Active ingredients: Cyclophosphamide
Endoxan Baxter 50 mg Coated tablets
Endoxan Baxter 200 mg Powder for solution for injection
Endoxan Baxter 500 mg Powder for solution for injection
Endoxan Baxter 1 g Powder for solution for injection
Why is Endoxan Baxter used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antineoplastic, analogues of nitrogen mustard
THERAPEUTIC INDICATIONS
Cytostatic treatment
Contraindications When Endoxan Baxter should not be used
Endoxan Baxter should not be given to patients with:
- hypersensitivity to the active substance, its metabolites or to any of the excipients
- severely impaired bone marrow function (particularly in patients who have undergone preliminary therapy with cytotoxic agents and / or radiotherapy),
- inflammation of the bladder (cystitis),
- obstruction of urinary flow,
- ongoing infections,
- during pregnancy and breastfeeding.
Precautions for use What you need to know before taking Endoxan Baxter
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 to treat life-threatening conditions. In these situations, an individual assessment of the expected benefit / risk ratio is necessary.
WARNINGS
Renal and urinary tract toxicity
- Haemorrhagic cystitis, pyelitis, urethritis and haematuria have been reported during cyclophosphamide therapy. Ulceration / necrosis of the bladder, fibrosis / contracture and secondary tumors may also develop.
- Urotoxicity may require discontinuation of treatment.
- In case of fibrosis, bleeding or secondary tumors, a cystectomy may be necessary.
- Cases of urotoxicity with fatal outcomes have been reported.
- Urotoxicity may occur in both short and long term cyclophosphamide treatments. Haemorrhagic cystitis has been reported after a single dose of cyclophosphamide.
- Subsequent or concomitant radiotherapy or busulfan treatment may increase the risk of cyclophosphamide-induced haemorrhagic cystitis.
- Generally, cystitis is initially sterile but secondary microbial colonization can occur.
- Before starting therapy, efferent urinary tract obstructions, cystitis and infections will need to be eliminated or corrected.
- Adequate therapy with Uromitexan (INN: mesna) or strong hydration can considerably reduce the frequency and severity of bladder toxicity. Ensure that patients empty their bladder at regular intervals.
- If cystitis associated with micro or macrohaematuria occurs during treatment with Endoxan Baxter, discontinue therapy with Endoxan Baxter until normalization. This usually happens a few days after stopping the medicine but cystitis can also persist.
- In the case of severe haemorrhagic cystitis, treatment with Endoxan Baxter should generally be discontinued.
- Cyclophosphamide has also been associated with nephrotoxicity including tubular necrosis.
- Hyponatremia associated with increased total body water, acute water intoxication and a SIADH-like syndrome (syndrome of insufficient secretion of antidiuretic hormone) have been reported in association with administration of cyclophosphamide. Fatal outcomes have also been reported.
- Patients with impaired renal function should be carefully monitored during treatment with Endoxan Baxter for the presence of erythrocytes and other signs of uro / nephrotoxicity (refer also to "Recommendations for dosage adjustment in patients with hepatic or renal insufficiency" in section "Dose, method and time of administration").
Myelosuppression, Immunosuppression, Infections
In general, Endoxan Baxter, like all other cytostatics, should be used with the utmost care in weak or elderly subjects, and in subjects who have previously undergone radiotherapy.
Individuals with weakened immune systems, such as those with diabetes mellitus, chronic liver or kidney disease, should also be closely monitored.
- Treatment with cyclophosphamide can 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 can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding) and anemia.
- Severe immunosuppression has led to severe, sometimes fatal infections. Sepsis and septic shock have also been reported. Infections reported with cyclophosphamide include both pneumonia and other infections of bacterial, fungal, viral, protozoal and parasitic origin.
- Latent infections can be reactivated. Reactivation has been reported for various infections of bacterial, fungal, viral, protozoal and parasitic origin.
- Infections must be treated appropriately.
- At the discretion of the treating physician, antimicrobial prophylaxis may be indicated in some cases of neutropenia.
- In case of neutropenic fever and / or leukopenia, antibiotics and / or antifungals should be administered as prophylaxis.
- If necessary, cyclophosphamide should be used with caution in patients with severe impairment of bone marrow function 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 decrease in peripheral blood cell and platelet counts and the time required for recovery is greater the higher the dosage.
- The lowest leukocyte and platelet counts usually occur one to two weeks after the start of treatment. The bone marrow recovers relatively quickly and blood values normally normalize after about 20 days.
- Therefore, it is advisable that, during treatment, all patients perform a careful haematological check with blood counts performed regularly. o Prior to each administration and at appropriate intervals, if necessary every day, white blood cell and platelet counts and hemoglobin values should be checked. o Leukocyte checks must be carried out regularly during treatment, at intervals of 5-7 days at the start of treatment and every 2 days if the count falls below 3000 / mm3 (also refer to the paragraph "Dose, method and time of administration ").
- Unless 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 urine sediment is also recommended for the presence of erythrocytes.
Cardiotoxicity, Use in patients with heart disease
- Myocarditis and myopicarditis have been reported during treatment with cyclophosphamide, which may be accompanied by significant pericardial effusion and cardiac tamponade and have led to severe, sometimes fatal, congestive heart failure.
- Histopathological examination showed mainly haemorrhagic myocarditis. Hemopericardium occurred as a secondary effect to haemorrhagic myocarditis and myocardial necrosis.
- Acute cardiac toxicity was 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 elongations 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 patients of advanced age and in patients who had had previous radiotherapy to the cardiac region and / or concomitant treatment with anthracyclines and pentostatin or other cardiotoxic agents (refer to section 4.5). ) can intensify the cardiotoxic effect of Endoxan Baxter. In this context, it will be necessary to have an electrolyte check regularly and to pay particular attention to patients with a "history of heart disease."
Pulmonary toxicity
- Pneumonia and pulmonary fibrosis have been reported concurrently with or subsequent to cyclophosphamide treatment. Pulmonary veno-occlusive diseases 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 of pneumonia (more than 6 months after starting treatment with cyclophosphamide) appears to be associated with particularly high mortality. Pneumonia can also arise years after treatment with cyclophosphamide.
- Acute pulmonary toxicity has been reported after a single dose of cyclophosphamide.
Secondary tumors
- As with cytostatic therapy in general, treatment with cyclophosphamide also carries the risk of secondary tumors and their precursors as late consequences.
- Increases the risk of developing urinary tract carcinoma as well as myelodysplastic changes that partly progress to acute leukemia. Other cancers reported after using cyclophosphamide or cyclophosphamide treatments include lymphoma, thyroid cancer and sarcomas.
- In some cases, the secondary cancer developed several years after cyclophosphamide treatment was terminated. Tumors have also been reported following in utero exposure.
- The risk of bladder cancer can be significantly reduced by preventing hemorrhagic cystitis.
Veno-occlusive pathology of the liver
- Veno-occlusive liver disease (VOLD) has been reported in patients given cyclophosphamide.
- .. Cytoreductive treatment in preparation for bone marrow transplantation, which consists of cyclophosphamide in combination with integral irradiation, busulfan or other agents, has been identified as the major risk factor for developing VOLD (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, the gradual development of VOLD has been reported in patients treated long-term with low-dose immunosuppressive doses of cyclophosphamide.
- As a complication of VOLD, hepatorenal syndrome and multiorgan failure can develop. A fatal outcome has been reported for cyclophosphamide-associated VOLD.
- Risk factors that predispose a patient to developing VOLD with high-dose cytoreductive therapies include: o pre-existing liver function disorders o radiation therapy of the abdomen and low performance score.
Genotoxicity
- Endoxan Baxter is genotoxic and mutagenic in both male and female somatic and germ cells. Therefore, women should avoid becoming pregnant and men should avoid conceiving children while taking Endoxan Baxter.
- Men should avoid conceiving children for up to 6 months after stopping treatment.
- Animal studies indicate that oocyte exposure during follicular development may result in a lower rate of implantation and non-risk pregnancies and a greater risk of malformations. This effect should be taken into account in the event of fertilization or pregnancy. voluntary after cessation of cyclophosphamide treatment The exact duration of follicular development in humans is not known, but may be longer than 12 months.
- Sexually active men and women will need to use effective methods of contraception during this period. Refer also to section 4.6.
Effect on fertility
- Cyclophosphamide interferes with oogenesis and spermatogenesis. It could cause infertility in both sexes.
- The development of infertility appears to depend on the dose of cyclophosphamide, the duration of therapy and the state of gonadal function at the time of treatment.
- Cyclophosphamide-induced sterility may be irreversible in some patients.
Female patients
- Transient or permanent amenorrhea, associated with decreased estrogen secretion and increased gonadotropin secretion, develops in a significant proportion of women treated with cyclophosphamide.
- In particular, for more mature women, amenorrhea can be permanent.
- Oligomenorrhea has also been reported in association with cyclophosphamide treatment.
- Girls treated with cyclophosphamide in prepubescence generally develop secondary sexual characteristics normally and have regular cycles.
- Girls treated with cyclophosphamide in prepubescence subsequently conceived children.
- Girls treated with cyclophosphamide who have maintained ovarian function after stopping treatment have a higher risk of developing premature menopause (interruption of the cycle 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 impaired in these patients.
- Boys treated with prepubescence cyclophosphamide may develop secondary sexual characteristics normally but may have oligospermia or azoospermia.
- Testicular atrophy may occur to varying degrees.
- Cyclophosphamide-induced azoospermia is reversible in some patients, although reversibility may not occur for several years after discontinuation of therapy.
- Men made temporarily sterile by cyclophosphamide later conceived children.
- As treatment with Endoxan Baxter may increase the risk of permanent infertility in men, men should be informed about sperm storage prior to treatment.
Anaphylactic reactions, cross-sensitivity with other alkylating agents
- Anaphylactic reactions including those with fatal outcomes have been reported in association with cyclophosphamide.
- Possible cross-sensitivity with other alkylating agents has been reported.
Alteration of the wound healing process
- Cyclophosphamide can interfere with the normal wound healing process.
PRECAUTIONS
Alopecia
- Alopecia has been reported and may occur more commonly with increasing dosage.
- Alopecia can progress to baldness.
- Hair should grow back after treatment with the medicine or even during treatment although it may differ in texture and color.
Nausea and vomit
- Administration of cyclophosphamide can cause nausea and vomiting.
- Current guidelines should be taken into consideration. on the use of antiemetics for the prevention and improvement of nausea and vomiting.
- Alcohol may increase the emetic effects and nausea induced by cyclophosphamide; for these reasons, alcohol consumption should be avoided in patients treated with cyclophosphamide.
Stomatitis
- Administration of cyclophosphamide can cause stomatitis (oral mucositis)
- Current guidelines for the prevention and improvement of stomatitis should be taken into consideration.
- Pay particular attention 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 administration by paravenous injection, immediately stop the infusion, aspirate the liquid transferred with the cannula applied and take other appropriate measures, eg irrigate the area with saline solution and immobilize the extremity. Use in patients with renal insufficiency In patients with renal insufficiency, particularly if severe, the decreased renal elimination may result in an increase in plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be taken into consideration when determining the dosage for this type of patient. Refer also to section 4.2.
Use in patients with hepatic insufficiency
Severe hepatic insufficiency may be associated with decreased activation of cyclophosphamide. This can alter the efficacy of cyclophosphamide therapy and should be taken into account in determining the dosage and interpreting the response to the chosen dosage. Alcohol abuse can increase the risk of developing liver dysfunction.
Use in adrenalectomised patients
Patients with adrenal insufficiency may require increased corticoid replacement dosage if exposed to stress resulting from the toxicity of cytostatics, including cyclophosphamide.
Diagnostic investigations
The blood sugar level must be checked regularly in diabetic patients in order to be able to promptly adapt the antidiabetic therapy (also refer to the paragraph "Interactions")
Interactions Which drugs or foods may change the effect of Endoxan Baxter
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
The concomitant or subsequent planned administration of other substances or treatments that could increase the likelihood or severity of toxic effects (through pharmacodynamic or pharmacokinetic interactions) requires careful individual consideration of the expected benefits and risks. Patients receiving such combinations should be carefully monitored for symptoms of toxicity and thus allow for prompt intervention. Patients treated with cyclophosphamide and agents that reduce its activation should be monitored for a 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 can 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 retard the activation of cyclophosphamide include:
- Openspitant
- Bupropion
- Busulfan: Administration of high-dose Endoxan Baxter within 24 hours of treatment with high-dose busulfan may result in decreased clearance and an "extension of the elimination half-life" of cyclophosphamide.
- Ciprofloxacin: Administration of fluoroquinolone-based antibiotics (such as ciprofloxacin) before the start of treatment with Endoxan Baxter (especially in the case of conditioning prior to a bone marrow transplant) may reduce the effectiveness of Endoxan Baxter and therefore give rise to a worsening of the primary pathology.
- Chloramphenicol: Concomitant administration of chloramphenicol leads to prolonged halving of cyclophosphamide and delayed metabolism.
- Fluconazole, Itraconazole: Azole antifungals (fluconazole, itraconazole) are known to inhibit the cytochrome P450 metabolising activity of cyclophosphamide. Increased exposure to the toxic metabolites of Endoxan Baxter has been observed in patients treated with itraconazole.
- Prasugrel
- Sulfonamides
- Thiotepa: Strong inhibition of the bioactivation of cyclophosphamide by thiotepa has been observed in high dose chemotherapy regimens when administered one "hour prior to Endoxan Baxter. The sequence and timing of administration of these two agents may be critical factors. importance.
An increase in the concentration of cytotoxic metabolites may occur with:
- Allopurinol
- Chloral hydrate
- Cimetidine
- Disulfiram
- Glyceraldehyde
- Inducers of human hepatic and extrahepatic microsomal enzymes (eg cytochrome P450 enzymes): The potential induction of hepatic and extrahepatic microsomal enzymes should be taken into account in case of previous or concomitant treatment with substances that are known to induce increased activity of such enzymes as rifampicin, phenobarbital, carbamazepine, benzodiazepines, fentoin, St. John's wort and corticosteroids.
- Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. In patients administered cyclophosphamide, doxorubicin and etoposide (CDE), the use of protease inhibitor treatments has been found to be associated at a higher incidence of infections and neutropenia than with the use of an NNRTI-based treatment.
- Ondansetron: Pharmacokinetic interactions have been detected between ondansetron and Endoxan Baxter (at high doses) 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 effectiveness, the patient should not consume grapefruit or grapefruit juice.
Pharmacodynamic interactions and interactions with unknown mechanisms affecting the use of cyclophosphamide
The combination or subsequent use of cyclophosphamide and other agents with similar toxicities may cause combined (major) toxic effects.
An increase in haematotoxicity and / or immunosuppression may result from the combination of the effects of cyclophosphamide and, for example:
- ACE inhibitors: ACE inhibitors can cause leukopenia.
- Natalizumab
- Paclitaxel: Increased haematotoxicity has been reported when cyclophosphamide was administered following an infusion with paclitaxel.
- Diuretics based on thiazide or Zidovudine
Increased cardiotoxicity may result from the combination of the effects of cyclophosphamide and, for example:
- Anthracyclines
- Pentostatin
- Cytarabine - The administration of high dosages of Endoxan Baxter and cytarabine on the same day, therefore in a very limited time interval, may result in an enhancement of the cardiotoxic effect, taking into account that each substance is already cardiotoxic in itself.
- Radiotherapy to the heart region.
- Trastuzumab
An increase in pulmonary toxicity may result from the combination of the effects of cyclophosphamide and, for example:
- Amiodarone
- G-CSF or GM-CSF (granulocyte macrophage colony stimulating factor and granulocyte colony stimulating factor): Reports suggest an increased risk of pulmonary toxicity (pneumonia, alveolar fibrosis) in patients receiving chemotherapy with cytotoxics who they include Endoxan Baxter and G-CSF or GM-CSF.
An increase in nephrotoxicity may result from the combination of the effects of cyclophosphamide and, for example:
- Amphotericin B
- Indomethacin: Simultaneous administration of indomethacin should be carried out with the utmost care, as acute water intoxication was detected in a single case.
Increase in other toxicities:
- Azathioprine: Increased risk of hepatotoxicity (liver necrosis) Busulfan: increased incidence of veno-occlusive pathologies and mucositis.
- Protease inhibitors: increased incidence of mucositis
Other interactions:
- Alcohol: Reduced antitumor activity was observed in animals with cancer when ethanol (alcohol) was taken concomitantly with 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, the addition of etanercept to standard cyclophosphamide treatment was associated with a higher incidence of non-cutaneous solid tumors.
- Metronidazole: Acute encephalopathy has been 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 the action of other medicinal products
- Bupropion: The metabolism of cyclophosphamide by CYP2B6 may inhibit the metabolism of bupropion.
- Coumarins: Both increased and decreased effect of warfarin have been reported in patients treated with warfarin and cyclophosphamide.
- Ciclosporins: In patients treated with a combination of Endoxan Baxter and cyclosporine, a lower serum concentration of cyclosporine was found than in patients administered cyclosporine alone. The interaction could result in an increased incidence of rejection reactions.
- Depolarizing muscle relaxants: If depolarizing muscle relaxants (eg succinylcholine halides) are applied simultaneously, prolonged "apnea caused by" significant and persistent inhibition of cholinesterase activity may result. If the patient was treated with cyclophosphamide within 10 days of a "general anesthesia, the anesthetist should be advised."
- Digoxin, β-acetyldigoxin: Cytostatic treatment has been reported to impair intestinal absorption of digoxin and β-acetyldigoxin tablets.
- Vaccines: Since cyclophosphamide has immunosuppressive effects, the patient may show a reduced response to concomitant vaccinations; vaccination with active vaccines may be associated with vaccine-induced infection.
- Verapamil: Cytostatic treatment has been reported to impair intestinal absorption of orally administered verapamil
Warnings It is important to know that:
Fertility, pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine
- A possible passage of Endoxan Baxter across the maternal placenta should be considered. Treatment with cyclophosphamide can cause genotype abnormalities in men and women.
- If there are any risks to the patient's life during the first trimester of pregnancy, it will be absolutely necessary to consult a doctor in order to terminate the pregnancy.
- Malformations have been reported in babies born to mothers treated with cyclophosphamide during the first trimester of pregnancy. However, children without malformations born to women exposed during the first trimester have also been reported.
- After the first trimester of pregnancy, if therapy cannot be delayed and the patient wishes to continue the pregnancy, chemotherapy may be used after informing the patient of the minor but possible risk of teratogenic effects.
- In utero exposure to cyclophosphamide may cause pregnancy termination, fetal growth retardation and fetotoxic effects occurring 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 becoming pregnant and men should avoid conceiving children.
- Results from animal studies suggest that an increased risk of pregnancy termination and malformations may persist after discontinuation of cyclophosphamide as long as there are oocytes / follicles that have been exposed to cyclophosphamide at any of the stages of maturation.
- If cyclophosphamide is used during pregnancy or if the patient becomes pregnant while taking this medicine or after stopping treatment, the patient should be informed of the potential risks to the fetus.
- Since cyclophosphamide passes into breast milk, mothers will not have to breastfeed during therapy. Neutropenia, thrombocytopenia, low hemoglobin and diarrhea have been reported in nursing infants of women receiving cyclophosphamide.
- Men who will be treated with Endoxan Baxter will need to be informed about sperm storage prior to treatment.
Effects on ability to drive and use machines
Due to the possibility of side effects resulting from cyclophosphamide administration, for example nausea, vomiting, dizziness, blurred vision and impaired vision which may impair the ability to drive or use machines, the physician will need to make an individual decision on the ability of the patient to drive vehicles or operate machinery
Important information about some of the ingredients
The tablets contain lactose and sucrose therefore in case of ascertained intolerance to sugars contact your doctor before taking the medicine.
Dosage and method of use How to use Endoxan Baxter: Dosage
- Endoxan Baxter should only be administered by medical personnel experienced in oncology.
- Treatment typically begins with intravenous injections. If the latter are not possible, Endoxan Baxter can be injected intramuscularly. In particular cases an intrapleural, intraperitoneal or in situ application is possible. For prolonged treatment or for maintenance dose therapy, after the regression of symptoms, oral administration is recommended.
- Activation of cyclophosphamide requires hepatic metabolism, therefore administration should preferably be done orally or intravenously.
Parenteral use
- Medicinal products to be used parenterally should be visually inspected prior to administration for the presence of particulate matter and discoloration of the solution, when the solution and container permit.
- Intravenous administration should preferably be given as an infusion.
- To reduce the likelihood of adverse reactions which appear to be related to the rate of administration (e.g. swelling of the face, headache, nasal congestion, inflammation of the scalp), the medicinal product should be injected or infused very slowly. In addition, the duration of the infusion should be adequate for the volume and type of transport solution to be infused.
- When injected directly, Endoxan Baxter solution must be reconstituted with physiological saline (0.9% sodium chloride). To prepare the solution for injection follow the instructions given in section 6.6
- Before parenteral administration, the medicinal product must be dissolved completely.
Dosage should be tailored to the needs of each individual patient, taking into account general reactions and blood picture. Unless otherwise prescribed, the following dosages are recommended:
a) continuous treatment: 3-6 mg / kg of body weight (equivalent to 120 - 240 mg / m2 of body surface) i.v .;
b) therapy at intervals of 2-5 days: 10-15 mg / kg of body weight (equivalent to 400 - 600 mg / m2 of body surface) i.v. ;
c) 10-20 day interval therapy: 20 to 40 mg / kg of body weight (equivalent to 800 - 1600 mg / m2 of body surface area) i.v.
The duration of therapy and the intervals between one administration and the other will depend on the indications, on the oncological drugs possibly associated with cyclophosphamide, on the general state of the patient, on the laboratory parameters in particular on the blood count.
For maintenance therapy 50-200 mg per day (1-4 coated tablets) are administered, if necessary higher doses can be administered.
Sufficient amounts of fluids to stimulate diuresis should be ingested or infused during or immediately after ingestion in order to reduce the risk of urinary toxicity. Therefore the medicinal product should preferably be taken in the morning. It is important to ensure that the patient provides the emptying of the bladder at regular intervals.
The posologies indicated above are mainly referred to treatments in which the active substance cyclophosphamide is used as mono-therapy. If Endoxan Baxter is combined with other cytostatics of similar toxicity, either a reduction in dosage or an extension of the interval periods may be necessary.
The use of hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) can be expected to reduce the risk of myelosuppressive complications and / or help facilitate the administration of the scheduled dosage.
Recommendations for dose reduction in patients with myelosuppression
Recommendations for dosage adjustment in patients with hepatic or renal insufficiency
- Severe hepatic or renal insufficiency requires a reduction in dosage.
- Severe hepatic insufficiency may be associated with decreased activation of cyclophosphamide. This can alter the efficacy of cyclophosphamide therapy and should be taken into account in determining the dosage and interpreting the response to the chosen dosage.
- In patients with renal insufficiency, particularly if severe, the decreased renal elimination may result in an increase in plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be taken into consideration when determining the dosage for this type of patient.
- A 25% reduction is recommended for serum bilirubin values between 3.1 and 5 mg / 100 mL and a 50% reduction for a glomerular filtration rate of less than 10 mL / minute.
- Cyclophosphamide and its metabolites are dialyzable, although there may be differences in clearance based on the type of dialysis technique used. In patients requiring dialysis, a significant interval should be maintained between administration of cyclophosphamide and the dialysis session.
Senior citizens
- In the elderly, monitoring for toxicity and the need for dosage adjustment should reflect the higher frequency of hepatic, renal, cardiac or other organ abnormalities and the concomitant presence of other diseases or therapy with other medicinal products.
Handling
- Handling and preparation of cyclophosphamide should always be performed in accordance with current guidelines for the safe handling of cytotoxic agents.
- The coating of the tablets prevents direct contact with the active ingredient by the people handling them. To prevent inadvertent exposure of third parties to the active substance, the tablets should not be divided or crushed.
Preparation of the solution for injection:
Endoxan Baxter for intravenous use is prepared in type III glass bottles. To prepare the solution for injection, the following amount of physiological solution (sodium chloride 0.9%) must be added to the dry powder:
Before parenteral administration the substance must be completely dissolved
The substance dissolves easily if the bottles, after the solvent (physiological solution) has been added, shake vigorously for half or one minute.
If the substance does not dissolve immediately without leaving residues, it is advisable to let the solution stand for a few minutes until it becomes clear. Injecting the solvent into the bottle produces an overpressure which can be avoided by introducing a second sterile needle into the rubber stopper so that the air escapes from the bottle.
Cyclophosphamide reconstituted in water is hypotonic and should not be injected directly.
When administered by infusion, cyclophosphamide can be reconstituted by adding sterile water and infused into the recommended intravenous solutions.
The medicinal product is compatible with the following solutions for infusion: 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 injected as soon as possible after preparation. Shelf life of the solution: from 2 to 3 hours.
Overdose What to do if you have taken too much Endoxan Baxter
- Serious consequences of overdose include manifestations of dose dependent toxicity such as myelosuppression, urotoxicity, cardiotoxicity (including heart failure), hepatic veno-occlusive disease and stomatitis. Refer to section 4.4.
- Since a specific antidote for cyclophosphamide is not known, it is advisable to proceed with great caution whenever it is used.
- Cyclophosphamide can be dialyzed. Therefore, in the event of overdose or accidental intoxication or for the purpose of suicide, rapid hemodialysis is therefore indicated. A dialysis clearance of 78 mL / min was calculated on the concentration of unmetabolized cyclophosphamide in the dialysate (normal renal clearance is approximately 5-11 mL / min). A second working 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.
- An overdose may result in myelosuppression, predominantly leukocytopenia, among other reactions. The severity and duration of myelosuppression depend on the extent of the overdose. Frequent checks of the blood count and monitoring of the patient are necessary. In case of neutropenia, prophylaxis of the infection and treat with antibiotics. If thrombocytopenia develops, ensure replacement of thrombocytes as needed.
- It is essential that cystitis prophylaxis is undertaken with Uromitexan (mesna) as it can help prevent or limit the urotoxic effects of an overdose of cyclophosphamide.
In case of accidental ingestion / intake of an overdose of ENDOXAN BAXTER, notify your doctor immediately or go to the nearest hospital.
Side Effects What are the side effects of Endoxan Baxter
Like all medicines, ENDOXAN BAXTER can cause side effects, although not everybody gets them.
Adverse reactions from clinical trials
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-
* including fatal outcomes
1 The following manifestations have been associated with myelosuppression and immunosuppression due to cyclophosphamide: increased risk and severity of pneumonia (including fatal outcomes), other bacterial, fungal, viral, protozoal and parasitic infections; reactivation of latent infections, including viral hepatitis, tuberculosis, JC virus with progressive multifocal leukoencephalopathy (including fatal outcomes), Pneumocystis jiroveci, herpes zoster, Strongyloides.
2 Acute myeloid leukemia, Acute promyelocytic leukemia
3 Non-Hodgkin's lymphoma
4 Myelosuppression manifests itself as bone marrow failure
5 complicated by bleeding
6 with thrombotic microangiopathy
7 Other cardiac pathologies are: congestive heart failure, left ventricular dysfunction, myocarditis, carditis. Pericardial effusion can progress to cardiac tamponade.
8 Other vascular pathologies: flushing
9 Other kidney diseases: Hemolytic Uremic Syndrome (HUS)
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date refers to the product in intact packaging, correctly stored. WARNING: do not use the medicine after the expiry date shown on the package.
Store the medicine at a temperature not exceeding + 25 ° C.
The bottles must not be stored at a temperature higher than that indicated as in this case there could be a degradation of the active ingredient identifiable by the yellowish color of the contents of the bottle which can take on the appearance of a melted substance.
Your doctor or healthcare professional should not use bottles whose contents have the appearance described above.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN
COMPOSITION
Endoxan Baxter 50 mg coated tablets
One coated tablet contains:
Active ingredient: Cyclophosphamide monohydrate 53.5 mg corresponding to anhydrous Cyclophosphamide 50 mg;
Excipients: 85% glycerol, gelatin, magnesium stearate, talc, dibasic calcium phosphate, lactose, corn starch;
Other components (coating): Ethylene glycol ester of montanic acid, Polysorbate 20, Carmellose sodium, Povidone, Colloidal silica, Macrogol 35000, Calcium carbonate, Talc, Sucrose, Titanium dioxide.
Endoxan Baxter 200 mg Powder for solution for injection
One type III glass bottle contains:
Active ingredient: Cyclophosphamide monohydrate 213.8 mg corresponding to anhydrous Cyclophosphamide 200 mg;
Excipient: none.
Endoxan Baxter 500 mg Powder for solution for injection
One type III glass bottle contains:
Active ingredient: Cyclophosphamide monohydrate 534.5 mg corresponding to anhydrous Cyclophosphamide 500 mg;
Excipient: none.
Endoxan Baxter 1 g Powder for solution for injection
One type III glass bottle contains:
Active ingredient: Cyclophosphamide monohydrate 1.069 g corresponding to anhydrous Cyclophosphamide 1 g; Excipient: none.
PHARMACEUTICAL FORM AND CONTENT
Coated tablets and powder for solution for injection.
Endoxan Baxter 50 mg Coated tablets: 50 tablets enclosed in 5 blisters of 10 tablets
Endoxan Baxter 200 mg Powder for solution for injection: 10 type III glass vials
Endoxan Baxter 500 mg Powder for solution for injection: 1 type III glass bottle
Endoxan Baxter 1 g Powder for solution for injection: 1 type III glass bottle
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ENDOXAN BAXTER
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Endoxan Baxter 50 mg Coated tablets
One coated tablet contains:
Active ingredient: Cyclophosphamide monohydrate 53.5 mg, corresponding to anhydrous cyclophosphamide 50 mg.
Excipients: lactose, sucrose
Endoxan Baxter 200 mg Powder for solution for injection
One type III glass bottle contains:
Active ingredient: Cyclophosphamide monohydrate 213.8 mg, corresponding to anhydrous cyclophosphamide 200 mg.
Endoxan Baxter 500 mg Powder for solution for injection
One type III glass bottle contains:
Active ingredient: Cyclophosphamide monohydrate 534.5 mg, corresponding to anhydrous cyclophosphamide 500 mg.
Endoxan Baxter 1 g Powder for solution for injection
One type III glass bottle contains:
Active ingredient: Cyclophosphamide monohydrate 1.069 g, corresponding to anhydrous cyclophosphamide 1 g.
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Powder for solution for injection.
Coated tablet.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Cytostatic treatment.
04.2 Posology and method of administration
• Endoxan Baxter should only be administered by medical personnel experienced in oncology.
• Treatment usually begins with intravenous injections. If the latter are not possible, Endoxan Baxter can be injected intramuscularly. In particular cases an intrapleural, intraperitoneal or in situ application is possible. For prolonged treatment or for maintenance dose therapy, after the regression of symptoms, oral administration is recommended.
• Activation of cyclophosphamide requires hepatic metabolism, therefore administration should preferably be done orally or intravenously.
Parenteral use
• Medicinal products to be used parenterally should be visually inspected prior to administration for the presence of particulate matter and discoloration of the solution, when the solution and container permit.
• Intravenous administration should preferably be given as an infusion.
To reduce the likelihood of adverse reactions which appear to be related to the rate of administration (e.g. swelling of the face, headache, nasal congestion, inflammation of the scalp), the medicinal product should be injected or infused very slowly. In addition, the duration of the infusion should be adequate for the volume and type of transport solution to be infused.
• If injected directly, Endoxan Baxter solution must be reconstituted with physiological saline (0.9% sodium chloride). To prepare the solution for injection follow the instructions given in section 6.6
• Before parenteral administration, the medicinal product must be dissolved completely.
Dosage should be tailored to the needs of each individual patient, taking into account general reactions and blood picture.
Unless otherwise prescribed, the following dosages are recommended.
For treatment, the following can be considered:
a) continuous treatment: 3-6 mg / kg of body weight (equivalent to 120 - 240 mg / m2 of body surface area) i.v.
b) therapy at intervals of 2-5 days: 10-15 mg / kg of body weight (equivalent to 400 - 600 mg / m2 of body surface) i.v.
c) 10-20 day interval therapy: 20 to 40 mg / kg of body weight (equivalent to 800 - 1600 mg / m2 of body surface area) i.v.
The duration of therapy and the intervals between one administration and the other will depend on the indications, on the oncological drugs possibly associated with cyclophosphamide, on the general state of the patient, on the laboratory parameters in particular on the blood count.
For maintenance therapy 50-200 mg per day (1-4 coated tablets) are administered, if necessary higher doses can be administered.
Sufficient amounts of fluids to stimulate diuresis should be ingested or infused during or immediately after administration in order to reduce the risk of urinary tract toxicity. Therefore, the medicinal product should preferably be taken in the morning. (refer to section 4.4). It is important to ensure that the patient empties his bladder at regular intervals. The posologies indicated above are mainly referred to treatments in which the active substance cyclophosphamide is used as mono-therapy.
If Endoxan Baxter is combined with other cytostatics of similar toxicity, either a reduction in dosage or an extension of the interval periods may be necessary.
The use of hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) can be expected to reduce the risk of myelosuppressive complications and / or help facilitate the administration of the scheduled dosage.
Recommendations for dose reduction in patients with myelosuppression
Recommendations for dosage adjustment in patients with hepatic or renal insufficiency
• Severe hepatic or renal insufficiency requires a reduction in dosage.
• Severe liver failure may be associated with decreased activation of cyclophosphamide. This can alter the efficacy of cyclophosphamide therapy and should be taken into account in determining the dosage and interpreting the response to the chosen dosage.
• In patients with renal insufficiency, particularly if severe, the decreased renal elimination may result in an increase in plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be taken into consideration when determining the dosage for this type of patient.
• A 25% reduction is recommended for serum bilirubin values between 3.1 and 5 mg / 100 mL and a 50% reduction for a glomerular filtration rate of less than 10 mL / minute.
• Cyclophosphamide and its metabolites are dialyzable, although there may be differences in clearance based on the type of dialysis technique used. In patients requiring dialysis, a significant interval should be maintained between administration of cyclophosphamide and the dialysis session.
Senior citizens
In the elderly, monitoring for toxicity and the need for dosage adjustment should reflect the higher frequency of hepatic, renal, cardiac or other organ abnormalities and the concomitant presence of other diseases or therapy with other medicinal products.
04.3 Contraindications
Endoxan Baxter should not be given to patients with:
- hypersensitivity to the active substance, its metabolites or to any of the excipients
- severely impaired bone marrow function (particularly in patients who have undergone preliminary therapy with cytotoxic agents and / or radiotherapy),
- inflammation of the bladder (cystitis),
- obstruction of urinary flow,
- ongoing infections,
- during pregnancy and lactation (see 4.6).
04.4 Special warnings and appropriate 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 to treat life-threatening conditions. In these situations, an individual assessment of the expected benefit / risk ratio is necessary.
WARNINGS
Renal and urinary tract toxicity
• Haemorrhagic cystitis, pyelitis, urethritis and haematuria have been reported during cyclophosphamide therapy. Ulceration / necrosis of the bladder, fibrosis / contracture and secondary tumors may also develop.
• Urotoxicity may require discontinuation of treatment.
• A cystectomy may be required for fibrosis, bleeding or secondary tumors.
• Cases of urotoxicity with fatal outcomes have been reported.
• Urotoxicity may occur in both short and long term cyclophosphamide treatments. Haemorrhagic cystitis has been reported after a single dose of cyclophosphamide.
• Subsequent or concomitant radiotherapy or busulfan treatment may increase the risk of cyclophosphamide-induced hemorrhagic cystitis.
• Generally, cystitis is initially sterile but secondary microbial colonization may occur.
• Efferent urinary tract obstructions, cystitis and infections must be eliminated or corrected before starting therapy.
• Adequate therapy with Uromitexan (INN: mesna) or strong hydration can considerably reduce the frequency and severity of bladder toxicity. Ensure that patients empty their bladder at regular intervals.
• If cystitis associated with micro or macrohematuria occurs during treatment with Endoxan Baxter, discontinue therapy with Endoxan Baxter until normalization.
This usually happens a few days after stopping the medicine but cystitis can also persist.
• In the case of severe haemorrhagic cystitis, treatment with Endoxan Baxter should generally be discontinued.
• Cyclophosphamide has also been associated with nephrotoxicity including tubular necrosis.
• Hyponatremia associated with increased total body water, acute water intoxication and a SIADH-like syndrome (syndrome of insufficient secretion of antidiuretic hormone) have been reported in association with administration of cyclophosphamide. Fatal outcomes have also been reported.
• Patients with impaired renal function should be monitored closely during treatment with Endoxan Baxter for the presence of erythrocytes and other signs of uro / nephrotoxicity (also refer to the "Recommendations for dosage adjustment in patients with hepatic or renal insufficiency" section 4.2 "Posology and method of administration").
Myelosuppression, Immunosuppression, Infections
In general, Endoxan Baxter, like all other cytostatics, should be used with the utmost care in weak or elderly subjects, and in subjects who have previously undergone radiotherapy.
Individuals with weakened immune systems, such as those with diabetes mellitus, chronic liver or kidney disease, should also be closely monitored.
• Treatment with cyclophosphamide can 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 can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding) and anemia.
• Severe immunosuppression has led to severe, sometimes fatal infections. Sepsis and septic shock have also been reported. Infections reported with cyclophosphamide include both pneumonia and other infections of bacterial, fungal, viral, protozoal and parasitic origin.
• Latent infections can be reactivated. Reactivation has been reported for various infections of bacterial, fungal, viral, protozoal and parasitic origin.
• Infections must be treated appropriately.
• At the discretion of the treating physician, antimicrobial prophylaxis may be indicated in some cases of neutropenia.
• In case of neutropenic fever and / or leukopenia, antibiotics and / or antifungals should be administered as prophylaxis.
• If necessary, cyclophosphamide should be used with caution in patients with severe impairment of bone marrow function and in patients with severe immunosuppression.
• Treatment with cyclophosphamide may not be indicated or should be stopped or the dosage reduced in patients who have or develop a severe infection.
• Theoretically, the decrease in peripheral blood cell and platelet counts and the time required for recovery is greater the higher the dosage.
• The lowest leukocyte and platelet counts usually occur one to two weeks after starting treatment. The bone marrow recovers relatively quickly and blood values normally normalize after about 20 days.
• Therefore it is advisable that, during treatment, all patients undergo a careful haematological check with blood counts performed regularly.
- White blood cell and platelet counts and hemoglobin values should be checked prior to each administration and at appropriate intervals, if necessary every day.
- Leukocyte checks should be performed regularly during treatment, at intervals of 5-7 days at the start of treatment and every 2 days if the count falls below 3000 / mm3 (refer also to section 4.2 "Posology and method of administration" ).
• Unless strictly necessary, Endoxan Baxter should not be administered to patients with a white blood cell count below 2,500 / mcl and / or a platelet count below 50,000 / mcl.
• Regular monitoring of urine sediment is also recommended for the presence of erythrocytes.
Cardiotoxicity, Use in patients with heart disease
• Myocarditis and myopicarditis have been reported during treatment with cyclophosphamide which may be accompanied by significant pericardial effusion and cardiac tamponade and have led to severe, sometimes fatal, congestive heart failure.
• Histopathological examination showed mainly haemorrhagic myocarditis. As a secondary effect to haemorrhagic myocarditis and myocardial necrosis, haemopericardium occurred.
• 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 elongations 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 patients of advanced age and in patients who had had previous radiotherapy to the cardiac region and / or concomitant treatment with anthracyclines and pentostatin or other cardiotoxic agents (refer to par. 4.5) can intensify the cardiotoxic effect of Endoxan Baxter. In this context, it will be necessary to have an electrolyte check regularly and to pay particular attention to patients with a "history of heart disease."
Pulmonary toxicity
• Pneumonia and pulmonary fibrosis have been reported in conjunction with or subsequent to treatment with cyclophosphamide. Pulmonary veno-occlusive diseases and other forms of pulmonary toxicity have also been reported. Pulmonary toxicity leading to respiratory failure has been reported.
• While the incidence of pulmonary toxicity associated with cyclophosphamide is low, the prognosis for affected patients is poor.
• Late onset of pneumonia (more than 6 months after starting treatment with cyclophosphamide) appears to be associated with particularly high mortality. Pneumonia can also arise years after treatment with cyclophosphamide.
• Acute pulmonary toxicity has been reported after a single dose of cyclophosphamide.
Secondary tumors
• As with cytostatic therapy in general, treatment with cyclophosphamide also carries the risk of secondary cancers and their precursors as late consequences.
• Increases the risk of developing urinary tract carcinoma as well as myelodysplastic changes that partly progress to acute leukemia. Other cancers reported after using cyclophosphamide or cyclophosphamide treatments include lymphoma, thyroid cancer and sarcomas.
• In some cases, secondary cancer has developed several years after cyclophosphamide treatment was terminated. Tumors have also been reported following in utero exposure.
• The risk of bladder cancer can be significantly reduced by preventing haemorrhagic cystitis.
Veno-occlusive pathology of the liver
• Veno-occlusive liver disease (VOLD) has been reported in patients receiving cyclophosphamide.
• Cytoreductive treatment in preparation for bone marrow transplantation, which consists of cyclophosphamide in combination with integral irradiation, busulfan or other agents, has been identified as the major risk factor for developing VOLD (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 VOLD has been reported in patients treated long-term with low-dose immunosuppressive doses of cyclophosphamide.
• As a complication of VOLD, hepatorenal syndrome and multiorgan failure can develop. A fatal outcome has been reported for cyclophosphamide-associated VOLD.
• Risk factors that predispose a patient to developing VOLD with high-dose cytoreductive therapies include:
- pre-existing disturbances of liver function
- radiation therapy of the abdomen e
- low performance score
Genotoxicity
• Endoxan Baxter is genotoxic and mutagenic in both male and female somatic and germ cells. Therefore, women should avoid becoming pregnant and men should avoid conceiving children while taking Endoxan Baxter.
• Men should avoid conceiving children for up to 6 months after stopping treatment.
• Animal studies indicate that exposure of oocytes during follicular development may result in a lower rate of implantation and non-risk pregnancies and a greater risk of malformations. This effect should be taken into account in case of fertilization or Voluntary pregnancy after termination of cyclophosphamide treatment The exact duration of follicular development in humans is not known but may be longer than 12 months.
• Sexually active men and women should use effective methods of contraception during this period.
Refer also to section 4.6.
Effect on fertility
• Cyclophosphamide interferes with oogenesis and spermatogenesis. It could cause infertility in both sexes.
• The development of infertility appears to depend on the dose of cyclophosphamide, the duration of therapy and the state of gonadal function at the time of treatment.
• Cyclophosphamide-induced sterility may be irreversible in some patients.
Female patients
• Transient or permanent amenorrhea, associated with decreased estrogen secretion and increased gonadotropin secretion, develops in a significant proportion of women treated with cyclophosphamide.
• Especially for older women, amenorrhea can be permanent.
• Oligomenorrhea has also been reported in association with cyclophosphamide treatment.
• Girls treated with cyclophosphamide in prepubescence generally develop secondary sexual characteristics normally and have regular cycles.
• Girls treated with cyclophosphamide in prepubescence subsequently conceived children.
• Girls treated with cyclophosphamide who have maintained ovarian function after stopping treatment have a higher risk of developing premature menopause (interruption of the cycle 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 impaired in these patients.
• Boys treated with cyclophosphamide in prepubescence may develop secondary sexual characteristics normally but may have oligospermia or azoospermia.
• Testicular atrophy may occur to varying degrees.
• Cyclophosphamide induced azoospermia is reversible in some patients, although reversibility may not occur for several years after discontinuation of therapy.
• Men made temporarily sterile by cyclophosphamide subsequently conceived children.
• As treatment with Endoxan Baxter may increase the risk of permanent infertility in men, men should be informed about sperm storage prior to treatment.
Anaphylactic reactions, cross-sensitivity with other alkylating agents
• Anaphylactic reactions including those with fatal outcomes have been reported in association with cyclophosphamide.
• Possible cross-sensitivity with other alkylating agents has been reported.
Alteration of the wound healing process
• Cyclophosphamide can interfere with the normal wound healing process.
Alopecia
• Alopecia has been reported and may occur more commonly with increasing dosage.
• Alopecia can progress to baldness.
• Hair should grow back after treatment with the medicine or even during treatment although it may differ in texture and color.
Nausea and vomit
• Administration of cyclophosphamide can cause nausea and vomiting.
• Current guidelines on the use of antiemetics for the prevention and improvement of nausea and vomiting should be considered.
• Alcohol may increase the emetic effects and nausea induced by cyclophosphamide; for these reasons, alcohol consumption should be avoided in patients treated with cyclophosphamide.
Stomatitis
• Administration of cyclophosphamide can cause stomatitis (oral mucositis)
• Current guidelines for the prevention and improvement of stomatitis should be taken into consideration.
• Pay particular attention to oral hygiene to reduce the incidence of stomatitis.
Diagnostic investigations
The blood sugar level should be checked regularly in diabetic patients in order to be able to promptly adapt the antidiabetic therapy (see also section 4.5 "Interactions with other medicinal products and other forms of" interaction ")
USAGE PRECAUTIONS
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 administration by paravenous injection, immediately stop the infusion, aspirate the liquid transferred with the cannula applied and take other appropriate measures, eg irrigate the area with saline solution and immobilize the extremity.
Use in patients with renal insufficiency
In patients with renal insufficiency, particularly if severe, the decreased renal elimination may result in an increase in plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be taken into consideration when determining the dosage for this type of patient. Refer also to section 4.2.
Use in patients with hepatic insufficiency
Severe hepatic insufficiency may be associated with decreased activation of cyclophosphamide. This can alter the efficacy of cyclophosphamide therapy and should be taken into account in determining the dosage and interpreting the response to the chosen dosage. Alcohol abuse can increase the risk of developing liver dysfunction.
Use in adrenalectomised patients
Patients with adrenal insufficiency may require increased corticoid replacement dosage if exposed to stress resulting from the toxicity of cytostatics, including cyclophosphamide.
The tablets contain lactose, so they are not suitable for people with lactase deficiency, galactosemia or glucose / galactose malabsorption syndrome; they also contain sucrose, so they are not suitable for people with hereditary fructose intolerance, glucose / galactose malabsorption syndrome or sucrase-isomaltase deficiency.
04.5 Interactions with other medicinal products and other forms of interaction
The concomitant or subsequent planned administration of other substances or treatments that could increase the likelihood or severity of toxic effects (through pharmacodynamic or pharmacokinetic interactions) requires careful individual consideration of the expected benefits and risks. Patients receiving such combinations should be carefully monitored for symptoms of toxicity and thus allow for prompt intervention. Patients treated with cyclophosphamide and agents that reduce its activation should be monitored for a potential reduction in therapeutic efficacy and the need for dosage adjustment.
Interactions affecting the pharmacokinetics of cyclophosphamide and its metabolites
• The hypoglycaemic effect of sulfonylureas can 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 retard the activation of cyclophosphamide include:
- Apripitant
- Bupropion
- Busulfan: Administration of Endoxan Baxter at high doses within 24 hours of treatment with high doses of busulfan may cause decreased clearance and an "extension of the elimination half-life" of cyclophosphamide.
- Ciprofloxacin: Administration of fluoroquinolone-based antibiotics (such as ciprofloxacin) before the start of treatment with Endoxan Baxter (especially in the case of conditioning prior to a bone marrow transplant) may reduce the effectiveness of Endoxan Baxter and therefore give rise to a worsening of the primary pathology.
- Chloramphenicol: Concomitant administration of chloramphenicol leads to prolonged halving of cyclophosphamide and delayed metabolism.
- Fluconazole, Itraconazole: Azole antifungals (fluconazole, itraconazole) are known to inhibit cytochrome P450 metabolising activity of cyclophosphamide. Increased exposure to the toxic metabolites of Endoxan Baxter has been observed in patients treated with itraconazole.
- Prasugrel
- Sulfonamides
- Thiotepa: Strong inhibition of the bioactivation of cyclophosphamide by thiotepa has been observed in high dose chemotherapy regimens when administered one "hour prior to Endoxan Baxter. The sequence and timing of administration of these two agents may be contributing factors. crucial.
• An increase in the concentration of cytotoxic metabolites may occur with:
- Allopurinol
- Chloral hydrate
- Cimetidine
- Disulfiram
- Glyceraldehyde
- Inducers of hepatic and extrahepatic human microsomal enzymes (eg cytochrome P450 enzymes): The potential induction of hepatic and extrahepatic microsomal enzymes must be taken into account in case of previous or concomitant treatment with substances which are known to induce an increase in " activity of such enzymes as rifampicin, phenobarbital, carbamazepine, benzodiazepines, fentoin, St. John's wort and corticosteroids.
- Protease inhibitors: The concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. In patients administered cyclophosphamide, doxorubicin and etoposide (CDE), the use of protease inhibitor treatments has been shown to be associated with a higher incidence of infections and neutropenia than with the use of an NNRTI-based treatment.
- Ondansetron: Pharmacokinetic interactions have been detected between ondansetron and Endoxan Baxter (at high doses) resulting in decreased AUC (area under the curve) for cyclophosphamide.
• Since grapefruit contains a compound that can inhibit the activation of cyclophosphamide and consequently its effectiveness, the patient should not consume grapefruit or grapefruit juice.
Pharmacodynamic interactions and interactions with unknown mechanisms affecting the use of cyclophosphamide
The combination or subsequent use of cyclophosphamide and other agents with similar toxicities may cause combined (major) toxic effects.
• Increased haematotoxicity and / or immunosuppression may result from the combination of the effects of cyclophosphamide and, for example:
- ACE inhibitors: ACE inhibitors can cause leukopenia.
- Natalizumab
- Paclitaxel: An increase in haematotoxicity has been reported when cyclophosphamide was administered following an infusion with paclitaxel.
- Thiazide-based diuretics
- Zidovudine
• Increased cardiotoxicity may result from the combination of the effects of cyclophosphamide and, for example:
- Anthracyclines
- Pentostatins
- Cytarabine - The administration of high dosages of Endoxan Baxter and cytarabine on the same day, therefore in a very limited time interval, may result in an enhancement of the cardiotoxic effect, taking into account that each substance is already cardiotoxic in itself. .
- Radiotherapy to the heart region.
- Trastuzumab
• An increase in pulmonary toxicity may result from the combination of the effects of cyclophosphamide and, for example:
- Amiodarone
- G-CSF or GM-CSF (granulocyte macrophage colony stimulating factor and granulocyte colony stimulating factor): Reports suggest an increased risk of pulmonary toxicity (pneumonia, alveolar fibrosis) in patients receiving cytotoxic chemotherapy which include Endoxan Baxter and GCSF
- GM-CSF.
• An increase in nephrotoxicity may result from the combination of the effects of cyclophosphamide and, for example:
- Amphotericin B
- Indomethacin: Simultaneous administration of indomethacin should be carried out with the utmost care, as acute water intoxication has been reported.
• Increase in other toxicities:
- Azathioprine: Increased risk of hepatotoxicity (liver necrosis)
- Busulfan: A higher incidence of veno-occlusive pathologies and mucositis has been reported.
- Protease inhibitors: increased incidence of mucositis.
Other interactions:
• Alcohol: Reduced antitumor activity was observed in animals with cancer when ethanol (alcohol) was taken concomitantly with 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, the addition of etanercept to standard cyclophosphamide treatment 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 the action of other medicinal products
• Bupropion: The metabolism of cyclophosphamide by CYP2B6 may inhibit the metabolism of bupropion.
• Coumarins: Both increased and decreased effect of warfarin have been reported in patients treated with warfarin and cyclophosphamide.
• Ciclosporins: In patients treated with a combination of Endoxan Baxter and cyclosporine a lower serum concentration of cyclosporine was found than in patients who were given cyclosporins alone. The interaction could result in an increased incidence of rejection reactions.
• Depolarizing muscle relaxants: If depolarizing muscle relaxants (eg succinylcholine halides) are applied simultaneously, prolonged "apnea caused by" significant and persistent inhibition of cholinesterase activity may result. If the patient was treated with cyclophosphamide within 10 days of a "general anesthesia," the anesthetist should be advised.
• Digoxin, β; -acetyldigoxine: Cytostatic treatment has been reported to impair intestinal absorption of digoxin and β; -acetyldigoxine tablets.
• Vaccines: Since cyclophosphamide has immunosuppressive effects, the patient may show a reduced response to concomitant vaccinations; vaccination with active vaccines may be associated with vaccine-induced infection.
• Verapamil: Cytostatic treatment has been reported to impair intestinal absorption of orally administered verapamil.
04.6 Pregnancy and lactation
• A possible passage of Endoxan Baxter across the maternal placenta should be considered. Treatment with cyclophosphamide can cause genotypic abnormalities when administered to pregnant women.
• In the event that risks to the patient's life arise during the first trimester of pregnancy, it will be absolutely necessary to consult a doctor in order to terminate the pregnancy.
• Malformations have been reported in babies born to mothers treated with cyclophosphamide during the first trimester of pregnancy. However, children without malformations born to women exposed during the first trimester have also been reported.
• After the first trimester of pregnancy, if therapy cannot be delayed and the patient wishes to continue the pregnancy, chemotherapy may be used after informing the patient of the minor but possible risk of teratogenic effects.
• In utero exposure to cyclophosphamide can cause pregnancy loss, fetal growth retardation and fetotoxic effects occurring in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia and grastroenteritis.
• During treatment with Endoxan Baxter and up to 6 months after the end of treatment, women should avoid becoming pregnant and men should avoid conceiving children.
• The results of animal studies suggest that an increased risk of pregnancy termination and malformations may persist after discontinuation of cyclophosphamide as long as there are oocytes / follicles that have been exposed to cyclophosphamide at any of the stages of maturation. reference to section 4.4, Genotoxicity.
• If cyclophosphamide is used during pregnancy or if the patient becomes pregnant while taking this medicine or after stopping treatment (refer to section 4.4, Genotoxicity), the patient should be informed of the potential risks to the fetus.
• Since cyclophosphamide passes into breast milk, mothers will not have to breastfeed during therapy. Neutropenia, thrombocytopenia, low hemoglobin and diarrhea have been reported in nursing infants of women receiving cyclophosphamide.
• Men who will be treated with Endoxan Baxter should be informed about sperm storage prior to treatment.
04.7 Effects on ability to drive and use machines
Due to the possibility of side effects from cyclophosphamide administration, (e.g. nausea, vomiting, dizziness, blurred vision and impaired vision) which may impair the ability to drive or use machines, the physician will need to decide on an individual basis. the patient's ability to drive vehicles or operate machines.
04.8 Undesirable effects
Adverse reactions from clinical trials
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-
* including fatal outcomes
1 The following manifestations have been associated with myelosuppression and immunosuppression due to cyclophosphamide: increased risk and severity of pneumonia (including fatal outcomes), other bacterial, fungal, viral, protozoal and parasitic infections; reactivation of latent infections, including viral hepatitis, tuberculosis, JC virus with progressive multifocal leukoencephalopathy (including fatal outcomes), Pneumocystis jiroveci, herpes zoster, Strongyloides.
2 Acute myeloid leukemia, Acute promyelocytic leukemia
3 Non-Hodgkin's lymphoma
4 Myelosuppression manifests itself as bone marrow failure
5 complicated by bleeding
6 with thrombotic microangiopathy
7 Other cardiac pathologies are: congestive heart failure, left ventricular dysfunction, myocarditis, carditis.
Pericardial effusion can progress to cardiac tamponade.
8 Other vascular pathologies: flushing
9 Other kidney diseases: Hemolytic Uremic Syndrome (HUS)
04.9 Overdose
• Serious consequences of overdose include manifestations of dose dependent toxicity such as myelosuppression, urotoxicity, cardiotoxicity (including heart failure), hepatic veno-occlusive disease and stomatitis. Refer to section 4.4.
• Since a specific antidote for cyclophosphamide is not known, it is advisable to proceed with great caution whenever it is used.
• Cyclophosphamide can be dialyzed. Therefore, rapid hemodialysis is indicated in the event of overdose or accidental intoxication or suicide. A dialysis clearance of 78 mL / min was calculated on the concentration of unmetabolized cyclophosphamide in the dialysate (normal renal clearance is approximately 5-11 mL / min). A second working 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.
• An overdose may result in myelosuppression, predominantly leukocytopenia, among other reactions. The severity and duration of myelosuppression depend on the extent of the overdose. Frequent checks of the blood count and monitoring of the patient are necessary. In case of neutropenia, prophylaxis of the infection and treat with antibiotics. If thrombocytopenia develops, ensure replacement of thrombocytes as needed.
• Cystitis prophylaxis with Uromitexan (mesna) can help prevent or limit the urotoxic effects of an overdose of cyclophosphamide.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastics, analogues of nitrogen mustard.
ATC code: L01AA01.
Cyclophosphamide is a cytostat of the oxazaphosphorine group and is chemically linked to N-methyl-bis (2-chloroethyl) amine.
Cyclophosphamide is inactivated in vitro and activated in vivo by liver microsomal enzymes into 4-hydroxycyclophosphamide, which is in equilibrium with its own tautomeric aldophosphamide.
The cytotoxic action of cyclophosphamide is based on the interaction between its alkylating metabolites and DNA. This alkylation produces the breaking and coupling of DNA strands and the formation of cross-links of DNA proteins. In the cell cycle the passage through the G2 phase is delayed. The cytotoxic effect is not specific to the cell cycle phase but to the cell cycle.
Cross resistance cannot be ruled out, especially with structurally similar cytostatics such as ifosfamide and other alkylating agents.
05.2 Pharmacokinetic properties
Cyclophosphamide is almost completely absorbed from the gastrointestinal tract.
In humans, single intravenous injections of labeled cyclophosphamide are followed within 24 hours by a marked reduction in plasma concentrations of cyclophosphamide and its metabolites, although detectable levels may persist in plasma for up to 72 hours. Cyclophosphamide is inactive in vitro and is bioactivated. only in the organism.
The mean half-life of cyclophosphamide serum is approximately 7 hours in adults and approximately 4 hours in children. Cyclophosphamide and its metabolites are largely excreted by the kidneys.
Blood levels after intravenous and oral doses are bioequivalent.
05.3 Preclinical safety data
Acute toxicity
Compared to other cytostatics, the acute toxicity of cyclophosphamide is relatively low. This has been demonstrated through experiments in mice, guinea pigs, rabbits and dogs. After a single intravenous injection, the LD50 in rats was approximately 160 mg / kg, in mice and guinea pigs 400 mg / kg, in rabbits 130 mg / kg and in dogs 40 mg / kg.
Chronic toxicity
Chronic administration of toxic doses has led to liver injury manifesting in the form of adipose degeneration followed by necrosis. The intestinal mucosa was not affected. The threshold for hepatotoxic effects is 100 mg / kg in rabbits and 10 mg / kg in dogs. In animal experiments, cyclophosphamide and its active metabolites exhibited mutagenic, carcinogenic and teratogenic effects.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Powder for solution for injection: none.
Coated tablets: Glycerol 85%, Gelatin, Magnesium stearate, Talc, Calcium dibasic phosphate, Lactose, Corn starch, Macrogol 35,000, Calcium carbonate, Colloidal silica, Povidone, Sodium caramelose, Polysorbate 20, Sucrose, Titanium dioxide, Ethylene glycol ester of the " montanic acid.
06.2 Incompatibility
Solutions containing benzyl alcohol can reduce the stability of cyclophosphamide.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store the medicine at a temperature not exceeding + 25 ° C.
The solution should be injected as soon as possible after preparation.
Shelf life of the solution: from 2 to 3 hours.
The bottles must not be stored at a temperature higher than that indicated as in this case there could be a degradation of the active ingredient identifiable by the yellowish color of the contents of the bottle which can take on the appearance of a melted substance.
Do not use bottles whose contents have the appearance described above.
06.5 Nature of the immediate packaging and contents of the package
White type III glass bottles with butyl rubber stopper and aluminum cap.
PVC / PVDC / aluminum blisters.
Packaging:
"200 mg powder for solution for injection" 10 200 mg type III glass vials;
"500 mg powder for solution for injection" 1 type III glass bottle 500 mg;
"1 g powder for solution for injection" 1 type III glass bottle 1 g;
"50 mg coated tablets" 5 blisters of 10 50 mg coated tablets.
Not all packs may be marketed.
06.6 Instructions for use and handling
Handling and preparation of cyclophosphamide should always be performed in accordance with current guidelines for the safe handling of cytotoxic agents.
The coating of the tablets prevents direct contact with the active ingredient by the people handling them. To prevent inadvertent exposure of third parties to the active substance, the tablets should not be divided or crushed.
Preparation of the solution for injection:
Endoxan Baxter for intravenous use is prepared in type III glass bottles.
To prepare the solution for injection, the following amount of physiological solution (sodium chloride 0.9%) must be added to the dry powder:
Before parenteral administration the substance must be completely dissolved. The substance dissolves easily if the bottles, after the solvent (physiological solution) has been added, shake vigorously for half or one minute.
If the substance does not dissolve immediately without leaving any residue, it is advisable to let the solution stand for a few minutes until it becomes clear. Injecting the solvent into the bottle produces an overpressure which can be avoided by introducing a second sterile needle into the rubber stopper so that the air escapes from the bottle.
Cyclophosphamide reconstituted in water is hypotonic and should not be injected directly.
When administered by infusion, cyclophosphamide can be reconstituted by adding sterile water and infused into the recommended intravenous solutions.
The medicinal product is compatible with the following solutions for infusion: sodium chloride solution, glucose solution, sodium chloride and glucose solution, sodium chloride and potassium chloride solution, potassium chloride and glucose solution.
07.0 MARKETING AUTHORIZATION HOLDER
Baxter S.p.A. - Piazzale dell "Industria, 20 - 00144 Rome
08.0 MARKETING AUTHORIZATION NUMBER
Endoxan Baxter
50 mg Coated tablets: AIC 015628011
200 mg Powder for solution for injection 10 type III glass bottles 200 mg: AIC 015628062
500 mg Powder for solution for injection 1 type III glass bottle 500 mg: AIC 015628074
1 g Powder for solution for injection 1 type III glass bottle 1g: AIC 015628086
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First A.I.C .: September 1959.
Last A.I.C Renewal: October 2012
10.0 DATE OF REVISION OF THE TEXT
AIFA Determination of October 2012
