Patient Information Leaflet

Genoxal 200 mg powder for injection and infusion

Ciclofosfamida

Read this leaflet carefully before you start using this medicine,because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only.Do not give it to others even if they have the same symptoms as you,as it may harm them.
• If you experience any side effects, consult your doctor or pharmacist,even if they are not listed in this leaflet. See section 4.

1.What Genoxal is and what it is used for.

2.What you need to know before you receive Genoxal.

3.How you will receive Genoxal

4.Possible side effects

5.Storage of Genoxal

6.Contents of the pack and additional information

Genoxalcontains as active substance Cyclophosphamide.It belongs to the group of medications known as “cytotoxic or antineoplastic drugs”, which act by stopping the growth of cancer cells.

Genoxalis usually used in monotherapy or in combination with other antineoplastic drugs or radiation therapy, in the treatment of various types of cancer. This includes:

-different forms of lymphomas that affect the immune system (Hodgkin's lymphoma, non-Hodgkin's lymphoma, and multiple myeloma),

-certain types of white blood cell cancer (acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia),

-ovarian cancer and breast cancer,

-Ewing's sarcoma (a type of bone cancer),

-microcytic lung carcinoma,

-in the treatment of metastatic or advanced central nervous system tumors (neuroblastoma)

Additionally,Genoxalis used in bone marrow transplant preparation.

In some cases, some doctors may prescribeGenoxalfor other conditions unrelated to cancer:

-life-threatening autoimmune diseases: progressive severe forms of lupus nephritis (kidney inflammation caused by an autoimmune disease) and Wegener's granulomatosis (a rare form of vasculitis).

Do not use:

• If you are allergic to cyclophosphamide, any of its metabolites, or any of the other components of this medication (listed in section 6).A severe allergic reaction may include difficulty breathing, wheezing, hives, itching, or inflammation of the face and lips.
• If you currently have an infection.
• If your bone marrow does not function properly (especially if you have previously undergone chemotherapy or radiation therapy). Blood tests will be performed to check the function of your bone marrow,
• If you have a urinary tract infection that may be recognized by pain while urinating (cystitis).
• If you have had kidney or bladder problems as a result of chemotherapy or radiation therapy.
• If you have a disease that reduces your ability to urinate (obstruction of urine flow).
• If you are pregnant or breastfeeding.
• In the treatment of non-malignant diseases, except for immunosuppression in life-threatening situations.

Warnings and precautions

Consult your doctorbefore starting to useGenoxalif:

• You have low blood cell counts,
• You have severe infections,
• You have liver or kidney problems. Your doctor will check through a blood test if your liver and kidneys are functioning correctly and if you have had your adrenal gland removed,
• You are receiving or have recently received radiation therapy or chemotherapy; you have heart problems or have received radiation therapy in the heart area,
• You have diabetes,
• You have a poor general health or are a fragile or elderly person,
• You have undergone surgery less than 10 days ago.

Severe allergic reactions (anaphylactic reactions) may occur during treatment withGenoxal.

Genoxalmay affect your blood and immune system.

Red blood cells, white blood cells, and platelets are produced in your bone marrow. These cells are of three types:

- Red blood cells, which transport oxygen in the body,

- White blood cells, which fight infections, and

- Platelets, which allow blood to clot.

After receivingcyclophosphamide, the count of blood cells for the three types of cells will decrease. This is an inevitable side effect of the medication.Your blood cell count will reach its lowest level approximately between 5 and 10 days after starting to receiveGenoxaland will remain low for a few days after completing the treatment cycle. Most people recover normal blood cell counts within 21 to 28 days. If you have received a large amount of chemotherapy in the past, it may take a bit longer to return to normal.

You are more likely to contract infections if your blood cell count is reduced. Try not to approach people who have a cold, flu, or other infections. Your doctor will treat you with the appropriate medication if they think you have an infection or are at risk of contracting one.

Your doctor will ensure that the count of erythrocytes, leukocytes, and platelets is high enough before starting treatment with cyclophosphamide and during treatment. You may need to reduce the amount of medication you receive or delay the next dose.

Genoxalmay affect the normal healing of wounds. Keep cuts clean and dry and check that they are healing normally. It is essential to maintain good oral health, as infections and mouth ulcers can occur. Consult your doctor if you are unsure.

Genoxalmay damage the lining of the urinary bladder and cause bleeding in the urine or pain while urinating. Your doctor knows that this can occur and, if necessary, will give you a medication called Mesna (Uromitexan) to protect your bladder. Mesna can be administered as a short injection or mixed with cyclophosphamide in the infusion solution. You can find more information about Mesna in the package insert that comes with Uromitexan.

Most people who receiveGenoxalwith Mesna do not develop bladder problems, but your doctor may want to analyze your urine to detect the presence of blood using a dipstick or microscope. If you notice blood in your urine, you must inform your doctor immediately.

Cancer treatments and radiation therapy may increase the risk of developing other types of cancer; this can occur several years after the completion of your treatment.Genoxalincreases the risk of developing cancer in the urinary bladder area.

Genoxalmay cause cardiac damage or affect the heart rate. This effect is more pronounced at higher doses ofGenoxal, if you are receiving or have recently received radiation therapy or other chemotherapy medications, or if you are an elderly person. Your doctor will closely monitor your heart during treatment.

Genoxalmay cause lung problems such as inflammation or pulmonary fibrosis.

This may occur more than six months after completing treatment. If you start experiencing difficulty breathing, inform your doctor immediately.

Genoxalmay have potentially fatal effects on your liver.

If you experience sudden weight gain, liver pain, and the skin or white part of your eyes turn yellow (jaundice), inform your doctor immediately.

Alopecia or hair loss may occur. Your hair should grow back normally, although its texture and color may be different.

Genoxalmay cause nausea and vomiting. This may last approximately 24 hours after taking the medication. You may need to take medication to prevent nausea and vomiting. Consult your doctor about this.

Children and adolescents

Based on established treatment regimens, in children and adolescents, doses similar to those recommended for adults should be used.

Use ofGenoxalwith other medications:

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.In particular, inform them of the following medications or treatments because they may be incompatible with the use ofGenoxal.

The following medications may reduce the effectiveness ofGenoxal:

• Aprepitant (used to prevent vomiting),
• Bupropion (an antidepressant),
• Busulfan, tiotepa (used to treat cancer),
• Ciprofloxacin, chloramphenicol (used to treat bacterial infections),
• Fluconazole, itraconazole (used to treat fungal infections),
• Prasugrel (used as an anticoagulant),
• Sulfonamides, such as sulfadiazine, sulfasalazine, sulfamethoxazole (used to treat bacterial infections).

The following medications may increase the toxicity ofGenoxal:

• Aloprim (used to treat gout),
• Chloral hydrate (used to treat insomnia),
• Cimetidine (used to reduce stomach acid),
• Disulfiram (used to treat alcoholism),
• Glyceryl aldehyde (used to treat warts),
• Protease inhibitors (used to treat viruses),
• Medications that increase liver enzymes such as: rifampicin (used to treat bacterial infections), carbamazepine, phenobarbital, phenytoin (used to treat epilepsy), St. John's Wort (a medicinal plant for mild depression), corticosteroids (used to treat inflammation),
• Benzodiazepines (used as anxiolytics),
• Ondansetron (used to prevent vomiting).

Medications that may increase the toxic effects ofGenoxalon blood cells and the immune system:

• ACE inhibitors (used to treat hypertension),
• Natalizumab (used to treat multiple sclerosis),
• Paclitaxel (used to treat cancer),
• Diuretics such as hydrochlorothiazide or clortalidone (used to treat hypertension or fluid retention),
• Zidovudine (used to treat viral infections),
• Clozapine (used to treat symptoms of certain psychiatric disorders).

Medications that may increase the toxic effects ofGenoxalon the heart:

• Anthracyclines such as bleomycin, doxorubicin, epirubicin,
• Cytarabine, pentostatin, trastuzumab (used to treat cancer),
• Radiation therapy in the heart area.

Medications that may increase the toxic effects ofGenoxalon the lungs:

• Amiodarone (used to treat irregular heartbeat),
• G-CSF, GM-CSF (used to increase white blood cell counts after chemotherapy).

Medications that may increase the toxic effects ofGenoxalon the kidneys:

• Amphotericin B (used to treat fungal infections),
• Indomethacin (used to treat pain and inflammation).

Other medications that may affectGenoxalor be affected by it include:

• Azathioprine (used to reduce immune system activity),
• Etanercept (used to treat rheumatoid arthritis),
• Metronidazole (used to treat bacterial or protozoal infections),
• Tamoxifen (used to treat breast cancer),
• Bupropion (used to quit smoking),
• Coumarins such as warfarin (used as an anticoagulant),
• Cyclosporine (used to reduce immune system activity),
• Suxamethonium (used as a muscle relaxant during medical procedures),
• Digoxin, acetildigoxin β (used to treat heart conditions),
• Vaccines,
• Verapamil (used to treat hypertension, angina, or irregular heartbeat),
• Sulfonilurea derivatives (glucose levels may decrease if cyclophosphamide and sulfonilurea derivatives are used simultaneously).

Use ofGenoxalwith food and drinks

Alcohol consumption should be avoided, as it may increase nausea and vomiting caused by cyclophosphamide.

Pomelo (in the form of fruit or juice) should not be consumed while takingGenoxal.

It may interfere with the usual effect of your medication and alter its efficacy.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, or think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medication.

Pregnancy

Genoxal may cause miscarriage or fetal damage.

If you are a woman, do not become pregnant during treatment with cyclophosphamide or for 12 months after completing treatment.Both men and women who are sexually active should use effective contraceptive methods during treatment and for 6 months after completing treatment.If you become pregnant during treatment, there is a possibility of receiving genetic counseling (medical advice to assess the potential risk of congenital malformations in the fetus).

Breastfeeding

You should not breastfeed while being treated with cyclophosphamide. Consult your doctor.

Fertility

Genoxal may cause sterility in both sexes.Consult your doctor about cryopreservation (freezing) of sperm or eggs before treatment, as there is a possibility of irreversible sterility due to treatment with cyclophosphamide. If you are considering becoming parents after treatment, you should discuss this with your doctor.

Driving and using machines

Some of the side effects of treatment with cyclophosphamide may affect your ability to drive and use machines safely. Your doctor will decide if you can do so safely.

Patients should exercise caution when performing tasks such as driving cars and operating machines until they have checked that the treatment with the medication does not affect their ability to perform these activities.

Genoxal will be administered by an experienced doctor in the use of antineoplastic chemotherapy (for cancer treatment).

Administration form

By intravenous route

Genoxal is administered as an injection and is usually added to a large container of liquid and infused slowly (infusion) directly into a vein. The vein may be in the arm, the back of the hand, or a large vein under the clavicle.

The infusion will last between 30 and 120 minutes, depending on the dose.

Genoxal is usually administered in combination with other antineoplastic medications or radiation therapy.

The recommended dose is:

Your doctor will decide how much medication you need and when you should receive it. This will depend on the type of disease you have, your body size and weight, your overall health, and if you are receiving other antineoplastic medications or radiation therapy.

It is recommended to administer Genoxal in the morning. Before, during, and after administration, it is essential to receive adequate amounts of fluid to prevent possible adverse effects on the urinary tract.

If you notice that Genoxal is too strong or weak, consult your doctor or pharmacist.

Your doctor may need to adjust the amount of medication you take and monitor you more closely if:

- you have problems with your liver or kidneys,

- you are an elderly person (over 65 years old)

Use in children and adolescents

Genoxal is also indicated in children. The safety profile of Genoxal in children is similar to that in adults.

If you are given moreGenoxalthan you should

Since Genoxal is administered under the supervision of your doctor, it is highly unlikely that you will receive too much. However, if you experience side effects after receiving the medication, inform your doctor immediately or go to the nearest hospital emergency department.

You may require urgent medical attention.

The symptoms of a cyclophosphamide overdose include the side effects listed in the "Side effects" section, but are usually more severe.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone 915.620.420, indicating the medication and the amount ingested.

Like all medicines,this medicinecancause side effects, although not everyone will experience them.

Inform your doctor immediately if you experience:

• Allergic reactions. Your symptoms would be difficulty breathing, wheezing, increased heart rate, decreased blood pressure, hives, itching, or inflammation of the face and lips. Severe allergic reactions could cause respiratory distress or shock, with a possible fatal outcome (anaphylactic shock, anaphylactic/anaphylactoid reaction).
• Appearance of bruises without being hit, or bleeding in the gums. This could be a sign that your blood platelet levels are too low.
• Severe infection or fever, cough, shortness of breath, signs of septicemia such as fever, rapid breathing, elevated heart rate, confusion, and edema. This could be a sign of a decrease in your white blood cell count and you may need antibiotics to fight infections.
• Pale skin, feeling tired and lethargic. This could be indicative of low red blood cell levels (anemia). Normally, no treatment is required, as your body will replenish red blood cells over time. In case of severe anemia, you may need a blood transfusion.
• Blood in the urine, pain while urinating, or reduced urine volume.
• Signs of septicemia such as fever, rapid breathing, elevated heart rate, confusion, and edema.
• Severe chest pain.
• Severe lung inflammation that causes shortness of breath, cough, and increased temperature.
• Symptoms such as weakness, loss of vision, speech difficulties, loss of touch sensation.

The following side effects may also occur during treatment withGenoxal.

Very Common(may affect more than 1 in 10 patients)

• Reduction in the number of blood cells (myelosuppression),
• reduction in white blood cells, which are important in fighting infections (leucopenia, neutropenia),
• Nausea and vomiting,
• Burning sensation while urinating and frequent need to urinate (cystitis),
• Blood in the urine (microhematuria),
• Hair loss (alopecia),
• Fever,
• Suppression of the immune system.

Common(may affect up to 1 in 10 patients)

• Reduction in white blood cell count and fever (neutropenic fever).
• Blood in the urine and pain while urinating (hemorrhagic cystitis),
• Blood in the urine (macrohematuria),
• Baldness,
• Infections,
• Chills,
• Feeling weak,
• General feeling of discomfort,
• Inflammation of mucous membranes (mucositis),
• Azoospermia in males.

Rare(may affect up to 1 in 100 patients)

• Increased lactate dehydrogenase in blood,
• Increased C-reactive protein,
• Changes in the electrocardiogram,
• Cardiac problems (myocarditis, cardiomyopathy, heart failure),
• Fast heart rate,
• Tendency to bruise due to thrombocytopenia (reduced platelet count),
• Anemia (low red blood cell count) that may cause fatigue and somnolence,
• Damage to nerves that may cause numbness, pain, and weakness (neuropathy),
• Pain in the distribution of a nerve (neuralgia),
• Reduced levels of sex hormones,
• Anorexia,
• Lung inflammation (pneumonia),
• Sepsis,
• Disorders in ovulation,
• Allergic reactions.

Very Rare(may affect up to 1 in 10,000 patients)

• Weight gain,
• Angina,
• Myocardial infarction,
• Cardiac arrest,
• Fibrillation of the ventricles,
• Pericarditis (inflammation of the pericardium),
• Fibrillation of the auricles,
• Formation of blood clots in all small blood vessels of the body (disseminated intravascular coagulation),
• Syndrome of hemolytic uremia (a condition that affects the blood and kidneys),
• Dizziness,
• Alteration of the sense of taste (dysgeusia, hypogeusia),
• Sensation of tingling, pinching, itching, or burning (paresthesia),
• Hepatic encephalopathy,
• Conjunctivitis, edema of the eye,Visual deterioration,
• Deafness,
• Pulmonary lesion (acute respiratory distress syndrome),
• Pulmonary fibrosis that causes difficulty breathing (chronic interstitial pulmonary fibrosis),
• Respiratory failure due to accumulation of fluid in the lungs (pulmonary edema),
• Difficulty breathing with wheezing or cough (bronchospasm),
• Shortness of breath,
• A condition in which the body or a region of the body lacks adequate oxygen supply (hypoxia),
• Cough,
• Unspecified pulmonary disorders,
• Intestinal inflammation,
• Pancreatitis,
• Accumulation of fluid in the abdominal cavity (ascites).
• Mucosal ulceration,
• Stomach or intestinal hemorrhage,
• Suburethral hemorrhage,
• Presence of fluid in the bladder wall,
• Renal problems, including renal insufficiency,
• Inflammation of the bladder wall,
• Inflammation, sclerosis, and contraction of the bladder,
• High levels of creatinine in the blood,
• Severe hypersensitivity reactions with fever (high), red skin rash, joint pain, and/or eye infection (Stevens-Johnson syndrome),
• Sudden severe reaction (hypersensitivity) with fever and blisters on the skin/skin peeling (toxic epidermal necrolysis),
• Itching,
• Severe skin reactions,
• Changes in the color of your nails and skin,
• Radiation erythema,
• Abnormal muscle degradation that may cause renal problems (rhabdomyolysis),
• Cramps,
• Increased release of antidiuretic hormone from the pituitary gland (SIADH). This affects the kidneys and causes low sodium levels in your body (hyponatremia) and fluid retention, leading to cerebral edema due to excessive fluid in your blood. Symptoms may include headache, changes in personality or behavior, confusion, and somnolence,
• Low sodium levels in the blood (hyponatremia),
• Sepsis shock,
• Complications that may occur after cancer treatment caused by products of cell death (tumor lysis syndrome),
• Blockage of a blood vessel due to a blood clot in the circulatory system (thromboembolism),
• High blood pressure (hypertension),
• Low blood pressure (hypotension),
• Headache,
• Multi-organ failure,
• Reaction at the injection site and perfusion,
• Blood clot in the liver (hepatic veno-occlusive disease),
• Activation of the hepatitis virus,
• Enlargement of the liver (hepatomegaly),
• Yellow eyes or skin,
• Confusion,
• Anaphylactic shock

Frequency not known(cannot be estimated from available data)

• Cerebral disorder (encephalopathy), neurotoxicity manifested as a syndrome characterized by headache, confusion, bone marrow disorders (myelopathy), seizures, and loss of vision (posterior reversible leukoencephalopathy syndrome), abnormal sensation (dysesthesia, hypoaesthesia),degenerative brain disease (encephalopathy),shaking, alteration of the sense of smell (parosmia), different types of cardiac disorders (ventricular tachycardia, cardiogenic shock, pericardial effusion,myocardial hemorrhage,left ventricular insufficiency, bradycardia, palpitations, prolongation of the QT interval on the electrocardiogram,decreased ejection fraction),
• Intrauterine death,
• Fetal malformation,
• Delayed fetal growth,
• Different types of blood disorders (low blood cell counts, agranulocytosis, lymphopenia, reduced hemoglobin),
• Increased tear production,
• Tinnitus and hearing defects
• Pleural effusion,
• Blockage of nasal passages (congestion),
• Unpleasant nasal sensation,
• Orofacial pain,
• Rhinorrhea,
• Stuffy nose,
• Pulmonary veno-occlusive disease,
• Obliterative bronchiolitis,
• Allergic alveolitis,
• Organizing pneumonia,
• Pneumonitis,
• Unpleasant abdominal sensation,
• Certain renal diseases (tubular necrosis, renal tubular disorder, toxic nephropathy, hemorrhagic ureteritis, ulcerative cystitis, vesical contracture, nephrogenic diabetes insipidus, atypical urinary epithelial cells, elevated urea nitrogen in blood),
• Itching, hives, blisters on the lips, eyes, or mouth, skin peeling (erythema multiforme, urticaria, erythema),
• Hand-foot syndrome,
• Facial swelling,
• Increased sweating,
• Hardening of the skin (scleroderma),
• Muscle spasms and pain,
• Joint pain,
• Water intoxication,
• Changes in the results of some blood tests (glucose, hormone levels),
• Different types of cancer, such as blood cancer (non-Hodgkin lymphoma), renal cancer, pelvic renal cancer, thyroid cancer, sarcoma,carcinogenic effecton offspring,
• Blockage of a blood vessel by a clot in the circulatory system (thromboembolic episodes), including the possibility of blockage of the pulmonary vessels (pulmonary embolism)
• Inflammation of the blood vessel wall (vasculitis).
• Peripheral ischemia,
• Redness,
• Swelling,
• Flu-like symptoms
• Premature birth,
• Renal disorders (hepatitis, cholestasis,hepatotoxicity with liver failure, elevated bilirubin levels, abnormal liver function, elevated liver enzymes)
• Azoospermia in males and females,
• Changes in menstrual frequency,
• Loss of ovarian function,
• Testicular atrophy.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that does not appear in this leaflet. You can also report them directly through theSpanish System for Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es.

By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not store at a temperature above 25°C. Store in the original packaging to protect it from light. Avoid exposure to direct sunlight or heat sources. The influence of temperature may cause the active ingredient cyclophosphamide to melt. If there are changes, the vials can be identified visually with ease as they will appear with a clear or yellowish viscous liquid (which is found in the affected vials as a distinct phase or in droplets). Vials with the active ingredient melted must be discarded.

Both the reconstituted solution and the diluted solution can be used up to 24 hours after reconstitution (do not store above 8°C).

Do not usethis medicationafter the expiration date that appears on the boxafter Lot/CAD. The expiration date is the last day of the month indicated.

The disposal of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations for cytotoxics.

Composition ofGenoxal

The active ingredient isCiclofosfamida.

One vial of Genoxal contains 200 mg of Ciclofosfamida (as 213.8 mg of Ciclofosfamida monohydrate).

Aspect of the product and contents of the package

Genoxal is a white crystalline powder.

Genoxal 200 mg powder for injectable solution and for perfusionis presented in a package containing 1vial.

The vials are packaged with or without a plastic protective envelope. This package does not come into direct contact with the medication and provides additional protection during transportation, increasing safety for medical and pharmaceutical personnel.

Holder of the marketing authorization:

Baxter S.L.
Pouet de Camilo 2,
46394 Ribarroja del Turia (Valencia)

Spain

Responsible for manufacturing:

Baxter Oncology GmbH

Kantstrasse 2, 33790 Halle/Westfalen

Germany

Last review date of this leaflet: November

The detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es/

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This information is intended solely for healthcare professionals

Genoxalmust be administered exclusively by doctors who have experience in antineoplastic chemotherapy.

Genoxalmust be administered onlywhere there are facilitiesfor the periodic monitoring ofclinical, biochemical, and hematological parametersbefore, during, andafter administration and under the directionof a specialist oncology service.

Dosage

The dosesand durationof treatment and/orintervals of treatment depend on thetherapeutic indication, thechemotherapy regimen, the patient's general health status, andthe organ function,and laboratory control results(particularly,hematological monitoring).

The recommended dosages refer mainly to the treatment with ciclofosfamida in monotherapy.In combination with other cistostatics of similar toxicity, a dose reduction or an extension of the treatment-free intervals may be required.

To reduce the risk of myelosuppressive complications and/or facilitate the administration of the planned dose, the use of hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered.

During or immediately after administration, an adequate amount of liquids should be ingested or infused to force diuresis and reduce the risk of urothelial toxicity. Therefore, ciclofosfamida should be administered in the morning. See section 4.4.

The activation of ciclofosfamida requires hepatic metabolism, therefore, oral and intravenous administration are preferred.

The dosage should be adapted individually to each patient.Recommended dosages, unless otherwise prescribed by a doctor:

• forcontinuous treatmentin adults and children,3 to6 mg/kg of body weight per day (equivalent to120 to240 mg/m2of body surface area).
• forintermittent treatmentin adults and children,10 to15 mg/kg of body weight (equivalent to400 to600 mg/m2of body surface area) at intervals of2 to5 days.
• forintermittent treatment with high dosesin adults and children,20 to40 mg/kg of body weight (equivalent to800 to1600 mg/m2of body surface area) at intervals of21 to28 days. Higher doses may be used in the context of hematopoietic stem cell transplantation: 60 mg/kg/day for 2 days. In these cases, MESNA rescue and adequate hydration are mandatory to prevent hemorrhagic cystitis.
• The dose is variable in chemotherapy combined with other cytotoxic agents. For example, in non-Hodgkin lymphoma, the usual dose of ciclofosfamida is 750 mg/m2i.v. on day 1, every 21 days as part of the CHOP or CHOP-R regimen. In breast cancer, the dose is 600 mg/m2i.v. as part of the CMF regimen.

Administration form

Intravenous route

Ciclofosfamida isinactiveuntil it is activatedby hepatic enzymes.However,as with all cytotoxics,reconstitution should be performed by trained personnel and in a designated area.

Precautions to be taken before handling or administering the medication:

During preparation,gloves of protection should be used.Care should be taken to avoid splashes in the eyes.The medicationshould not be handledby women who are pregnant or breastfeeding.

Medicaments for intravenous administration shouldbe visually inspected for particles and discoloration before administration, whenever the solution and package permit.

Intravenous administration should be carried outpreferablyas a perfusion.

To reduce the probability of adverse reactions that appear to be dependent on the rate of administration (e.g., facial swelling, headache, nasal congestion, scalp burning, etc.), Genoxalshould be injected or infused very slowly.

The duration of the perfusionshould also be appropriate for the type of solution and volume in which the medication will be dissolved (usually 30 minutes to 2 hours).

Direct injection

Ifdirectly injected,Genoxalfor intravenous administrationshould be reconstitutedwith a physiological saline solution(sodium chloride 0.9%)by introducing the saline solution into the vial and agitating vigorouslyuntil the powder is completely dissolved.The result ofreconstitution is a transparent solution with a pH of4 to6.

For detailed instructions on reconstitution, see section 6.6.

Perfusion

For perfusion,Genoxalshould be reconstitutedwithwater for injection or with a physiological saline solution(sodium chloride 0.9%)and infusedin the recommended intravenous solutions.Genoxalreconstituted with water for injectionishypotonicand should not be injecteddirectly.

Ciclofosfamida iscompatible with the following perfusion solutions:sodium chloride solution,glucose solution,glucosaline solution,sodium chloride and potassium chloride solution,glucose and potassium chloride solution, or Ringer's solution.

Beforeintravenous administration,the substancemust be completely dissolved.

For detailed instructions on reconstitution, see section 6.6.

Treatment duration

The treatment cycles of the intermittent regimen may be repeated every 3-4 weeks.The duration of treatment and intervals depend on the therapeutic indication, the chemotherapy regimen, the patient's general health status, laboratory control results, and hematological recovery.

Special dosage recommendations:

Reduction of dose in patients with myelodepression

If treatment is combined with other myelodepressants, a dose reduction may be necessary.Particularly, a reduced dose of cistostatics is recommended.For cytotoxic agents administered concomitantly, consult the relevant dose adjustment table based on hematological results at the start of the cycle.

Patients with liver insufficiency

Use in patients who already suffer from liver deterioration before starting treatment should be evaluated on a case-by-case basis.Severe liver insufficiency requires a dose reduction.A 25% dose reduction is recommended when serum bilirubin is 3.1 to 5 mg/100 ml (See section 4.4).

Patients with renal insufficiency

A 50% dose reduction is recommended when creatinine clearance is less than 10 ml/min (See section 4.4).

Pediatric population

Based on established treatment regimens, in children and adolescents, similar doses to those recommended for adults should be used.

Older patients and debilitated patients

Generally, the dose in older patients and debilitated patients will be selected with caution, taking into account the higher frequency of liver, renal, or cardiac function deterioration and concomitant diseases or treatments with other medications (See section 4.4).

Special precautions for elimination and other manipulations

The preparation of cytotoxic drug injectable solutions should be carried out by specialized personnel, trained, with knowledge of the drugs used, and in conditions that ensure protection of the environment and, in particular, protection of personnel handling the drugs. A reserved preparation area is required. Smoking, eating, or drinking are prohibited in this area.

Personnel should have the necessary equipment, long-sleeved gowns, face masks, caps, protective glasses, sterile disposable gloves, protective covers for the work area, and waste bags.

Needles and perfusion equipment should be carefully assembled to avoid spills (the use of Luer lock is recommended).

Spills and leaks should be cleaned up.

Care should be taken to avoid exposure of pregnant women who are part of the personnel to the medication.

Strictly avoid any contact with the eyes. If this occurs, immediately wash the eye with normal saline solution. In case of irritation, consult an ophthalmologist. In case of skin contact, wash the affected area with an abundant amount of water.

Preparation of the solution

To prepare the injectable solution, the corresponding amount of physiological saline solution is added to the powder for injectable solution and perfusion in the vials.

The powder dissolves rapidly by vigorously agitating the vials once the solvent has been added.If the substance does not dissolve immediately and completely, it is recommended to leave the vial for a few minutes.

When to be administered by intravenous perfusion at short term, the Genoxalsolution preparedis added tosodium chloride solution,glucose solution,glucosaline solution,sodium chloride and potassium chloride solution,glucose and potassium chloride solution, or Ringer's solution, to obtain a total volume of approximately 500 ml.

The solutionshould be administered only by intravenous route,preferably in the form of a perfusion.The duration of the infusion may vary between 30 minutes and 2 hours, depending on the volume.

Before proceeding with the injection, ensure that the cannula is exactly in the vein. If the solution infiltrates into the surrounding tissue during intravenous administration, the injection should be interrupted and the vein irrigated with a saline solution, administering the remaining dose in another vein.

Elimination

After finishing, the exposed surfaces should be thoroughly cleaned, and hands and face should be washed.

Excreta and vomit should be handled with care.

The unused medication and all materials that have come into contact with it should be disposed of in accordance with local regulations for cytotoxics.