Ciclophosphamide Accord

Leaflet attached to the packaging: patient information

Cyclophosphamide Accord, 200 mg/mL,

concentrate for solution for injection/infusion
Cyclophosphamide

Read the leaflet carefully before taking the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor, pharmacist, or nurse.
• This medicine has been prescribed specifically for you. Do not pass it on to others. The medicine may harm another person, even if their symptoms are the same.
• If the patient experiences any side effects, including any not listed in this leaflet, they should tell their doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet

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

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

Cyclophosphamide Accord contains the active substance cyclophosphamide.
Cyclophosphamide is a cytotoxic medicine or an anticancer medicine.
Its action involves destroying cancer cells, which is sometimes called
“chemotherapy”.
Cyclophosphamide Accord is used in chemotherapy alone or in combination with other
medicines in the following cases:

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

In addition, cyclophosphamide is used in preparation for bone marrow transplantation to treat various types of blood cancers (acute lymphoblastic leukemia, chronic myeloid leukemia, and acute myeloid leukemia).
Occasionally, some doctors may prescribe cyclophosphamide to treat other non-cancerous diseases:

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

2. Important information before taking Cyclophosphamide Accord

When not to take 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 radiation therapy). The doctor will prescribe blood tests to check the bone marrow function
• if the patient has a urinary tract infection, which may cause pain when urinating (cystitis)
• if the patient has had kidney or bladder diseases due to previous chemotherapy or radiation therapy
• if the patient has difficulty urinating (urinary retention)
• if the patient is breastfeeding
• if the patient has other non-cancerous diseases, except for life-threatening immune system disorders.

Warnings and precautions

Before taking Cyclophosphamide Accord, the patient should discuss it with their doctor, pharmacist, or
nurse:

• if the patient has a low blood cell count
• if the patient has severe infections
• if the patient has liver or kidney disease; the doctor will prescribe blood tests to check liver and kidney function
• if the patient has had their adrenal glands removed
• if the patient has recently undergone or is undergoing radiation therapy or chemotherapy
• if the patient has heart disease or has been irradiated in the chest area
• if the patient has diabetes
• if the patient is in poor general health or is weakened
• if the patient is elderly
• if the patient has undergone surgery in the last 10 days.

Particular caution should be exercised when taking Cyclophosphamide Accord:

• During cyclophosphamide treatment, potentially life-threatening allergic reactions (anaphylactic reactions) may occur.
• Cyclophosphamide may affect the blood and immune system.
• Blood cells are produced in the bone marrow. There are three different types:
• red blood cells, which transport oxygen in the body,
• white blood cells, which fight infection, and
• platelets, which help blood clot.
• After receiving cyclophosphamide, the number of all three types of blood cells decreases. This is an unavoidable side effect of cyclophosphamide. The lowest number of blood cells is usually observed after 5-10 days from the start of cyclophosphamide treatment and remains low for several days after the end of the treatment cycle. In most people, the number of blood cells returns to normal within 21 to 28 days. If the patient has been treated with chemotherapy in the past, the period of normalization of blood cell count may take a little longer.
• During the time when the number of blood cells decreases, the patient may be more susceptible to infection. The patient should avoid close contact with people who cough, have a cold, or have other infections. If the doctor believes that the patient has an infection or is at risk of developing an infection, they will prescribe appropriate treatment.
• Before and during cyclophosphamide treatment, the doctor will check if the number of red blood cells, white blood cells, and platelets is sufficient. It may be necessary to reduce the dose of the medicine or delay the administration of the next dose.
• Cyclophosphamide may affect the healing process of wounds. The patient should take care to keep any cuts clean and dry and check if they are healing properly. It is essential to take care of gum health, as mouth ulcers and oral infections may occur. In case of

doubts, the patient should ask their doctor.

• Cyclophosphamide may damage the tissue lining the bladder, causing blood in the urine and pain when urinating. This effect is known to the doctor, so they may prescribe a medicine called mesna, which protects the bladder.
• Mesna can be administered by injection, added to the cyclophosphamide infusion, or taken in tablet form. More information about mesna can be found in the patient leaflet for the injection and tablet forms.
• In most people taking cyclophosphamide with mesna, there are no problems with the bladder, but the doctor may order a urine test to detect blood using a dipstick or microscope. If the patient notices blood in their urine, they should immediately tell their doctor.
• Cancer medicines and radiation therapy may increase the risk of developing other cancers, even years after the end of treatment. Cyclophosphamide increases the risk of bladder cancer.
• Cyclophosphamide may damage the heart or affect its rhythm. This effect is increased when high doses of cyclophosphamide are used, when radiation therapy or other chemotherapy medicines are used, or in elderly people. During treatment, the doctor will closely monitor the heart function.
• Cyclophosphamide may cause lung diseases, such as non-infectious inflammation or scarring of the lungs. This may occur more than 6 months after the end of treatment. If the patient experiences difficulty breathing, they should immediately inform their doctor.
• Cyclophosphamide may have a life-threatening effect on the liver. In case of sudden weight gain, liver pain, and yellowing of the skin or whites of the eyes (jaundice), the patient should immediately inform their doctor.
• It is possible to experience hair loss or baldness. Hair should grow back 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. It may be necessary to take anti-emetic medicines. The patient should consult their doctor about this.

Cyclophosphamide Accord and other medicines

The patient should tell their doctor or pharmacist about all medicines they are currently taking or have recently taken, as well as any medicines they plan to take. They should inform them especially about the use of the following medicines or treatments, as they may not work properly with cyclophosphamide.
The following medicines may reduce the effect of cyclophosphamide:

• aprepitant, ondansetron (anti-emetic medicine)
• bupropion (antidepressant medicine)
• busulfan, tiotepa (cancer medicines)
• ciprofloxacin, chloramphenicol, sulfonamides, such as sulfadiazine, sulfasalazine, sulfamethoxazole (antibacterial medicines)
• fluconazole, itraconazole (antifungal medicines)
• prasugrel (antiplatelet medicine)

The following medicines may increase the effect of cyclophosphamide:

• allopurinol (medicine for gout)
• azathioprine (medicine to suppress the immune system)
• chloral hydrate (medicine for insomnia)
• cimetidine (medicine to reduce stomach acid)
• disulfiram (medicine for alcohol dependence)
• aldehyde glyceryl (used to treat warts)
• protease inhibitors (medicines for viral infections)
• dabrafenib (anticancer medicine)
• medicines that increase the activity of liver enzymes, such as:
• rifampicin (antibacterial medicine)
• phenobarbital, carbamazepine, phenytoin (antiepileptic medicines)
• St. John's Wort (herbal medicine for mild depression)
• glucocorticosteroids (medicines for inflammation)

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

• angiotensin-converting enzyme inhibitors, thiazide diuretics, such as hydrochlorothiazide or chlorthalidone (used to treat high blood pressure or fluid retention)
• natalizumab (medicine for multiple sclerosis)
• paclitaxel (medicine for cancer)
• zidovudine (medicine for viral infections)
• clozapine (medicine for certain mental disorders)

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

• anthracyclines, such as bleomycin, doxorubicin, epirubicin, mitomycin (cancer medicines)
• cytarabine, pentostatin, trastuzumab (cancer medicines)
• radiation to the chest area

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

• amiodarone (medicine for heart rhythm disorders)
• G-CSF, GM-CSF hormones (used to increase the number of white blood cells after chemotherapy)

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

• etanercept (medicine for rheumatoid arthritis)
• metronidazole (antibacterial or antiprotozoal medicine)
• tamoxifen (medicine for breast cancer)
• bupropion (medicine to help quit smoking)
• coumarins, such as warfarin (anticoagulant medicines)
• cyclosporin (medicine to suppress the immune system)
• succinylcholine (medicine to relax muscles during surgery)
• digoxin, beta-acetyldigoxin (medicines for heart conditions)
• vaccines
• verapamil (medicine for high blood pressure, angina, or heart rhythm disorders)
• concomitant use of sulfonylurea derivatives with cyclophosphamide (may cause a decrease in blood sugar levels)

Cyclophosphamide Accord with food, drink, and alcohol

Drinking alcohol may increase the nausea and vomiting caused by cyclophosphamide.
The patient should not consume grapefruits (as fruit or juice) while taking cyclophosphamide.
They may interfere with the proper functioning of the medicine and change its effectiveness.

Contraception, pregnancy, breastfeeding, and fertility

Contraception in men and women
Women should not become pregnant while taking Cyclophosphamide Accord and for 12 months after the end of treatment.
Men should take appropriate precautions, including the use of effective contraception, to avoid fathering a child while taking Cyclophosphamide Accord and for 6 months after the end of treatment.
Pregnancy
If the patient is pregnant or breastfeeding, thinks they may be pregnant, or plans to have a child, they should consult their doctor before taking this medicine.
Cyclophosphamide may cause miscarriage or harm to the fetus. Given the available information, cyclophosphamide should not be used 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, so women should not breastfeed during treatment. See section 2 “When not to take Cyclophosphamide Accord”.
Fertility
Cyclophosphamide may affect the ability to have children in the future and may cause infertility. The patient should consult their doctor about the possibility of cryopreservation (freezing) of sperm before treatment. Patients planning to become parents after the end of treatment should discuss this with their doctor.
In young women with ovarian reserve, premature menopause may develop after cyclophosphamide treatment.

Driving and using machines

After taking cyclophosphamide, side effects such as dizziness, blurred vision, and vision disturbances may occur, which may affect the ability to drive vehicles or operate machines. The decision to drive or operate machines is 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, which corresponds to 34 mg/mL.
Before administering the medicine to a child under 4 weeks of age, the doctor or pharmacist should be consulted, especially if the child is taking other medicines containing propylene glycol or alcohol.

Cyclophosphamide Accord contains ethanol (alcohol)

This medicine contains 620 mg of ethanol in each milliliter of concentrate, which corresponds 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) of this medicine 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 changes in behavior. It may also affect their ability to concentrate and engage in physical activities.
The amount of alcohol in this medicine may affect the ability to drive vehicles or operate machines, as it may affect judgment and reaction time.
If the patient has epilepsy or liver problems, they should consult their doctor or pharmacist before taking this medicine.
The amount of alcohol in this medicine may change the effect of other medicines. If the patient is taking other medicines, they should consult their doctor or pharmacist.
If the patient is pregnant or breastfeeding, they should consult their doctor or pharmacist before taking this medicine.
If the patient is addicted to alcohol, they should consult their doctor or pharmacist before taking this medicine.

3. How to take Cyclophosphamide Accord

Cyclophosphamide Accord will be administered to the patient by a doctor or nurse with experience in cancer chemotherapy.
The medicine is usually given intravenously. The administration time usually lasts from 30 minutes to 2 hours, depending on the administered volume.
Cyclophosphamide is often used with other anticancer medicines or with radiation therapy.
Recommended dose
The doctor will decide on the amount of medicine to be administered to the patient and the time of administration.
The duration of treatment and/or breaks in treatment depend on the indications for use, the scheme of combined therapy, the patient's overall health, laboratory test results, and blood cell regeneration.
It is recommended to administer cyclophosphamide in the morning. It is essential to ensure that the patient receives sufficient fluids before, during, and after administration to prevent adverse effects on the urinary tract.
In case of any questions about taking this medicine, the patient should consult their doctor or pharmacist.

Overdose of Cyclophosphamide Accord

Cyclophosphamide is administered under the supervision of a doctor, so it is very unlikely that an overdose will occur. However, if the patient experiences any side effects after taking cyclophosphamide, they should immediately inform their doctor. Emergency medical attention may be necessary.
The symptoms of cyclophosphamide overdose are the side effects listed below in section 4 “Possible side effects”, but they are usually more severe.

Missed dose of Cyclophosphamide Accord

In case of a missed dose, the patient should immediately consult their doctor.
In case of any further doubts about taking this medicine, the patient should consult their doctor or pharmacist.

4. Possible side effects

Like all medicines, Cyclophosphamide Accord can cause side effects, although not everybody gets them.

The patient should immediately consult their doctor if:

• an allergic reaction occurs. Symptoms are shortness of breath, wheezing, rapid heartbeat, low blood pressure (severe exhaustion), rash, itching, or swelling of the face and lips. Severe allergic reactions can cause breathing difficulties or shock, which can be life-threatening (anaphylactic shock, anaphylactic reaction, or pseudoanaphylactic reaction).
• unexplained bruising or bleeding from the gums occurs. These may be signs of a low 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 signs of a low white blood cell count and may require the use of antibiotics to fight the infection, hemolysis, low platelet count, and kidney failure (hemolytic-uremic syndrome).

Other side effects may occur:

Very common: may occur in more than 1 in 10 people

• decrease in blood cell count (myelosuppression)
• decrease in white blood cell count, which is important for fighting infection (leukopenia, neutropenia)
• hair loss (alopecia)
• burning sensation or pain when urinating, or frequent urination (cystitis)
• blood in the urine
• fever
• suppression of the immune system

Common: may occur in up to 1 in 10 people

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

Uncommon: may occur in up to 1 in 100 people

• anemia (low red blood cell count), which may cause fatigue and sleepiness
• easy bruising due to low platelet count (thrombocytopenia)
• pneumonia
• sepsis
• allergic reactions
• infertility in women (may be permanent)
• chest pain
• rapid heartbeat
• heart rhythm disorders
• changes in the results of some blood tests
• sudden redness of the skin (flushing)
• nerve damage, causing numbness, tingling, and weakness (neuropathy)
• nerve pain, which can also feel like pain or burning (neuralgia)
• loss of appetite
• hearing loss

Rare: may occur in up to 1 in 1000 people

• increased risk of developing certain types of cancer, such as leukemia and other cancers (bladder cancer, ureteral cancer)
• ineffective production of a certain type of blood cell (myelodysplastic syndrome)
• increased release of antidiuretic hormone by the pituitary gland, which 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. Symptoms may include headache, personality or behavioral changes, confusion, and sleepiness.
• changes in heart rhythm
• hepatitis
• rash
• dermatitis
• amenorrhea
• oligomenorrhea
• dizziness
• vision disturbances, blurred vision
• changes in nail and skin color
• dehydration
• seizures
• bleeding

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

• shock
• complications of cancer treatment due to the breakdown of cancer cells (tumor lysis syndrome)
• low sodium levels in the blood
• high blood pressure (hypertension)
• low blood pressure (hypotension)
• angina pectoris
• heart attack
• lung damage (acute respiratory distress syndrome)
• scarring of the lungs, causing shortness of breath (chronic interstitial lung disease)
• breathing difficulties with wheezing or coughing (bronchospasm)
• shortness of breath (dyspnea)
• insufficient oxygen supply to one or more parts of the body (hypoxia)
• cough
• pain or ulcers in the mouth and throat (stomatitis)
• nausea, vomiting, or diarrhea
• constipation
• inflammation of the intestine
• pancreatitis
• blood clots
• enlargement of the liver (hepatomegaly)
• reactivation of viral hepatitis
• jaundice
• redness of the skin (erythema multiforme)
• itching, toxic dermatitis
• taste disturbances
• tingling, numbness, or burning sensations (paresthesia)
• smell disturbances
• muscle cramps
• bladder disorders
• kidney disorders, including kidney failure
• ulcerative cystitis
• headache
• multi-organ failure
• reactions at the injection site
• weight gain
• confusion
• conjunctivitis, eye swelling
• fluid accumulation in the abdominal cavity (ascites)

Frequency not known: cannot be estimated from the available data

• various types of cancer, such as lymphoma, kidney cancer, thyroid cancer, sarcoma
• various blood disorders (lymphopenia, decreased hemoglobin levels)
• increased tearing
• tinnitus
• nasal congestion (rhinitis)
• mouth and throat pain
• allergic symptoms or flu-like symptoms (rhinorrhea)
• sneezing
• lung disorders that can cause shortness of breath, cough, and fever (non-infectious pneumonia, bronchiolitis obliterans, pulmonary fibrosis), fluid in the lungs or around the lungs (pleural effusion), chest pain
• bleeding in the stomach or intestines
• gastrointestinal disorders/bleeding
• liver function disorders
• cytolytic hepatitis
• rash, redness of the skin, blistering of the lips, eyes, or mouth, peeling of the skin (erythema multiforme, urticaria, rash)
• hand-foot syndrome
• facial swelling
• increased sweating
• scleroderma
• muscle spasms and pain
• joint pain
• inflammation, scarring, and contraction of the bladder
• kidney disorders, including kidney failure
• effect on the fetus, such as damage or death, intrauterine death, birth defects, developmental delay, carcinogenic effect on offspring
• changes in the results of some blood tests (glucose levels, hormone levels)
• brain disorders (encephalopathy), a syndrome called reversible posterior leukoencephalopathy, which can cause headache, confusion, seizures, and vision loss, abnormal sensation (dysesthesia, hypoaesthesia), tremors, changes in taste (dysgeusia) or loss of taste (hypogeusia), smell disturbances (parosmia)
• decreased ability of the heart to pump enough blood in the body, which can be life-threatening (cardiogenic shock, heart failure, or cardiac arrest), rapid heartbeat (tachycardia), which can be life-threatening (ventricular tachycardia), slow heartbeat (bradycardia), fluid accumulation in the sac around the heart (pericardial effusion), abnormal heart rhythm (arrhythmia), which can be noticeable (palpitations), left ventricular failure, myocardial hemorrhage
• changes in menstrual frequency
• parotitis
• acute overhydration
• edema
• flu-like illness

Reporting side effects

If the patient experiences any side effects, including any not listed in this leaflet, they should tell their doctor, pharmacist, or nurse.
Side effects can be reported directly to the Department of Drug Safety Monitoring of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorization holder.
By reporting side effects, more information can be collected on the safety of the medicine.

5. How to store Cyclophosphamide Accord

The medicine should be stored out of sight and reach of children.
Do not use Cyclophosphamide Accord after the expiration date (EXP) stated on the packaging. The expiration date refers to the last day of the specified month.
Store in a refrigerator (2°C - 8°C).
After opening
Store the partially used multidose vial in the original carton at a temperature of 2°C - 8°C for a maximum of 28 days. Discard any unused medicine after 28 days.
After dilution
Chemical and physical stability of the diluted solution has been demonstrated for 7 days at a temperature of 2°C to 8°C (in the absence of light) and 24 hours at a temperature of 20°C to 25°C (under normal lighting conditions).
From a microbiological point of view, the diluted medicine should be used immediately. If not used immediately, the responsibility for the storage conditions and duration before use lies with the user.
Normally, the storage time should not exceed 24 hours at a temperature of 2°C to 8°C, if the dilution is performed under controlled and validated aseptic conditions.
Medicines should not be disposed of via wastewater or household waste. The patient should ask their pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

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

What Cyclophosphamide Accord looks like and contents of the pack

A 2 mL clear glass type I vial with a chlorobutyl rubber stopper and a blue aluminum flip-off cap, in a carton, containing 1 mL of concentrate.
A 5 mL clear glass type I vial with a chlorobutyl rubber stopper and a yellow aluminum flip-off cap, in a carton, containing 2.5 mL of concentrate.
A 5 mL clear glass type I vial with a chlorobutyl rubber stopper and a blue aluminum flip-off cap, in a carton, containing 5 mL of concentrate.
A 10 mL clear glass type I vial with a chlorobutyl rubber stopper and a blue aluminum flip-off cap, in a carton, containing 10 mL of concentrate.
Pack size: 1, 5, 6, 10 vials.
Not all pack sizes may be marketed.

Marketing authorization holder

Accord Healthcare Polska Sp. z o.o.
ul. Taśmowa 7
02-677 Warsaw
Phone: +48 22 577 28 00

Manufacturer/Importer

Accord Healthcare Polska Sp. z o.o.
ul. Lutomierska 50
95-200 Pabianice

This medicine is authorized in the Member States of the European Economic Area under the following names:

Date of last revision of the leaflet:

Information intended for healthcare professionals only:

Cyclophosphamide Accord should only be administered by a doctor with experience in the use of anticancer chemotherapy. This medicinal product should only be administered in facilities where regular monitoring of clinical, biochemical, and hematological parameters is possible before, during, and after administration, under the supervision of an oncology specialist.
Dosing
The dose should be determined individually for each patient. The dose and duration of treatment and/or breaks in treatment depend on the therapeutic indication, the scheme of combined therapy, the patient's overall health, and the function of organs, as well as the results of laboratory tests (in particular, blood cell counts).
In combination therapy with other cytostatic agents with similar toxicity, it may be necessary to reduce the dose or prolong the intervals between treatment cycles.
The use of hematopoietic growth factors (colony-stimulating factors and erythropoiesis-stimulating factors) may be considered to reduce the risk of complications associated with bone marrow suppression and/or to facilitate the administration of the planned dose.
To reduce the risk of toxic effects on the urinary tract, the patient should be given a sufficient amount of fluid (orally or by infusion) before, during, or immediately after administration of the medicinal product to induce diuresis. Therefore, Cyclophosphamide Accord should be administered in the morning.

Decision to use cyclophosphamide in accordance with applicable treatment guidelines is the responsibility of the physician.

The doses given below can be considered as general guidelines.

Hematological malignancies and solid tumors

• Continuous treatment: 3-6 mg/kg body weight (=120-240 mg/m body surface area) by intravenous injection
• Intermittent treatment: 10-15 mg/kg body weight (=400-600 mg/m body surface area) by intravenous injection, at intervals of 2 to 5 days
• Intermittent treatment with high dose: 20-40 mg/kg body weight (=800-1600 mg/m body surface area) by 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 by intravenous injection.
If a treatment regimen including busulfan and cyclophosphamide (Bu/Cy) is used, the first dose of cyclophosphamide should be administered no earlier than 24 hours after the last dose of busulfan.
Autoimmune diseases
500-1000 mg/m body surface area per month
Patients with liver function disorders
Severe liver function disorders may be associated with reduced activation of cyclophosphamide.
This, in turn, may alter the effectiveness of treatment with the medicinal product Cyclophosphamide Accord
and such action should be taken into account when determining the dose and evaluating the response to the medicinal product
(see section 4.4).
In patients with severe liver function disorders, a reduced dose should be used. If the serum bilirubin concentration is 3.1-5 mg/100 mL (=0.053-0.086 mmol/L), a 25% dose reduction is recommended.
Patients with renal function disorders
In patients with renal function disorders, especially severe ones, reduced renal excretion may lead to increased concentrations of cyclophosphamide and its metabolites in plasma.
This, in consequence, may lead to increased toxicity, and therefore this should be taken into account when determining the dosage in these patients. If the 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 there may be differences in clearance depending on the dialysis system used. In patients requiring dialysis, consideration should be given to maintaining constant intervals between administration of the medicinal product Cyclophosphamide Accord and dialysis.
Elderly patients
When determining monitoring of toxic effects and the need to adjust the dose, consideration should be given to the more frequent occurrence in elderly patients of liver, kidney, heart, or other organ disorders and concomitant diseases or other medications used.
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
During treatment with cyclophosphamide, the white blood cell and platelet counts should be regularly determined. If signs of bone marrow suppression occur, the dose should be adjusted as necessary.
Reference should be made to the table below. It is also recommended to systematically check the urine sediment for the presence of erythrocytes.

In combination therapy, further dose reduction may be necessary.

Method of administration

Cyclophosphamide is inactive until activated by liver 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 preparation and administration of the medicinal product
Persons preparing the medicinal product should wear protective gloves. Care should 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 should be inspected for particulate matter or discoloration prior to administration, if the solution and container permit.
Infusion
The preferred method of intravenous administration is infusion.
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/mL using one of the following diluents:

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

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/mL using one of the following diluents:

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

Do not use sterile water for injections for dilution, as this will result in a hypotonic solution that should not be administered by direct injection.

In order to reduce the likelihood of adverse reactions whose occurrence appears to be related to the rate of administration (e.g., facial swelling, headache, nasal congestion, sensation of burning skin), cyclophosphamide should be administered in slow injection or slow infusion. The duration of the infusion should be adjusted according to the volume and type of fluid used as a carrier.

Storage and shelf-life of the solution after dilution

After opening
After the first use, store the partially used multidose vial in the original carton at a temperature of 2°C to 8°C for a maximum of 28 days. Discard any unused portion of the medicinal product after 28 days.
After dilution
Chemical and physical stability of the diluted solution has been demonstrated for 7 days at a temperature of 2°C to 8°C (in the absence of light) and 24 hours at a temperature of 20°C to 25°C (under normal lighting conditions).
From a microbiological point of view, the diluted medicinal product should be used immediately.
If not used immediately, the user is responsible for the storage time and conditions prior to use, and the storage time should normally not exceed 24 hours at a temperature of 2°C to 8°C, unless dilution has been carried out under controlled and validated aseptic conditions.