Leaflet: information for the user

Doxorubicina Accord 2 mg/ml concentrate for infusion solution EFG

Hidrocloruro de doxorubicina

Read this leaflet carefully before you start using this medicine, because it contains important information for you.

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

Doxorubicina Accord is part of a group of medicines called anthracyclines.These medicines are also known as cancer medicines, chemotherapy or "chemo". They are used in the treatment of various types of cancer to slow down or stop the growth of cancer cells. Often a combination of different types of cancer medicines is used to achieve better results and minimize side effects.

Doxorubicina Accordis used to treat the following types of cancer:

• breast cancer
• soft tissue, ligament, bone, muscle cancer (sarcoma)
• cancer developed in the stomach or intestine
• lung cancer
• lymphomas, a cancer that affects the immune system
• leukemia, a cancer that causes abnormal production of blood cells
• thyroid cancer
• advanced ovarian and endometrial cancer (a cancer of the uterus lining or uterus)
• bladder cancer
• advanced neuroblastoma (a cancer of the nerve cells that commonly appears in children)
• advanced malignant renal tumor in children (Wilms tumor)
• multiple myeloma (bone marrow cancer)

No use Doxorubicina Accord

• if you are allergic tohydrochloride doxorubicinor to any of the other components ofthis medication (listed in section 6), anthracyclines, or to another anthracycline.
• if you have persistent suppression of your bone marrow's ability to produce blood cells (myelosuppression)
• if you have previously received doxorubicin or other similar chemotherapy medications such as idarubicin, epirubicin, or danorubicin, as previous treatment with these similar medications may increase the risk of side effects with Doxorubicina Accord.
• if you have any type of infection.
• if your liver does not function properly.
• if you have had a myocardial infarction.
• if you have any cardiac function abnormalities.
• if you have any severe arrhythmia.
• if you are breastfeeding (see section “Pregnancy, breastfeeding, and fertility”)

Do not receive the medication through a catheter (a thin, flexible tube) in the bladder:

• if you are allergic tohydrochloride doxorubicinor to any of the other components ofthis medication (listed in section 6), anthracyclines, or to another anthracycline.
• if you have a tumor that has grown in the bladder wall
• if you have a urinary tract infection
• if you have inflammation of the urinary bladder
• if you have blood in your urine (hematuria)
• if you have problems with catheter insertion
• if you are breastfeeding (see section “Pregnancy, breastfeeding, and fertility”)

Warnings and precautions

Consult your doctor or pharmacist if you suffer or have suffered from any of the following medical conditions or diseases:

• low production of blood cells in the bone marrow
• cardiac problems
• liver disorders
• renal disorders

You must also inform your doctor:

• if you have ever received doxorubicin or any other anticancer medication (anthracycline) for cancer treatment.
• if you have received radiation therapy in the upper part of the body.
• if you are currently using or have recently used Trastuzumab (a medication used in the treatment of certain types of cancer). Trastuzumab may remain in the body for up to 7 months. As Trastuzumab may affect the heart, you should not use doxorubicina until 7 months after stopping Trastuzumab. If you use doxorubicina before this time, your cardiac function must be carefully monitored.

Your doctor will perform the following tests before starting treatment with Doxorubicina Accord and during treatment:

• blood analysis
• tests of heart, liver, and kidney function

During treatment with doxorubicin, it is possible that your bone marrow will no longer be able to produce enough blood cells and platelets, and your blood count may change; therefore, blood tests should be performed before and during each treatment. The following symptoms may occur as a result of a lack of blood cells and/or platelets: fever, infections, blood poisoning, bleeding, and tissue damage. In case of fever, you should immediately contact your attending doctor.

The skin rash along the vein in which the medication is administered is not uncommon and may be followed by inflammation of the vein (phlebitis). The wall of the vein may become hardened or thickened, especially if the medication is administered repeatedly in a thin vein. If the medication leaks from the blood vessel into the surrounding tissue (extravasation), it may cause local pain, severe inflammation of the subcutaneous tissue (cellulitis), and tissue damage. Inform a nurse if you experience a burning sensation during injection: the infusion should be stopped immediately and the needle should be reintroduced into another vein.

Your doctor will carefully monitor your cardiac function during treatment, as:

• doxorubicin may damage the heart muscle.
• treatment with doxorubicin may lead to heart failure after a certain accumulated dose (addition of single doses).
• the risk of heart muscle damage is higher if you have previously received medications that may damage the heart or radiation therapy in the upper part of the body.

Generally, this medication is not recommended in combination with live attenuated vaccines. You should avoid contact with people who have recently been vaccinated against polio.

During treatment with doxorubicin, inflammation of the mucous membranes (mainly in the mouth, less frequently in the esophagus) may occur. This manifests as pain or burning sensation, skin rash, superficial mucosal ulceration (often on the sides or under the tongue), bleeding, and infections. Any inflammation in the mouth usually occurs shortly after medication administration and, in severe cases, may progress to mucosal ulcers within a few days; however, in most cases, the patient recovers from this side effect by the third week of treatment.

Nausea, vomiting, and occasional diarrhea may occur. These can be prevented or alleviated with appropriate treatment that your doctor may prescribe.

Urine discoloration (which is normal and related to the color of the medication). Inform your doctor if it does not stop within a few days or if you think there is blood in your urine. Inform your doctor if you experience these symptoms.

Doxorubicin may cause fertility problems and damage reproductive cells. Both men and women should use effective contraceptive methods during treatment and for a period after completing treatment with doxorubicina (see the section “Pregnancy, breastfeeding, and fertility”). If you wish to become pregnant after treatment with doxorubicina, you should discuss genetic counseling and fertility preservation options with your doctor before starting treatment.

Skin reactions and hypersensitivity reactions:

• hair loss and interruption of beard growth may occur. This side effect is usually reversible, with complete hair growth within two to three months after completing treatment.
• redness, skin discoloration, and sensitivity to sunlight may occur.
• in rare cases, allergic reactions (hypersensitivity) may occur; the signs or symptoms of these reactions may vary from skin rash and itching (pruritus, urticaria) to fever, chills, and anaphylactic shock.

Use of Doxorubicina Accord with other medications

Inform your doctor or pharmacist if you are using or have used recently or may need to use any other medication.

The following medications may interact with Doxorubicina Accord:

• other cytostatics (cancer medications), e.g. trastuzumab, anthracyclines (daunorubicin, epirubicin, idarubicin), cisplatin, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, fluorouracil, mitomycin C, taxanes (e.g. paclitaxel), mercaptopurine, methotrexate, streptozocin
• cyclosporine: which may potentiate the effects of doxorubicin and may cause prolonged suppression of bone marrow and blood cells (also described as coma and convulsions with concomitant administration of cyclosporine and doxorubicin)
• cardioactive medications (heart medications), e.g. calcium antagonists, verapamil, and digoxin
• cytochrome P-450 inhibitors (medications that cause the cytochrome P-450 substance, which is important for the body's detoxification, to stop working: e.g. cimetidine), cytochrome P-450 inducers (e.g. rifampicin, barbiturates, such as phenobarbital)
• antiepileptic medications (e.g. carbamazepine, phenytoin, valproate)
• antipsychotics: clozapine (a medication used for schizophrenia)
• warfarin (prevents blood clotting)
• antiretroviral medications (medications against certain types of viruses)
• chloramphenicol and sulfonamides (bacterial medications)
• amphotericin B (medications used against fungal diseases)
• live vaccines (e.g. polio, malaria)
• Some medications affect the concentration and clinical effect of doxorubicin (e.g. St. John's wort).
• Paclitaxel: which may potentiate the effects of doxorubicin

Be aware that this may also apply to medications used recently.

Pregnancy, breastfeeding, and fertility

Pregnancy

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor or pharmacist before using this medication.

In animal experiments, doxorubicin has been shown to cross the placenta and cause damage to the fetus. If you are pregnant, your doctor will only administer doxorubicin if the benefits of treatment outweigh the potential risks to the fetus. Inform your doctor immediately if you are pregnant or think you may be.

Women should not become pregnant during treatment with doxorubicin or for 7 months after treatment. Men should take the necessary precautions to ensure that their partner does not become pregnant during treatment with doxorubicin or for 4 months after treatment.

Breastfeeding

Do not breastfeed while being treated with Doxorubicina Accord and for at least 14 days after the last dose. The medication may pass into the baby through breast milk and potentially harm your child.

Fertility

Men should seek advice on sperm cryopreservation (or cryopreservation) before treatment, due to the possibility of irreversible infertility as a result of treatment with Doxorubicina Accord.

If you are considering becoming parents after treatment, consult your doctor.

Consult your doctor or pharmacist before using any medication.

Driving and operating machines

Due to the frequent occurrence of nausea and vomiting, do not drive or operate machines.

Doxorubicina Accord contains sodium

Patients with low-sodium diets should note that this medication contains 3.5 mg (0.15 mmol) of sodium per ml. The different sizes of this medication container contain the following amounts of sodium:

This medication contains less than 1 mmol of sodium (23 mg) in each 5 ml vial, i.e. it is essentially “sodium-free”.

This medication contains 35.42 mg of sodium (main component of table salt) in each 10 ml vial. This is equivalent to 1.77% of the maximum recommended daily sodium intake for an adult.

This medication contains 88.55 mg of sodium (main component of table salt) in each 25 ml vial. This is equivalent to 4.43% of the maximum recommended daily sodium intake for an adult.

This medication contains 177.10 mg of sodium (main component of table salt) in each 50 ml vial. This is equivalent to 8.85% of the maximum recommended daily sodium intake for an adult.

This medication contains 354.20 mg of sodium (main component of table salt) in each 100 ml vial. This is equivalent to 17.71% of the maximum recommended daily sodium intake for an adult.

Administration Form and Routes

Doxorubicina Accord should only be administered under the supervision of a doctor with experience in cancer treatment.

Your doctor will decide on the dose you will receive.

Do not administer the medication yourself. The medication will be administered as part of an intravenous infusion, in a vein, under the supervision of specialists. You will undergo regular check-ups, during and after treatment. If you have superficial bladder cancer, it may be possible to receive the medication directly into the bladder (intravesical use).

Dosage

Your doctor will decide on the dose you should receive.

The dose is usually calculated based on your body surface area. 60-75 mg per square meter of body surface area can be administered every 3 weeks when only this medication is used. It may be necessary to reduce the dose to 30-60 mg per square meter of body surface area and prolong the treatment interval when administered in combination with other antitumor medications. Your doctor will indicate the necessary amount. If administered weekly, the recommended dose is 15 to 20 mg per square meter of body surface area. Your doctor will indicate the necessary amount.

Patients with Reduced Liver and Kidney Function

In the case of reduced liver or kidney function, the dose must be reduced. Your doctor will indicate the necessary amount.

Children/Elderly or Patients after Radiation Therapy

It may be necessary to reduce the dose in children and the elderly or if you have received radiation therapy. Your doctor will indicate the necessary amount.

Patient with Bone Marrow Suppression

It may be necessary to reduce the dose in patients with bone marrow suppression. Your doctor will indicate the necessary amount.

Obese Patients

In obese patients, the initial dose may be reduced or the dosing interval prolonged. Your doctor will indicate the necessary amount and frequency.

If You Take More Doxorubicina Accord Than You Should

During and after treatment, your doctor or nurse will closely monitor your progress. Symptoms of an overdose are an extension of the possible side effects of Doxorubicina Accord, particularly changes in the blood, gastrointestinal, and cardiac problems. Cardiac problems may occur up to six months after receiving the overdose.

In the case of an overdose, your doctor will take the necessary measures, such as blood transfusion and/or antibiotic treatment.

Inform your doctor if you experience any of the symptoms.

If You Forget to Take a Dose of Doxorubicina Accord

Your doctor will decide on the duration of your treatment with Doxorubicina Accord. If treatment is interrupted before completing the recommended treatment cycles, the effects of Doxorubicina Accord therapy may be reduced. Consult with your doctor if you wish to interrupt treatment.

If You Interrupt Treatment with Doxorubicina Accord

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

Like all medicines, Doxorubicina Accord may cause side effects, although not everyone will experience them.

In certain individuals, this medication may cause a severe allergic reaction (anaphylaxis) that is potentially fatal. Contact a doctor immediately if you notice the sudden onset of breathing difficulties, swelling of the face and throat, and general discomfort (shock).

Doxorubicina significantly reduces the immune system's response capacity, thereby increasing the risk of infection or infestation that may cause a generalized infection related to the entry of microorganisms into the blood (blood poisoning). Contact a doctor immediately in case of high fever, as blood poisoning can be fatal.

Other possible side effects include the following:

Very common:may affect more than 1 in 10 people

• Infection
• Loss of appetite (anorexia)
• Mouth inflammation (stomatitis)/inflammation of mucous membranes (mucositis)
• Diarrhea
• Nausea or vomiting
• Reduction in the number of blood cells: red blood cells (anemia), all or some white blood cells (leucopenia, neutropenia), and platelets (thrombocytopenia)
• Redness, swelling, numbness, pain, and tingling in the palms of the hands and feet (erythrodystesia palmoplantar or acral erythema)
• Loss of hair on the head and body (alopecia and interruption of beard growth)
• Fever, feeling of weakness (asthenia), chills
• Abnormal ECG (this is a heart electrical tracing)
• Asymptomatic reductions in left ventricular ejection fraction
• Changes in liver enzyme levels (transaminases)
• Weight gain in early breast cancer patients
• Cardiac muscle damage (cardiotoxicity).

Common:may affect up to 1 in 10 people

• Conjunctivitis, inflammation of the membrane covering the front of the eye and the interior of the eyelids
• Changes in heart function, particularly in heart rhythm (sinus tachycardia), reduction in the amount of blood pumped by the heart throughout the body (congestive heart failure)
• Esophagitis, inflammation of the esophagus
• Stomach pain
• Itching, hives, skin discoloration (hyperpigmentation), and nail discoloration.
• Blood poisoning
• Redness and swelling at the injection site may occur.
• Local side effects when administered in the bladder, such as chemical cystitis.

Uncommon:may affect up to 1 in 100 people

• Embolism (blood clot in a blood vessel).

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

• Secondary leukemia (blood cancer developed after treatment for another cancer), when doxorubicina is used in combination with other cancer medications that damage DNA.
• Tumor lysis syndrome (complications of receiving chemotherapy due to the breakdown products of dying cancer cells, which, for example, may affect the blood and kidneys).

Frequency not known:(the frequency cannot be estimated from available data)

• Dehydration
• Increased urea in the blood (hyperuricemia)
• Blood cancer (acute lymphocytic leukemia, acute myeloid leukemia)
• Shock
• Corneal inflammation, increased tear production.
• Increased heart rate (arrhythmias), loss of heart impulses (atrioventricular block and branch block)
• Phlebitis, total obstruction of a vein (thrombophlebitis), redness, bleeding problems (hemorrhage)
• Irritation or bleeding in the intestines, mouth pain or ulcers that may not appear until 3 to 10 days after treatment, mouth discoloration.
• Increased skin sensitivity to sunlight.
• Colitis, inflammation of the intestinal lining, and inflammation of the stomach lining.
• Itching in the skin and other skin disorders.
• Sensitivity of irradiated skin (radiation recall reactions)
• Red urine discoloration.
• Women may also notice that their periods stop (amenorrhea), but their periods should return to normal after stopping the medication. In some cases, premature menopause may occur.
• In men, doxorubicina may cause a decrease or absence in sperm count (oligospermia, azoospermia), but this may return to normal after stopping the medication.
• Feeling of discomfort
• Liver toxicity
• Temporary increase in liver enzymes.
• Condition in which the kidney stops functioning (acute renal failure)
• Difficulty breathing due to bronchospasm.

Reporting of adverse effects:

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

• Keep this medication out of the sight and reach of children.
• Do not use this medication after the expiration date that appears on the vial or on the outer packaging after CAD. The expiration date is the last day of the month indicated.
• Store in refrigerator (between 2°C and 8°C). Store the vial in the outer packaging to protect it from light.
• Do not use this medication if you observe that the solution is not transparent, red, and free of particles.

• For single use only.

All materials used for preparation and administration, or those that have come into contact with cisplatin in any way, must be disposed of in accordance with local cytotoxic requirements.

Unopened vials: 18 months

Opened vials: The product must be used immediately after opening the vial.

Physical and chemical stability has been demonstrated in sodium chloride 0.9% injection and in dextrose 5% injection for a maximum of 28 days at 2-8°C and for a maximum of 7 days at 25°C, if prepared in light-protected glass containers.

From a microbiological point of view, the product must be used immediately. If not used immediately, the storage times during use and the conditions prior to use are the responsibility of the user. Normally, they should not exceed 24 hours, and the temperature should oscillate between 2°C and 8°C, unless the dilution has been carried out in controlled and validated aseptic conditions.

Composition of Doxorubicin Accord

The active ingredient ishydrochloride of doxorubicin.

Each ml contains 2 mg of hydrochloride of doxorubicin.

Each vial of 5 ml contains 10 mg ofhydrochloride of doxorubicin.

Each vial of 10 ml contains 20 mg ofhydrochloride of doxorubicin.

Each vial of 25 ml contains 50 mg ofhydrochloride of doxorubicin.

Each vial of 50 ml contains 100 mg ofhydrochloride of doxorubicin.

Each vial of 100 ml contains 200 mg ofhydrochloride of doxorubicin.

Aspect of the product and contents of the package

Doxorubicin Accord 2 mg/ml concentrate for solution for infusion EFGis a transparent, red-colored solution and is practically free of particles.

Package sizes:

• 1 vial of 5 ml
• 1 vial of 10 ml
• 1 vial of 25 ml
• 1 vial of 50 ml
• 1 vial of 100 ml

Some package sizes may not be marketed.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6th floor

08039 Barcelona

Spain

Responsible for manufacturing

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,

95-200 Pabianice, Poland

or

Accord Healthcare B.V.,

Winthontlaan 200,

3526 KV Utrecht,

Netherlands

or

Accord Healthcare single member S.A.

64th Km National Road Athens,

Lamia, Schimatari, 32009,

Greece

This medicinal product is authorized in the member states of the European Economic Area with the following names

Last review date of this leaflet: November 2023

For detailed and updated information on this medicinal product, please visit the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/

This information is intended solely for medical professionals or healthcare professionals

Dosage and administration

Doxorubicin injection should only be administered under the supervision of a qualified doctor with extensive experience in cytotoxic treatment. In addition, patients should be closely monitored and frequently during treatment.

Due to the risk ofcardiomyopathy, which is often fatal, it is necessary to evaluate the risks and benefits of each patient before each administration.

Doxorubicin is administered by intravenous and intravesical routes and should not be administered orally, subcutaneously, intramuscularly, or intrathecally. Doxorubicin can be administered by intravenous injection for a few minutes, short infusion of up to one hour, or continuous infusion of up to 96 hours.

The solution is administered through a uniform flow tube system for intravenous infusion with a sodium chloride injection solution of 9mg/ml (0.9%) or with a 5% dextrose injection solution during 3-10 minutes. This technique minimizes the risk of thrombophlebitis or perivenous extravasation, which can lead to severe local cellulitis, vesicle formation, and tissue necrosis.Direct intravenous injection is not recommended due to the risk of extravasation, which can occur even in the presence of adequate return of blood through aspiration with a needle.

Intravenous administration:

Thedose of doxorubicin depends on the dosage regimen, the patient's overall health status, and previous treatment.The dosing regimen ofhydrochloride of doxorubicinmay vary according to the indication (solid tumors or acute leukemia) and according to its use in the specific treatment regimen (as a single agent or in combination with other cytotoxic agents, or as part of multidisciplinary procedures that include a combination of chemotherapy, surgery, radiation therapy, and hormone therapy).

Monotherapy

The dose is usually calculated based on the patient's body surface area (mg/m2). Based on this, a dose of 60-75 mg/m2of body surface area every three weeks is recommended when doxorubicin is used as a single agent.

Combination regimen

Whendoxorubicinis administered in combination with other antitumor agents with overlapping toxicities, such as high-dose IV cyclophosphamide or related anthracycline compounds, such as daunorubicin, idarubicin, and/or epirubicin, the dose of doxorubicin should be reduced to 30-60 mg/m2every 3-4 weeks.

In patients who cannot receive the full dose (e.g., in cases of immunosuppression, old age), an alternative dosing regimen is 15-20 mg/m² of body surface area per week.

Intravesical administration:

Doxorubicin can be administered by intravesical instillation in the treatment of superficial bladder cancer or in the prevention of tumor recurrence after transurethral resection (RTU) in patients at high risk of recurrence. The recommended dose ofdoxorubicinfor the local intravesical treatment of superficial bladder tumors is the instillation of 30-50 mg in 25-50 ml of 0.9% sodium chloride injection solution for injection. The optimal concentration is approximately 1 mg/ml. In general, the solution should be maintained intravesically for 1-2 hours. During this period, the patient should be turned 90° every 15 minutes. The patient should not drink liquids for 12 hours before treatment to avoid undesirable effects of urine dilution (this should reduce urine production to approximately 50 ml/h). The instillation can be repeated with an interval of 1 week to 1 month, depending on whether the treatment is therapeutic or prophylactic.

Patients with liver insufficiency

Since doxorubicin is primarily excreted through the liver and in the bile, the elimination of the drug may be reduced in patients with liver insufficiency or bile flow obstruction, and this could lead to severe side effects.

The general recommendations for dose adjustment in patients with liver insufficiency are based on serum bilirubin concentration:

Doxorubicin is contraindicated in patients with severe liver insufficiency.

Patients with renal insufficiency

In patients with renal insufficiency (GFR <10)

To avoid cardiomyopathy, it is recommended that the total accumulated dose of doxorubicin (including related drugs, such as daunorubicin) not exceed 450-550 mg/m2of body surface area.If a patient with concomitant heart disease receivesmediastinal and/or cardiac irradiation or previous treatment with alkylating agents, or if the patient is at high risk (hypertension for more than 5 years, previous coronary, valvular, or myocardial lesions, or age over 70 years),the total maximum dose should not exceed 400mg/m2of body surface area and cardiac function should be monitored.

Dose in children

The dose in children may need to be reduced, consult the treatment protocols and specialized literature.

Obese patientsand patients with bone marrow infiltration

In the case of obese patientsand patients with bone marrow infiltration, it may be considered to administer a reduced initial dose or a prolonged dosing interval.

Incompatibilities

Doxorubicin should not be mixed with heparin, as it may form a precipitate, and should not be mixed with 5‑fluorouracil, as it may lead to degradation. Prolonged contact with any alkaline solution should be avoided, as it will lead to the hydrolysis of the drug.

Until detailed information on the compatibility of mixtures is available, doxorubicin should not be mixed with other medications apart from a 0.9% sodium chloride injection solution and a 5% dextrose injection solution.

Prepared infusion solutions

Physical and chemical stability has been demonstrated in 0.9% sodium chloride injection solution and 5% dextrose injection solution for up to 28 days at 2-8°C and for up to 7 days at 25°C, if prepared in glass containers protected from light.

From a microbiological point of view, the product should be used immediately. If not used immediately, the storage times during use and the conditions prior to use are the responsibility of the user. Normally, they should not exceed 24 hours, and the temperature should range from 2°C to 8°C, unless the dilution has been carried out in controlled and validated aseptic conditions

Elimination

The remaining drug, as well as all materials used for dilution and administration, should be destroyed in accordance with the standard hospital procedures applicable to cytotoxic agents, and in accordance with the current legislation on the disposal of hazardous waste.

All unused medication or waste material should be disposed of in accordance with local regulations for cytotoxic agents.

Validity period and storage

Unopened vials: 18 months.

Opened vials: the product should be used immediately after opening the vial.

Store in refrigerator (between 2°C and 8°C).

Keep the vial in the outer packaging to protect it from light.