CYCLOPHOSPHAMIDE ACCORD 200 MG/ML CONCENTRATE FOR INJECTION AND INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

Ciclofosfamida Accord 200 mg/ml Concentrate for Solution for Injection and Infusion

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

1. What is Ciclofosfamida Accord and what is it used for

This medicine contains the active substance cyclophosphamide.

It belongs to a group of medicines known as cytotoxic or antineoplastic medicines.

It works by killing cancer cells, this is sometimes called chemotherapy.

This medicine is used in chemotherapy alone or in combination with other medicines in the following cases:

• certain types of white blood cell cancer (acute lymphocytic leukemia, chronic lymphocytic leukemia),
• various forms of lymphomas that affect the immune system (Hodgkin's lymphoma, non-Hodgkin's lymphoma, and multiple myeloma),
• ovarian 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, cyclophosphamide is used in preparation for bone marrow transplants to treat certain types of white blood cell cancer (acute lymphoblastic leukemia, chronic myeloid leukemia, and acute myeloid leukemia).

Occasionally, some doctors may prescribe cyclophosphamide 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 Ciclofosfamida Accord

Do not use Ciclofosfamida Accord:

• if you are allergic to the active substance, its metabolites, or any of the other ingredients of this medicine (listed in section 6).
• 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 breastfeeding.
• if you have other conditions unrelated to cancer, except for immunosuppression in life-threatening situations.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you start using this medicine:

• 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,
• if you have had your adrenal glands removed,
• if you are receiving or have recently received radiotherapy or chemotherapy;
• if 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 person,
• if you are an elderly person,
• if you have had surgery in the last 10 days.

Be careful with Ciclofosfamida Accord

• Potentially life-threatening allergic reactions (anaphylactic reactions) may occur during treatment with cyclophosphamide.
• Cyclophosphamide may have effects on your blood and immune system.
• Blood cells are produced in your bone marrow. Three types of blood cells are produced:
• • 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 approximately 5 to 10 days after starting to receive cyclophosphamide and will remain low for some days after the treatment cycle ends. Most people recover normal blood cell counts over 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 the number of red blood cells, white blood cells, and platelets is high enough before treatment with cyclophosphamide and during treatment. You may need to reduce the amount of medicine you receive or delay the next dose.
• Cyclophosphamide 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. Talk to your doctor if you have any doubts.
• Cyclophosphamide may damage the lining of the urinary bladder and cause bleeding in the urine or pain when urinating. Your doctor knows 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, or in tablets. You can find more information about Mesna in the package leaflet of Mesna injection or tablets.
• Most people who receive cyclophosphamide with Mesna do not develop bladder problems, but your doctor may want to check your urine for blood with a dipstick or microscope. If you notice blood in your urine, you must tell 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. Cyclophosphamide carries a higher risk of causing cancer in the bladder area.
• Cyclophosphamide may cause heart damage or affect the rhythm of your heartbeat. This effect is greater at higher doses of cyclophosphamide, if you are being treated with radiotherapy or other cancer medicines, or if you are an elderly person. Your doctor will closely monitor your heart during treatment.
• Cyclophosphamide may cause lung problems such as inflammation or lung fibrosis.
• This can happen more than six months after the end of treatment. If you start to have difficulty breathing, tell your doctor immediately.
• Cyclophosphamide 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.
• Hair loss or baldness may occur. Your hair should grow back normally, although its texture and color may be different.
• This medicine 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. Talk to your doctor about this.

Other medicines and Ciclofosfamida Accord

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 cyclophosphamide.

The following medicines may reduce the effectiveness of cyclophosphamide:

• aprepitant, ondansetron (used to prevent vomiting)
• bupropion (an antidepressant)
• busulfan, tiotepa (used to treat cancer)
• ciprofloxacin, chloramphenicol, sulfonamides such as sulfadiazine, sulfasalazine, sulfamethoxazole (used to treat bacterial infections)
• fluconazole, itraconazole (used to treat fungal infections)
• prasugrel (used as an anticoagulant)

The following medicines may increase the effect of cyclophosphamide:

• allopurinol (used to treat gout),
• azathioprine (used to reduce immune system activity)
• 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),
• dabrafenib (anticancer medicine)
• medicines that increase liver enzymes such as:
• • rifampicin (used to treat bacterial infections),
  • phenobarbital, carbamazepine, phenytoin (used to treat epilepsy),
  • St. John's Wort (a herbal medicine for mild depression),
  • corticosteroids (used to treat inflammation),

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

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

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

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

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

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

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

• 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 immune system activity),
• succinylcholine (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 at the same time).

Using Ciclofosfamida Accord with food, drinks, and alcohol

Consuming alcohol may increase the nausea and vomiting caused by cyclophosphamide.

You should not consume grapefruit (as fruit or juice) while taking this medicine. It may interfere with the usual effect of your medicine and alter its effectiveness.

Contraception, pregnancy, breastfeeding, and fertility

Contraception in men and women

If you are a woman, you must not become pregnant during treatment with this medicine and for a period of 12 months after the end of treatment.

If you are a man, you must use effective contraception during treatment with this medicine and for a period of 6 months after the end of treatment.

Pregnancy

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.

This medicine may cause miscarriage or harm to the fetus. Taking into account all available information, the use of cyclophosphamide is not recommended during pregnancy, especially in the first trimester, and your doctor will decide if it can be used.

Breastfeeding

Since cyclophosphamide passes into breast milk, women must not breastfeed during treatment. See section 2 "Do not use Ciclofosfamida Accord".

Fertility

This medicine may affect your ability to have children in the future and cause infertility. Talk to your doctor about the freezing (cryopreservation) of sperm or eggs before treatment. If you are considering becoming a parent after treatment, you should discuss this with your doctor.

Young women with reserved ovarian function may develop premature menopause after receiving treatment with cyclophosphamide.

Driving and using machines

After administration of cyclophosphamide, side effects such as dizziness, blurred vision, or vision disturbances may occur that can affect your ability to drive and use machines. The decision to drive and use machines will be made by your doctor on a case-by-case basis.

Ciclofosfamida Accord contains propylene glycol

This medicine contains 34 mg of propylene glycol in each 1 ml vial of concentrate, which is equivalent to 34 mg/ml.

If your baby is less than 4 weeks old, talk to your doctor or pharmacist before giving this medicine, especially if the baby is taking other medicines that contain propylene glycol or alcohol.

Ciclofosfamida Accord contains ethanol (alcohol)

This medicine contains 620 mg of ethanol per ml of solution, which is equivalent to 13 g per maximum dose of 60 mg/kg. The amount in the maximum dose (60 mg/kg in patients weighing 70 kg) of this medicine is equivalent to 323 ml of beer or 130 ml of wine.

The alcohol in this preparation is likely to affect children. These effects may include drowsiness and changes in behavior. It may also affect their ability to concentrate and participate in physical activities.

The amount of alcohol in this medicine may affect your ability to drive or use machines. This is because it can affect your judgment and reaction speed.

If you have epilepsy or liver problems, talk to your doctor or pharmacist before taking this medicine.

The amount of alcohol in this medicine may alter the effects of other medicines. Talk to your doctor or pharmacist if you are taking other medicines.

If you are pregnant or breastfeeding, talk to your doctor or pharmacist before taking this medicine.

If you are addicted to alcohol, talk to your doctor or pharmacist before taking this medicine.

3. How to use Ciclofosfamida Accord

This medicine will be given to you by a doctor or nurse with experience in the use of anticancer chemotherapy.

The medicine is usually given into a vein. The duration of administration is usually 30 minutes to 2 hours, depending on the volume to be administered.

Cyclophosphamide is usually given in combination with other cancer medicines or radiotherapy.

The recommended dose is:

Your doctor will decide how much medicine you need and when you should receive it.

The duration of treatment and/or treatment intervals will depend on the indications for use, the combination therapy regimen, your general state of health, laboratory test results, and the recovery of blood cells.

It is recommended to administer this medicine 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 have any doubts about the use of this medicine, ask your doctor or pharmacist.

If you are given too much Ciclofosfamida Accord

Since this medicine is administered 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 section 4, "Side effects", but they are usually more severe.

If you miss a dose of Ciclofosfamida Accord

If you forget to take the medicine, please consult your doctor immediately.

If you have any doubts 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.

Tell your doctor immediately if you experience:

• Allergic reactions. Their signs would be difficulty breathing, wheezing, increased heart rate, reduced blood pressure, rash, itching or swelling 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 platelet levels in your blood are too low
• Severe infection or fever, mouth ulcers, 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, red blood cell collapse, decrease in platelet count, and kidney failure (Hemolytic Uremic Syndrome)
• Pallor, feeling of fatigue and tiredness. 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, you may need a blood transfusion
• Severe hypersensitivity reactions with fever (high), red spots on the skin, joint pain, and/or eye infection (Stevens-Johnson syndrome), sudden severe hypersensitivity reaction, with fever and blisters/peeling of the skin (toxic epidermal necrolysis)
• Abnormal muscle breakdown that can lead to kidney problems (rhabdomyolysis)
• Different types of blood disorders (Agranulocytosis)
• Blood in the urine, pain when urinating, or reduced urine volume
• Severe chest pain
• Symptoms such as weakness, vision loss, speech difficulties, loss of touch

The following adverse effects can also occur during treatment with this medicine.

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

• Reduction in the number of blood cells (myelosuppression)
• Reduction of white blood cells that are important in fighting infections (leukopenia, neutropenia)
• Hair loss (alopecia)
• Burning sensations when urinating and frequent need to do so (cystitis)
• Presence of blood in the urine
• Fever
• Suppression of the immune system

Common (may affect up to 1 in 10 patients)

• Infections
• Inflammation of mucous membranes
• Abnormal kidney function
• Male infertility
• Chills
• Feeling of weakness
• General feeling of discomfort
• Reduction in white blood cell count and fever (febrile neutropenia)

Uncommon (may affect up to 1 in 100 patients)

• Anemia (low red blood cell count) that can cause fatigue and drowsiness
• Predisposition to bruising due to thrombocytopenia (low platelet count)
• Lung inflammation (pneumonia)
• Septicemia
• Allergic reactions
• Female infertility (may be permanent)
• Chest pain
• Rapid heartbeat
• Heart problems
• Changes in the results of some blood tests
• Redness of the skin (rash)
• Nerve damage that can cause numbness, tingling, and weakness (neuropathy)
• Nerve pain that can make you feel painful or with a burning sensation (neuralgia)
• Loss of appetite (anorexia)
• Deafness

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

• Increased risk of white blood cell cancer (acute leukemia) and some other cancers (bladder cancer, ureter cancer)
• Ineffective production of a certain type of blood cells (myelodysplastic syndrome)
• Increased release of antidiuretic hormone from the pituitary gland. This affects the kidneys, causing low sodium levels in the blood (hyponatremia) and water retention, resulting in brain swelling due to excessive water in the blood. The signs of this may be headache, changes in personality or behavior, confusion, drowsiness
• Changes in heart rhythm
• Liver inflammation
• Skin rash
• Skin inflammation
• Lack of menstruation (periods)
• Lack of sperm
• Dizziness
• Vision problems, blurred vision
• Changes in the color of your nails or skin
• Dehydration
• Seizures
• Bleeding

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

• Shock
• Complications that can occur after cancer treatment caused by the rejection products of dying cancer cells (tumor lysis syndrome)
• Low sodium levels in your blood
• High blood pressure (hypertension)
• Low blood pressure (hypotension)
• Angina
• Myocardial infarction
• Lung injury (acute respiratory distress syndrome)
• Pulmonary fibrosis that causes breathing difficulties (chronic interstitial pulmonary fibrosis)
• Difficulty breathing with wheezing or cough (bronchospasm)
• Respiratory failure (dyspnea)
• A condition in which the body or a region of the body lacks adequate oxygen supply (hypoxia)
• Cough
• Mouth ulcers (stomatitis)
• Nausea, vomiting, or diarrhea
• Constipation
• Intestinal inflammation
• Pancreatitis
• Blood clots
• Liver enlargement (hepatomegaly)
• Activation of viral hepatitis
• Yellow eyes or skin
• Redness of the skin (radiation erythema)
• Itching, toxic dermatitis
• Alteration of taste
• Sensation of tingling, pricking, itching, pinching, or burning (paresthesia)
• Alteration of smell
• Muscle cramps
• Bladder problems
• Kidney problems, including kidney failure
• Ulcerative cystitis
• Headache
• Multi-organ failure
• Reactions at the injection/infusion site
• Weight gain
• Confusion
• Conjunctivitis, eye edema
• Fluid in the lungs or around them (pulmonary edema)
• Fluid accumulation in the abdominal cavity (ascites)

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

• Various types of cancer, e.g., blood cancer (non-Hodgkin's lymphoma), kidney cancer, thyroid cancer, sarcoma
• Various types of blood disorders (lymphopenia, reduction of hemoglobin)
• Increased tearing
• Tinnitus
• Nasal congestion (nasal blockage)
• Oropharyngeal pain
• Flu-like symptoms or allergy symptoms (rhinorrhea)
• Sneezing
• Conditions that cause lung inflammation that can cause respiratory failure, cough, and increased temperature or fibrosis in the lungs (pneumonitis, bronchiolitis obliterans, allergic alveolitis), fluid in and around the lungs (pleural effusion), abdominal pain
• Bleeding in the stomach or intestines
• Intestinal problems/bleeding
• Liver disorder
• Cytolytic hepatitis
• Rash, redness of the skin, 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
• Inflammation, scarring, and contraction of the bladder
• Effects on the fetus such as damage or death of the fetus, intrauterine death, fetal malformation, fetal growth retardation, carcinogenic effects in the offspring
• Changes in the results of some blood tests (glucose levels, hormone levels)
• Effects on the brain (encephalopathy), a syndrome called posterior reversible leukoencephalopathy syndrome, which can cause brain inflammation, headache, confusion, seizures, and vision loss, changes in your sense of touch (dysesthesia) or loss of sensation (hypoesthesia), tremors, changes in the sense of taste (dysgeusia) or loss of taste (hypogeusia), changes in your sense of smell (parosmia)
• Decreased ability of your heart to pump blood around your body, which can be life-threatening (cardiogenic shock, heart failure, or cardiac arrest), faster heart rate (tachycardia), which can be life-threatening (ventricular tachycardia), slower heart rate (bradycardia), fluid accumulation in the space around your heart (pericardial effusion), abnormal electrocardiogram (electrocardiogram with prolonged QT), changes in your heart rhythm (arrhythmia) that can be noticeable (palpitations), left ventricular failure, diffuse intramyocardial hemorrhage
• Changes in menstrual frequency
• Inflammation of the salivary glands
• Acute water intoxication
• Edema
• Flu-like illness

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 leaflet. 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 Cyclophosphamide Accord

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

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

Store in a refrigerator (2°C - 8°C).

After opening:

After opening, store the partially used multiple-dose vial in the original box at a temperature between 2°C and 8°C for a maximum of 28 days. Discard the unused portion after 28 days.

After dilution:

The chemical and physical stability of the diluted solution has been demonstrated for 7 days at 2°C - 8°C (protected from light) and 24 hours at 20°C - 25°C (normal ambient light).

From a microbiological point of view, the diluted medicine should be used immediately. If not used immediately, the storage times and conditions before use are the responsibility of the user and normally should not exceed 24 hours at 2°C - 8°C, unless the dilution has been performed under controlled and validated aseptic conditions.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medicines. This will help protect the environment.

6. Container Content and Additional Information

Composition of Cyclophosphamide Accord

• The active ingredient is cyclophosphamide.
• The excipients are propylene glycol, macrogol, monothioglycerol, anhydrous ethanol.

1 ml of concentrate contains cyclophosphamide monohydrate equivalent to 200 mg of cyclophosphamide.

A 1 ml vial of concentrate contains cyclophosphamide monohydrate equivalent to 200 mg of cyclophosphamide.

A 2.5 ml vial of concentrate contains cyclophosphamide monohydrate equivalent to 500 mg of cyclophosphamide.

A 5 ml vial of concentrate contains cyclophosphamide monohydrate equivalent to 1,000 mg of cyclophosphamide.

A 10 ml vial of concentrate contains cyclophosphamide monohydrate equivalent to 2,000 mg of cyclophosphamide.

Appearance of the Product and Container Content

Transparent, colorless, tubular type I glass vial of 2 ml with a chlorobutyl rubber stopper and blue flip-off seal with 1 ml of concentrate.

Transparent, colorless, tubular type I glass vial of 5 ml with a chlorobutyl rubber stopper and yellow flip-off seal with 2.5 ml of concentrate.

Transparent, colorless, tubular type I glass vial of 5 ml with a chlorobutyl rubber stopper and blue flip-off seal with 5 ml of concentrate.

Transparent, colorless, tubular type I glass vial of 10 ml with a chlorobutyl rubber stopper and blue aluminum flip-off seal with 10 ml of concentrate.

Container Size

Container of 1 vial

Container of 5 vials

Container of 6 vials

Container of 10 vials

Only some container sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,

08039 Barcelona,

Spain

Manufacturer:

Accord Healthcare Polska Sp.z o.o.

ul. Lutomierska 50,

95-200 Pabianice

Poland

or

Laboratori Fundació Dau

C/ C, 12-14 Pol. Ind. Zona Franca,

08040, Barcelona

Spain

Date of the Last Revision of this Prospectus:March 2024

Detailed information about 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 only for healthcare professionals:

This medication should be administered exclusively under the supervision of a physician with experience in antineoplastic chemotherapy. This medication 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.

Posology

Doses should be adjusted individually for each patient. The dose, duration of treatment, and/or treatment intervals depend on the therapeutic indication, the scheme of combination therapy, the patient's general state of health, organic function, laboratory test results, and recovery of blood cells.

In combination with other cytostatics of similar toxicity, a reduction in dose or an extension of 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 hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered.

Before, during, and immediately after administration, an adequate amount of fluids should be ingested or perfused to force diuresis in order to reduce the risk of toxicity in the urinary tract. Therefore, this medication should be administered in the morning.

It is the responsibility of the physician to decide on the use of cyclophosphamide in accordance with the treatment guidelines.

The following doses may be considered as general guidelines:

Hematological and solid tumors.

• For daily treatment:

3 - 6 mg/kg of body weight (= 120 - 240 mg/m2 of body surface area), administered intravenously

• For intermittent treatment:

10 - 15 mg/kg of body weight (= 400 - 600 mg/m2 of body surface area), administered intravenously, with treatment-free intervals of 2 to 5 days

• For high-dose intermittent treatment:

20 - 40 mg/kg of body weight (= 800 - 1600 mg/m2 of body surface area), administered intravenously, with treatment-free intervals of 21 to 28 days.

As preparation for bone marrow transplantation.

2 days 60 mg/kg or 4 days 50 mg/kg of body weight administered intravenously.

If a busulfan-cyclophosphamide regimen (Bu/Cy) is applied, the first dose of cyclophosphamide should be administered at least 24 hours after the last dose of busulfan.

Autoimmune diseases

500 – 1000 mg/m2 of body surface area per month.

Patients with hepatic insufficiency.

Severe hepatic insufficiency may be associated with a decrease in the activation of cyclophosphamide. This may alter the efficacy of treatment with this medication and should be taken into account when selecting the dose and estimating the response to the medication.

The dose should be reduced in patients with severe hepatic insufficiency. A dose reduction of 25% is recommended in patients with serum bilirubin concentrations of 3.1 – 5 mg/100 ml (= 0.053 - 0.086 mmol/l).

Patients with renal insufficiency

In patients with renal insufficiency, particularly in patients with severe insufficiency, the decrease in renal excretion may lead to an increase in plasma levels of cyclophosphamide and its metabolites. This may lead to an increase in toxicity and should be taken into account when determining the dose in these patients. (See section 4.4). A dose reduction of 50% is recommended for a glomerular filtration rate below 10 ml/minute.

Cyclophosphamide and its metabolites are dialyzable, although there may be differences in clearance depending on the dialysis system used. In patients who require dialysis, a constant interval between dialysis cycles and cyclophosphamide administration should be considered.

Elderly patients

In elderly patients, monitoring of toxicities and the need to adjust the dose should reflect the higher frequency of decreased hepatic, renal, or cardiac function, or other organ function and concomitant diseases or other pharmacological treatments in this population.

Pediatric population

Cyclophosphamide has been administered to children. The safety profile of cyclophosphamide in pediatric patients is similar to that of the adult population.

Dose modification due to myelosuppression.

During treatment with cyclophosphamide, a white blood cell and platelet count should be performed periodically. It is recommended to adjust the dose, if necessary, if signs of myelosuppression become apparent.

Please refer to the table below. The urine sediment should also be periodically monitored to detect the presence of erythrocytes.

In combination therapy, additional dose reductions may need to be considered.

Method of Administration

Cyclophosphamide is inert until activated by liver enzymes. However, as with all cytotoxic agents, it is recommended that dilution be performed by trained personnel in a designated area.

Precautions to be taken before handling or administering the product.

Persons handling the preparation should wear protective gloves. Care should be taken to avoid splashing the material into the eyes. The material should not be handled by pregnant or lactating women.

Intravenous route

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

Infusion:

Intravenous administration should be performed preferably in the form of infusion.

If the solution is to be used for intravenous infusion, Cyclophosphamide Accord should be diluted to a minimum concentration of 2 mg/ml using any of the following diluents:

• Sodium chloride 0.9% injectable solution,
• sodium chloride 0.45% injectable solution,
• glucose 5% injectable solution,
• glucose 5% and sodium chloride 0.9% injectable solution.

Direct injection:

If the solution is to be used for direct injection, Cyclophosphamide Accord should be diluted to a minimum concentration of 20 mg/ml using any of the following diluents:

• Sodium chloride 0.9% injectable solution,
• sodium chloride 0.45% injectable solution,
• glucose 5% injectable solution,
• glucose 5% and sodium chloride 0.9% injectable solution.

Do not use water for injectable preparations for dilution because it results in a hypotonic solution and should not be injected directly.

To reduce the probability of adverse reactions that seem to depend on the rate of administration (e.g., facial swelling, headache, nasal congestion, scalp burning), cyclophosphamide should be injected or infused very slowly. The duration of the infusion should be appropriate for the volume and type of fluid carrier to be infused.

Storage and Shelf Life of the Diluted Solution.

After opening:

After the first use, store the partially used multiple-dose vial in the original carton at a temperature of 2°C - 8°C for up to 28 days. Discard the unused portion after 28 days.

After dilution

The chemical and physical stability of the diluted solution has been demonstrated for 7 days at 2 °C - 8 °C (protected from light) and 24 hours at 20 °C - 25 °C (normal ambient light)

From a microbiological point of view, the diluted medication should be used immediately. If not used immediately, the in-use storage times and conditions before use are the responsibility of the user and, in general, should not exceed 24 hours at 2°C - 8°C, unless the dilution has been carried out under controlled and validated aseptic conditions.