GENOXAL 200 mg POWDER FOR INJECTABLE SOLUTION AND FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Genoxal 200 mg powder for solution for injection and infusion

Cyclophosphamide

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

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

Contents of the pack:

1. What is Genoxal and what is it used for.
2. What you need to know before you are given Genoxal.
3. How Genoxal will be given to you.
4. Possible side effects.
5. Storing Genoxal.
6. Contents of the pack and other information.

1. What is Genoxal and what is it used for

Genoxal contains the active substance cyclophosphamide. It belongs to a group of medicines known as "cytotoxic or antineoplastic medicines", which work by stopping the growth of cancer cells.

Genoxal is usually used alone or in combination with other antineoplastic medicines or radiotherapy, 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),
• small cell lung cancer,
• in the treatment of metastatic or advanced tumors of the central nervous system (neuroblastoma).

In addition, Genoxal is used in the preparation of bone marrow transplants.

On occasion, some doctors may prescribe Genoxal for conditions unrelated to cancer:

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

2. What you need to know before you are given Genoxal

Do not useGenoxalif:

• You are allergic to cyclophosphamide, any of its metabolites, or any of the other components of this medicine (listed in section 6). An allergic reaction may include difficulty breathing, wheezing, rash, itching, or swelling of the face and lips.
• You currently have an infection.
• Your bone marrow is not functioning properly (especially if you have previously undergone chemotherapy or radiotherapy). You will have blood tests to check your bone marrow function,
• You have a urinary tract infection that can be recognized by pain when urinating (cystitis).
• You have had kidney or bladder problems as a result of chemotherapy or radiotherapy.
• You have a disease that reduces your ability to urinate (obstruction of urine flow).
• You are pregnant or breastfeeding.
• In the treatment of non-malignant diseases, except for immunosuppression in life-threatening situations.

Warnings and precautions

Tell your doctor before starting Genoxal if:

• 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 working properly and if you have had your adrenal gland removed,
• You are receiving or have recently received radiotherapy or chemotherapy; you have heart problems or have received radiotherapy in the heart area,
• You have diabetes,
• You are in poor general health or are a frail or elderly person,
• You have had surgery in the last 10 days.

Potentially life-threatening allergic reactions (anaphylactic reactions) may occur during treatment with Genoxal.

Genoxal may affect your blood and immune system.

Blood cells are produced in your bone marrow. These cells are of three types:

• red blood cells, which carry oxygen in the body,
• white blood cells, which fight infections, and
• platelets, which allow blood to clot.

After receiving cyclophosphamide, the count of blood cells for all three types of cells will decrease. This is an inevitable side effect of the medicine. Your blood count will reach its lowest level about 5 to 10 days after starting Genoxal and will remain low for a few days after the treatment cycle ends. 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 little longer to return to normal.

You are more likely to get infections if your blood cell count is low. Try to avoid close contact with people who have coughs, colds, and other infections. Your doctor will treat you with the appropriate medicine if they think you have an infection or are at risk of getting one.

Your doctor will make sure that your red blood cell, white blood cell, and platelet counts are high enough before treatment with cyclophosphamide and during treatment. You may need to have the amount of medicine you receive reduced or the next dose delayed.

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

Genoxal may damage the lining of the urinary bladder, causing bleeding in the urine or pain when urinating. Your doctor is aware that this can happen and, if necessary, will give you a medicine called Mesna (Uromitexan) to protect your bladder. Mesna can be given as a short injection or mixed with cyclophosphamide in the infusion solution. You can find more information about Mesna in the leaflet that comes with the Uromitexan pack.

Most people who receive Genoxal with Mesna do not develop bladder problems, but your doctor may want to check your urine for blood using a dipstick or microscope. If you notice blood in your urine, you must tell your doctor immediately.

Cancer medicines and radiotherapy may increase the risk of developing other types of cancer; this can happen several years after the end of your treatment. Genoxal carries a higher risk of causing cancer in the bladder area.

Genoxal may cause heart damage or affect the rhythm of your heartbeat. This effect is greater at higher doses of Genoxal, if you are being treated with radiotherapy or other chemotherapy medicines, or if you are an elderly person. Your doctor will closely monitor your heart during treatment.

Genoxal may cause lung problems such as inflammation or scarring of the lungs.

This can happen more than six months after the end of treatment. If you start to have difficulty breathing, tell your doctor immediately.

Genoxal may have potentially life-threatening effects on your liver.

If you experience a sudden increase in weight, liver pain, and your skin or the whites of your eyes turn yellow (jaundice), tell your doctor immediately.

Genoxal may cause hair loss or baldness. Your hair should grow back normally, although its texture and color may be different.

Genoxal may cause you to feel sick or vomit. This can last for about 24 hours after taking the medicine. You may need to take medicines to stop feeling sick or vomiting. Consult your doctor about this.

Children and adolescents

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

Using Genoxal with other medicines:

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines. In particular, tell them about the following medicines or treatments, as they may be incompatible with the use of Genoxal.

The following medicines may reduce the effectiveness of Genoxal:

• aprepitant (used to prevent vomiting),
• bupropion (an antidepressant),
• busulfan, thiotepa (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 medicines may increase the toxicity of Genoxal:

• allopurinol (used to treat gout),
• chloral hydrate (used to treat insomnia),
• cimetidine (used to reduce stomach acid),
• disulfiram (used to treat alcoholism),
• glyceraldehyde (used to treat warts),
• protease inhibitors (used to treat viruses),
• medicines that increase liver enzymes, such as rifampicin (used to treat bacterial infections), carbamazepine, phenobarbital, phenytoin (used to treat epilepsy), St. John's Wort (a herbal remedy for mild depression), corticosteroids (used to treat inflammation),
• benzodiazepines (used as anxiolytics),
• ondansetron (used to prevent vomiting).

Medicines that may increase the toxic effects of Genoxal on blood cells and immunity:

• ACE inhibitors (used to treat high blood pressure),
• natalizumab (used to treat multiple sclerosis),
• paclitaxel (used to treat cancer),
• thiazide diuretics, such as hydrochlorothiazide or chlorthalidone (used to treat high blood pressure or fluid retention),
• zidovudine (used to treat viral infections),
• clozapine (used to treat symptoms of some psychiatric disorders).

Medicines that may increase the toxic effects of Genoxal on the heart:

• anthracyclines, such as bleomycin, doxorubicin, epirubicin,
• cytarabine, pentostatin, trastuzumab (used to treat cancer),
• radiotherapy in the heart area.

Medicines that may increase the toxic effects of Genoxal on the lungs:

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

Medicines that may increase the toxic effects of Genoxal on the kidneys:

• amphotericin B (used to treat fungal infections),
• indomethacin (used to treat pain and inflammation).

Other medicines that may affect Genoxal or be affected by it include:

• azathioprine (used to reduce the activity of the immune system),
• etanercept (used to treat rheumatoid arthritis),
• metronidazole (used to treat bacterial or protozoal infections),
• tamoxifen (used to treat breast cancer),
• bupropion (used to help stop smoking),
• coumarins, such as warfarin (used as an anticoagulant),
• cyclosporin (used to reduce the activity of the immune system),
• suxamethonium (used as a muscle relaxant during medical procedures),
• digoxin, acetyldigoxin ß (used to treat heart conditions),
• vaccines,
• verapamil (used to treat high blood pressure, angina, or irregular heartbeat),
• sulfonylurea derivatives (it may be necessary to reduce blood sugar levels if cyclophosphamide and sulfonylurea derivatives are used at the same time).

Using Genoxal with food and drink

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

Grapefruit (as a fruit or juice) should not be consumed while taking Genoxal.

It may interfere with the usual effect of your medicine and alter its effectiveness.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, or think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy

Genoxal may cause miscarriage or harm to the unborn baby.

If you are a woman, you must not become pregnant during treatment with cyclophosphamide or for up to 12 months after the end of treatment. Both men and women who are sexually active must use effective contraception during treatment and for up to 6 months after the end of treatment. If you become pregnant during treatment, there is a possibility that you may receive genetic counseling (medical advice to assess the possible risk of congenital malformations in the baby).

Breastfeeding

You must not breastfeed while being treated with cyclophosphamide. Ask your doctor for advice.

Fertility

Genoxal may cause infertility in both men and women. Consult your doctor about the freezing (cryopreservation) of sperm or eggs before treatment, as there is a possibility of irreversible infertility due to treatment with cyclophosphamide. If you are considering becoming a parent 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 or use machines safely. Your doctor will decide if you can do so safely.

Patients should be cautious when performing tasks such as driving cars and operating machinery until they have checked that treatment with the medicine does not affect their ability to perform these activities.

3. How Genoxal will be given to you

Genoxal will be given to you by a doctor who is experienced in the use of antineoplastic chemotherapy (for the treatment of cancer).

Method of administration

By intravenous route

Genoxal is given as an injection and is usually added to a large bag of fluid and given slowly (infusion) directly into a vein. The vein may be in your arm, the back of your hand, or a large vein under your collarbone.

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

Genoxal is usually given in combination with other antineoplastic medicines or radiotherapy.

The recommended dose is:

Your doctor will decide how much medicine you need and when you should receive it. This will depend on the type of disease you have, your build (a combination of your height and weight), your overall health, and whether you are receiving other antineoplastic medicines or radiotherapy.

It is recommended to give Genoxal in the morning. Before, during, and after administration, it is important that you receive adequate amounts of fluid to avoid possible side effects on the urinary tract.

If you think that Genoxal is too strong or too weak, talk to your doctor or pharmacist.

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

• You have liver or kidney problems,
• 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 too much Genoxal

Since Genoxal is given under the supervision of your doctor, it is very unlikely that you can receive too much. However, if you experience side effects after receiving the medicine, tell your doctor immediately.

You may need urgent medical attention.

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

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, telephone 915.620.420, indicating the medicine and the amount taken.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Tell your doctor immediately if you experience:

• Allergic reactions. The signs would be difficulty breathing, wheezing, increased heart rate, reduced blood pressure, rash, itching, or inflammation of the face and lips. Severe allergic reactions could cause breathing difficulties 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 the levels of platelets in your blood are too low.
• Severe infection or fever, cough, shortness of breath, signs of septicemia such as fever, rapid breathing, increased heart rate, confusion, and edema. This could be a sign of a reduction in your white blood cell count, and antibiotics may be needed to fight infections.
• Pallor, feeling of lethargy, and fatigue. This could be indicative of a low level of red blood cells (anemia). Normally, no treatment is required, as your body will replace the red blood cells over time. In cases of pronounced anemia, a blood transfusion may be necessary.
• Blood in the urine, pain when urinating, or reduced urine volume.
• Signs of septicemia such as fever, rapid breathing, increased 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.

The following adverse effects can also occur during treatment with Genoxal.

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 (leukopenia, neutropenia),
• nausea and vomiting,
• burning sensations when urinating and frequent need to do so (cystitis),
• presence of 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 (febrile neutropenia).
• blood in the urine and pain when urinating (hemorrhagic cystitis),
• presence of blood in the urine (macrohematuria),
• hair loss,
• infections,
• chills,
• feeling of weakness,
• general feeling of discomfort,
• inflammation of the mucous membranes (mucositis),
• sterility in males.

Uncommon(may affect up to 1 in 100 patients)

• Increased lactate dehydrogenase in the blood,
• increased C-reactive protein,
• changes in the electrocardiogram,
• heart problems (myocardial disease, myocarditis, heart failure),
• rapid heartbeat,
• propensity to bruising due to thrombocytopenia (reduced platelet count),
• anemia (low red blood cell count) that can cause fatigue and drowsiness,
• nerve damage that can cause numbness, pain, and weakness (neuropathy),
• nerve pain (neuralgia),
• reduced concentration of sex hormones,
• loss of appetite,
• lung inflammation (pneumonia),
• septicemia,
• ovulation disorders,
• allergic reactions.

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

• Changes in heart rhythm,
• seizures,
• blurred vision,
• pain or ulcers in the mouth (stomatitis),
• diarrhea,
• constipation,
• abdominal pain
• inflammation of the salivary glands,
• rash,
• dermatitis,
• skin inflammation,
• irreversible ovulation disorders,
• dehydration,
• increased risk of white blood cell cancer (acute leukemia) and other cancers (bladder cancer, ureteral cancer),
• ineffective production of the myeloid class of blood cells (myelodysplastic syndrome),
• bleeding,
• chest pain,
• liver function abnormalities,
• liver inflammation,
• absence of menstruation (periods),
• absence of sperm.

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

• Weight gain,
• angina,
• myocardial infarction,
• cardiac arrest,
• ventricular fibrillation,
• pericarditis (inflammation of the pericardium),
• atrial fibrillation,
• formation of blood clots in all small blood vessels of the body (disseminated intravascular coagulation),
• hemolytic uremic syndrome (a condition that affects the blood and kidneys),
• dizziness,
• alteration of the sense of taste (dysgeusia, hypogeusia),
• tingling, pinching, itching, or burning sensation (paresthesia),
• hepatic encephalopathy,
• conjunctivitis, eye edema, visual impairment,
• deafness,
• pulmonary injury (acute respiratory distress syndrome),
• pulmonary fibrosis that causes difficulty breathing (chronic interstitial pulmonary fibrosis),
• respiratory failure due to fluid accumulation in the lungs (pulmonary edema),
• difficulty breathing with wheezing or cough (bronchospasm),
• shortness of breath (dyspnea),
• a condition in which the body or a region of the body lacks adequate oxygen supply (hypoxia),
• cough,
• non-specific pulmonary disorders,
• inflammation of the intestine,
• inflammation of the pancreas,
• fluid accumulation in the abdominal cavity (ascites).
• ulceration of the mucosa,
• stomach or intestinal bleeding,
• suburethral bleeding,
• presence of fluid in the bladder wall,
• kidney problems, including kidney failure,
• inflammation of the bladder wall,
• inflammation, sclerosis, and contraction of the bladder,
• high creatinine levels in the blood,
• severe hypersensitivity reactions with fever (high), red spots on the skin, joint pain, and/or eye infection (Stevens-Johnson syndrome),
• sudden severe reaction (hypersensitivity) with fever and blisters on the skin/desquamation of the skin (toxic epidermal necrolysis),
• itching,
• severe skin reactions,
• changes in the color of your nails and skin,
• radiation erythema,
• abnormal muscle breakdown that can cause kidney problems (rhabdomyolysis),
• cramps,
• increased release of antidiuretic hormone from the pituitary gland (inappropriate antidiuretic hormone secretion syndrome). This affects the kidneys and causes low sodium levels in your body (hyponatremia) and fluid retention, leading to brain swelling due to excess water in your blood. The signs may include headache, changes in personality or behavior, confusion, and drowsiness,
• low sodium levels in the blood (hyponatremia),
• septic shock,
• complications that may occur after cancer treatment caused by breakdown products of dying cancer cells (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,
• liver hypertrophy (hepatomegaly),
• yellow eyes or skin,
• confusion,
• anaphylactic shock

Frequency Not Known(frequency cannot be estimated from the available data)

• brain disorder (encephalopathy), neurotoxicity manifested as a syndrome characterized by headache, confusion, spinal cord disorders (myelopathy), seizures, and loss of vision (reversible posterior leukoencephalopathy syndrome), abnormal sensation (dysesthesia, hypesthesia), degenerative brain disease (encephalopathy), tremor, alteration of the sense of smell (parosmia), various types of heart disorders (ventricular tachycardia, cardiogenic shock, pericardial effusion, myocardial hemorrhage, left ventricular failure, bradycardia, palpitations, prolonged QT interval in the electrocardiogram, decreased ejection fraction),
• intrauterine death,
• fetal malformation,
• fetal growth retardation,
• various types of blood disorders (low blood cell counts, agranulocytosis, lymphopenia, reduced hemoglobin),
• increased tearing,
• ringing in the ears and hearing defects
• pleural effusion,
• nasal congestion (nasal blockage),
• nasal discomfort,
• oropharyngeal pain,
• rhinorrhea,
• sneezing,
• veno-occlusive pulmonary disease,
• obliterative bronchiolitis,
• allergic alveolitis,
• organizing pneumonia,
• pneumonitis,
• abdominal discomfort,
• certain kidney diseases (renal tubular necrosis, renal tubular disorder, toxic nephropathy, hemorrhagic ureteritis, ulcerative cystitis, bladder contracture, nephrogenic diabetes insipidus, atypical epithelial cells of the urinary bladder),
• itching, rash, blisters on the lips, eyes, or mouth, skin peeling (erythema multiforme, urticaria, erythema),
• hand-foot syndrome,
• facial swelling,
• increased sweating,
• skin hardening (scleroderma),
• muscle spasms and pain,
• joint pain,
• water intoxication,
• changes in the results of some blood tests (glucose, hormone levels),
• various types of cancer, such as blood cancer (non-Hodgkin's lymphoma), kidney cancer, renal pelvis cancer, thyroid cancer, sarcoma, carcinogenic effect on 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 walls (vasculitis).
• peripheral ischemia,
• flushing,
• edema,
• flu-like symptoms
• premature birth,
• liver disorders (hepatitis, cholestasis, hepatotoxicity with liver failure, increased bilirubin levels, abnormal liver function, elevated liver enzymes)
• sterility 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 is not listed in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es.

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

5. Storage of Genoxal

Keep this medicine out of sight and reach of children.

Do not store above 25°C. Store in the original package to protect from light. Avoid exposure to direct sunlight or heat sources. Temperature influence can cause the active ingredient cyclophosphamide to melt. If changes occur, the vials can be easily identified visually as they will show a clear or yellowish viscous liquid (which is found in the affected vials as a distinct phase or in drops). Vials with melted active ingredient must be discarded.

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

Do not use this medicine after the expiration date shown on the box after Lot/CAD. The expiration date is the last day of the month indicated.

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

6. Container Contents and Additional Information

Composition ofGenoxal

The active ingredient is Cyclophosphamide.

A vial of Genoxal contains 200 mg of Cyclophosphamide (as 213.8 mg of Cyclophosphamide monohydrate).

Appearance of the Product and Container Contents

Genoxal is a white crystalline powder.

Genoxal 200 mg powder for solution for injection and infusion is presented in a container containing 1 vial.

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

Marketing Authorization Holder:

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

Spain

Manufacturer:

Baxter Oncology GmbH

Kantstrasse 2, 33790 Halle/Westfalen

Germany

Date of Last Revision of this Prospectus: November

Detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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This information is intended solely for healthcare professionals

Genoxal should be administered exclusively by doctors with experience in antineoplastic chemotherapy.

Genoxal should be administered only where there are facilities for periodic monitoring of clinical, biochemical, and hematological parameters before, during, and after administration, and under the direction of a specialist oncology service.

Dosage

The doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of combination therapy, the patient's general state of health, and organ function, and laboratory test results (in particular, hematite monitoring).

The posological recommendations refer mainly to treatment with cyclophosphamide in monotherapy. In combination with other cytostatics of similar toxicity, a dose reduction or an extension of the treatment-free intervals may be required.

In order to reduce the risk of myelosuppressive complications and/or facilitate the administration of the planned dose, the use of hematopoietic stimulants (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered.

During or immediately after administration, an adequate amount of fluids should be ingested or perfused to force diuresis in order to reduce the risk of urothelial toxicity. Therefore, cyclophosphamide should be administered in the morning. See section 4.4.

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

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

• for continuous treatment in adults and children, 3 to 6 mg/kg of body weight per day (equivalent to 120 to 240 mg/m2of body surface area).
• for intermittent treatment in adults and children, 10 to 15 mg/kg of body weight (equivalent to 400 to 600 mg/m2of body surface area) at intervals of 2 to 5 days.
• for high-dose intermittent treatment in adults and children, 20 to 40 mg/kg of body weight (equivalent to 800 to 1600 mg/m2of body surface area) at intervals of 21 to 28 days. Higher doses may be used in the context of hematopoietic progenitor cell transplantation: 60 mg/kg/day for 2 days. In these cases, rescue with MESNA and adequate hydration is mandatory to avoid hemorrhagic cystitis.
• The doses are variable in combined chemotherapy with other cytostatic agents. For example, in non-Hodgkin's lymphoma, the usual dose of cyclophosphamide 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.

Method of Administration

Intravenous Route

Cyclophosphamide is inert until activated by hepatic enzymes. However, as with all cytotoxics, reconstitution should be performed by trained personnel and in an area designated for this purpose.

Precautions to be taken before handling or administering the medication:

During preparation, protective gloves should be used. Care should be taken to avoid splashing in the eyes. The medication should not be handled by pregnant or breastfeeding women.

Medicines for intravenous administration should be visually inspected for particles and discoloration before administration, whenever the solution and container permit.

Intravenous administration should be performed preferably as an infusion.

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

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

Direct Injection

If administered directly, Genoxal for intravenous administration should be reconstituted with a physiological saline solution (0.9% sodium chloride) by introducing the saline solution into the vial and shaking vigorously until the powder is completely dissolved. The result of the reconstitution is a clear solution with a pH between 4 and 6.

For detailed instructions on reconstitution, see section 6.6.

Infusion

For infusion, Genoxal should be reconstituted with water for injectable preparations or with a physiological saline solution (0.9% sodium chloride) and infused in the recommended intravenous solutions. Genoxal reconstituted in water for injectable preparations is hypotonic and should not be injected directly.

Cyclophosphamide is compatible with the following infusion solutions: sodium chloride solution, glucose solution, glucosaline solution, sodium chloride and potassium chloride solution, glucose and potassium chloride solution, or Ringer's solution.

Before intravenous administration, the substance should be completely dissolved.

For detailed instructions on reconstitution, see section 6.6.

Duration of Treatment

The treatment cycles of the intermittent regimen may be repeated every 3-4 weeks. The duration of treatment and the treatment-free intervals depend on the therapeutic indication, the combined treatment protocol, the patient's general state of health, laboratory test results, and the recovery of hemogram values.

Special Dosage Recommendations:

Dose Reduction in Patients with Myelodepression

If the treatment is combined with other myelodepressors, a dose reduction may be necessary. In particular, a reduced dose of cytostatics to a minimum is recommended. For cytotoxic medications administered concomitantly, consult the relevant dose adjustment table according to the hemogram results at the start of the cycle.

Patient with Hepatic Insufficiency

The use in patients who already suffer from hepatic impairment before the start of treatment should be evaluated individually. Severe hepatic 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).

Patient with Renal Insufficiency

A 50% dose reduction is recommended when the creatinine clearance is less than 10 ml/minute (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.

Geriatric Patients and Debilitated Patients

In general, the dose in geriatric patients and debilitated patients should be selected with caution, taking into account the higher frequency of hepatic, renal, or cardiac function impairment and concomitant diseases or treatments with other medications (see section 4.4).

Special Precautions for Elimination and Other Handling

The preparation of injectable solutions of cytotoxic medications should be carried out by specialized personnel, trained and knowledgeable about the medications used, and under conditions that guarantee environmental protection and, in particular, protection of the personnel handling the medications. A dedicated preparation area is required. In this area, smoking, eating, or drinking is prohibited.

Personnel must have adequate equipment, long-sleeved gowns, protective masks, caps, protective glasses, single-use sterile gloves, protective covers for the work area, and trash bags.

Syringes and infusion equipment should be assembled carefully to avoid spills (Luer closure is recommended).

Spills and leaks should be cleaned up.

Pregnant women who are part of the personnel should be cautious to avoid exposure to the medication.

Any contact with the eyes should be strictly avoided. If it occurs, the eye should be rinsed immediately with a normal saline solution. In case of irritation, an ophthalmologist should be consulted. In case of skin contact, the affected area should be washed with a large 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 solution for injection and infusion of the vials.

The powder dissolves rapidly when the vials are shaken vigorously once the solvent is added. If the substance does not dissolve immediately and completely, it is advisable to let the vial rest for a few minutes.

When administered as a short-term intravenous infusion, the prepared Genoxal solution is added to a sodium 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 solution should be administered only intravenously, preferably as an infusion. The infusion duration may vary between 30 minutes and 2 hours, depending on the volume.

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

Elimination

After completion, any exposed surface should be thoroughly cleaned, and hands and face should be washed.

Excretions and vomit should be handled with care.

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