Cyclophosphamide accord

Package leaflet: Information for the patient

Cyclophosphamide Accord, 200 mg/mL,
concentrate for solution for injection / infusion
Cyclophosphamidum
Please read all of this leaflet carefully before the medicine is administered, as it contains
important information for you.

• Keep this leaflet so that you can read it again if necessary.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• This medicine has been prescribed for a specific individual. Do not give it to others. This medicine may harm another person, even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet

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 package 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 agent.
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:

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

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

2. Important information before using Cyclophosphamide Accord

When not to use Cyclophosphamide Accord

• if the patient is allergic to cyclophosphamide or any of its metabolites or 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 after chemotherapy or radiotherapy). The doctor will recommend blood tests to monitor bone marrow function
• if the patient has a urinary tract infection, which may manifest as pain during urination (cystitis)
• if the patient has ever had kidney or bladder disorders due to previous chemotherapy or radiotherapy
• if the patient has difficulty passing urine (urinary outflow obstruction)
• if the patient is breastfeeding
• if the patient has other non-cancer-related diseases, except for life-threatening immune disorders.

Warnings and precautions
Before using Cyclophosphamide Accord, discuss this with your 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 had adrenal glands removed
• if the patient has recently undergone or is undergoing radiotherapy or chemotherapy
• if the patient has heart disease or has been irradiated in the area of the heart
• if the patient has diabetes
• if the patient is in poor general condition or is weakened
• 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 are formed:

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

• white blood cells, which fight infection, and

• platelets, which aid blood clotting.

• After receiving cyclophosphamide, the number of all three types of blood cells decreases. This is an unavoidable adverse effect of cyclophosphamide. The lowest blood cell count is typically observed about 5–10 days after starting treatment and remains 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, the recovery period may take longer.

• During the time when blood cell counts are reduced, the patient may be more susceptible to infection. 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 number of red blood cells, white blood cells, and platelets is sufficiently high. It may be necessary to reduce the dose or delay the next administration.

• Cyclophosphamide may impair normal wound healing. It is important to keep any cuts clean and dry and to monitor whether they are healing properly. Oral health should be carefully maintained, as mouth ulcers and infections may occur. In case of
  doubt, consult your doctor.

• Cyclophosphamide may damage the tissue lining the urinary bladder, causing blood in the urine and pain during urination. This is known to physicians, and if necessary, the doctor may prescribe a medicine called mesna, which protects the urinary bladder.

• Mesna may be administered as a short intravenous injection, added to the cyclophosphamide infusion, or given orally as tablets. More information about mesna can be found in the patient leaflet for the injectable and tablet forms of the medicine.

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

• Anticancer medicines and radiotherapy may increase the risk of developing other cancers, even 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 doses of cyclophosphamide, during radiotherapy, when using other chemotherapeutic agents, or in elderly patients. During treatment, the doctor will closely monitor heart function.

• Cyclophosphamide may cause lung diseases, 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 a life-threatening effect 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 medicines may be necessary. Consult your doctor about this.

Cyclophosphamide Accord and other medicines
Tell your doctor or pharmacist about all medicines currently or recently taken, as well as any medicines the patient plans to use. Inform them especially about the use of the medicines or treatments listed below, as they may not work properly with cyclophosphamide.
The following medicines may reduce the effect of cyclophosphamide:

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

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

• angiotensin-converting enzyme inhibitors, thiazide diuretics such as hydrochlorothiazide or chlorthalidone (used to treat high blood pressure or fluid retention)
• natalizumab (medicine used to treat multiple sclerosis)
• paclitaxel (medicine used to treat cancer)
• zidovudine (medicine used to treat viral infections)
• clozapine (medicine 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 (medicines used to treat cancer)
• cytarabine, pentostatin, trastuzumab (medicines used to treat cancer)
• irradiation of the area around the heart

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

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

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

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

Cyclophosphamide Accord with food, drink, and alcohol
Drinking alcohol may worsen nausea and vomiting caused by cyclophosphamide.
During treatment with cyclophosphamide, grapefruit (as fruit or juice) should not be consumed.
They may interfere with the proper action of the medicine and alter its effectiveness.
Contraception, pregnancy, breastfeeding, and effect 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 using effective contraception, to avoid fathering a child during treatment with Cyclophosphamide Accord and for 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 fetal harm. Based on available information, cyclophosphamide is not recommended during pregnancy, especially during the first trimester, and the decision to use it will be made by the doctor.
Breastfeeding
Cyclophosphamide passes into human milk; therefore, women must not breastfeed during treatment. See section 2 "When not to use Cyclophosphamide Accord."
Fertility
Cyclophosphamide may affect the ability to have children in the future and may cause infertility. Consult your doctor about the possibility of sperm cryopreservation (freezing) before treatment. Patients planning parenthood after treatment should discuss this with their doctor.
In young women with ovarian reserve, premature menopause may develop 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 motor vehicles and operate machinery. The decision whether driving or operating machinery is safe should be made individually by the doctor.
Cyclophosphamide Accord contains propylene glycol (E 1520)
This medicine contains 34 mg of propylene glycol in each 1 mL of concentrate in the vial, equivalent to 34 mg/mL.
Before administering the medicine to a child under 4 weeks of age, consult a doctor or pharmacist, especially if the child is taking other medicines containing propylene glycol or alcohol.
Cyclophosphamide Accord contains ethanol (alcohol)
This medicine contains 620 mg of alcohol (ethanol) per millilitre of concentrate, equivalent to 13 g per maximum dose of 60 mg/kg body weight. The amount of alcohol in the maximum dose (60 mg/kg body weight in a patient weighing 70 kg) is equivalent to 323 mL of beer or 130 mL of wine.
The alcohol in this medicine may affect children. Symptoms may include drowsiness and behavioural changes. It may also affect their concentration and physical activity.
The amount of alcohol in this medicine may affect the ability to drive and operate machinery, as it may impair situational judgment and reaction speed.
If the patient has epilepsy or liver problems, they should consult a doctor or pharmacist before using this medicine.
The amount of alcohol in this medicine may alter the effects of other medicines. If the patient is taking other medicines, they should consult a doctor or pharmacist.
If the patient is pregnant or breastfeeding, they should consult a doctor or pharmacist before using this medicine.
If the patient is alcohol-dependent, they should consult a doctor or pharmacist before using this medicine.

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 administration 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.

Dosed as recommended
The doctor will decide the amount of medicine to be given to the patient and the timing of administration.
The duration of treatment and (or) treatment breaks depend on the indication, the combined therapy regimen, the patient's general health status, 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 is administered under medical supervision, so it is highly unlikely that an excessive dose will be given. However, if any adverse reactions occur after administration of cyclophosphamide, the doctor must be informed immediately. Emergency medical assistance may be required.
Symptoms of cyclophosphamide overdose include the adverse reactions listed in section 4, "Possible side effects", but they are usually more severe.

Missed dose of Cyclophosphamide Accord
If a dose is missed, consult your doctor immediately.
If you have any further doubts about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences 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 exhaustion), rash, itching, or swelling of the face and lips. Severe allergic reactions may cause difficulty breathing or shock, which may be fatal (anaphylactic shock, anaphylactic or pseudoanaphylactic 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 may require antibiotic treatment 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 touch sensation.

Other adverse reactions 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 no more than 1 in 10 people

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

Uncommon: may affect no more 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
• sudden skin flushing (mainly face)
• nerve damage causing numbness, tingling, and weakness (neuropathy)
• nerve pain which may also resemble burning or stinging (neuralgia)
• loss of appetite
• deafness

Rare: may affect no more than 1 in 1,000 people

• increased risk of developing white blood cell cancer (acute leukaemia) and certain other tumours (bladder cancer, ureter cancer)
• ineffective production of a specific type of blood cell (myelodysplastic syndrome)
• increased release of antidiuretic hormone from the pituitary gland. This affects the kidneys, causing low sodium levels in the blood (hyponatraemia) and water retention, 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 no more than 1 in 10,000 people

• shock
• complications of anticancer treatment due to tumour 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)
• pulmonary fibrosis causing shortness of breath (chronic interstitial pulmonary fibrosis)
• breathing difficulties with wheezing or coughing (bronchospasm)
• feeling of breathlessness (dyspnoea)
• inadequate oxygen supply to one or more parts of the body (tissue hypoxia)
• cough
• pain or ulcers in the mouth (stomatitis)
• nausea, vomiting, or diarrhoea
• constipation
• enteritis
• pancreatitis
• blood clots
• enlarged liver (hepatomegaly)
• reactivation of viral hepatitis
• yellowing of eyes or skin
• skin redness (radiodermatitis)
• itching, toxic dermatitis
• taste disturbances
• tingling, tickling, pricking, stinging, or burning sensations (paraesthesia)
• smell disturbances
• muscle cramps
• bladder disorders
• kidney function disorders, including kidney failure
• ulcerative cystitis
• 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 (nasal mucosa congestion)
• mouth and throat pain
• conditions causing lung inflammation which may lead to breathlessness, cough, and elevated temperature or pulmonary 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
• cytolytic hepatitis
• rash, skin redness, blistering on lips, eyes or in the 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 bladder
• effects on the foetus such as foetal damage or death, intrauterine death, foetal malformations, delayed foetal development, carcinogenic effects on offspring
• changes in results of certain blood tests (glucose levels, hormone levels)
• brain function disorder (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 (parosmia)
• reduced ability of the heart to pump sufficient blood, 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 around the heart (pericardial effusion), abnormal ECG (prolonged QT interval on electrocardiogram), changes in heart rhythm (arrhythmia), which may be noticeable (palpitations), left ventricular failure, diffuse haemorrhage into the heart muscle
• changes in menstrual frequency
• sialadenitis
• acute overhydration
• swelling
• influenza-like illness

Reporting of adverse reactions
If any adverse reactions occur in adult patients or children, including any adverse reactions not listed in this leaflet, inform a doctor, pharmacist, or nurse. Adverse reactions 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 reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store Cyclophosphamide Accord
Keep the medicine out of the 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 opening
Store the partially used multidose vial in the original cardboard box at 2°C - 8°C for up to 28 days. Discard any unused portion after 28 days.

After dilution
Chemical and physical stability of the diluted solution has been demonstrated for 7 days at 2°C - 8°C (in the absence of light) and for 24 hours at 20°C - 25°C (under normal lighting conditions).
From a microbiological standpoint, the diluted medicine should be used immediately. If not used immediately, the user is responsible for storage conditions and duration prior to use.
Typically, storage should not exceed 24 hours at 2°C - 8°C, provided dilution was performed under controlled and validated aseptic conditions.

Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What Cyclophosphamide Accord contains

• The active substance is cyclophosphamide.
• Excipients: propylene glycol (E 1520), macrogol, monothioglycerol, anhydrous ethanol.

1 mL of concentrate contains monohydrate cyclophosphamide equivalent to 200 mg of cyclophosphamide.
One vial containing 1 mL of concentrate contains monohydrate cyclophosphamide equivalent to 200 mg of cyclophosphamide.
One vial containing 2.5 mL of concentrate contains monohydrate cyclophosphamide equivalent to 500 mg of cyclophosphamide.
One vial containing 5 mL of concentrate contains monohydrate cyclophosphamide equivalent to 1000 mg of cyclophosphamide.
One vial containing 10 mL of concentrate contains monohydrate cyclophosphamide equivalent to 2000 mg of cyclophosphamide.

What Cyclophosphamide Accord looks like and contents of the pack
A 2 mL vial made of colourless Type I glass, with a chlorobutyl rubber stopper and blue aluminium flip-off cap, in a cardboard box, containing 1 mL of concentrate.
A 5 mL vial made of colourless Type I glass, with a chlorobutyl rubber stopper and yellow aluminium flip-off cap, in a cardboard box, containing 2.5 mL of concentrate.
A 5 mL vial made of colourless Type I glass, with a chlorobutyl rubber stopper and blue aluminium flip-off cap, in a cardboard box, containing 5 mL of concentrate.
A 10 mL vial made of colourless Type I glass, with a chlorobutyl rubber stopper and blue aluminium flip-off cap, in a cardboard box, containing 10 mL of concentrate.

Pack sizes: 1, 5, 6, 10 vials.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Accord Healthcare Polska Sp. z o.o.
Taśmowa 7 Street
02-677 Warsaw
Tel: +48 22 577 28 00

Manufacturer/Importer
Accord Healthcare Polska Sp. z o.o.
Lutomierska 50 Street
95-200 Pabianice, Poland

Accord Healthcare s.a.r.l.
64th Km National Road Athens,
Lamia, Schimatari,
32009, Greece
This medicinal product is authorised in the Member States of the European Economic Area under the following names:

Information intended exclusively for medical professionals:

Cyclophosphamide Accord should be administered only by a physician experienced in the use of antineoplastic chemotherapy. This medicinal product should be administered only in facilities where equipment is available for regular monitoring of clinical, biochemical, and hematological parameters both before and during, as well as after administration, under the supervision of an oncology specialist.
Dosage
The dose should be individually determined for each patient. Doses and duration of treatment and (or) treatment intervals depend on the therapeutic indication, combination therapy regimen, the patient's general health status and organ function, as well as results of laboratory monitoring tests (particularly blood cell counts).
When used in combination with other cytostatic agents with similar toxicity, it may be necessary to reduce the dose or extend intervals between treatment cycles.
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 induce forced diuresis. Therefore, Cyclophosphamide Accord should be administered in the morning.
The decision to use cyclophosphamide according to current guidelines for treatment regimens lies with the physician.
The doses listed below may be regarded as general guidelines.
Hematological malignancies and solid tumors

• Continuous treatment: 3–6 mg/kg body weight (=120–240 mg/m² body surface area) as intravenous injection
• Intermittent treatment: 10–15 mg/kg body weight (=400–600 mg/m² body surface area) as intravenous injection, at intervals of 2 to 5 days
• High-dose intermittent treatment: 20–40 mg/kg body weight (=800–1600 mg/m² body surface area) as intravenous injection, at intervals of 21 to 28 days

Preparation for bone marrow transplantation
60 mg/kg body weight for 2 days or 50 mg/kg body weight for 4 days as intravenous injection.
If the treatment regimen includes busulfan and cyclophosphamide (Bu/Cy), the first dose of cyclophosphamide should be administered no earlier than 24 hours after the last dose of busulfan.
Autoimmune diseases
500–1000 mg/m² body surface area per month

Patients with impaired liver function
Severe impairment of liver function may be associated with reduced activation of cyclophosphamide. This, in turn, may alter the efficacy of treatment with Cyclophosphamide Accord, and this effect should be taken into account when determining the dose and assessing the response to the medicinal product (see section 4.4).
In patients with severe hepatic impairment, a reduced dose should be used. If serum bilirubin concentration is 3.1–5 mg/100 mL (=0.053–0.086 mmol/L), a 25% dose reduction is recommended.

Patients with impaired renal function
In patients with impaired renal function, especially severe impairment, reduced renal excretion may lead to increased plasma concentrations of cyclophosphamide and its metabolites. This may consequently increase toxicity, and this should be taken into account when determining dosage in these patients. If glomerular filtration rate is less than 10 mL/min, a 50% dose reduction is recommended.
Cyclophosphamide and its metabolites can be removed by dialysis, although clearance may vary depending on the dialysis system used. In patients requiring dialysis, consideration should be given to maintaining consistent intervals between administration of Cyclophosphamide Accord and dialysis.

Elderly patients
When determining monitoring for toxic effects and the need for dose adjustment, one should take into account the more frequent occurrence in elderly patients of impaired liver, kidney, heart, or other organ functions, concomitant diseases, or concomitant medications.

Children and adolescents
Cyclophosphamide has been used in children. The safety profile of the drug in children and adolescents is similar to that in adults.

Dose modification due to myelosuppression
Leukocyte and platelet counts should be regularly monitored during cyclophosphamide therapy. If signs of bone marrow suppression occur, the dose should be adjusted as necessary. Please refer to the table below. Regular microscopic examination of urinary sediment for erythrocytes is also recommended.

Dose reduction may be necessary in combination therapy.
Method of administration
Cyclophosphamide is inactive until activated by hepatic enzymes. However, as with all cytotoxic drugs, it is recommended that the medicinal product be prepared by trained medical personnel in a designated area.

Precautions to be taken before preparing and administering the medicinal product
Personnel preparing the medicinal product should wear protective gloves. Care must be taken to avoid contact of the medicinal product with the eyes. Pregnant or breastfeeding women should not prepare or administer the medicinal product.

Intravenous administration
The medicinal product for intravenous administration must be inspected visually for particulate matter or discoloration before administration, whenever possible depending on the type of solution and container.

Infusion
Infusion is the preferred method of intravenous administration.
If the solution is to be administered by intravenous infusion, the medicinal product Cyclophosphamide Accord should be diluted to a minimum concentration of 2 mg per mL using one of the following diluents:

• 0.9% sodium chloride solution for injection
• 0.45% sodium chloride solution for injection
• 5% glucose solution for injection
• 5% glucose and 0.9% sodium chloride solution for injection

Direct injection
If the solution is to be administered by direct injection, the medicinal product Cyclophosphamide Accord should be diluted to a minimum concentration of 20 mg per mL using one of the following diluents:

• 0.9% sodium chloride solution for injection
• 0.45% sodium chloride solution for injection
• 5% glucose solution for injection
• 5% glucose and 0.9% sodium chloride solution for injection

Sterile water for injection should not be used for dilution, as this results in a hypotonic solution which must not be administered by direct injection.
To reduce the likelihood of adverse reactions that appear to depend on the rate of administration (e.g., facial swelling, headache, nasal mucosal hyperemia, burning sensation of the scalp), cyclophosphamide should be administered by slow injection or slow infusion. The duration of infusion should be adjusted according to the volume and type of carrier fluid used.

Storage and shelf life of the diluted solution
After opening
After first use, partially used multidose vials should be stored in the original cardboard carton at a temperature of 2°C to 8°C for up to 28 days. Any unused portion of the medicinal product should be discarded after 28 days.

After dilution
Chemical and physical stability of the diluted solution has been demonstrated for 7 days at 2°C to 8°C (protected from light) and for 24 hours at 20°C to 25°C (under normal lighting conditions).
From a microbiological standpoint, the diluted medicinal product should be used immediately. If not used immediately, the user is responsible for the storage conditions and duration prior to use, and storage should generally not exceed 24 hours at 2°C to 8°C, unless dilution was carried out under controlled and validated aseptic conditions.