Cyclophosphamide accord

Package leaflet: Information for the patient

Cyclophosphamide Accord, 500 mg, powder for solution for injection/infusion
Cyclophosphamide Accord, 1000 mg, powder for solution for injection/infusion
Cyclophosphamidum
Please read carefully the entire leaflet before using this medicine, as it contains
important information for the patient.

• Keep this leaflet for future reference.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• This medicine has been prescribed for a specific individual. Do not share it with others. This medicine may harm others, even if their symptoms are similar.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Table of contents:

1. What Cyclophosphamide Accord is and what it is used for
2. Important information before using Cyclophosphamide Accord
3. How to use Cyclophosphamide Accord
4. Possible side effects
5. How to store Cyclophosphamide Accord
6. Contents of the pack and other information

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

Cyclophosphamide Accord contains the active substance cyclophosphamide.
Cyclophosphamide is a cytotoxic medicine, also known as an anticancer medicine.
It works by destroying cancer cells, which is sometimes referred to as "chemotherapy".
Cyclophosphamide Accord is used in chemotherapy either alone or in combination with other medicines in the following conditions:

• Treatment of certain types of white blood cell cancer (acute lymphoblastic leukaemia, chronic lymphocytic leukaemia);
• Treatment of various forms of lymphoma affecting the immune system (Hodgkin's disease, non-Hodgkin's lymphoma, and multiple myeloma);
• Treatment of ovarian cancer and breast cancer;
• Treatment of Ewing's sarcoma (a type of bone cancer);
• Treatment of small cell lung cancer;
• Treatment of advanced or metastatic central nervous system cancer (neuroblastoma).

Additionally, cyclophosphamide is used in preparation for bone marrow transplantation to treat various types of white blood cell cancers (acute lymphoblastic leukaemia, chronic myeloid leukaemia, and acute myeloid leukaemia).
Occasionally, some physicians may prescribe cyclophosphamide for the treatment of other non-cancerous conditions:

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

2. Important information before using Cyclophosphamide Accord

When not to use Cyclophosphamide Accord

• if the patient is allergic to cyclophosphamide or to any of its metabolites or to any of the other ingredients of this medicine (listed in section 6);
• if the patient currently has any infection;
• if the patient has severe bone marrow disorders (especially following chemotherapy or radiotherapy). The doctor will recommend blood tests to monitor bone marrow function;
• if the patient currently has a urinary tract infection, which may present as pain during urination (cystitis);
• if the patient has ever previously had kidney or bladder disorders due to prior chemotherapy or radiotherapy;
• if the patient has problems with urination (urinary outflow obstruction);
• if the woman is breastfeeding;
• if the patient has other non-cancerous diseases, except for life-threatening immune disorders.

Warnings and precautions
Before using Cyclophosphamide Accord, discuss this with the doctor, pharmacist, or nurse:

• if the patient has low blood cell counts;
• if the patient has severe infections;
• if the patient has liver or kidney disease; the doctor will recommend blood tests to monitor liver and kidney function;
• if the patient has undergone adrenalectomy;
• if the patient has recently undergone or is currently undergoing radiotherapy or chemotherapy;
• if the patient has heart function disorders or has been irradiated in the heart area;
• if the patient has diabetes;
• if the patient is in poor general condition or is weak;
• if the patient is elderly;
• if the patient has undergone surgery within the last 10 days.

Special caution is required when using Cyclophosphamide Accord:

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

• Cyclophosphamide may affect blood and the immune system.

• Blood cells are produced in the bone marrow. Three different types of blood cells are formed:

• red blood cells, which transport oxygen in the body,

• white blood cells, which fight infection,

• platelets, which help blood clotting.

• After receiving cyclophosphamide, the number of all three types of blood cells may decrease. This is an unavoidable adverse effect of cyclophosphamide. The lowest blood cell counts are typically observed approximately 5 to 10 days after starting treatment and remain low for several days after the treatment cycle ends. In most people, blood cell counts return to normal within 21 to 28 days. If the patient has previously undergone multiple chemotherapy treatments, normalization of blood cell counts may take longer.

• During periods of low blood cell counts, the patient may be more susceptible to infections. Close contact with people who are coughing, have colds, or other infections should be avoided. If the doctor determines that the patient has an infection or is at risk of developing one, appropriate treatment will be initiated.

• Before administering cyclophosphamide and during treatment, the doctor will check whether the counts of red blood cells, white blood cells, and platelets are sufficiently high. It may be necessary to reduce the dose or delay administration of the next dose.

• Cyclophosphamide may impair normal wound healing. Any cuts or abrasions should be kept clean and dry, and monitored for proper healing. Oral health should be carefully maintained, as mouth ulcers and infections may occur. Consult the doctor if in doubt.

• Cyclophosphamide may damage the tissue lining the bladder, leading to blood in the urine and pain during urination. This effect is known to doctors, who may therefore prescribe a medication called mesna, which protects the bladder.

• Mesna is administered by intravenous injection; it can be added to the cyclophosphamide infusion or taken orally as tablets. More information about mesna can be found in the patient leaflet provided with mesna injections and tablets.

• Most patients receiving cyclophosphamide together with mesna do not experience bladder problems, but the doctor may order urine tests to detect blood using dipstick tests or microscopy. If the patient notices blood in the urine, they should inform the doctor immediately.

• Anticancer drugs and radiotherapy may increase the risk of developing other cancers, even several years after treatment ends. Cyclophosphamide increases the risk of bladder cancer.

• Cyclophosphamide may damage the heart or affect its rhythm. This effect is more pronounced with high-dose cyclophosphamide, concurrent radiotherapy or other chemotherapy, or in elderly patients. The doctor will closely monitor heart function during treatment.

• Cyclophosphamide may cause lung problems, such as non-infectious pneumonia or pulmonary fibrosis. This may occur more than 6 months after treatment ends. If the patient experiences breathing difficulties, they should inform the doctor immediately.

• Cyclophosphamide may have life-threatening effects on the liver. If sudden weight gain, liver pain, or yellowing of the skin or whites of the eyes (jaundice) occurs, the doctor should be informed immediately.

• Hair thinning or hair loss may occur. Hair should regrow normally, although it may have a different texture or color.

• Cyclophosphamide may cause nausea or vomiting. This may last for about 24 hours after administration. Antiemetic medications may be necessary. Consult the doctor about this.

Cyclophosphamide Accord and other medicines
Inform the doctor or pharmacist about all medicines currently or recently taken, as well as any medicines the patient plans to use. Special attention should be paid to the following medicines or therapies, as cyclophosphamide may interfere with their action.
The following medicines may reduce the effect of cyclophosphamide:

• aprepitant, ondansetron (antiemetic medicines)
• bupropion (antidepressant)
• busulfan, thiotepa (medicines used in cancer treatment)
• ciprofloxacin, chloramphenicol, sulfonamides such as sulfadiazine, sulfasalazine, sulfamethoxazole (medicines used to treat bacterial infections)
• fluconazole, itraconazole (medicines used to treat fungal infections)
• prasugrel (medicine used to prevent blood clotting)

The following medicines may increase the effect of cyclophosphamide:

• allopurinol (used in the treatment of gout)
• azathioprine (used to suppress immune system activity)
• chloral hydrate (used to treat insomnia)
• cimetidine (reduces stomach acid secretion)
• disulfiram (used in the treatment of alcoholism)
• glyceryl aldehyde (used in the treatment of delirium tremens)
• protease inhibitors (used to treat viral infections)
• dabrafenib (anticancer medicine)
• medicines that increase liver enzyme activity, such as:
• rifampicin (used to treat bacterial infections)
• phenobarbital, carbamazepine, phenytoin (antiepileptic medicines)
• St. John's wort (herbal medicine used to treat mild depression)
• glucocorticosteroids (used to treat inflammatory conditions)

Medicines that may increase the toxic effects of cyclophosphamide on the hematopoietic and immune systems:

• 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 certain 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)
• irradiation of the heart area

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

• amiodarone (used to treat heart rhythm disorders)
• G-CSF, GM-CSF hormones (used to increase white blood cell counts after chemotherapy)

Other medicines that may affect the action of cyclophosphamide or whose action may be affected by cyclophosphamide:

• etanercept (used to treat rheumatoid arthritis)
• metronidazole (used to treat bacterial or protozoal infections)
• tamoxifen (used to treat breast cancer)
• bupropion (used to aid smoking cessation)
• coumarins, such as warfarin (anticoagulants)
• cyclosporine (used to suppress immune system activity)
• suxamethonium (used to relax muscles during surgical procedures)
• digoxin, beta-acetyldigoxin (used to treat heart conditions)
• vaccines
• verapamil (used to treat high blood pressure, angina, or heart rhythm disorders)
• concurrent use of sulfonylurea derivatives with cyclophosphamide (may cause decreased blood glucose levels)

Cyclophosphamide Accord, food, drink, and alcohol
Alcohol consumption may worsen nausea and vomiting caused by cyclophosphamide.
Grapefruit (in fruit or juice form) should not be consumed during treatment with cyclophosphamide. Grapefruit may interfere with the medicine's normal action and alter its effectiveness.

Contraception, pregnancy, breastfeeding, and effects on fertility
Contraception in men and women
Women should not become pregnant during treatment with Cyclophosphamide Accord and for 12 months after treatment ends.
Men should take appropriate precautions, including effective contraception, to avoid fathering a child during treatment with Cyclophosphamide Accord and for up to 6 months after treatment ends.

Pregnancy
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult her doctor before using this medicine.
Cyclophosphamide may cause miscarriage or harm the unborn child. Based on available information, the use of cyclophosphamide during pregnancy, especially during the first trimester, is not recommended, and the decision to use it will be made by the doctor.

Breastfeeding
Since cyclophosphamide passes into breast milk, women must not breastfeed during treatment. See section 2 "When not to use Cyclophosphamide Accord."

Effect on fertility
Cyclophosphamide may affect future fertility and may cause infertility. Patients should consult their doctor about the possibility of sperm cryopreservation (freezing) before treatment. Patients planning parenthood after treatment should discuss this with their doctor.
Young women with ovarian reserve may develop premature menopause after cyclophosphamide treatment.

Driving and operating machinery
After administration of cyclophosphamide, adverse effects such as dizziness, blurred vision, and visual disturbances may occur, which could affect the ability to drive or operate machinery. The decision whether it is safe to drive or operate machinery should be made individually by the doctor.

3. How to use Cyclophosphamide Accord

Cyclophosphamide Accord will be administered to the patient by a doctor or nurse experienced in cancer chemotherapy.
The medicine is usually given intravenously. The infusion time typically lasts from 30 minutes to 2 hours, depending on the volume administered.
Cyclophosphamide is often used together with other anticancer medicines or in combination with radiotherapy.

Dose recommended
Your doctor will decide the amount of medicine to be given and the timing of administration.
The duration of treatment and (or) treatment breaks depend on the indication, combination therapy regimen, the patient's general health condition, laboratory test results, and blood cell regeneration.

It is recommended to administer cyclophosphamide in the morning. It is important that the patient receives adequate fluid intake before, during, and after administration of the medicine to prevent undesirable effects on the urinary tract.

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

Overdose of Cyclophosphamide Accord
Cyclophosphamide Accord is administered under medical supervision, so it is very unlikely that too much medicine will be given. However, if any adverse reactions occur after administration of the medicine, the doctor should be informed immediately. Emergency treatment may be necessary.
Symptoms of cyclophosphamide overdose include the adverse reactions listed below in section "Undesirable effects", but they may be more severe.

Missed dose of Cyclophosphamide Accord
If a dose has been missed, consult your doctor immediately.

If you have any further doubts concerning the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
You should contact a doctor immediately if you experience:

• an allergic reaction; symptoms include shortness of breath, wheezing, rapid heartbeat, low blood pressure (extreme fatigue), rash, itching or swelling of the face and lips. Severe allergic reactions may lead to breathing difficulties or shock, even resulting in death (anaphylactic shock, anaphylactic or pseudo-anaphylactic reaction).
• unexplained bruising or bleeding from the gums. These may be symptoms of a reduced platelet count.
• severe infection or fever, mouth ulcers, cough, shortness of breath, symptoms of sepsis such as fever, rapid breathing, rapid heartbeat, confusion and swelling. These may be symptoms of a reduced white blood cell count, and antibiotic treatment may be necessary to combat infection, red blood cell breakdown, reduced platelet count and kidney failure (haemolytic uraemic syndrome).
• significant paleness, lethargy and fatigue. These may be symptoms of a low red blood cell count (anaemia). Usually no treatment is required – the body will replenish the missing red blood cells. Severe anaemia may require blood transfusion.
• severe hypersensitivity reactions with (high) fever, red skin patches, joint pain and (or) eye infection (Stevens-Johnson syndrome), severe sudden (hypersensitive) reaction with fever and blisters on the skin/skin peeling (toxic epidermal necrolysis).
• abnormal muscle breakdown which may lead to kidney problems (rhabdomyolysis).
• various types of blood disorders (agranulocytosis).
• presence of blood in the urine, pain during urination or reduced urine output.
• severe chest pain.
• symptoms such as weakness, vision loss, speech disturbances, loss of sense of touch.

Other side effects may also occur:
Very common: may affect more than 1 in 10 people

• reduction in blood cells (myelosuppression)
• reduction in white blood cells important for fighting infection (leukopenia, neutropenia)
• hair loss (alopecia)
• burning sensation or pain during urination and frequent need to urinate (cystitis)
• presence of blood in the urine
• fever
• suppression of immune system function

Common: may affect less than 1 in 10 people

• infections
• mucositis
• abnormal liver function
• infertility in men
• chills
• feeling of weakness
• general malaise
• reduction in white blood cells with fever (febrile neutropenia)

Uncommon: may affect less than 1 in 100 people

• anaemia (low red blood cell count), which may cause fatigue and drowsiness
• easy bruising due to thrombocytopenia (low platelet count)
• pneumonia
• sepsis
• allergic reactions
• infertility in women (may be permanent)
• chest pain
• rapid heartbeat
• heart function disorders
• changes in results of certain blood tests
• skin redness
• nerve damage causing numbness, tingling and weakness (neuropathy)
• nerve pain which may also feel like burning or stinging (neuralgia)
• loss of appetite
• deafness

Rare: may affect less than 1 in 1,000 people

• increased risk of developing white blood cell cancer (acute leukaemia) and certain other cancers (bladder cancer, ureter cancer)
• ineffective production of a specific type of blood cell (myelodysplastic syndrome)
• increased release of antidiuretic hormone by the pituitary gland. This affects the kidneys, causing low sodium levels in the blood (hyponatremia) and water retention, potentially leading to brain swelling due to excess water in the blood. Symptoms may include headache, personality or behavioural changes, confusion and drowsiness.
• changes in heart rhythm
• hepatitis
• rash
• dermatitis
• absence of menstruation
• absence of semen
• dizziness
• vision disturbances, blurred vision
• changes in nail and skin pigmentation
• dehydration
• seizures
• bleeding

Very rare: may affect less than 1 in 10,000 people

• shock
• complications of anticancer treatment due to cancer cell breakdown (tumour lysis syndrome)
• low sodium levels in the blood
• high blood pressure (hypertension)
• low blood pressure (hypotension)
• angina pectoris
• myocardial infarction
• lung damage (acute respiratory distress syndrome)
• lung fibrosis causing shortness of breath (chronic interstitial lung fibrosis)
• breathing difficulties with wheezing or coughing (bronchospasm)
• breathlessness (dyspnoea)
• inadequate oxygen supply to one or more parts of the body (tissue hypoxia)
• cough
• pain or ulceration in the mouth (stomatitis)
• nausea, vomiting or diarrhoea
• constipation
• enteritis
• pancreatitis
• blood clots
• liver enlargement (hepatomegaly)
• yellowing of eyes or skin
• skin redness (radiodermatitis)
• itching
• taste disturbances
• tingling, tickling, pricking, stinging or burning sensations (paraesthesia)
• smell disturbances
• muscle cramps
• bladder disorders
• kidney function disorders, including kidney failure
• headache
• multi-organ failure
• injection site reactions
• weight gain
• confusion
• conjunctivitis, eye swelling
• fluid accumulation in the abdominal cavity (ascites)

Frequency not known: cannot be estimated from 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, reduced haemoglobin concentration)
• excessive tearing
• tinnitus
• nasal congestion (stuffy nose)
• mouth and throat pain
• allergy-like symptoms or flu-like symptoms (runny nose)
• sneezing
• conditions causing lung inflammation which may lead to breathlessness, cough and fever or lung fibrosis (non-infectious pneumonia, bronchiolitis obliterans, allergic alveolitis), fluid in or around the lungs (pleural effusion), abdominal pain
• bleeding in the stomach or intestines
• intestinal disorders/bleeding
• liver function disorders
• rash, skin redness, blistering around lips, eyes or mouth, skin peeling (erythema multiforme, urticaria, erythema)
• hand-foot syndrome
• facial swelling
• excessive sweating
• skin hardening (scleroderma)
• muscle cramps and pain
• joint pain
• inflammation, scarring and shrinkage of the urinary bladder
• effects on the foetus, such as foetal damage or death, intrauterine death, foetal developmental abnormalities, delayed foetal development, carcinogenic effects on offspring
• changes in results of certain blood tests (glucose levels, hormone levels)
• effects on the brain (encephalopathy), a syndrome called reversible posterior leukoencephalopathy syndrome, which may cause headache, confusion, seizures and vision loss, abnormal sensation (sensory disturbance, hypoesthesia), tremor, taste changes (dysgeusia) or loss of taste (hypogeusia), smell disturbances
• reduced ability of the heart to pump sufficient blood through the body, which may be life-threatening (cardiogenic shock, heart failure or cardiac arrest), rapid heartbeat (tachycardia) which may be life-threatening (ventricular tachycardia), slow heartbeat (bradycardia), fluid accumulation in the space around the heart (pericardial effusion), abnormal ECG readings (prolongation of the QT interval on electrocardiogram), heart rhythm changes (arrhythmia) which may be noticeable (palpitations)
• changes in menstrual frequency
• parotitis

Reporting of side effects
If any adverse effects occur in adult patients or children, including any adverse effects not listed in this leaflet, you should inform your doctor, pharmacist or nurse. Adverse effects can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Tel: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse effects can also be reported to the marketing authorisation holder.
Reporting adverse effects helps to provide more information on the safety of this medicine.

5. How to store Cyclophosphamide Accord
Keep this medicine out of sight and reach of children.
Do not use Cyclophosphamide Accord after the expiry date (EXP) stated on the packaging. The expiry date refers to the last day of the stated month.
Store in a refrigerator (2°C - 8°C).

After preparation of the solution for intravenous administration
Chemical and physical stability of the solution after reconstitution (concentration 20 mg/mL) and dilution (concentration 2 mg/mL) has been demonstrated for 48 hours at a temperature of 2°C to 8°C.
From a microbiological point of view, the medicine should be used immediately. If not used immediately, the user is responsible for the storage conditions and duration prior to use. Usually, storage time should not exceed 24 hours at a temperature of 2°C to 8°C, provided reconstitution was carried out under controlled and validated aseptic conditions.
Do not use this medicine if a deterioration in product quality is observed, such as formation of sediment or visible particles in the solution after reconstitution/dilution.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What Cyclophosphamide Accord contains

• The active substance is cyclophosphamide.
• The excipient is mannitol.

Each vial of Cyclophosphamide Accord 500 mg, powder for solution for injection/infusion, contains 534.5 mg of monohydrate cyclophosphamide, corresponding to 500 mg of cyclophosphamide.
Each vial of Cyclophosphamide Accord 1000 mg, powder for solution for injection/infusion, contains 1069.0 mg of monohydrate cyclophosphamide, corresponding to 1000 mg of cyclophosphamide.

What Cyclophosphamide Accord looks like and contents of the pack
Cyclophosphamide Accord 500 mg is a white powder or agglomerated form in a 30 mL glass vial.
Cyclophosphamide Accord 1000 mg is a white powder or agglomerated form in a 50 mL glass vial.
Pack size: 1 vial.

Marketing Authorisation Holder
Accord Healthcare Polska Sp. z o.o.
ul. Taśmowa 7
02-677 Warsaw
Poland

Manufacturer/Importer
Accord Healthcare Polska Sp. z o.o.
ul. Lutomierska 50
95-200 Pabianice
Poland
Pharmadox Healthcare Ltd.
KW20A Kordin Industrial Park,
Paola, PLA3000
Malta
Laboratori Fundació Dau
C/ C, 12-14 Pol. Ind. Zona Franca
08040 Barcelona
Spain
Accord Healthcare B.V.
Winthontlaan 200
3526KV Utrecht
The Netherlands

This medicinal product is authorised in the European Economic Area countries under the following names:

Information intended exclusively for medical professionals:

The medicinal product Cyclophosphamide Accord should be administered only by a physician experienced in the use of anticancer chemotherapy. It must be given only in facilities where equipment is available for regular monitoring of clinical, biochemical and hematological parameters both before, during and after administration, under the supervision of an oncology specialist.

Dosage

The dose should be determined individually for each patient. The duration of treatment and (or) treatment intervals depend on the therapeutic indication, combination therapy regimen, the patient's general health condition, as well as on the results of laboratory monitoring tests and bone marrow recovery.

When used in combination with other cytostatic agents with similar toxicity, dose reduction or prolonged intervals between treatment cycles may be necessary.

The use of hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered to reduce the risk of complications associated with bone marrow suppression and (or) to facilitate delivery of the intended dose.

To reduce the risk of toxic effects on the urinary tract, an adequate amount of fluid (administered orally or by infusion) should be given before, during or immediately after administration of the medicinal product to ensure forced diuresis. Therefore, Cyclophosphamide Accord should be administered in the morning.

Cyclophosphamide is inactive until activated by hepatic enzymes. However, as with all cytotoxic drugs, reconstitution should be performed by trained personnel in a designated area.

Handling of the medicinal product

The choice of solvent for reconstitution of Cyclophosphamide Accord depends on the route of administration.

Infusion

Intravenous infusion is the preferred method of intravenous administration.

If the solution is to be used for intravenous infusion, Cyclophosphamide Accord should be dissolved by adding sterile water for injections or sterile 9 mg/mL (0.9%) sodium chloride solution. The reconstituted solution of Cyclophosphamide Accord should then be diluted prior to infusion with 50 mg/mL (5%) dextrose solution or 9 mg/mL (0.9%) sodium chloride solution.

Direct injection

If the solution is to be administered as a direct injection, Cyclophosphamide Accord should be prepared by adding sterile 9 mg/mL (0.9%) sodium chloride solution.

Note that only Cyclophosphamide Accord reconstituted in sterile 9 mg/mL (0.9%) sodium chloride solution may be administered as an intravenous bolus injection.

The reconstituted Cyclophosphamide Accord solution in water is hypotonic and should not be administered by direct injection.

To reconstitute the vial containing Cyclophosphamide Accord, powder for solution for injection/infusion, add the following volumes of sterile water for injections or 9 mg/mL (0.9%) sodium chloride solution:

• Vial containing 500 mg cyclophosphamide: 25 mL
• Vial containing 1000 mg cyclophosphamide: 50 mL

Injection of solvent into the vial may create high pressure, which disappears immediately after inserting a second sterile needle through the rubber stopper of the vial. Vigorous shaking ensures rapid dissolution of the powder, resulting in a clear solution. If the powder does not dissolve immediately, continue shaking the vial for several minutes until complete dissolution. The solution should be used immediately after preparation.

Intravenous administration

Intravenous infusion is the preferred method of intravenous administration.

If Cyclophosphamide Accord is exposed to temperatures above the recommended maximum (e.g., during transport), the cyclophosphamide contained in the vial may melt. Vials with melted cyclophosphamide can be visually identified. Cyclophosphamide is a white powder, whereas the melted form appears as a transparent or yellowish sticky liquid (often as droplets on the vial walls). Vials with melted cyclophosphamide are not suitable for use.

Guidelines for safe handling of antineoplastic drugs

• Preparation and administration of Cyclophosphamide Accord must comply with established principles and guidelines for handling cytotoxic drugs.

• If possible, reconstitution should be performed in a laminar flow cabinet.

• Personnel preparing the medicinal product must wear a protective mask and gloves.

• In case of spillage, the surface should be thoroughly rinsed with water. Pregnant or breastfeeding women should not participate in the preparation of cytotoxic drugs.

• The drug should be diluted by trained personnel and performed in a designated area.

• The working surface should be covered with an absorbent pad with a waterproof disposable film.

• Syringes and equipment with Luer-lock connectors should be used. Needles with a large bore are recommended to minimize pressure and the risk of aerosol formation. The risk of aerosol formation can also be reduced by using a vented needle.

• Any unused remnants of the drug should be discarded. Appropriate precautions should be taken when disposing of equipment used for dilution of cyclophosphamide solution.

• All drug residues or contaminated materials should be placed in high-risk waste bags.

• Sharp objects (needles, syringes, vials, etc.) should be placed in an appropriate rigid container.

• Personnel involved in collecting and disposing of such waste should be warned of potential hazards.

• Any unused medicinal product or waste material should be disposed of in accordance with local regulations for cytotoxic drugs.

Storage and stability of the reconstituted solution

Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C to 8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, the responsibility for storage conditions and duration prior to use lies with the user and should generally not exceed 24 hours at 2°C to 8°C, unless reconstitution/dilution was carried out under controlled and validated aseptic conditions.