Genoxal 50 mg film-coated tablets

Package leaflet: Information for the user

Introduction

Package leaflet: information for the patient

GENOXAL 50 mg coated tablets

Cyclophosphamide

Read the entire leaflet carefully before you start taking 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 and should not be given to other people, even if they have the same symptoms, as it may harm them.
• If you experience any adverse reactions, consult your doctor or pharmacist, even if they are adverse reactions not listed in this leaflet. See section 4.

Contents of the leaflet:

1. What GENOXAL is and what it is used for.
2. What you need to know before taking GENOXAL.
3. How to take GENOXAL.
4. Possible side effects.
5. How to store GENOXAL.
6. Contents of the pack and other information.

1. What GENOXAL is and what it is 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 as monotherapy or in combination with other antineoplastic medicines or radiotherapy for the treatment of various types of cancer. This includes:

• various forms of lymphomas affecting 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 carcinoma,
• treatment of metastatic or advanced central nervous system tumors (neuroblastoma).

Additionally, Genoxal is used in preparation for bone marrow transplantation.

In some cases, physicians 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 taking GENOXAL

Do not take Genoxal:

• If 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.
• If you currently have an infection.
• If your bone marrow is not functioning properly (especially if you have previously received chemotherapy or radiotherapy). Blood tests will be performed to check your bone marrow function.
• If you have a urinary tract infection that causes pain when urinating (cystitis).
• If you have had kidney or bladder problems as a result of chemotherapy or radiotherapy.
• If you have a disease that reduces your ability to urinate (urinary flow obstruction).
• If you are pregnant or breastfeeding.
• For the treatment of non-malignant diseases, except for life-threatening immunosuppression.

Warnings and precautions

Talk to your doctor or pharmacist before starting Genoxal:

• If you have low blood cell counts.
• If you have serious infections.
• If you have liver or kidney problems. Your doctor will check, through a blood test, whether your liver and kidneys are functioning properly and whether you have had your adrenal gland removed.
• If you are receiving or have recently received radiotherapy or chemotherapy; if you have heart problems or have received radiotherapy to the heart area.
• If you have diabetes.
• If you are in poor general health, frail, or elderly.
• If you have undergone surgery within the last 10 days.

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

Genoxal can 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 throughout the body,
• white blood cells, which fight infections, and
• platelets, which allow blood to clot.

After receiving cyclophosphamide, the count of all three types of blood cells will decrease. This is an inevitable side effect of the medicine. Your blood count will reach its lowest level approximately between 5 and 10 days after starting Genoxal and will remain low for several days after treatment ends. Most people recover normal blood counts within 21 to 28 days. If you have previously received large amounts of chemotherapy, it may take longer to return to normal.

You are more likely to contract infections if your blood cell count is reduced. Try to avoid contact with people who have coughs, colds, or other infections. Your doctor will treat you with appropriate medication if they suspect you have an infection or are at risk of developing one.

Your doctor will ensure that your red blood cell, white blood cell, and platelet counts are sufficiently high before and during treatment with cyclophosphamide. You may need to reduce the dose of medication you receive or delay the next dose.

Genoxal may impair normal wound healing. Keep cuts clean and dry and monitor them for normal healing. It is important to maintain good gum health, as infections and mouth ulcers may occur. Consult your doctor if you have any doubts.

Genoxal can damage the inner lining of the urinary bladder, causing bleeding in the urine or pain when urinating. Your doctor is aware of this possibility and, if necessary, will give you a medicine called Mesna (Uromitexan) to protect your bladder. Mesna can be administered as a short injection or mixed with cyclophosphamide in the infusion solution. More information about Mesna can be found in the package leaflet included with Uromitexan.

Most people receiving Genoxal with Mesna do not develop bladder problems, but your doctor may wish to test your urine for blood using a dipstick or microscope. If you notice blood in your urine, inform your doctor immediately.

Cancer medicines and radiotherapy may increase the risk of developing other types of cancer; this may occur several years after completion of treatment. Genoxal carries an increased risk of causing cancer in the urinary bladder area.

Genoxal may cause heart damage or affect your heart rhythm. This effect is greater at higher doses of Genoxal, if you are receiving radiotherapy or other chemotherapy drugs, or if you are elderly. Your doctor will closely monitor your heart during treatment.

Genoxal may cause lung problems such as inflammation or pulmonary fibrosis.

This may occur more than six months after treatment ends. If you develop breathing difficulties, inform your doctor immediately.

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

If you experience sudden weight gain, liver pain, or yellowing of the skin or whites of the eyes (jaundice), inform your doctor immediately.

Hair loss or baldness (alopecia) may occur. Your hair should regrow normally, although its texture and color may be different.

Genoxal may cause nausea and vomiting. This may last approximately 24 hours after taking the medicine. You may need to take medication to prevent nausea and vomiting. Discuss this with your doctor.

Children and adolescents

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

Taking Genoxal with other medicines:

Inform your doctor or pharmacist if you are using, have recently used, or might need to use any other medicines. In particular, inform them about the following medicines or treatments, as they may be incompatible with 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 acidity),
• disulfiram (used to treat alcoholism),
• glycerol (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 hypertension),
• natalizumab (used to treat multiple sclerosis),
• paclitaxel (used to treat cancer),
• thiazide diuretics such as hydrochlorothiazide or chlorthalidone (used to treat hypertension or fluid retention),
• zidovudine (used to treat viral infections),
• clozapine (used to treat symptoms of certain 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 to 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 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, acetyldigoxin ß (used to treat heart conditions),
• vaccines,
• verapamil (used to treat high blood pressure, angina, or irregular heartbeat),
• sulfonylurea derivatives (blood glucose may decrease if cyclophosphamide and sulfonylurea derivatives are used simultaneously).

Taking Genoxal with food, drinks, and alcohol

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

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

It may interfere with the normal effect of your medicine and alter its efficacy.

Pregnancy, breastfeeding, and fertility

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

Pregnancy

Genoxal may cause miscarriage or fetal harm.

If you are a woman, you must not become pregnant during treatment with cyclophosphamide or for 12 months after treatment ends. Both men and women who are sexually active must use effective contraception during treatment and for 6 months after stopping treatment. If you become pregnant during treatment, you may be offered genetic counselling (medical advice to assess the possible risk of congenital malformations in the fetus).

Breastfeeding

You must not breastfeed while being treated with Genoxal. Seek advice from your doctor.

Fertility

Genoxal may cause infertility in both sexes. Discuss sperm or egg cryopreservation (freezing) with your doctor before treatment due to the possibility of irreversible infertility caused by cyclophosphamide. If you are considering having children after treatment, you should discuss this with your doctor.

Driving and using machines:

Some of the adverse effects of cyclophosphamide treatment may affect your ability to drive or operate machinery safely. Your doctor will decide whether you can do so safely.

Patients should exercise caution when performing tasks such as driving or operating machinery until they know how the medicine affects their ability to perform these activities.

Genoxal contains lactose and sucrose

This medicine contains lactose and sucrose. If your doctor has informed you of an intolerance to certain sugars, consult them before taking this medicine.

3. How to take GENOXAL

Follow exactly the instructions for use of this medicine given by your doctor. If in doubt, consult your doctor or pharmacist.

Recommended dose:

Your doctor will prescribe a treatment schedule and the correct dose for you. The recommended dose, unless otherwise prescribed by your doctor, is 1 to 4 tablets (50 to 200 mg) daily for continuous treatment; if your doctor considers it necessary, more tablets may be taken.

Method of administration:

Genoxal is administered orally. Take the tablets in the morning. The tablets should be swallowed whole, and you should drink a sufficient amount of liquid during or immediately after administration.

Duration of treatment:

Intermittent treatment cycles may be repeated every 3 or 4 weeks. The duration of treatment and intervals will be determined by your doctor.

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 take more Genoxal than you should

You may require urgent medical attention.

Symptoms of overdose with cyclophosphamide include the adverse effects listed in the section "Side effects", but they are usually more severe in nature.

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

If you forget to take Genoxal

If you accidentally miss a dose, simply take your next dose at the scheduled time. Do not take a double dose to make up for missed doses. If you have any questions about the use of this medicine, consult your doctor.

If you stop treatment with Genoxal

There are no side effects caused by stopping treatment with Genoxal.

If you have any further questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone experiences them.

Tell your doctor immediately if you experience:

• Allergic reactions. Signs may include difficulty breathing, wheezing, increased heart rate, low blood pressure, rash, itching, or swelling of the face and lips. Severe allergic reactions could lead to breathing difficulties or shock, possibly resulting in death (anaphylactic shock, anaphylactic/anaphylactoid reaction).
• Appearance of bruises without injury, or bleeding gums. This could indicate that your blood platelet levels are too low.
• Severe infection or fever, cough, shortness of breath, signs of sepsis such as fever, rapid breathing, increased heart rate, confusion, and edema. This could indicate a reduction in your white blood cell count, and antibiotics may be needed to fight infections.
• Paleness, feeling lethargic and tired. This could indicate low red blood cell levels (anemia). Treatment is usually not required, as your body will eventually replenish red blood cells. In cases of severe anemia, a blood transfusion may be necessary.
• Blood in the urine, pain when urinating, or reduced urine volume.
• Signs of sepsis such as fever, rapid breathing, increased heart rate, confusion, and edema.
• Severe chest pain.
• Severe lung inflammation causing shortness of breath, cough, and increased temperature.
• Symptoms such as weakness, vision loss, speech difficulties, or loss of sense of touch.

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

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

• Reduction in blood cell count (myelosuppression),
• reduction in white blood cells, which are important for fighting infections (leukopenia, neutropenia),
• nausea and vomiting,
• burning sensation when urinating and frequent need to urinate (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),
• baldness,
• infections,
• chills,
• feeling of weakness,
• general malaise,
• inflammation of mucous membranes (mucositis),
• male infertility.

Uncommon (may affect up to 1 in 100 patients)

• Increased lactate dehydrogenase in blood,
• increased C-reactive protein,
• changes in electrocardiogram,
• heart problems (cardiomyopathy, myocarditis, heart failure),
• rapid heartbeat,
• tendency to bruise due to thrombocytopenia (low platelet count),
• anemia (low red blood cell count) which may cause fatigue and drowsiness,
• nerve damage which may cause numbness, pain, and weakness (neuropathy),
• pain along the distribution of a nerve (neuralgia),
• reduced levels of sex hormones,
• anorexia,
• lung inflammation (pneumonia),
• sepsis,
• ovulation disorders,
• allergic reactions.

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

• Changes in heart rhythm,
• seizures,
• blurred vision,
• mouth pain or ulcers (stomatitis),
• diarrhea,
• constipation,
• abdominal pain,
• inflammation of the salivary glands,
• skin rash,
• dermatitis,
• skin inflammation,
• irreversible ovulation disorders,
• dehydration,
• increased risk of white blood cell cancer (acute leukemia) and some other cancers (bladder cancer, ureter cancer),
• ineffective production of myeloid blood cells (myelodysplastic syndrome),
• bleeding,
• chest pain,
• abnormal liver function,
• 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 vessels of the body (disseminated intravascular coagulation),
• hemolytic uremic syndrome (a condition affecting blood and kidneys),
• dizziness,
• altered sense of taste (dysgeusia, hypogeusia),
• tingling, prickling, stinging, or burning sensations (paresthesia),
• hepatic encephalopathy,
• conjunctivitis, eye edema, visual deterioration,
• deafness,
• lung injury (acute respiratory distress syndrome),
• pulmonary fibrosis causing breathing difficulty (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 lacks adequate oxygen supply (hypoxia),
• cough,
• nonspecific pulmonary disorders,
• intestinal inflammation,
• pancreatitis,
• fluid accumulation in the abdominal cavity (ascites),
• mucosal ulceration,
• gastric or intestinal bleeding,
• suburethral hemorrhage,
• presence of fluid in the bladder wall,
• kidney problems, including renal failure,
• inflammation of the bladder wall,
• inflammation, sclerosis, and contraction of the bladder,
• high creatinine levels in blood,
• severe hypersensitivity reactions with fever (high), red skin spots, joint pain and/or eye infection (Stevens-Johnson syndrome),
• sudden severe hypersensitivity reaction with fever and skin blisters/skin peeling (toxic epidermal necrolysis),
• itching,
• severe skin reactions,
• changes in the color of your nails and skin,
• radiation erythema,
• abnormal muscle breakdown which may cause kidney problems (rhabdomyolysis),
• cramps,
• increased release of antidiuretic hormone from the pituitary gland (syndrome of inappropriate antidiuretic hormone secretion). This affects the kidneys and causes low sodium levels in the body (hyponatremia) and fluid retention, leading to brain swelling due to excess water in the blood. Symptoms may include headache, personality or behavioral changes, confusion, and drowsiness,
• low blood sodium levels (hyponatremia),
• septic shock,
• complications that may occur after cancer treatment caused by degradation 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,
• blood clot in the liver (hepatic veno-occlusive disease),
• reactivation of hepatitis virus,
• liver enlargement (hepatomegaly),
• yellowing of eyes or skin,
• confusion,
• anaphylactic shock.

Frequency not known (cannot be estimated from available data)

• Brain disorder (encephalopathy), neurotoxicity manifested as a syndrome characterized by headache, confusion, spinal cord disorders (myelopathy), seizures, and vision loss (posterior reversible leukoencephalopathy syndrome), abnormal sensation (dysesthesia, hypoesthesia), degenerative brain disease (encephalopathy), tremor, altered sense of smell (parosmia), various types of cardiac disorders (ventricular tachycardia, cardiogenic shock, pericardial effusion, myocardial hemorrhage, left ventricular failure, bradycardia, palpitations, QT interval prolongation on electrocardiogram, reduced ejection fraction),
• intrauterine death,
• fetal malformation,
• fetal growth retardation,
• various types of blood disorders (low blood cell counts, agranulocytosis, lymphopenia, reduced hemoglobin),
• increased lacrimation,
• tinnitus and hearing defects,
• pleural effusion,
• nasal blockage (nasal congestion),
• nasal discomfort,
• oropharyngeal pain,
• rhinorrhea,
• sneezing,
• veno-occlusive lung 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 in urinary bladder, elevated blood urea nitrogen),
• itching, rash, blisters on lips, eyes or mouth, skin peeling (erythema multiforme, urticaria, erythema),
• hand-foot syndrome,
• facial swelling,
• increased sweating,
• skin hardening (scleroderma),
• muscle spasm and pain,
• joint pain,
• water intoxication,
• changes in results of certain blood tests (blood glucose, hormone levels),
• various types of cancer, such as blood cancer (non-Hodgkin lymphoma), kidney cancer, renal pelvis cancer, thyroid cancer, sarcoma, carcinogenic effect in offspring,
• blockage of a blood vessel by a clot in the circulatory system (thromboembolic episodes), including possible blockage of pulmonary vessels (pulmonary embolism),
• inflammation of blood vessel walls (vasculitis),
• peripheral ischemia,
• flushing,
• edema,
• flu-like symptoms,
• premature delivery,
• liver disorders (hepatitis, cholestasis, hepatotoxicity with liver failure, increased bilirubin levels, abnormal liver function, elevated liver enzymes),
• infertility in males and females,
• changes in menstrual frequency,
• loss of ovarian function,
• testicular atrophy.

Reporting of adverse effects

If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are possible adverse effects not listed in this leaflet. You may also report them directly via the Spanish Pharmacovigilance System for Human Medicines: www.notificaRAM.es.

By reporting adverse effects, you can help provide 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 container to protect from light. Exposure to direct sunlight or sources of heat should be avoided, as they may cause changes in the appearance of the product, although this does not affect the active substance.

Do not use this medicine after the expiry date stated on the packaging after EXP. The expiry date refers to the last day of the month indicated.

Medicines must not be disposed of via wastewater or household waste. Unused medicines and their containers should be returned to the SIGRE point at your pharmacy. If you are in doubt, ask your pharmacist how to dispose of medicines and containers you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of Genoxal

The active substance is Cyclophosphamide. Each coated tablet contains 50 mg of Cyclophosphamide (equivalent to 53,500 mg of monohydrate cyclophosphamide).

The other components (excipients) are:

Tablet core: Glycerol 85%, gelatin, magnesium stearate, talc, calcium hydrogen phosphate dihydrate, lactose monohydrate, corn starch.

Tablet coating: Sucrose, calcium carbonate (E170), titanium dioxide (CI=77891, E-171), talc, polyethylene glycol 35000 (macrogol 35000), colloidal silicon dioxide, povidone K25 (polyvidone 25), sodium carmellose (sodium carboxymethylcellulose), polysorbate 20, montanglycol wax.

Appearance of the product and contents of the pack

Genoxal are white, round, coated tablets.

They are presented in blisters, and each package contains 20 coated tablets.

Marketing Authorization Holder:

Baxter S.L.

Pouet de Camilo 2, 46394 Ribarroja del Turia (Valencia)

Spain

Manufacturer:

Prasfarma S.L. C/ San Joan 11-15, 08560 Manlleu (Barcelona)

Spain

Date of the most recent revision of this leaflet: March 2017

Detailed and up-to-date information on this medicinal product is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.gob.es/