Cyclophosphamide sandoz

Package leaflet: Information for the patient

Cyclophosphamide Sandoz, 100 mg/mL,
concentrate for solution for injection / infusion
Cyclophosphamide
Please read this leaflet carefully before using this medicine, as it contains
important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Leaflet contents

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

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

Cyclophosphamide Sandoz contains the active substance cyclophosphamide.
Cyclophosphamide is a cytotoxic medicine, also known as an anticancer agent. It works by destroying cancer cells, a treatment sometimes referred to as "chemotherapy".
Cyclophosphamide is commonly used alone or in combination with other anticancer medicines or radiotherapy for the treatment of various cancers in adults and children over 5 years of age. These include:
certain types of white blood cell cancers (acute lymphoblastic leukaemia, chronic lymphocytic leukaemia);
various forms of lymphomas 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 to treat various types of white blood cell cancers (acute lymphoblastic leukaemia, chronic myeloid leukaemia, and acute myeloid leukaemia) in adults and children over 5 years of age.
Occasionally, some doctors may prescribe cyclophosphamide for the treatment of other, non-cancer-related conditions:
life-threatening autoimmune diseases, such as severe, progressive forms of lupus nephritis (kidney inflammation caused by an immune system disorder) and Wegener's granulomatosis (a rare form of blood vessel inflammation) in adults and children over 5 years of age.

2. Important information before using Cyclophosphamide Sandoz

Cyclophosphamide Sandoz will not be administered to children under 5 years of age, because it contains excipients harmful to patients in this age group [see "Cyclophosphamide Sandoz contains propylene glycol" and "Cyclophosphamide Sandoz contains ethanol (alcohol)"].

When not to use Cyclophosphamide Sandoz

Do not use Cyclophosphamide Sandoz if the patient:

• Is allergic to cyclophosphamide, any of its metabolites, or any of the other components of this medicine. Symptoms of an allergic reaction may include: shortness of breath, wheezing, rash, itching, or swelling of the face and lips.
• Currently has any infection.
• Has bone marrow dysfunction (especially if the patient has previously undergone chemotherapy or radiotherapy). The doctor will order blood tests to monitor bone marrow function.
• Has a urinary tract infection, which may present as pain during urination (cystitis).
• Has previously had kidney or bladder disorders due to prior chemotherapy or radiotherapy, or has difficulty passing urine (urinary outflow obstruction).
• Is breastfeeding.
• Has an autoimmune disease that is not life-threatening.

Warnings and precautions

Before starting treatment with Cyclophosphamide Sandoz, discuss with the doctor if the patient:

• Has a low blood cell count;
• Has severe infections;
• Has liver or kidney disease. The doctor will recommend blood tests to monitor liver and kidney function;
• Has had adrenal glands removed;
• Is currently or has recently undergone radiotherapy or chemotherapy;
• Has heart disease or has undergone radiotherapy to the chest area;
• Has diabetes;
• Has a poor general health condition or is weakened;
• Is elderly;
• Has undergone surgery within the last 10 days.

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 are formed:

• Red blood cells, which carry oxygen throughout the body,
• White blood cells, which fight infections,
• Platelets, which help blood clotting.

Following administration of cyclophosphamide, the number of all three types of blood cells decreases. This is an unavoidable adverse effect of cyclophosphamide. The lowest blood cell counts occur approximately 5–10 days after starting treatment and remain low for several days after the end of a treatment cycle. In most patients, blood cell counts return to normal within 21 to 28 days. If the patient has undergone multiple prior chemotherapy treatments, normalization may take longer.

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

Before and during cyclophosphamide treatment, the doctor will monitor whether red blood cell, white blood cell, and platelet counts are sufficiently high. It may be necessary to reduce the dose or delay the next dose.

Cyclophosphamide may impair proper wound healing. All cuts or wounds should be kept clean and dry, and healing should be monitored. Oral health is important, as mouth ulcers and infections may occur. Consult the doctor if in doubt.

Cyclophosphamide may damage the tissue lining the bladder, causing blood in the urine and pain during urination. This is well known to doctors, who may prescribe a drug called mesna, which protects the bladder. Mesna may be given either as a short intravenous injection, added to the cyclophosphamide infusion, or taken orally as tablets.

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

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

Cyclophosphamide may damage the heart or affect its rhythm. This risk increases with high doses of cyclophosphamide, concurrent radiotherapy, other chemotherapy drugs, or in elderly patients. Heart function will be closely monitored during treatment.

Cyclophosphamide may cause lung diseases such as inflammation or lung 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, inform the doctor 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, which may last about 24 hours after administration. Antiemetic medications may be needed. Consult the doctor about this.

Children and adolescents

Cyclophosphamide Sandoz will not be given to children under 5 years of age due to the risk associated with excipients. (See section 2 "Important information before using Cyclophosphamide Sandoz", "Cyclophosphamide Sandoz contains propylene glycol" and "Cyclophosphamide Sandoz contains ethanol (alcohol)").

Cyclophosphamide has been used in children. The safety profile of the active substance cyclophosphamide in children and adolescents is similar to that in adults.

Cyclophosphamide Sandoz and other medicines

Tell the doctor about all medicines currently or recently taken, and any medicines planned for future use. Inform the doctor especially about the following medicines or treatments, as they may not work properly with cyclophosphamide:

The following medicines may reduce the effectiveness of cyclophosphamide:

• Aprepitant (antiemetic)
• Bupropion (antidepressant)
• Busulfan, thiotepa (anticancer drugs)
• Ciprofloxacin, chloramphenicol, rifampicin (antibiotics for bacterial infections)
• Fluconazole, itraconazole (antifungals)
• Prasugrel (antiplatelet agent)
• Sulfonamides, such as sulfadiazine, sulfasalazine, sulfamethoxazole (antibiotics for bacterial infections)
• Ondansetron (antiemetic)
• St. John’s wort (herbal preparation used for mild depression)

The following medicines may increase the toxicity of cyclophosphamide:

• Allopurinol (used in gout treatment)
• Azathioprine (used to suppress immune function)
• Chloral hydrate (used for insomnia)
• Cimetidine (reduces stomach acid secretion)
• Disulfiram (used in alcoholism treatment)
• Glyceryl trinitrate (used in angina treatment)
• Protease inhibitors (used in viral infections)
• Drugs that increase liver enzyme activity, such as: rifampicin (antibiotic), carbamazepine, phenobarbital, phenytoin (antiepileptics), St. John’s wort (herbal antidepressant), corticosteroids (used in inflammatory conditions)
• Dabrafenib (used in cancer treatment)

Medicines that may increase the toxic effects of cyclophosphamide on the blood-forming and immune systems:

• ACE inhibitors (used for high blood pressure)
• Natalizumab (used in multiple sclerosis)
• Paclitaxel (anticancer drug)
• Thiazide diuretics, such as hydrochlorothiazide or chlorthalidone (used for high blood pressure or fluid retention)
• Zidovudine (used in viral infections)
• Clozapine (used for certain psychiatric disorders)

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

• Anthracyclines, such as bleomycin, doxorubicin, epirubicin
• Mitomycin (anticancer drugs)
• Cytarabine, pentostatin, trastuzumab (anticancer drugs)
• Radiotherapy to the chest area

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

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

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

• Amphotericin B (antifungal)
• Indomethacin (used for pain and inflammation)

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

• Etanercept (used for rheumatoid arthritis)
• Metronidazole (used for bacterial or protozoal infections)
• Tamoxifen (used for breast cancer)
• Bupropion (used as an aid to stop smoking)
• Coumarins such as warfarin (anticoagulants)
• Cyclosporine (used to suppress immune function)
• Succinylcholine (used to relax muscles during surgery)
• Digoxin, beta-acetyldigoxin (used for heart conditions)
• Vaccines
• Verapamil (used for hypertension, angina, or heart rhythm disorders)
• Sulfonylureas (antidiabetic drugs) (concurrent use with cyclophosphamide may lower blood glucose levels)

Using Cyclophosphamide Sandoz with food, drink, and alcohol

Alcohol may worsen nausea and vomiting caused by cyclophosphamide.

Do not consume grapefruit (as fruit or juice) during cyclophosphamide treatment. Grapefruit may interfere with the normal action of the medicine and alter its effectiveness.

Pregnancy, breastfeeding, and effects on fertility

If the patient is pregnant, breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult the doctor before using this medicine.

Pregnancy

Cyclophosphamide may cause miscarriage or harm the unborn child.

Women should not become pregnant during treatment with Cyclophosphamide Sandoz 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 Sandoz and for 6 months after treatment ends.

If a girl is treated with cyclophosphamide before puberty, sexual development is usually normal and pregnancy may be possible. However, if ovaries function normally after treatment, there is a risk of premature menopause.

Breastfeeding

Do not breastfeed during treatment with this medicine, as cyclophosphamide passes into human milk and may harm the nursing infant. Consult the doctor before using this medicine.

Fertility

Cyclophosphamide may affect the ability to have children in the future. Discuss with the doctor the possibility of cryopreservation (freezing) of sperm or oocytes before starting treatment, due to the risk of irreversible infertility caused by cyclophosphamide. Patients planning parenthood after treatment should discuss this with their doctor.

Driving and operating machinery

After administration of cyclophosphamide, adverse effects such as seizures and visual disturbances may occur, which could affect the ability to drive or operate machinery. The alcohol content in this medicine may also affect the ability to drive or operate machinery (see "Cyclophosphamide Sandoz contains ethanol (alcohol)"). The decision whether driving or operating machinery is safe should be made individually by the doctor.

Cyclophosphamide Sandoz contains ethanol (alcohol)

This medicine contains 585 mg of alcohol (ethanol) per millilitre. The amount of alcohol in 1 mL of this medicine is equivalent to 15 mL of beer or 6 mL of wine.

The alcohol in this medicine may affect children. Symptoms may include drowsiness and changes in behaviour. It may also affect their concentration and physical activity.

This medicine should not be used in children under 5 years of age.

The amount of alcohol in this medicine may affect the ability to drive or operate machinery, as it may impair judgment and reaction time.

If the patient has epilepsy or liver disease, consult the doctor or pharmacist before using this medicine.

The alcohol content in this medicine may alter the effects of other medicines.

If the patient is taking other medicines, consult the doctor or pharmacist.

If the patient is pregnant or breastfeeding, consult the doctor or pharmacist before using this medicine.

If the patient is alcohol-dependent, consult the doctor or pharmacist before using this medicine.

Cyclophosphamide Sandoz contains propylene glycol

This medicine contains 192 mg of propylene glycol per millilitre. Therefore, it should not be used in children under 5 years of age.

Do not administer this medicine to a child under 5 years of age without medical advice.

Pregnant or breastfeeding women should not take this medicine without medical advice. The doctor may decide to perform additional monitoring in such patients.

Patients with impaired liver or kidney function should not take this medicine without medical advice. The doctor may decide to perform additional monitoring during treatment.

3. How to use Cyclophosphamide Sandoz

Method of administration
Intravenous administration
Cyclophosphamide Sandoz will be administered to the patient by a doctor or nurse experienced in the use of anticancer chemotherapy. Cyclophosphamide Sandoz is given as an intravenous injection and is usually added to a large bag of fluid, then infused slowly (by intravenous infusion) directly into a vein. This may be a vein in the arm, the back of the hand, or a large vein beneath the collarbone.
Depending on the dose, the infusion usually lasts between 30 and 120 minutes.
Cyclophosphamide is often used together with other anticancer drugs or in combination with radiotherapy.

Recommended dose:
The doctor determines the amount of drug to be administered and the timing of administration.
The amount of cyclophosphamide given depends on:

• the type of disease;
• the patient's body size (height and weight);
• the patient's general health;
• the use of other anticancer drugs or radiotherapy.

It is recommended that cyclophosphamide be administered in the morning. It is important that the patient receives adequate amounts of fluid before, during, and after administration of the drug to prevent undesirable effects on the urinary tract.
If the patient notices that Cyclophosphamide Sandoz is having too strong or too weak an effect, they should contact their doctor or pharmacist.
The doctor may consider it necessary to adjust the drug dose and closely monitor the patient’s condition if:
the patient has liver or kidney disease
the patient is elderly

Use of a higher than recommended dose of Cyclophosphamide Sandoz
Cyclophosphamide is administered under medical supervision, so it is very unlikely that an excessive amount will be given. However, if any adverse reactions occur after administration of the drug, the doctor should be informed immediately or the patient should go to the emergency department of the nearest hospital. Urgent medical assistance may be required.
Symptoms of cyclophosphamide overdose include the adverse reactions listed below under “Side effects”, but they are usually more severe.
If there are any further doubts regarding the use of this medicine, consult the doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
You should contact your 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 can be fatal (anaphylactic
shock, anaphylactic or pseudo-anaphylactic reaction).
the appearance of bruises without injury or bleeding from the gums. These may be signs of
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
signs of reduced white blood cell count and antibiotic treatment may be necessary to
treat the infection.
significant paleness, lethargy and fatigue. These may be signs of low red blood cell count
(anaemia). Usually no treatment is required – the body will naturally replenish red blood
cells. Severe anaemia may require blood transfusion.
blood in the urine, pain during urination or reduced urine output
severe chest pain
symptoms such as weakness, loss of vision, speech disturbances, loss of sense of touch
severe hypersensitivity reactions with (high) fever, red skin patches, joint pain and (or)
eye infection (Stevens-Johnson syndrome)
severe, sudden (hypersensitivity) reaction with fever and blisters on the skin/shedding of
skin (toxic epidermal necrolysis)
abnormal muscle breakdown which may lead to kidney problems (rhabdomyolysis)
reduced number of white blood cells, which play an important role in fighting infection
(agranulocytosis).

Cyclophosphamide may also cause the following side effects:

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 during urination and frequent need to urinate (cystitis)
presence of blood in urine detectable only by urine test (microhematuria)
fever
suppression of immune system function

Common: may affect up to 1 in 10 people
infections
mucosal inflammation
presence of blood in urine and painful urination (haemorrhagic cystitis)
visible presence of blood in urine (macrohematuria)
liver function abnormalities
infertility in men
chills
feeling of weakness
general malaise
low white blood cell count with fever (febrile neutropenia)

Uncommon: may affect up to 1 in 100 people
anaemia (low red blood cell count), which may cause fatigue and drowsiness
easy bruising due to low platelet count (thrombocytopenia)
lung inflammation
sepsis
allergic reactions
infertility in women (rarely 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 (neuralgia)
eating disorders (loss of appetite)
deafness

Rare: may affect up to 1 in 1,000 people
increased risk of developing white blood cell cancer (acute leukaemia) and certain other cancers (bladder cancer, ureter cancer)
ineffective production of myeloid blood cells (myelodysplastic syndrome)
increased release of antidiuretic hormone by the pituitary gland (syndrome of inappropriate antidiuretic hormone secretion). 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. Symptoms may include headache, personality or behavioural changes, confusion and drowsiness.
changes in heart rhythm
liver inflammation
rash
skin inflammation
absence of menstruation
absence of semen
dizziness
vision disturbances, blurred vision
changes in nail and skin pigmentation
dehydration
seizures
bleeding

Very rare: may affect up to 1 in 10,000 people
red blood cell breakdown and kidney failure (haemolytic-uraemic syndrome)
blood clot formation in small blood vessels throughout the body (disseminated intravascular coagulation)
shock
complications of anticancer treatment due to breakdown of cancer cells (tumour lysis syndrome)
low sodium levels in the blood (hyponatremia)
high blood pressure (hypertension)
low blood pressure (hypotension)
angina pectoris
myocardial infarction
blockage of blood vessel due to blood clot in the circulatory system (thromboembolic disease)
lung damage (acute respiratory distress syndrome)
lung fibrosis causing shortness of breath (chronic interstitial lung fibrosis)
difficulty breathing with wheezing or cough (bronchospasm)
feeling of breathlessness (dyspnoea)
a condition in which the body or part of the body is deprived of adequate oxygen supply (hypoxia)
cough
pain or ulceration in the mouth (stomatitis)
nausea, vomiting or diarrhoea
constipation
intestinal inflammation
pancreatitis
blood clot in the liver (hepatic veno-occlusive disease)
liver enlargement (hepatomegaly)
yellowing of eyes or skin
skin redness (radiation erythema)
itching
taste disturbances (dysgeusia, hypogeusia)
tingling, tickling, pricking, stinging or burning sensations (paresthesia)
smell disturbances (parosmia)
muscle cramps
urinary bladder disorders
kidney function disorders, including kidney failure
headache
multi-organ failure
injection site reactions
weight gain
confusion
eye inflammation (conjunctivitis), eye swelling
acute kidney failure with reduced red blood cells and platelets (haemolytic-uraemic syndrome)
respiratory failure due to fluid accumulation in the lungs (pulmonary oedema)
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 (a type of cancer)
various blood disorders (lymphopenia, reduced haemoglobin concentration)
blockage of blood vessel due to blood clot in the circulatory system (thromboembolic events), including possible blockage of lung vessels (pulmonary embolism)
excessive tearing
tinnitus (ringing in the ears)
nasal congestion (nasal hyperaemia)
pain in mouth and throat
runny nose
coughing
blockage of small veins in the lungs (pulmonary veno-occlusive disease)
blockage of the smallest airways in the lungs due to inflammation (obliterative bronchiolitis)
lung alveoli inflammation due to allergic reaction (allergic alveolitis)
pneumonia
fluid in the lungs (pleural effusion)
abdominal pain
bleeding in the stomach or intestines
intestinal disorders/bleeding
liver function disorders
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 urinary bladder
harm or death to the foetus
intrauterine death
birth defects
delayed foetal development
carcinogenic effects on offspring
changes in results of certain blood tests (glucose concentration, hormone concentration)
impaired brain function (encephalopathy), neurotoxicity manifesting as a syndrome characterised by headache, disorientation, seizures and vision loss (posterior reversible encephalopathy syndrome), sensory disturbances (dysesthesia, hypoesthesia), tremor, disturbances of taste sensation (dysgeusia, hypogeusia), disturbances of smell sensation (parosmia)
various types of heart function disorders (ventricular tachycardia, cardiogenic shock, pericardial effusion, bradycardia, palpitations, QT interval prolongation on electrocardiogram)
infertility in women and men
changes in menstrual frequency
salivary gland inflammation (usually in the cheek area; parotitis)

If any of the side effects worsen or if any side effects not listed in this leaflet occur, inform your doctor, pharmacist or nurse.

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

5. How to store Cyclophosphamide Sandoz

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton following:
Expiry date (EXP). The expiry date refers to the last day of the stated month.
Store in a refrigerator (2 °C – 8 °C).
After first opening:
A partially used vial must be stored in the refrigerator at a temperature of 2°C to 8°C. The medicine should be used within 28 days of first opening. Any remaining medicine should be discarded.
After dilution:
Chemical and physical in-use stability of the diluted solution has been demonstrated as shown in the table below.
Table: Storage of diluted cyclophosphamide solutions

From a microbiological standpoint, the diluted medicinal product should be used immediately. If the diluted medicinal product is not used immediately, the user is responsible for the storage conditions and duration prior to use. Usually, this period should not exceed 24 hours at a temperature of 2°C - 8°C, unless the dilution was carried out under controlled and validated aseptic conditions. Medicinal products must not be disposed of via wastewater. Ask your pharmacist how to dispose of medicines no longer required. Such measures will help protect the environment.

6. Contents of the pack and other information

What Cyclophosphamide Sandoz contains

• The active substance is cyclophosphamide. Each millilitre contains cyclophosphamide monohydrate equivalent to 100 mg of cyclophosphamide. Each 5 mL vial of concentrate contains cyclophosphamide monohydrate equivalent to 500 mg of cyclophosphamide. Each 10 mL vial of concentrate contains cyclophosphamide monohydrate equivalent to 1000 mg of cyclophosphamide. Each 20 mL vial of concentrate contains cyclophosphamide monohydrate equivalent to 2000 mg of cyclophosphamide.
• Other ingredients: anhydrous ethanol and propylene glycol (see sections “Cyclophosphamide Sandoz contains ethanol (alcohol)” and “Cyclophosphamide Sandoz contains propylene glycol”).

What Cyclophosphamide Sandoz looks like and contents of the pack
Cyclophosphamide Sandoz is a clear solution, colourless to pale yellow, practically free from visible particles.
Cyclophosphamide Sandoz is supplied in a multi-dose vial made of colourless type I glass, closed with a bromobutyl rubber stopper type I and sealed with an aluminium cap with a dark orange plastic flip-off cap.
Pack sizes:

• 1 multi-dose vial containing 5 mL concentrate for solution for injection/infusion, equivalent to 500 mg cyclophosphamide.
• 1 multi-dose vial containing 10 mL concentrate for solution for injection/infusion, equivalent to 1000 mg cyclophosphamide.
• 1 multi-dose vial containing 20 mL concentrate for solution for injection/infusion, equivalent to 2000 mg cyclophosphamide.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50C
02-672 Warsaw
tel. 22 209 70 00

Manufacturer
Fareva Unterach GmbH
Mondseestrasse 11
4866 Unterach Am Attersee
Austria

This medicinal product is authorised in the European Economic Area member states under the following names:
Denmark Cyclophosphamide Sandoz
Austria Cyclophosphamid Sandoz 100 mg/ml –Konzentrat zur Herstellung einer Injektions-/Infusionslösung
Bulgaria Cyclophosphamide Sandoz 100 mg/mL concentrate for solution for injection/infusion
Poland Cyclophosphamide Sandoz
Sweden Cyclophosphamide Sandoz

Information intended exclusively for medical professionals:

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

Dosage and method of administration

Dosage must be individually determined for each patient. Doses, 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 of similar toxicity, dose reduction or prolonged intervals between treatment cycles may be necessary.

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

To reduce the risk of toxic effects on the urinary tract, adequate fluid intake should be ensured before, during, and immediately after administration of Cyclophosphamide Sandoz, either orally or by infusion, to induce forced diuresis. Therefore, Cyclophosphamide Sandoz should be administered in the morning.

Handling of the medicinal product

Cyclophosphamide is inactive until activated by hepatic enzymes. However, as with all cytotoxic drugs, the medicinal product should be prepared by trained medical personnel in a designated area.

Precautions to be taken before preparation or administration of the medicinal product

Personnel 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 have direct contact with this medicinal product.

The volume of solvent required to reconstitute Cyclophosphamide Sandoz containing cyclophosphamide depends on the route of administration.

Direct injection

If Cyclophosphamide Sandoz (containing cyclophosphamide) is to be administered by direct intravenous injection, the concentrate at a concentration of 100 mg/mL should be diluted to a concentration of 20 mg/mL with an appropriate volume of one of the following diluents:

• 0.9% sodium chloride solution
• 0.45% sodium chloride solution
• 5% dextrose solution
• Solution containing 5% dextrose and 0.9% sodium chloride

Infusion

If Cyclophosphamide Sandoz (containing cyclophosphamide) is to be administered by intravenous infusion, the concentrate at a concentration of 100 mg/mL should be diluted with an appropriate volume of one of the following diluents:

• 0.9% sodium chloride solution
• 0.45% sodium chloride solution
• 5% dextrose solution
• Solution containing 5% dextrose and 0.9% sodium chloride

The reconstituted Cyclophosphamide Sandoz (containing cyclophosphamide) in water is hypotonic and should not be administered by direct injection.

Intravenous administration
Intravenous infusion is the preferred route of intravenous administration.

The decision to use cyclophosphamide according to current treatment guidelines lies with the physician.

Example volumes of cyclophosphamide concentrate and diluents required to achieve concentrations ranging from 20 mg/mL (for direct injection) to 0.4 mg/mL (for infusion) are provided in the table below as guidance for a 100 mg dose.

Table: Examples of dilution volumes for cyclophosphamide

Preparation of dilution for infusion or injection
Step 1
Allow the required number of vials of cyclophosphamide concentrate for solution for infusion to stand for 5 minutes at 20–25°C.
Each millilitre of medicinal product contains 100 mg of cyclophosphamide.
To achieve a dose appropriate for the patient, it may be necessary to use more than one vial of cyclophosphamide concentrate for solution for infusion at a concentration of 100 mg/mL. Under aseptic conditions, withdraw the required amount of cyclophosphamide concentrate for solution for infusion using a calibrated syringe. For example, a dose of 1000 mg cyclophosphamide requires withdrawal of 10.00 mL of concentrate.
Step 2
For direct injection, dilute the withdrawn concentrate to a concentration of 20 mg/mL by adding the appropriate volume of 0.9% sodium chloride solution, 0.45% sodium chloride solution, 5% dextrose solution, or a solution containing 5% dextrose and 0.9% sodium chloride.
For infusion, the required volume of cyclophosphamide concentrate for solution for infusion should be injected into an infusion bag containing 0.9% sodium chloride solution, 0.45% sodium chloride solution, 5% dextrose solution, or a solution containing 5% dextrose and 0.9% sodium chloride. The resulting infusion solution should have a minimum concentration of 0.4 mg/mL.
Step 3
Remove the syringe and gently mix the contents of the infusion bag or bottle by manual agitation.
Step 4
As with all parenteral medicinal products, the resulting infusion solution should be visually inspected for the presence of particulate matter and discoloration prior to administration, as far as the solution and container permit. After dilution, the solution is clear and colourless to pale yellow. Only clear solutions should be used. Since the infusion solution is supersaturated, it may crystallize over time. In such cases, the solution must not be used and should be discarded.
Step 5
To reduce the likelihood of adverse reactions that appear to be rate-related (e.g. facial swelling, headache, nasal mucosal congestion, scalp burning), cyclophosphamide should be administered by slow injection or infusion.
The duration of infusion (from 30 minutes to 2 hours) should be adjusted according to the volume and type of carrier solution administered.
Preparation and use of the medicinal product Cyclophosphamide Sandoz must be carried out in accordance with the principles and regulations governing the use of cytostatic drugs. Dilution should, whenever possible, be performed in a safety cabinet with laminar air flow. The person preparing the medicinal product must wear a protective mask and protective gloves. In case of spillage of the solution, the surface should be thoroughly rinsed with water.
Guidelines for safe handling of antineoplastic drugs
Pregnant women should not participate in the preparation of cytotoxic drugs. The medicinal product should be diluted by trained personnel. This should be carried out in a designated area. The work surface should be covered with disposable absorbent paper with an underlying plastic-backed sheet.
Appropriate protective gloves, masks, and clothing must be worn. Precautions should be taken to avoid accidental contact of the medicinal product with skin or mucous membranes; any exposed area should be thoroughly washed with soap and water. In case of accidental eye contamination, eyes should be immediately and thoroughly rinsed with water.
Syringes and equipment with Luer-lock fittings should be used. Use of needles with a large bore is recommended to minimize pressure and the risk of aerosol formation. The risk of aerosol formation may also be reduced by using a vented needle.
Any unused remnants of the drug should be discarded. Appropriate precautions should be taken when disposing of equipment used for dilution of cyclophosphamide. Any drug residue or contaminated materials should be placed in high-risk waste bags. Sharp objects (needles, syringes, vials, etc.) should be placed in an appropriate rigid container. Personnel involved in collecting and disposing of such waste should be aware of the associated hazards.
All unused medicinal product or waste should be disposed of in accordance with local regulations regarding cytotoxic drugs.
Storage and shelf life
After first opening:
Partially used vials should be stored in a refrigerator at 2°C to 8°C. The medicinal product should be used within 28 days of first opening. Any remaining medicinal product should be discarded.
After dilution:
Chemical and physical stability of the diluted solution has been demonstrated as shown in the table below.
Table: Storage of diluted cyclophosphamide solutions

From a microbiological standpoint, the diluted medicinal product should be used immediately.
If the medicinal product is not used immediately, the user is responsible for the storage time and
conditions prior to use, and this period usually should not exceed 24 hours at a temperature of
2°C - 8°C, unless the dilution was carried out under controlled and validated aseptic conditions.