GENOXAL 50 mg FILM-COATED TABLETS

Introduction

Package Leaflet:information for the patient

GENOXAL 50 mg coated tablets

Cyclophosphamide

Read all of this leaflet carefully before you start taking 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 signs of illness are the same as yours.
• If you get 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 and other information:

1. What is GENOXAL and what is it used for.
2. What you need to know before you take GENOXAL.
3. How to take GENOXAL
4. Possible side effects
5. Storage of GENOXAL
6. Contents of the pack and further 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 works 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 different 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 take 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 working properly (especially if you have previously undergone chemotherapy or radiotherapy). You will have blood tests to check your bone marrow function.
• If you have a urinary tract infection that can be recognized by 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 (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 doctor or pharmacist before starting Genoxal:

• If you have low blood cell counts.
• If you have severe infections.
• If 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,
• If you are receiving or have recently received radiotherapy or chemotherapy; you have heart problems or have received radiotherapy in the heart area.
• If you have diabetes.
• If you are in poor general health or are a frail or elderly person.
• If you have had surgery in the last 10 days.

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

Genoxal may have effects on 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 the three types of cells will decrease. This is an inevitable side effect of the medicine. Your blood count will reach its lowest level approximately 5 to 10 days after starting Genoxal and will remain low for some days after the end of 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 little longer to return to normal.

You are more likely to get infections if your blood cell count is low. Try not to get close to 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 and during treatment with cyclophosphamide. You may need to reduce the amount of medicine you receive or delay the next dose.

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 package leaflet included in the Uromitexan package.

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 inform your doctor immediately.

Cancer medicines and radiotherapy can 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 pulmonary fibrosis.

This can happen more than six months after the end of treatment. If you start to have difficulty breathing, inform 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 white of your eyes turn yellow (jaundice), inform 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 nausea and vomiting. This can last for approximately 24 hours after taking the medicine. You may need to take medicines to stop nausea and 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.

Taking 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 because 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 acidity),
• 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 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),
• cyclosporin (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 (it is possible that blood sugar levels 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 the nausea and vomiting caused by cyclophosphamide

Grapefruit (as 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 taking this medicine.

Pregnancy

Genoxal may cause miscarriage or harm to the fetus.

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 contraceptive methods during treatment and for up to 6 months after the end of treatment. If you become pregnant during treatment, you may be offered genetic counseling (medical advice to assess the possible risk of congenital malformations in the fetus).

Breastfeeding

You must not breastfeed while being treated with Genoxal. 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 and 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 machines until they have checked that treatment with the medicine does not affect their ability to perform these activities.

Genoxal contains lactose and sucrose

This medicine contains lactose and sucrose. If your doctor has told you that you have an intolerance to some sugars, consult them before taking this medicine.

3. How to take GENOXAL

Follow the instructions for administration of this medicine exactly as prescribed by your doctor. If you are unsure, consult your doctor or pharmacist.

The recommended dose is:

Your doctor will prescribe a treatment regimen and the correct dose for you. The recommended dose, unless otherwise prescribed by your doctor, is 1 to 4 tablets (50 to 200 mg) per day 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, during administration or immediately after taking, drink a sufficient amount of liquid.

Duration of treatment:

Treatment cycles of the intermittent regimen may be repeated every 3 or 4 weeks. The duration of treatment and the intervals will be decided 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 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, phone 915.620.420, indicating the medicine and the amount taken.

If you forget to take Genoxal

If you accidentally miss a dose, simply take your normal dose when it is due next. Do not take a double dose to make up for missed doses. If you have any doubts about the use of this medicine, consult your doctor.

If you stop taking Genoxal

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

If you have any other 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 all people suffer from them.

Inform 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 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 the platelet levels 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 over time your body will replace the red blood cells. In case of pronounced anemia, you may need a blood transfusion.
• 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 pulmonary inflammation that causes shortness of breath, cough, and increased temperature.
• Symptoms such as weakness, loss of vision, speech difficulties, loss of touch sense.

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 of 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,
• mucosal inflammation (mucositis),
• sterility in males.

Uncommon(may affect up to 1 in 100 patients)

• Increased lactate dehydrogenase in blood,
• increased C-reactive protein,
• changes in the electrocardiogram,
• cardiac problems (cardiomyopathy, 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 levels of sex hormones,
• anorexia,
• pulmonary 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,
• 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 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, 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,
• unspecified pulmonary disorders,
• intestinal inflammation,
• pancreatitis,
• fluid accumulation in the abdominal cavity (ascites).
• mucosal ulceration,
• gastric 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 levels of creatinine in 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 (syndrome of inappropriate antidiuretic hormone secretion). 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 can 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,
• blood clot in the liver (veno-occlusive liver disease),
• activation of the hepatitis virus,
• liver hypertrophy (hepatomegaly),
• yellow 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, 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,
• tinnitus 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, elevated blood urea nitrogen),
• 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 the 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, as they can cause changes in the appearance of the product, although this does not imply alteration of the active principle.

Do not use this medicine after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

Medicines should not be thrown away through the drains or into the trash. Deposit the packaging and medicines that you no longer need in the SIGRE Point of the pharmacy. In case of doubt, ask your pharmacist how to dispose of the packaging and medicines that you no longer need. This way, you will help protect the environment.

6. Package Contents and Additional Information

Composition ofGenoxal

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

The other components (excipients) are:

Core of the tablet: Glycerol 85%, gelatin, magnesium stearate, talc, calcium phosphate dihydrate, lactose monohydrate, cornstarch.

Coating of the tablet: Sucrose, calcium carbonate (E170), titanium dioxide (CI=77891, E-171), talc, polyethylene glycol 35000 (macrogol 35000), colloidal silicon dioxide, povidone K25 (povidone 25), sodium carmellose (sodium carboxymethyl cellulose), polysorbate 20, montanglicol wax.

Appearance of the Product and Package Contents

Genoxal is a white, round, coated tablet.

It is 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 Last Revision of this Prospectus:March 2017

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