis. o Protease inhibitors: increased incidence of mucositis.

Other interactions:

• Alcohol: In tumor-bearing animals, reduced antitumor activity has been observed with concomitant ethanol (alcohol) intake at low oral doses of cyclophosphamide. In some patients, alcohol may increase the emetic effects and nausea induced by cyclophosphamide.
• Etanercept: In patients with Wegener's granulomatosis, addition of etanercept to standard treatment with cyclophosphamide was associated with a higher incidence of non-cutaneous solid tumors.
• Metronidazole: Acute encephalopathy was observed in a patient treated with cyclophosphamide and metronidazole. The causal association is unclear. In an animal study, the combination of cyclophosphamide and metronidazole was associated with increased toxicity of cyclophosphamide.
• Tamoxifen: Simultaneous use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

Interactions affecting the pharmacokinetics and/or action of other medicinal products

• Bupropion: Metabolism of cyclophosphamide by CYP2B6 may inhibit bupropion metabolism.
• Coumarins: Both increased and decreased effects of warfarin have been reported in patients treated with warfarin and cyclophosphamide.

Endoxan Baxter Patient Information Leaflet

• Cyclosporine: In patients treated with a combination of Endoxan Baxter and cyclosporine, lower serum concentrations of cyclosporine were observed compared to patients receiving cyclosporine alone. This interaction could result in increased incidence of rejection reactions.
• Depolarizing muscle relaxants: If depolarizing muscle relaxants (e.g., succinylcholine halides) are applied simultaneously, prolonged apnea may result from significant and persistent inhibition of cholinesterase activity. If the patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist must be informed.
• Digoxin, -acetyldigoxin: It has been reported that cytostatic treatment alters intestinal absorption of digoxin and -acetyldigoxin tablets.
• Vaccines: Since cyclophosphamide has immunosuppressive effects, patients may show a reduced response to concomitant vaccinations; vaccination with live vaccines may be associated with vaccine-induced infection.
• Verapamil: It has been reported that cytostatic treatment alters intestinal absorption of orally administered verapamil.

SPECIAL WARNINGS
Fertility, pregnancy and lactation
Consult your doctor or pharmacist before taking any medicinal product

• Passage of Endoxan Baxter through the maternal placenta should be considered. Treatment with cyclophosphamide may cause genotypic abnormalities in men and women.
• If life-threatening risks arise for the patient during the first trimester of pregnancy, it is absolutely necessary to consult a doctor regarding termination of pregnancy.
• Malformations have been reported in children born to mothers treated with cyclophosphamide during the first trimester of pregnancy. However, children without malformations have also been reported born to women exposed during the first trimester.
• After the first trimester of pregnancy, if therapy cannot be delayed and the patient wishes to continue the pregnancy, chemotherapy may be considered after informing the patient of the lower but possible risk of teratogenic effects.
• In utero exposure to cyclophosphamide may cause pregnancy termination, fetal growth retardation and fetotoxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia and gastroenteritis.
• During treatment with Endoxan Baxter and up to 6 months after the end of treatment, women should avoid pregnancy and men should avoid conceiving children.
• Results of animal studies suggest that an increased risk of pregnancy termination and malformations may persist after discontinuation of cyclophosphamide treatment as long as oocytes/follicles exposed to cyclophosphamide at any stage of maturation are present.
• If cyclophosphamide is used during pregnancy or if the patient becomes pregnant while taking this medicinal product or after discontinuation of treatment, the patient should be informed of the potential risks to the fetus.
• Since cyclophosphamide passes into breast milk, mothers should not breastfeed during therapy. Neutropenia, thrombocytopenia, low hemoglobin values and diarrhea have been reported in infants breastfed by women treated with cyclophosphamide.
• Men to be treated with Endoxan Baxter should be informed about sperm preservation before treatment.

Endoxan Baxter Patient Information Leaflet
Effects on ability to drive vehicles and use of machinery
Due to the possibility of side effects arising from the administration of cyclophosphamide, such as nausea, vomiting, dizziness, blurred vision and visual disturbances that may impair the ability to drive or use machinery, the physician should decide on an individual basis regarding the patient's ability to drive vehicles or operate machinery
Important information on some excipients
The tablets contain lactose and sucrose; therefore, in case of confirmed sugar intolerance, contact your physician before taking the medicinal product.
DOSAGE, METHOD AND DURATION OF ADMINISTRATION

• Endoxan Baxter should be administered only by medical personnel experienced in oncology.
• Treatment generally starts with intravenous injections. If these are not possible, Endoxan Baxter may be injected intramuscularly. In special cases, intrapleural, intraperitoneal or local application is possible. For prolonged treatment or maintenance therapy, after symptom regression, oral administration is recommended.
• Activation of cyclophosphamide requires hepatic metabolism; therefore, administration should preferably be oral or intravenous. Parenteral use
• Medicinal products for parenteral use should be visually inspected before administration for the presence of particulate matter and discoloration of the solution, when the solution and container permit.
• Intravenous administration should preferably be performed as an infusion.
• To reduce the likelihood of adverse reactions that appear to be related to the rate of administration (e.g., facial swelling, headache, nasal congestion, scalp inflammation), the medicinal product should be injected or infused very slowly. In addition, the duration of infusion should be appropriate for the volume and type of carrier solution to be infused.
• If injected directly, Endoxan Baxter solution must be reconstituted with physiological saline (sodium chloride 0.9%). To prepare the injectable solution, follow the instructions in section 6.6
• Before parenteral administration, the medicinal product must be completely dissolved.

Dosage should be adjusted to the needs of each individual patient, taking into account general reactions and blood picture.
If not otherwise prescribed, the following dosages are recommended:
a) continuous treatment: 3-6 mg/kg body weight (equivalent to 120 – 240 mg/m² body surface area) i.v.;
b) intermittent therapy every 2-5 days: 10-15 mg/kg body weight (equivalent to 400 – 600 mg/m² body surface area) i.v.;
c) intermittent therapy every 10-20 days: 20 to 40 mg/kg body weight (equivalent to 800 – 1600 mg/m² body surface area) i.v.
The duration of therapy and intervals between administrations will depend on indications, other oncological medicinal products possibly associated with cyclophosphamide, the patient's general condition and laboratory parameters, particularly blood counts.
For maintenance therapy, 50-200 mg daily (1-4 coated tablets) are administered; if necessary, higher doses may be administered.
Endoxan Baxter Patient Information Leaflet
Sufficient amounts of fluids should be ingested or infused during or immediately after administration to stimulate diuresis and reduce the risk of urinary tract toxicity. Therefore, the medicinal product should preferably be taken in the morning. It is important to ensure that the patient empties the bladder at regular intervals.
The dosages listed above mainly refer to treatments in which the active substance cyclophosphamide is used as monotherapy.
If Endoxan Baxter is combined with other cytostatics of similar toxicity, dosage reduction or extension of intervals may be necessary.
It may be assumed that the use of agents stimulating hematopoiesis (colony-stimulating factors and erythropoiesis-stimulating agents) reduces the risk of myelosuppressive complications and/or helps facilitate administration of the scheduled dosage.
Recommendations for dose reduction in patients with myelosuppression

Dosage adjustment recommendations in patients with hepatic or renal impairment

• Severe hepatic or renal impairment requires dose reduction.
• Severe hepatic impairment may be associated with reduced activation of cyclophosphamide. This may alter the efficacy of cyclophosphamide therapy and should be taken into account when determining the dose and interpreting the response to the selected dose.
• In patients with renal impairment, especially if severe, reduced renal elimination may result in increased plasma levels of cyclophosphamide and its metabolites. This may lead to increased toxicity and should be considered when determining the dose for these patients.
• A 25% dose reduction is recommended for serum bilirubin levels between 3.1 and 5 mg/100 ml, and a 50% reduction for glomerular filtration rate below 10 ml/min.
• Cyclophosphamide and its metabolites are dialyzable, although clearance may vary depending on the type of dialysis technique used. In patients requiring dialysis, a significant interval should be maintained between cyclophosphamide administration and dialysis session.

Elderly

• In elderly patients, monitoring for toxicity and the need for dose adjustment should reflect the higher frequency of impaired hepatic, renal, cardiac, or other organ function, as well as the presence of concomitant diseases or therapies with other medicinal products.

Handling

• Handling and preparation of cyclophosphamide must always be performed in accordance with current guidelines for the safe handling of cytotoxic agents.
• The tablet coating prevents direct contact with the active substance for those handling the tablets. To prevent unintentional exposure of third parties to the active substance, tablets must not be divided or crushed.

Endoxan Baxter Package leaflet
Preparation of the injectable solution:
Endoxan Baxter for intravenous use is supplied in Type III glass vials. To prepare the injectable solution, add the following volume of physiological saline (sodium chloride 0.9%) to the dry powder:

Before parenteral administration, the substance must be completely dissolved.
The substance dissolves easily if the vials, after addition of the solvent (physiological solution), are shaken vigorously for about one minute.
If the substance does not dissolve immediately and leaves residues, it is advisable to let the solution stand for a few minutes until it becomes clear. When injecting the solvent into the vial, hyperpressure may develop, which can be avoided by inserting a second sterile needle into the rubber stopper to allow air to escape from the vial.
Cyclophosphamide reconstituted in water is hypotonic and must not be injected directly.
When administered by infusion, cyclophosphamide may be reconstituted by adding sterile water and infused into the recommended intravenous solutions.
The medicinal product is compatible with the following infusion solutions: sodium chloride solution, glucose solution, sodium chloride and glucose solution, sodium chloride and potassium chloride solution, potassium chloride and glucose solution.
The solution should be administered as soon as possible after preparation. Stability of the solution: 2 to 3 hours.
OVERDOSE

• Serious consequences of overdose include dose-dependent toxic manifestations such as myelosuppression, urotoxicity, cardiotoxicity (including heart failure), hepatic veno-occlusive disease, and stomatitis. Refer to section 4.4.
• Since no specific antidote for cyclophosphamide is known, extreme caution is advised whenever this drug is used.
• Cyclophosphamide can be dialyzed. Therefore, in cases of overdose or accidental or suicidal intoxication, prompt hemodialysis is indicated. A dialysis clearance of 78 ml/min has been calculated based on the concentration of unmetabolized cyclophosphamide in the dialysate (normal renal clearance is about 5–11 ml/min). Another study group reported a value of 194 ml/min. After 6 hours of dialysis, 72% of the administered dose of cyclophosphamide was found in the dialysate.
• Overdose may result, among other reactions, in myelosuppression, predominantly leukopenia. The severity and duration of myelosuppression depend on the extent of the overdose. Frequent blood count monitoring and patient surveillance are required. In case of neutropenia, infection prophylaxis should be implemented and antibiotics administered. If thrombocytopenia develops, platelet transfusions should be provided as needed.

Endoxan Baxter Package leaflet

• It is essential to initiate prophylaxis against cystitis with Uromitexan (mesna), which may help prevent or limit urotoxic effects due to cyclophosphamide overdose. In case of accidental ingestion/overdose of ENDOXAN BAXTER, contact your doctor immediately or go to the nearest hospital.

UNDESIRABLE EFFECTS
Like all medicines, ENDOXAN BAXTER can cause undesirable effects, although not everybody experiences them.
Adverse reactions from clinical studies
The list of adverse reactions related to cyclophosphamide is based on post-marketing data (see below).
Post-marketing adverse reactions
Frequency is based on the following scale: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (adverse reactions reported from post-marketing experience).

Endoxan Baxter Package leaflet

Endoxan Baxter Package Leaflet

Endoxan Baxter Package leaflet

Endoxan Baxter Patient Information Leaflet

Endoxan Baxter Package leaflet

Following the instructions in this leaflet reduces the risk of adverse effects.
If any of the side effects worsen, or if you notice any side effects not listed in this leaflet, inform your doctor or pharmacist.
EXPIRY DATE AND STORAGE:
Expiry date: see the date printed on the packaging.
The expiry date refers to the product in its original, unopened packaging stored under recommended conditions.
WARNING: Do not use this medicine after the expiry date stated on the packaging.
Endoxan Baxter Patient Information Leaflet
Store this medicine at a temperature not exceeding +25°C.
Vials must not be stored at temperatures above the recommended limit, as this may cause degradation of the active substance, which can be identified by a yellowish discoloration of the vial contents, possibly appearing as a melted substance.
Doctors or healthcare professionals must not use vials whose contents have the appearance described above.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
KEEP THIS MEDICINE OUT OF SIGHT AND REACH OF CHILDREN
COMPOSITION
Endoxan Baxter 50 mg coated tablets
One coated tablet contains:
Active substance: Cyclophosphamide monohydrate 53.5 mg, equivalent to anhydrous Cyclophosphamide 50 mg;
Excipients: Glycerol 85%, Gelatin, Magnesium stearate, Talc, Dibasic calcium phosphate, Lactose, Maize starch; Other components (coating): Ethylene glycol ester of montanic acid, Polysorbate 20, Sodium carmellose, Povidone, Colloidal silica, Macrogol 35000, Calcium carbonate, Talc, Sucrose, Titanium dioxide.
Endoxan Baxter 200 mg Powder for injectable solution
One type III glass vial contains:
Active substance: Cyclophosphamide monohydrate 213.8 mg, equivalent to anhydrous Cyclophosphamide 200 mg;
Excipient: none.
Endoxan Baxter 500 mg Powder for injectable solution
One type III glass vial contains:
Active substance: Cyclophosphamide monohydrate 534.5 mg, equivalent to anhydrous Cyclophosphamide 500 mg;
Excipient: none.
Endoxan Baxter 1 g Powder for injectable solution
One type III glass vial contains:
Active substance: Cyclophosphamide monohydrate 1.069 g, equivalent to anhydrous Cyclophosphamide 1 g;
Excipient: none.
PHARMACEUTICAL FORM AND CONTENTS
Coated tablets and powder for injectable solution.
Endoxan Baxter 50 mg Coated tablets: 50 tablets in 5 blisters of 10 tablets each
Endoxan Baxter 200 mg Powder for injectable solution: 10 type III glass vials
Endoxan Baxter 500 mg Powder for injectable solution: 1 type III glass vial
Endoxan Baxter 1 g Powder for injectable solution: 1 type III glass vial
MARKETING AUTHORISATION HOLDER
Baxter S.p.A. – Piazzale dell’Industria, 20 - 00144 ROMA
MANUFACTURER
Coated tablets:
Baxter Oncology GmbH – D-33790 Halle (Germany)
Powder for injectable solution:
Baxter Oncology GmbH – D-33790 Halle (Germany)