Cyclophosphamide Accord

Package leaflet: Information for the patient

Cyclophosphamide Accord 200 mg/mL concentrate for solution for injection/infusion

cyclophosphamide

Read all of this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

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

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

Ciclofosfamide Accord contains the active substance cyclophosphamide.
Ciclofosfamide Accord is a cytotoxic or antineoplastic medicine that works by killing tumour cells (a treatment known as "chemotherapy").
Ciclofosfamide Accord is used in chemotherapy alone or in combination with other medicines in the following conditions:
certain types of blood leukaemia (acute lymphocytic 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 form 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 to treat certain types of blood leukaemia (acute lymphoblastic leukaemia, chronic myeloid leukaemia and acute myeloid leukaemia).
Occasionally, some physicians may prescribe cyclophosphamide for other non-cancer 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. What you need to know before taking Cyclophosphamide Accord

Do not take Cyclophosphamide Accord

• if you are allergic to cyclophosphamide or any of its metabolites or to any of the other ingredients of this medicine (listed in section 6)
• if you have any active infection
• if you have severe bone marrow disorder (particularly after chemotherapy or radiotherapy). You will have blood tests to monitor your bone marrow function
• if you have a urinary tract infection, which may present as pain during urination (cystitis)
• if you have previously had kidney or bladder problems due to prior chemotherapy or radiotherapy
• if you suffer from a condition that reduces your ability to urinate (urinary outflow obstruction)
• if you are breastfeeding
• if you have other non-cancer-related conditions, except for life-limiting immune disorders.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before being administered
Cyclophosphamide Accord:

• if you have low blood cell counts
• if you have serious infections
• if you have liver or kidney problems. Your doctor will check your liver and kidney function with blood tests
• if your adrenal glands have been removed
• if you have previously or recently undergone radiotherapy or chemotherapy
• if you have heart problems or have received radiotherapy to the heart area
• if you have diabetes
• if your general health condition is poor or you are frail
• if you are elderly
• if you have had surgery less than 10 days ago.

Take special care with Cyclophosphamide Accord:

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

• Cyclophosphamide may affect blood cells and the immune system.

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

• red blood cells, which carry oxygen throughout the body,

• white blood cells, which fight infections, and

• platelets, which help blood to clot.

• After receiving cyclophosphamide, the count of all three types of blood cells will decrease. This is an unavoidable side effect of cyclophosphamide. Blood cell counts typically reach their lowest point approximately 5 to 10 days after starting treatment and remain low for several days after completing the treatment course. Most people recover to normal blood cell levels within 21–28 days. If you have previously undergone multiple chemotherapy treatments, it may take longer to return to normal levels.

• You may be more likely to develop infections when your blood cell levels are low. Try to avoid close contact with people who have coughs, colds, or other infections. Your doctor will treat you with appropriate medication if they suspect you have or are at risk of an infection.

• Your doctor will monitor your red blood cell, white blood cell, and platelet counts before and during treatment with cyclophosphamide. It may be necessary to reduce your dose or delay the next dose.

• Cyclophosphamide may impair normal wound healing. Keep any wounds clean and dry and monitor them for normal healing. It is important to maintain good oral hygiene, as mouth ulcers and infections may occur. Consult your doctor if you are unsure.

• Cyclophosphamide may damage the lining of the bladder, causing blood in the urine and pain during urination. Your doctor is aware of this risk and, if necessary, will administer a medicine called Mesna to protect the bladder.

• Mesna may be given as a short injection, mixed into the cyclophosphamide infusion solution, or taken as tablets. More information about Mesna can be found in the patient information leaflet for injectable Mesna or Mesna tablets.

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

• Cancer medicines and radiotherapy may increase the risk of developing other tumours; this may occur several years after treatment has ended. Cyclophosphamide carries an increased risk of causing cancer in the bladder area.

• Cyclophosphamide may cause heart damage or affect heart rhythm. This risk increases with higher doses of cyclophosphamide, if you are receiving radiation therapy or other chemotherapy drugs, or if you are elderly. Your doctor will closely monitor your heart during treatment.

• Cyclophosphamide may cause lung problems such as inflammation or scarring in the lungs. This may occur more than six months after treatment. If you develop breathing difficulties, inform your doctor immediately.

• Cyclophosphamide may cause severe liver damage.

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

• Hair thinning or hair loss may occur. Hair should regrow normally, although it may differ in texture or colour.

• Cyclophosphamide may cause nausea or vomiting. This may last for about 24 hours after taking cyclophosphamide. You may need to take medications to prevent nausea and vomiting. Speak to your doctor about this.

Other medicines and Cyclophosphamide Accord
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, inform your doctor or pharmacist about the following medicines or treatments, as they may not interact well with cyclophosphamide:
The following medicines may reduce the effect of cyclophosphamide:

• aprepitant, ondansetron (used to prevent vomiting)
• bupropion (an antidepressant)
• busulfan, thiotepa (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 to thin the blood).

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)
• glycerol (used to treat warts)
• protease inhibitors (used to treat viruses)
• dabrafenib (an anticancer drug)
• 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 remedy for mild depression)
• corticosteroids (used to treat inflammation).

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

• 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 viruses)
• 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)
• radiation therapy to 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 or be affected by cyclophosphamide 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 quit smoking)
• coumarins such as warfarin (used to thin the blood)
• ciclosporin (used to reduce immune system activity)
• suxamethonium (used to relax muscles during medical procedures)
• digoxin, β-acetyldigoxin (used to treat heart conditions)
• vaccines
• verapamil (used to treat high blood pressure, angina, or irregular heartbeat)
• concomitant use of sulfonylurea derivatives with cyclophosphamide (blood glucose levels may decrease).

Cyclophosphamide Accord with food, drinks, and alcohol
Alcohol consumption may increase nausea and vomiting caused by cyclophosphamide.
Grapefruit (fruit or juice) must not be consumed during treatment with cyclophosphamide. It may interfere with the normal effect of the medicine and alter the efficacy of cyclophosphamide.

Contraception, pregnancy, breastfeeding, and fertility
Contraception in men and women
If you are a woman, you must not become pregnant during treatment with Cyclophosphamide Accord and for a period of 12 months after stopping treatment.
If you are a man, you must use effective contraception to prevent fathering a child during treatment with Cyclophosphamide Accord and for a period of 6 months after stopping treatment.
Pregnancy
If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, consult your doctor or pharmacist before taking this medicine.
Cyclophosphamide may cause miscarriage or harm to your unborn child.
Given the available information, the use of cyclophosphamide during pregnancy, especially in the first trimester, is not recommended, and your doctor will decide whether it can be used.
Breastfeeding
Since cyclophosphamide passes into breast milk, women must not breastfeed during treatment.
See section 2 "Do not use Cyclophosphamide Accord".
Fertility
Cyclophosphamide may affect your ability to have children in the future and may cause infertility.
Discuss sperm cryopreservation (freezing) with your doctor before treatment. If you are considering becoming a parent after treatment, discuss this with your doctor.
Young women with reduced ovarian function may develop premature menopause after cyclophosphamide treatment.

Driving and using machines
After taking cyclophosphamide, side effects such as dizziness, blurred vision, or impaired vision may occur, which could affect your ability to drive or operate machinery. The decision whether you may drive or use machinery will be made by your doctor on an individual basis.

Cyclophosphamide Accord contains propylene glycol
This medicine contains 34 mg of propylene glycol in each 1 mL vial of concentrate, equivalent to 34 mg/mL.
If your child is less than 4 weeks old, talk to your doctor or pharmacist before giving this medicine, especially if the child is receiving other medicines containing propylene glycol or alcohol.

Cyclophosphamide Accord contains ethanol (alcohol)
This medicine contains 620 mg of ethanol per mL of solution, equivalent to 13 g per maximum dose of 60 mg/kg. The amount in the maximum dose (60 mg/kg in a 70 kg patient) of this medicine is equivalent to 323 mL of beer or 130 mL of wine.
The alcohol in this preparation may affect children. These effects may include drowsiness and changes in behaviour. 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 machinery. This is because it may impair 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 alcohol-dependent, talk to your doctor or pharmacist before taking this medicine.

3. How to take Ciclofosfamide Accord

Ciclofosfamide Accord will be administered to you by a doctor or a nurse experienced in the use of chemotherapy for cancer treatment.
The medicine is usually given into a vein. The duration of administration is typically from 30 minutes to 2 hours, depending on the volume to be administered.
Cyclophosphamide is often administered in combination with other anticancer medicines or radiotherapy.

Dose recommended
Your doctor will decide how much medicine you need and when it should be administered to you.
The duration of treatment and/or treatment intervals depend on the indications for use, the regimen of a combination therapy, your general health status, laboratory monitoring results, and the recovery of blood cells.
It is recommended to administer cyclophosphamide in the morning. Before, during, and after administration, it is important that you receive adequate amounts of fluids to prevent potential adverse effects on the urinary tract.
If you have any questions about the use of this medicine, ask your doctor or pharmacist.

If you receive more Ciclofosfamide Accord than you should
Since cyclophosphamide is administered under medical supervision, it is very unlikely that you will receive an excessive dose. However, if you experience any adverse effects after receiving cyclophosphamide, inform your doctor immediately. Urgent medical care may be required.
Symptoms of cyclophosphamide overdose include the adverse effects listed below in section 4, "Possible side effects", but are generally more severe in nature.

If you miss a dose of Ciclofosfamide Accord
If you have missed the administration of the medicine, consult your doctor immediately.
If you have any doubts about 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 gets them.
Contact your doctor immediately if you notice any of the following:

• allergic reactions. Signs may include shortness of breath, wheezing, increased heart rate, decreased blood pressure (extreme tiredness), rash, itching or swelling of the face and lips. Severe allergic reactions could lead to breathing difficulties or shock, possibly resulting in death (anaphylactic shock, anaphylactic/anaphylactoid reaction)
• bruising without injury, or bleeding gums. This could be a sign that platelet levels in your blood are becoming too low
• severe infection or fever, mouth ulcers, cough, shortness of breath, signs of sepsis such as fever, rapid breathing, elevated heart rate, confusion and edema. This could indicate a drop in white blood cell levels, and antibiotics may be needed to fight infections, red blood cell breakdown, reduced platelet count, and kidney failure (hemolytic uremic syndrome)
• looking very pale, feeling tired and weak. This could be a sign of low red blood cell levels (anemia). Usually, no treatment is needed, as the body will eventually replace the red blood cells. If you are severely anemic, a blood transfusion may be required
• severe hypersensitivity reactions with (high) fever, red skin rashes, joint pain and/or eye infection (Stevens-Johnson syndrome), severe sudden (hypersensitive) reaction with fever and skin blisters/skin peeling (toxic epidermal necrolysis)
• abnormal muscle breakdown that may lead to kidney problems (rhabdomyolysis)
• various types of blood disorders (agranulocytosis)
• blood in the urine, pain during urination, or less frequent urination
• severe chest pain
• symptoms such as weakness, vision loss, speech impairment, loss of touch sensation

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

• decrease in blood cells (myelosuppression)
• decrease in white blood cells important for fighting infections (leucopenia, neutropenia)
• hair and body hair loss (alopecia)
• burning sensations or pain during urination and frequent need to urinate (bladder infection)
• presence of blood in the urine
• fever
• suppression of the immune system

Common: may affect up to 1 in 10 people

• infections
• mucosal inflammation
• abnormal liver function
• infertility in men
• chills
• feeling weak
• general feeling of discomfort
• decrease in white blood cells and fever (febrile neutropenia)

Uncommon: may affect up to 1 in 100 people

• anemia (low red blood cell levels) which may make you feel tired and drowsy
• easy bruising due to thrombocytopenia (low platelet levels)
• lung inflammation (pneumonia)
• sepsis
• allergic reactions
• infertility in women (this may be permanent)
• chest pain
• rapid heartbeat
• heart problems
• changes in results of certain blood tests
• skin flushing (redness)
• nerve damage causing numbness, pain and weakness (neuropathy)
• nerve pain, which may feel like burning or stabbing pain (neuralgia)
• loss of appetite (anorexia)
• hearing loss

Rare: may affect up to 1 in 1,000 people

• increased risk of white blood cell cancer (acute leukemia) and some other types of cancer (bladder cancer, ureter cancer)
• ineffective production of a certain 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 (hyponatremia) and water retention, leading to brain swelling due to excess water in the blood. Signs may include headache, personality or behavioral changes, confusion, drowsiness
• changes in heart rhythm
• liver inflammation
• skin rash
• skin inflammation
• absence of menstruation
• absence of sperm
• dizziness
• vision impairment, blurred vision
• changes in nail and skin color
• dehydration
• seizures
• bleeding

Very rare: may affect up to 1 in 10,000 people

• shock
• complications that may occur after cancer treatment due to breakdown products of dying tumor cells (tumor lysis syndrome)
• low sodium levels in the blood
• high blood pressure (hypertension)
• low blood pressure (hypotension)
• angina
• heart attack
• lung injury (acute respiratory distress syndrome)
• lung scarring causing shortness of breath (chronic interstitial pulmonary fibrosis)
• difficulty breathing with wheezing or cough (bronchospasm)
• shortness of breath (dyspnea)
• condition in which the body or part of the body is deprived of adequate oxygen supply (hypoxia)
• cough
• mouth pain or ulcers (stomatitis)
• feeling unwell (nausea), vomiting or diarrhea
• constipation
• intestinal inflammation
• inflammation of the pancreas
• blood clots
• liver enlargement (hepatomegaly)
• reactivation of viral hepatitis
• yellowing of eyes or skin
• skin redness (radiation recall dermatitis)
• itching sensation, toxic dermatitis
• impaired sense of taste
• tingling, prickling, stinging, or burning sensations (paresthesia)
• impaired sense of smell
• 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 swelling
• fluid in or around the lungs (pulmonary edema)
• fluid accumulation in the abdominal cavity (ascites)

Not known: frequency cannot be estimated from available data

• various types of cancer, e.g. blood cancer (non-Hodgkin lymphoma), kidney cancer, thyroid cancer, sarcoma
• various types of blood disorders (lymphopenia, low hemoglobin)
• increased lacrimation
• tinnitus
• nasal passage obstruction (nasal congestion)
• oropharyngeal pain
• allergy symptoms or flu-like symptoms (rhinorrhea)
• sneezing
• conditions causing lung inflammation that may lead to shortness of breath, cough, high temperature or lung scarring (pneumonitis, obliterative bronchiolitis, allergic alveolitis), fluid in or around the lungs (pleural effusion), abdominal pain
• bleeding in the stomach or intestines
• intestinal problems/bleeding
• liver impairment
• cytolytic hepatitis
• skin rash, skin redness, blisters on 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 fetal damage or death, intrauterine death, fetal malformations, fetal growth retardation, carcinogenic effect 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 brain swelling, headache, confusion, seizures and vision loss, changes in sense of touch (dysesthesia) or loss of sensitivity (hypoesthesia), tremor, changes in sense of taste (dysgeusia) or loss of taste (hypogeusia), changes in sense of smell (parosmia)
• reduced ability of the heart to pump sufficient blood, which may be life-threatening (cardiogenic shock, heart failure or cardiac arrest), faster heartbeat (tachycardia), which may be life-threatening (ventricular tachycardia), slower heartbeat (bradycardia), fluid accumulation in the membrane surrounding the heart (pericardial effusion), abnormal ECG trace (prolonged QT interval on electrocardiogram), changes in heart rhythm (arrhythmia) that may 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 side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system at:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Cyclophosphamide Accord

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

After opening:
After opening, store the partially used multidose vial in the original packaging at 2°C - 8°C for a maximum of 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 (protected from light) and for 24 hours at 20°C - 25°C (under normal light conditions).
From a microbiological standpoint, the diluted medicine should be used immediately. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2°C - 8°C, unless dilution has been carried out under controlled and validated aseptic conditions.

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

6. Package contents and other information

What Ciclofosfamide Accord contains

• The active substance is cyclophosphamide.
• The excipients are propylene glycol (E 1520), macrogol, monothioglycerol, and anhydrous ethanol.

One 1 mL vial of concentrate contains monohydrate cyclophosphamide equivalent to 200 mg
of cyclophosphamide.
One 2.5 mL vial of concentrate contains monohydrate cyclophosphamide equivalent to 500 mg
of cyclophosphamide.
One 5 mL vial of concentrate contains monohydrate cyclophosphamide equivalent to 1,000 mg
of cyclophosphamide.
One 10 mL vial of concentrate contains monohydrate cyclophosphamide equivalent to 2,000 mg
of cyclophosphamide.

Description of the appearance of Ciclofosfamide Accord and package contents

2 mL colourless transparent type I glass vial with a chlorobutyl rubber stopper and a blue flip-off seal, containing 1 mL of concentrate.
5 mL colourless transparent type I glass vial with a chlorobutyl rubber stopper and a yellow flip-off seal, containing 2.5 mL of concentrate.
5 mL colourless transparent type I glass vial with a chlorobutyl rubber stopper and a blue flip-off seal, containing 5 mL of concentrate.
10 mL colourless transparent type I glass vial with a chlorobutyl rubber stopper and a blue flip-off seal, containing 10 mL of concentrate.

Packaging

1 vial
5 vials
6 vials
10 vials

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Accord Healthcare S.L.U.
World Trade Center,
Moll De Barcelona s/n,
Edifici Est, 6th Floor,
Barcelona, 08039, Spain

Manufacturer

Accord Healthcare Polska Sp.z o.o.
ul. Lutomierska 50,
95-200 Pabianice
Poland
Or
Laboratori Fundació Dau
C/c 12-14 Poligon Industrial Zona Franca
Barcelona, 08040, Spain
Or
Accord Healthcare single member S.A.
64th Km National Road Athens,
Lamia, Schimatari,
32009, Greece

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

| Member State | Medicinal Name | |------------------|--------------------| | Cyprus | Cyclophosphamide Accord 200 mg/ml concentrate |

The following information is intended for healthcare professionals only:
Cyclophosphamide Accord must be used only under the supervision of a physician experienced
in the use of antineoplastic chemotherapy. This medicinal product must be administered
exclusively in facilities equipped with equipment for regular monitoring of clinical, biochemical,
and hematological parameters before, during, and after administration, and under the direction
of a specialized oncology service.
Dosage
The dosage must be individualized. Doses, duration of treatment, and/or intervals between
treatments depend on the therapeutic indication, the combination therapy regimen, the patient's
general health status and organ function, as well as laboratory monitoring results (particularly
monitoring of blood cells).
When used in combination with other cytostatic agents of similar toxicity, a dose reduction or
prolongation of treatment-free intervals may be necessary.
The use of hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-
stimulating agents) may be considered to reduce the risk of myelosuppressive complications
and/or to facilitate administration of the intended dose.
Adequate amounts of fluids must be administered orally or by infusion before, during, or
immediately after administration to force diuresis and thereby reduce the risk of urinary tract
toxicity. Therefore, Cyclophosphamide Accord should be administered in the morning.
It is the physician's responsibility to decide on the use of cyclophosphamide in accordance
with established treatment guidelines.
The following doses may be considered as general guidelines:
Hematological and solid tumors
For daily treatment:
3 – 6 mg/kg body weight (= 120 – 240 mg/m² body surface area), administered intravenously
For intermittent treatment:
10 – 15 mg/kg body weight (= 400 – 600 mg/m² body surface area), administered
intravenously, with treatment-free intervals of 2–5 days
For high-dose intermittent treatment:
20 – 40 mg/kg body weight (= 800 – 1,600 mg/m² body surface area), administered
intravenously, with treatment-free intervals of 21–28 days.
As preparation for bone marrow transplantation
2 days 60 mg/kg or 4 days 50 mg/kg body weight administered intravenously.
If a busulfan-cyclophosphamide (Bu/Cy) regimen is used, the first dose of cyclophosphamide
must be administered at least 24 hours after the last dose of busulfan.
Autoimmune diseases
500 – 1,000 mg/m² body surface area per month.
Patients with hepatic impairment
Severe hepatic impairment may be associated with reduced activation of cyclophosphamide.
This may alter the efficacy of treatment with Cyclophosphamide Accord and should be taken
into account when selecting the dose and evaluating response to the medicinal product.
The dose should be reduced in patients with severe hepatic impairment. A 25% dose reduction is
recommended in patients with serum bilirubin concentrations of 3.1 – 5 mg/100 mL (= 0.053 –
0.086 mmol/L).
Patients with renal impairment
In patients with renal impairment, particularly those with severe impairment, reduced renal
excretion may lead to increased plasma levels of cyclophosphamide and its metabolites. This
may result in increased toxicity and should be considered when determining dosage in these
patients. (See section 4.4). A 50% dose reduction is recommended for a glomerular filtration
rate below 10 mL/min.
Cyclophosphamide and its metabolites are dialyzable, although clearance may vary depending
on the dialysis system used. In patients requiring dialysis, a consistent interval between dialysis
cycles and administration of Cyclophosphamide Accord should be considered.
Elderly patients
In elderly patients, monitoring for toxicity and the need for dose adjustment should reflect the
higher frequency of impaired hepatic, renal, or cardiac function, or other organ functions, as well
as concomitant diseases or other pharmacological therapies in this population.
Pediatric population
Cyclophosphamide has been administered to children. The safety profile of cyclophosphamide
in pediatric patients is similar to that in the adult population.
Dose modification due to myelosuppression
Regular monitoring of white blood cell and platelet counts should be performed during
treatment with cyclophosphamide. Dose adjustment is recommended as needed if signs of
myelosuppression occur.
Please refer to the table below. Urine sediment should also be monitored regularly for the
presence of erythrocytes.

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

Method of administration
Cyclophosphamide is inert until activated by hepatic enzymes. However, as with all cytotoxic agents, dilution should be carried out by trained personnel in a designated area.

Precautions to be taken before handling or administering the product
Those handling the preparation must wear protective gloves. Care must be taken to avoid splashing material into the eyes. The product must not be handled by pregnant or breastfeeding women.

Intravenous use
Medicinal products for intravenous use must be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Infusion:
Intravenous administration should preferably be performed as an infusion.
If the solution is to be used for intravenous infusion, Cyclophosphamide Accord must be diluted to a minimum concentration of 2 mg per mL using one of the following diluents:
0.9% Sodium Chloride Injection,
0.45% Sodium Chloride Injection,
5% Glucose Injection,
5% Glucose and 0.9% Sodium Chloride Injection.

Direct injection:
If the solution is to be used for direct injection, Cyclophosphamide Accord must be diluted to a minimum concentration of 20 mg per mL using one of the following diluents:
0.9% Sodium Chloride Injection,
0.45% Sodium Chloride Injection,
5% Glucose Injection,
5% Glucose and 0.9% Sodium Chloride Injection.

Do not use sterile water for injectable preparations for dilution, as this results in a hypotonic solution which must not be injected directly.

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

Storage and stability of the diluted solution
After opening:
After first use, partially used multi-dose vials should be stored in their original packaging at 2°C - 8°C for a maximum of 28 days. Any unused portion must be discarded after 28 days.

After dilution:
Chemical and physical stability of the diluted solution has been demonstrated for 7 days at 2°C - 8°C (protected from light) and for 24 hours at 20°C - 25°C (under normal light conditions).

From a microbiological standpoint, the diluted medicinal product should be used immediately. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user and normally should not exceed 24 hours at 2°C - 8°C, unless dilution has been carried out under controlled and validated aseptic conditions.