CYCLOPHOSPHAMIDE VIVANTA 1000 mg POWDER FOR INJECTABLE SOLUTION AND FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Ciclofosfamida Vivanta 1,000 mg powder for injectable and infusion solution EFG

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

Keep this leaflet, you may need to read it again.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the pack:

1. What Ciclofosfamida Vivanta is and what it is used for.
2. What you need to know before you are given Ciclofosfamida Vivanta.
3. How Ciclofosfamida Vivanta will be given to you.
4. Possible side effects.
5. Storing Ciclofosfamida Vivanta.
6. Contents of the pack and other information.

1. What Ciclofosfamida Vivanta is and what it is used for

This medicine contains the active substance called cyclophosphamide. Cyclophosphamide is a cytotoxic or anticancer medicine. It works by killing cancer cells; this is sometimes called "chemotherapy".

Cyclophosphamide is used alone or in combination with other medicines in the following cases:

• certain types of white blood cell cancer (acute lymphoblastic leukemia, chronic lymphocytic leukemia),
• different forms of lymphomas that affect the immune system (Hodgkin's lymphoma, 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 metastatic or advanced tumors of the central nervous system (neuroblastoma).

In addition, cyclophosphamide is used in preparation for bone marrow transplants to treat certain types of white blood cell cancer (acute lymphoblastic leukemia, chronic myeloid leukemia, and acute myeloid leukemia).

Occasionally, some doctors may prescribe cyclophosphamide for conditions unrelated to cancer:

• 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 vasculitis).

2. What you need to know before you are given Ciclofosfamida Vivanta

Ciclofosfamida Vivanta will not be given to you:

• if you are allergic to cyclophosphamide or any of its metabolites or to any of the other components of this medicine (listed in section 6).
• if you currently have any infection.
• if your bone marrow is not working properly (especially if you have previously undergone chemotherapy or radiation therapy). You will have blood tests to check your bone marrow function.
• if you have a urinary tract infection that can be recognized by pain when urinating (cystitis).
• if you have had kidney or bladder problems as a result of previous chemotherapy or radiation therapy.
• if you have a disease that reduces your ability to urinate (obstruction of urine flow).
• if you are breastfeeding.
• if you have other conditions unrelated to cancer, except for immune system disorders in life-threatening situations.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you start taking this medicine:

• if you have low blood cell counts,
• if you have severe infections,
• if you have liver or kidney problems. Your doctor will check through a blood test if your liver and kidneys are working properly,
• if you have had your adrenal glands removed,
• if you are receiving or have recently received radiation therapy or chemotherapy,
• if you have heart problems or have received radiation therapy in the heart area,
• if you have diabetes,
• if you are in poor general health or are a frail person,
• if you are an elderly person,
• if you have had surgery in the last 10 days.

Be careful with Ciclofosfamida Vivanta

• Potentially life-threatening allergic reactions (anaphylactic reactions) may occur during treatment with cyclophosphamide.
• Cyclophosphamide may affect your blood and immune system.
• Blood cells are produced in your bone marrow. There are three types of blood cells:

• red blood cells, which carry oxygen in the body,
• white blood cells, which fight infections, and
• platelets, which allow blood to clot.

• After receiving cyclophosphamide, the count of blood cells for all three types of cells will decrease. This is an inevitable side effect of the medicine. Your blood count will reach its lowest level about 5 to 10 days after starting to receive cyclophosphamide and will remain low for some days after the treatment cycle ends. Most people recover normal blood cell counts over 21 to 28 days. If you have received a large amount of chemotherapy in the past, it may take a little longer to return to normal.
• You are more likely to get infections if your blood cell count is low. Try to avoid close contact with people who have coughs, colds, and other infections. Your doctor will treat you with the appropriate medicine if they think you have an infection or are at risk of getting one.
• Your doctor will check that the number of red blood cells, white blood cells, and platelets is high enough before and during treatment with cyclophosphamide. You may need to reduce the amount of medicine you receive or delay the next dose.
• Cyclophosphamide may affect the normal healing of wounds. Keep cuts clean and dry and check that they are healing normally. It is important to maintain good oral health, as infections and mouth ulcers can occur. Consult your doctor if you are unsure.

• Cyclophosphamide may damage the lining of the urinary bladder and cause bleeding in the urine or pain when urinating. Your doctor knows that this can happen and, if necessary, will give you a medicine called Mesna to protect your bladder. Mesna can be given as a short injection or mixed with cyclophosphamide in the infusion solution, or in tablets. You can find more information about Mesna in the package leaflet for Mesna injection and Mesna tablets.
• Most people who receive cyclophosphamide with Mesna do not develop any bladder problems, but your doctor may want to check your urine for blood with a "dipstick" or microscope. If you notice blood in your urine, you must tell your doctor immediately.
• Cancer medicines and radiation therapy may increase the risk of developing other types of cancer; this can happen several years after the end of your treatment. Cyclophosphamide carries a higher risk of causing cancer in the bladder area.
• Cyclophosphamide may cause heart damage or affect the rhythm of your heartbeat. This effect is greater at higher doses of cyclophosphamide, if you are being treated with radiation therapy or other chemotherapy medicines, or if you are an elderly person. Your doctor will closely monitor your heart during treatment.
• Cyclophosphamide may cause lung problems such as inflammation or scarring in your lungs. This can happen more than six months after your treatment. If you start to have difficulty breathing, tell your doctor immediately.
• Cyclophosphamide may have potentially life-threatening effects on your liver.

If you experience a sudden increase in weight, liver pain, and your skin or the white of your eyes turn yellow (jaundice), tell your doctor immediately.

• You may experience hair loss or baldness. Your hair should grow back normally, although its texture and color may be different.
• Cyclophosphamide may make you feel sick or be sick. This can last for about 24 hours after taking the medicine. You may need to be given medicines to stop feeling or being sick. Talk to your doctor about this.

Other medicines and Ciclofosfamida Vivanta

Tell your doctor if you are taking, have recently taken, or might take any other medicines. In particular, tell them about the following medicines or treatments because they may be incompatible with the use of cyclophosphamide.

The following medicines may reduce the effectiveness of cyclophosphamide:

• aprepitant, ondansetron (used to prevent sickness)
• bupropion (an antidepressant)
• busulfan, tiotepa (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 acidity),
• disulfiram (used to treat alcoholism),
• glycerol (used to treat warts),
• protease inhibitors (used to treat viruses),
• dabrafenib (anticancer medicine)
• 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 immunity:

• 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 viral infections),
• clozapine (used to treat symptoms of some psychiatric disorders).

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

• anthracyclines such as bleomycin, doxorubicin, epirubicin, mitomycin (used to treat cancer),
• cytarabine, pentostatin, trastuzumab (used to treat cancer),
• radiation therapy in the heart area.

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

• amiodarone (used to treat irregular heartbeat),
• G-CSF, GM-CSF hormones (used to increase the number of white blood cells after chemotherapy).

Medicines that may increase the toxic effects of cyclophosphamide on your kidneys.

• amphotericin B (used to treat fungal infections),
• indomethacin (used to treat pain and inflammation).

Other medicines that may affect cyclophosphamide or be affected by it 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 stop smoking),
• coumarins such as warfarin (used to thin the blood),
• cyclosporin (used to reduce immune system activity),
• succinylcholine (used to relax muscles during medical procedures)
• digoxin, acetyldigoxin ß (used to treat heart conditions),

• vaccines,
• verapamil (used to treat high blood pressure, angina, or irregular heartbeat),
• The concomitant use of sulfonylurea derivatives with cyclophosphamide (blood sugar levels may decrease).

Using Ciclofosfamida Vivanta with food, drinks, and alcohol

Consuming alcohol may increase the nausea and vomiting caused by cyclophosphamide.

You should not consume grapefruit (in any form or juice) while taking cyclophosphamide. It may interfere with the usual effect of your medicine and alter its effectiveness.

Contraception, pregnancy, breastfeeding, and fertility

Contraception in men and women

If you are a woman, you must not become pregnant during treatment with this medicine and for 12 months after stopping treatment.

If you are a man, you must use effective contraception to ensure you do not father a child during treatment with this medicine and for 6 months after stopping treatment.

Pregnancy

If you are pregnant or breastfeeding, or think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Cyclophosphamide may cause a miscarriage or harm the unborn baby. Given the available information, the use of cyclophosphamide during pregnancy is not recommended, especially in the first trimester, and it will be up to your doctor to decide if it can be used.

Breastfeeding

Since cyclophosphamide passes into breast milk, women must not breastfeed during treatment. See section 2.

Fertility

Cyclophosphamide may affect your ability to have children in the future and cause infertility. Talk to your doctor about the cryopreservation (freezing) of sperm or eggs before treatment. If you are considering becoming a parent after treatment, talk to your doctor.

Young women with reserved ovarian function may develop premature menopause after receiving treatment with cyclophosphamide.

Driving and using machines

After receiving cyclophosphamide, side effects such as dizziness, blurred vision, and visual impairment may occur, which could affect your ability to drive and use machines. The decision to allow you to drive or use machines will be made by your doctor on an individual basis.

3. How to use Ciclofosfamida Vivanta

This medicine will be given to you by a doctor or nurse with experience in the use of anticancer chemotherapy. The medicine is usually given into a vein. The duration of administration is usually 30 minutes to 2 hours, depending on the volume to be administered.

Cyclophosphamide is usually given in combination with other anticancer medicines or radiation therapy.

The recommended dose is:

• Your doctor will decide how much medicine you need and when you should receive it.

The duration of treatment and/or treatment intervals will depend on the indications for use, the combination therapy regimen, your general state of health, laboratory test results, and the recovery of blood cells.

It is recommended to administer this medicine in the morning. Before, during, and after administration, it is important that you receive adequate amounts of fluid to avoid possible side effects on the urinary tract.

If you notice that Ciclofosfamida Vivanta is too strong or too weak, talk to your doctor or pharmacist.

Your doctor may need to change the amount of medicine they give you and monitor you more closely if:

• you have liver or kidney problems;
• you are an elderly person.

Use in children and adolescents

Cyclophosphamide is also indicated in children. The safety profile of cyclophosphamide in children is similar to that in adults.

If you receive more Ciclofosfamida Vivanta than you should

Since this medicine is given under the supervision of your doctor, it is very unlikely that you can receive too much. However, if you experience any side effects after receiving the medicine, tell your doctor immediately. You may need urgent medical attention.

The symptoms of an overdose with cyclophosphamide include the side effects listed in section 4, "Side effects", but are usually more severe.

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

4. Possible Adverse Effects

Like all medicines, cyclophosphamide can cause adverse effects, although not all people suffer from them.

Tell your doctor immediately if you experience:

• Allergic reactions. The signs would be difficulty breathing, wheezing, increased heart rate, reduced blood pressure (extreme fatigue), rash, itching, or swelling of the face and lips. Severe allergic reactions could cause breathing difficulties or shock, with a possible fatal outcome (anaphylactic shock, anaphylactic/anaphylactoid reaction).
• Appearance of bruises without being hit, or bleeding in the gums. This could be a sign that the levels of platelets in your blood are too low.
• Severe infection or fever, mouth ulcers, cough, shortness of breath, signs of septicemia such as fever, rapid breathing, increased heart rate, confusion, and edema. This could be a sign of a reduction in your white blood cell count, and antibiotics may be needed to fight infections, red blood cell collapse, decrease in platelet count, and kidney failure (hemolytic uremic syndrome).
• Pallor, feeling of fatigue, and tiredness. This could be indicative of a low level of red blood cells (anemia). Normally, no treatment is required, as your body will replace the red blood cells over time. If you are very anemic, you may need a blood transfusion.
• Severe hypersensitivity reactions with fever (high), red spots on the skin, joint pain, and/or eye infection (Stevens-Johnson syndrome), sudden severe reaction (hypersensitive), with fever and blisters/peeling of the skin (toxic epidermal necrolysis).
• Abnormal muscle breakdown that can lead to kidney problems (rhabdomyolysis).
• Different types of blood disorders (agranulocytosis).
• Having blood in the urine, pain when urinating, or urinating less.
• Severe chest pain.
• Symptoms such as weakness, vision loss, speech difficulties, loss of touch.

Other adverse effects that may occur:

Very common: may affect more than 1 in 10 people

• Reduction in the number of blood cells (myelosuppression),
• Reduction in white blood cells that are important in fighting infections (leukopenia, neutropenia),
• Hair loss (alopecia),
• Burning sensations when urinating and frequent need to do so (bladder infection),
• Presence of blood in the urine (microhematuria),
• Fever,
• Suppression of the immune system.

Common: may affect up to 1 in 10 people

• Infections,
• Inflammation of mucous membranes,
• Blood in the urine and pain when urinating (hemorrhagic cystitis),
• Appearance of blood in the urine (macrohematuria),
• Abnormal liver function,
• Infertility in males,
• Chills,
• Feeling of weakness,
• General feeling of discomfort,
• Reduction in white blood cell count and fever (febrile neutropenia).

Uncommon: may affect up to 1 in 100 people

• Anemia (low red blood cell count) that can cause fatigue and drowsiness,
• Propensity to bruising due to thrombocytopenia (low platelet count),
• Inflammation of the lungs (pneumonia),
• Septicemia,
• Allergic reactions,
• Infertility in women (this can rarely be permanent),
• Chest pain,
• Rapid heartbeat,
• Heart problems,
• Changes in the results of some blood tests,
• Redness of the skin (rash),
• Nerve damage that can cause numbness, tingling, and weakness (neuropathy),
• Nerve pain, which can also feel like a sensation of pain or burning (neuralgia),
• Lack of appetite (anorexia),
• Deafness.

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

• Increased risk of white blood cell cancer (acute leukemia) and some other cancers (bladder cancer, ureter cancer),
• Ineffective production of a certain type of blood cells (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, resulting in brain swelling due to excess water in the blood. The signs of this can be headache, changes in personality or behavior, confusion, drowsiness,
• Changes in heart rate,
• Liver inflammation,
• Rash,
• Skin inflammation,

• Lack of menstruation (periods),
• Lack of sperm,
• Dizziness,
• Vision problems, blurred vision,
• Changes in the color of your nails and skin,
• Dehydration,
• Seizures,
• Bleeding.

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

• Blood clots in all small blood vessels in the body (disseminated intravascular coagulation),
• Shock,
• Complications that can occur after cancer treatment caused by the breakdown products of dying cancer cells (tumor lysis syndrome),
• Low sodium levels in your blood (hyponatremia),
• High blood pressure (hypertension),
• Low blood pressure (hypotension),
• Chest pain (angina),
• Heart attack (myocardial infarction),
• Blockage of a blood vessel due to a blood clot in the circulatory system (thromboembolism),
• Lung injury (acute respiratory distress syndrome),
• Scarring of the lungs that causes breathing difficulties (chronic interstitial pulmonary fibrosis),
• Difficulty breathing with wheezing or cough (bronchospasm),
• Difficulty breathing (dyspnea),
• A condition in which the body or a region of the body is deprived of adequate oxygen supply (hypoxia),
• Cough,
• Pain or ulcers in the mouth (stomatitis),
• Feeling of discomfort (nausea), discomfort (vomiting), or diarrhea,
• Constipation,
• Inflammation of the intestine,
• Inflammation of the pancreas,
• Blood clots in the liver (hepatic veno-occlusive disease),
• Enlargement of the liver (hepatomegaly),
• Yellow eyes or skin,
• Redness of the skin (radiation erythema),
• Itching,
• Alteration of the sense of taste (dysgeusia, hypogeusia),
• Sensation of tingling, tingling, itching, pinching, or burning (paresthesia),
• Alteration of the sense of smell (parosmia),
• Cramps,
• Bladder problems,
• Kidney problems, including kidney failure,
• Headache,
• Multi-organ failure,
• Reactions at the injection/infusion site,
• Weight gain,
• Confusion,
• Conjunctivitis, eye edema,
• Acute kidney failure with decreased red blood cell and platelet count (hemolytic uremic syndrome),
• Respiratory failure due to fluid accumulation in the lungs (pulmonary edema),
• Fluid accumulation in the abdominal cavity (ascites).

Frequency not known: cannot be estimated from the available data

• Various types of cancer, e.g., blood cancer (non-Hodgkin's lymphoma), kidney cancer, thyroid cancer,
• Sarcoma,
• Various types of blood disorders (agranulocytosis, lymphopenia, reduction of hemoglobin)
• Blockage of a blood vessel due to a blood clot in the circulatory system (thromboembolic events), including the possibility of blockage of the pulmonary vessels (pulmonary embolism),
• Increased tearing,
• Tinnitus,
• Nasal congestion (nasal congestion),
• Oropharyngeal pain,
• Allergy or flu-like symptoms (rhinorrhea),
• Sneezing,
• Pulmonary veno-occlusive disease,
• Conditions that cause inflammation of the lungs, which can cause difficulty breathing, cough, and increased temperature or scarring in the lungs (pneumonitis, bronchiolitis obliterans, allergic alveolitis), fluid in or around the lungs (pleural effusion),
• Abdominal pain,
• Bleeding in the stomach or intestines,
• Intestinal problems/bleeding,
• Liver disorder,
• Rash, redness of the skin, blisters on the lips, eyes, or mouth, skin peeling (erythema multiforme, urticaria, erythema),
• Hand-foot syndrome,
• Facial swelling,
• Increased sweating,
• Hardening of the skin (scleroderma),
• Muscle spasms and pain,
• Joint pain,
• Inflammation, scarring, and contraction of the bladder,
• Effects on the fetus, such as damage or death of the fetus, intrauterine death, fetal malformation, growth retardation, carcinogenic effects on the offspring,
• Changes in the results of some blood tests (glucose levels, hormone levels),
• Effects on the brain (encephalopathy),

• A syndrome called posterior reversible leukoencephalopathy syndrome, which can cause brain inflammation, headache, confusion, seizures, and vision loss, changes in the sense of touch (dysesthesia) or loss of sensation (hypoesthesia), tremors, changes in the sense of taste (dysgeusia) or loss of taste (hypogeusia), changes in the sense of smell (parosmia),
• Decreased ability of the heart to pump enough blood through the body, which can be life-threatening (cardiogenic shock, heart failure, or cardiac arrest), faster heart rate (tachycardia), which can be life-threatening (ventricular tachycardia), slower heart rate (bradycardia), fluid accumulation in the space around the heart (pericardial effusion), abnormal electrocardiogram (prolonged QT interval), changes in heart rhythm (arrhythmia) that can be perceived (palpitations),
• Infertility in women and men,
• Changes in menstrual frequency,
• Inflammation of the salivary glands (usually in the area of the cheeks; parotid gland inflammation).

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that is not listed in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Cyclophosphamide Vivanta

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

Store in the refrigerator (2°C - 8°C).

After preparation for intravenous administration

Chemical and physical stability has been demonstrated in the use of the reconstituted solution with 0.9% sodium chloride (concentration 20 mg/ml) for 2 days at 2°C - 8°C.

Chemical and physical stability has been demonstrated in the use of the reconstituted solution with 0.9% sodium chloride or water for injection and additionally diluted with 5% glucose or 5% glucose and 0.9% sodium chloride (concentration 2 mg/ml) for 24 hours at 2°C - 8°C.

From a microbiological point of view, the medicine should be used immediately. If not used immediately, the storage times and conditions before use are the responsibility of the user and normally would not exceed 24 hours at 2°C - 8°C, if the reconstitution has been carried out in controlled and validated aseptic conditions.

Compatibility studies with diluents were performed by diluting the reconstituted solution immediately. Therefore, the information on stability is applicable to the storage of the reconstituted solution or to the storage of the diluted solution (but not to both).

Do not use this medicine if you observe that the product is deteriorated, i.e., the aggregate melts and there are visible particles in the reconstituted or diluted solution.

Medicines should not be thrown down the drain. Ask your pharmacist how to dispose of the packaging and medicines that are no longer needed. This will help protect the environment.

6. Container Content and Additional Information

Composition of Cyclophosphamide Vivanta

• The active ingredient is cyclophosphamide.
• Excipient: Mannitol.

Each vial of Cyclophosphamide Vivanta 1,000 mg powder for injectable and infusion solution contains cyclophosphamide monohydrate, equivalent to 1,000 mg of cyclophosphamide.

Appearance of the Product and Container Content

Cyclophosphamide Vivanta 1,000 mg is a white powder or agglomerate available in 50 ml glass vials.

Container sizes:

1, 5, or 10 vials.

Only some container sizes may be marketed.

Marketing Authorization Holder:

Vivanta Generics s.r.o.

Trtinova 260/1, Cakovice,

19600, Prague 9

Czech Republic

Manufacturer:

Pharmadox Healthcare Limited,

KW20A Kordin Industrial Park, Paola, PLA3000, Malta

or

MSN Labs Europe Limited,

KW20A Corradino Industrial Park, Paola, PLA3000, Malta

This Medicinal Product is Authorized in the Following Reference Member States (EEA) Under the Following Names:

Germany: Cyclophosphamid Vivanta 1000 mg Pulver zur Herstellung einer Injektions-/Infusionslösung

Spain: Cyclophosphamide Vivanta 1,000 mg powder for injectable and infusion solution EFG

France: Cyclophosphamide Vivanta 1000 mg poudre pour solution injectable/pour perfusion

Date of the Last Revision of this Leaflet: 03/2024

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es/)

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This Information is Intended Exclusively for Healthcare Professionals:

Cyclophosphamide Vivanta should be administered exclusively under the supervision of a physician with experience in the use of cancer chemotherapy. This medicinal product should be administered only where there are facilities for periodic monitoring of clinical, biochemical, and hematological parameters before, during, and after administration, and under the direction of a specialized oncology service.

Dosage

Doses should be adjusted individually for each patient. The duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of combination therapy, the patient's general state of health, laboratory analysis results, and the recovery of blood cells.

In combination with other cytostatics of similar toxicity, a reduction in dose or an extension of treatment-free intervals may be required.

In order to reduce the risk of myelosuppressive complications and/or facilitate the administration of the planned dose, the use of hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered.

Before, during, and immediately after administration, an adequate amount of fluids should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, this medicinal product should be administered in the morning.

Cyclophosphamide is inert until it is activated by enzymes in the liver. However, as with all cytotoxic agents, it is recommended that reconstitution be performed by trained personnel in a designated area.

Preparation

The choice of solvent for reconstituting this medicinal product containing cyclophosphamide depends on the route of administration used.

Infusion

Intravenous administration should be performed preferably as an infusion.

If the solution is to be used for intravenous infusion, this medicinal product is reconstituted by adding sterile water for injectable preparations or sterile sodium chloride 9 mg/ml (0.9%) solution.

Reconstituted cyclophosphamide should be further diluted in glucose 50 mg/ml (5%) or glucose 50 mg/ml (5%) and sodium chloride 9 mg/ml (0.9%) solution before infusion.

Direct Injection

If the solution is to be used for direct injection, cyclophosphamide is reconstituted by adding a sterile sodium chloride 9 mg/ml (0.9%) solution.

Please note that cyclophosphamide is only suitable for bolus injection when reconstituted in sterile sodium chloride 9 mg/ml (0.9%) solution.

Cyclophosphamide reconstituted in water is hypotonic and should not be injected directly.

The following amounts of water for injectable preparations or sodium chloride 9 mg/ml (0.9%) solution are added to the vials containing this medicinal product.

Vial of 1,000 mg: 50 ml

Injection of the solvent into the vial for injection creates abnormally high pressure, which disappears as soon as a second sterile needle is inserted into the rubber stopper of the injectable vial. The powder dissolves easily when the injectable vial is vigorously shaken to produce a clear solution. If the powder does not dissolve immediately, continue shaking the vial vigorously for several minutes until the powder is completely dissolved. The solution should be administered as soon as possible after its reconstitution.

Intravenous route.

Intravenous administration should be performed preferably as an infusion.

If this medicinal product is stored (e.g., during transportation) at a temperature above the maximum temperature, cyclophosphamide may melt. Vials for injectables containing melted cyclophosphamide can be visually recognized. Cyclophosphamide is a white powder. Melted cyclophosphamide is a viscous, clear, or yellowish liquid (generally found in the form of droplets in the affected vials). Vials for injectables containing melted cyclophosphamide can no longer be used.

Guidelines for the Safe Handling of Antineoplastic Agents

• The rules and regulations for handling cytotoxics in general should be followed when reconstituting or handling this medicinal product.
• Reconstitution should be performed, whenever possible, in a laminar flow safety cabinet.
• The person handling the product should wear a protective mask and gloves.
• In the event of spills, the area should be thoroughly rinsed with water. Cytotoxic preparations should not be handled by pregnant or breastfeeding personnel. Trained personnel should dilute the medicinal product.
• Dilution should be performed in a designated area. The work surface should be covered with absorbent paper with a plastic backing.
• Luer-lock accessories should be used on all syringes and devices. The use of large-caliber needles is recommended to minimize pressure and possible aerosol formation. The latter can also be reduced by using a venting needle. Any unused contents should be discarded. Care and caution should be exercised when disposing of items used for the dilution of cyclophosphamide. Any unused product or contaminated materials should be placed in a high-risk waste bag. Sharps (needles, syringes, vials, etc.) should be placed in a suitable rigid container. Personnel involved in the disposal of these wastes should be aware of the danger involved.
• Any unused product or waste materials should be disposed of in accordance with the standard procedures applicable to a cytotoxic agent.

Storage and Validity Period of the Reconstituted/Diluted Solution.

The reconstituted solution with sodium chloride 0.9% (concentration of 20 mg/ml) is physically and chemically stable for 2 days when stored at a temperature of 2°C to 8°C.

The reconstituted solution with sodium chloride 0.9% or water for injectable preparations and further diluted with glucose 5% or glucose 5% and sodium chloride 0.9% (concentration of 2 mg/ml) is physically and chemically stable for 24 hours when stored at a temperature of 2-8°C.

From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, the in-use storage times and conditions before use are the responsibility of the user and normally would not exceed 24 hours at 2°C - 8°C, unless the reconstitution/dilution has taken place in controlled and validated aseptic conditions.