Doxorubicin Teva

Package leaflet: Information for the user

Doxorubicina Teva 2 mg/ml concentrate for solution for infusion

Generic medicine
Please read all of this leaflet carefully before you use this medicine because it contains important information for you.

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

What is in this leaflet

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

1. What Doxorubicina Teva is and what it is used for

The active substance in this medicine is doxorubicin hydrochloride. Doxorubicin belongs to a group of anticancer medicines (anti-tumour agents) called anthracyclines. Doxorubicin damages tumour (cancerous) cells and prevents their growth.
Doxorubicin is used to treat:
breast cancer
bone tumour (osteosarcoma), administered before and after surgery
soft tissue tumours (advanced soft tissue sarcoma in adults)
lung cancer (small cell lung carcinoma)
lymphatic tissue tumours (Hodgkin's and non-Hodgkin's lymphoma)
certain blood cancers (acute lymphatic or myeloblastic leukaemias)
bone marrow cancer (multiple myeloma)
lining of the uterus cancer (advanced or recurrent endometrial carcinoma)
thyroid tumours (advanced papillary/follicular thyroid carcinoma, anaplastic thyroid carcinoma)
certain bladder tumours (locally advanced or metastatic). It is also used intravesically (into the bladder) for early-stage (superficial) bladder cancer to prevent recurrence of bladder tumour after surgery.
recurrent ovarian cancer
a specific childhood kidney tumour (Wilms' tumour)
a childhood nervous tissue tumour (advanced neuroblastoma).
Doxorubicin may also be used in combination with other anticancer medicines.
Since Doxorubicina Teva is an anticancer medicine, it will be administered in a specialised unit and under the supervision of a doctor experienced in the use of anticancer medicines. The staff at the unit will explain what you need to pay particular attention to during and after treatment.
This leaflet will help you remember what you need to do.

2. What you should know before using Doxorubicina Teva

Do not use Doxorubicina Teva if

• you are allergic to doxorubicin hydrochloride, to other medicines of the same class known as anthracyclines or anthracenediones, or to any of the excipients of this medicine (listed in section 6)
• you are breastfeeding.

Doxorubicina Teva must not be administered intravenously (into a vein) if

• you have a reduced production of blood cells, impaired bone marrow function (myelosuppression), or mouth inflammation (stomatitis) due to previous treatment with anticancer medicines and/or radiotherapy.
• you have an infectious disease.
• your liver function is severely impaired.
• you have heart problems (severe disturbances in heart rhythm, reduced cardiac function, [previous] heart attack, heart inflammation). These conditions may develop rapidly and follow a short but severe course.
• you have previously been treated with doxorubicin or similar anticancer drugs such as daunorubicin, epirubicin, idarubicin and/or with other medicines belonging to the anthracycline and anthracenedione group (see "Other medicines and Doxorubicina Teva") and have already received the maximum cumulative dose of these drugs.

Doxorubicina Teva must not be administered intravesically (into the bladder) if

• the tumour has spread to the bladder wall.
• you have a urinary tract infection.
• you have bladder inflammation.
• you have problems with catheter use (a small tube inserted into the bladder for urine drainage).
• you have blood in your urine (haematuria).

Warnings and precautions
Talk to your doctor before using Doxorubicina Teva.
Take special care with Doxorubicina Teva and inform your doctor before treatment if

• you are elderly or overweight.
• you have or have previously had heart disease.
• you have received or are due to receive vaccinations with live or live attenuated vaccines.
• you have liver or kidney problems.
• you have had bone marrow damage.
• you have been treated with radiotherapy in the chest cavity (mediastinum).
• you have been treated with similar anticancer products (other anthracyclines or anthracenediones).

Important information about Doxorubicina Teva

• Doxorubicin may cause infertility, which can be permanent, in both men and women (see also "Pregnancy, breastfeeding and fertility").
• If you feel sharp pain or a burning sensation at the site where doxorubicin was injected, this may be due to leakage of doxorubicin from the vein. If this occurs, inform your doctor immediately: they will switch administration to another vein and closely monitor the affected area.
• Your urine may turn reddish during treatment with Doxorubicina Teva.
• During treatment with Doxorubicina Teva, you may experience severe nausea, vomiting, and inflammation of the mucous membranes of the mouth or nose. If you experience any of these symptoms, inform your doctor immediately; they will provide the necessary treatment.
• Vaccinations are not recommended during treatment with Doxorubicina Teva. You should also avoid contact with people who have recently been vaccinated with the polio vaccine.

Before and during treatment with Doxorubicina Teva, your doctor:

• must check your blood count before each treatment cycle, as treatment with doxorubicin can damage the bone marrow, causing a decrease in white blood cells and making your body more susceptible to infections and bleeding. If severe bone marrow damage occurs, your doctor may reduce, stop, or delay treatment.
• must examine your lungs and chest to ensure your lungs are functioning properly during treatment.
• must perform an electrocardiogram (ECG), a test that records heart activity, before starting doxorubicin treatment and throughout the treatment period, as doxorubicin can cause inflammation of the heart muscle (cardiomyopathy). This is particularly likely if you have had heart disease, are over 70 or under 15 years of age, have previously been treated with doxorubicin (or related medicines in the anthracycline group), or have undergone radiotherapy in the chest cavity. A cumulative dose of 450–550 mg/m² must not be exceeded, as the risk of developing heart failure increases significantly at higher doses, especially in children and patients with prior heart disease. Typically, the maximum cumulative dose for children is calculated as 300 mg/m² (under 12 years of age) and 450 mg/m² (over 12 years of age). For newborns, the maximum cumulative dose may be even lower. Your doctor may perform additional tests to monitor your heart function.
• must monitor your blood uric acid levels and ensure you drink sufficient fluids, as doxorubicin can increase uric acid levels in the blood (hyperuricaemia).
• must regularly check your mouth and throat during treatment, as doxorubicin can cause changes in the lining of the mouth and throat.
• must monitor the function of your kidneys. A dose reduction may be necessary.
• must monitor the function of your liver (through blood tests). A dose reduction may be necessary if liver function is impaired.
• must assess your general health status, as doxorubicin must not be used in the presence of inflammation, ulcers, or diarrhoea. Any existing infections should be treated by your doctor before you start taking Doxorubicina Teva.

Other medicines and Doxorubicina Teva
Inform your doctor or pharmacist if you are currently using, have recently used, or might use any other medicines.
Inform your doctor if

• you have been treated with other anthracyclines or other medicines that may damage the heart, such as 5-fluorouracil, cyclophosphamide, or paclitaxel (anticancer medicines), or other medicines that affect heart function (e.g., calcium channel blockers such as verapamil).
• you have been treated or are about to be treated with trastuzumab (an anticancer medicine), as your doctor must monitor your heart function.
• you have been treated with 6-mercaptopurine (an anticancer medicine), as you have an increased risk of liver-related adverse effects.
• you have been treated with medicines that affect bone marrow function, such as cytostatic agents (e.g., cytarabine, cisplatin, or cyclophosphamide), sulfonamides (for infections), chloramphenicol (for infections), phenytoin (for epilepsy), amidopyrine derivatives (for pain and inflammation), antiretroviral drugs (for AIDS). This may cause bone marrow damage leading to a reduction in blood cells.
• you are taking cyclosporine (to suppress normal immune defences) or cimetidine (for gastric ulcers), as these may increase the amount of doxorubicin in your blood. Your doctor may consider reducing the dose.
• you are taking phenobarbital (for epilepsy) or rifampicin (an antibiotic), as the amount of doxorubicin in your blood may decrease, resulting in reduced effectiveness of Doxorubicina Teva.
• you are currently undergoing or have previously undergone radiotherapy, as adverse effects may increase.
• you have taken cyclophosphamide (an anticancer medicine), as this increases the risk of bladder-related adverse effects (haemorrhagic cystitis, a bladder infection that may sometimes cause blood in the urine).
• you are currently being treated or have previously been treated with paclitaxel (an anticancer medicine), as this may increase the effects or side effects of doxorubicin.
• you are taking medicines that lower uric acid levels. Dose adjustments of these medicines may be necessary, as doxorubicin can cause increased uric acid levels in the blood.
• you are taking digoxin (for heart conditions), as the effect of digoxin may be reduced.
• you are taking antiepileptic medicines such as phenytoin, carbamazepine, or valproate, as the effect of these medicines may be reduced.
• you are taking herbal medicines including St. John’s wort.
• you are also taking heparin (used to prevent blood clotting) or 5-fluorouracil (an anticancer medicine). If administered in the same infusion, doxorubicin may bind to these medicines and neutralise their effect.
• you are taking sorafenib (for inoperable liver cancer and advanced kidney cancer).

Pregnancy, breastfeeding and fertility
If you are a woman, you must avoid becoming pregnant during treatment with doxorubicin and for 6 months after treatment ends. Doxorubicin must not be taken during pregnancy.
If you are a man, you must take necessary precautions to prevent your partner from becoming pregnant during treatment with doxorubicin and for 6 months after treatment ends. Therefore, both men and women must use an effective contraceptive method during treatment and for 6 months after treatment ends.
Since doxorubicin may cause permanent infertility, you should discuss with your doctor the possibility of freezing sperm before starting treatment (cryopreservation).
Breastfeeding must be discontinued for the duration of treatment with Doxorubicina Teva, as some of the medicine may pass into breast milk and possibly harm the infant.

Driving and using machines
Do not drive or operate tools or machinery if you do not feel well and experience nausea, vomiting, or dizziness.

Doxorubicina Teva contains sodium
This medicine contains 18 mg of sodium (a main component of table salt) per 5 ml vial. This corresponds to 0.9% of the maximum daily recommended dietary intake for an adult.
This medicine contains 35 mg of sodium (a main component of table salt) per 10 ml vial. This corresponds to 1.8% of the maximum daily recommended dietary intake for an adult.
This medicine contains 89 mg of sodium (a main component of table salt) per 25 ml vial. This corresponds to 4.4% of the maximum daily recommended dietary intake for an adult.
This medicine contains 354 mg of sodium (a main component of table salt) per 100 ml vial. This corresponds to 17.7% of the maximum daily recommended dietary intake for an adult.

3. How to use Doxorubicin Teva

Doxorubicin Teva will be administered to you by a doctor. Your doctor may carry out certain tests, such as blood tests, ECG, etc., before starting treatment or during treatment in order to determine the appropriate dose of Doxorubicin Teva.

Doxorubicin is administered intravenously via intravenous infusion, or into the bladder.
Preparation and administration of the medicinal product must be performed exclusively by a qualified healthcare professional in a hospital setting.

The dose will depend on your age (the dose may be reduced for children and elderly patients), your body size, weight, and general medical condition. It will also depend on any other treatments you may have received for your tumour. Your doctor will calculate your body surface area in square metres (m²). The medicine will be administered every 3 weeks for a duration of 6–12 months. When administered into the bladder, the dose may be repeated at intervals ranging from 1 week to 1 month. The exact duration of your treatment will depend on your individual condition.

Patients with renal or hepatic impairment
If you have impaired kidney or liver function, a dose reduction may be necessary.

If you are given more Doxorubicin Teva than you should
Since the medicine is administered by a doctor, overdose is unlikely. However, if you have any concerns, inform your doctor or nurse immediately.

Effects of an overdose of Doxorubicin Teva may include inflammation of the stomach and intestine (particularly the lining), heart problems, and severe bone marrow damage (myelosuppression). These effects may be accompanied by an increased risk of bleeding and bruising, and a higher risk of infections (leucopenia).

Treatment takes place in hospital and includes administration of antibiotics and blood transfusions (particularly white blood cells and platelets), as well as management of any adverse effects. You may be transferred to a sterile room. If heart problems occur, you will be examined by a specialist (cardiologist). Cardiac disorders may occur up to six months after the overdose.

If you have any doubts about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.

Tell your doctor or nurse immediately if you

• have dizziness, mild fever, shortness of breath with a feeling of tightness in the chest or throat, or develop a rash with itching. This type of allergic reaction can be very serious.
• feel tired and drowsy. These could be signs of anaemia (reduced number of red blood cells).
• have fever or other signs of infection. These could be signs of reduced white blood cell count (cells that fight infections).
• bruise more easily or experience increased bleeding. These could be signs of reduced platelet count in your blood (cells that help blood to clot).

Very common: may affect more than 1 in 10 people

• Nausea, vomiting, gastrointestinal problems, diarrhoea
• Hair loss (reversible)
• Red discolouration of urine
• Bone marrow damage (myelosuppression) with reduced white blood cells and platelets, increasing the risk of infection and the risk of bleeding or bruising
• Anaemia (a reduction in red blood cells, which may make the skin look pale and cause weakness or shortness of breath)
• Damage to the heart muscle (cardiotoxicity). The risk increases if the patient is treated with radiotherapy or other heart-toxic medicines, if the patient is elderly, or if the patient has high blood pressure. Effects may occur immediately after treatment or may appear several years after treatment.
• Inflammation of the mucous membranes of the nose, mouth or vagina (mucositis)
• Inflammation or ulceration of the lining of the mouth (stomatitis), nose or throat (oesophagitis), e.g. mouth ulcers and cold sores
• Inflammation of the colon (colitis)
• Skin sensitivity to artificial or natural light (photosensitivity), skin redness
• Fever, weakness (asthenia), chills
• Loss of appetite
• Infection
• Redness, swelling, numbness, pain and tingling in palms and soles (palmar-plantar erythrodysesthesia syndrome)
• Abnormalities in electrocardiogram (ECG) laboratory tests
• Abnormal levels of liver enzymes (transaminases)
• Weight gain in patients with initial breast cancer

Common: may affect up to 1 in 10 people

• Blood poisoning (sepsis/septicaemia)
• Heart rhythm disorders (irregular heartbeat, increased heart rate, decreased heart rate), ventricular contractions, reduced amount of blood pumped by the heart to the body, deterioration of heart muscle function (cardiomyopathy) which may lead to death
• Inflammation of the outer layer of the eye (conjunctivitis)
• Abdominal pain
• Bleeding problems (haemorrhage)
• Local allergic reactions at sites previously treated with radiotherapy (so-called radiation recall reaction)
• Itching
• Skin rash (exanthema), hives
• Darkening of areas of the skin and nails (hyperpigmentation)

Following administration into the bladder, the following common side effects may be observed:

• Difficulty, pain or burning sensation during urination (micturition)
• Reduced urine output
• Increased frequency of urination
• Bladder cramps
• Inflammation of the bladder, sometimes causing blood in the urine
• Local side effects with bladder administration, such as inflammation of the bladder (chemical cystitis)

Uncommon: may affect up to 1 in 100 people

• When used in combination with other anticancer medicines, doxorubicin may cause certain forms of blood cancer (leukaemia). These cancers may appear many years after treatment.
• Bleeding in the stomach or intestines
• Ulcers and possible death of tissue cells (necrosis) in the large intestine with bleeding and infections in combination therapy with cytarabine (an anticancer medicine). Embolism (formation of a blood clot in blood vessels)
• Loss of body water (dehydration)

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

• Nail detachment (onycholysis)
• Dizziness
• Reactions at the injection site, including itching, rash and pain, inflammation of the vein (phlebitis), thickening or hardening of the vein walls (phlebosclerosis)
• Severe allergic reaction causing difficulty in breathing or dizziness (anaphylactic reaction)
• Sensation of stinging or burning at the site of administration due to leakage of the medicine from the vein. This may cause local tissue cell death and requires appropriate treatment, sometimes including surgical measures.

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

• Heart rhythm disorders (non-specific changes in the ECG trace)
• Isolated cases of potentially fatal irregular heartbeat (arrhythmias), left-sided heart failure, inflammation of the lining of the heart causing chest pain and fluid accumulation around the heart (pericarditis), inflammation of the heart muscle and the sac surrounding the heart (pericarditis-myocarditis syndrome), loss of nerve impulses to the heart (atrioventricular block, bundle branch block)
• Ulcers in the lining of the mouth, throat, oesophagus, stomach or intestine, discolouration (pigmentation) of the lining of the mouth
• Swelling and numbness of hands and feet (acral erythema), blistering
• Condition in which the kidneys stop functioning properly (acute renal failure)
• Excessively high levels of uric acid in the blood (hyperuricaemia), which may cause gout, kidney stones or kidney damage due to rapid breakdown of the tumour
• Absence of menstrual periods (amenorrhoea)
• Fertility problems in men (reduced or absent active sperm)
• Flushing of the face

Not known: frequency cannot be estimated from the available data

• Shortness of breath due to spasms of the airway muscles (bronchospasm)
• Temporary increase in liver enzymes
• Severe liver damage which may occasionally progress to permanent damage of normal liver tissue (cirrhosis)
• Inflammation of the cornea (keratitis), increased tear production
• Severe joint pain and swelling
• Radiation-induced damage (to skin, lungs, throat, oesophagus, lining of stomach and intestine, heart) that was already healing but may reappear with doxorubicin treatment
• Thick, scaly or crusted skin patches (actinic keratosis)
• Malaise
• Shock

Reporting of side effects

If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Doxorubicin Teva

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label or carton after
EXP. The expiry date refers to the last day of that month.
Storage conditions
Before opening: Store in a refrigerator (2-8 °C). Do not freeze.
After opening: The product must be used immediately after opening the vial.
After dilution:
Chemical and physical in-use stability after dilution to a concentration of 0.5 mg/ml (in sodium
chloride 9 mg/ml (0.9%) solution for infusion or in glucose 50 mg/ml (5%) solution for infusion)
has been demonstrated for 7 days, protected from light, at room temperature (15-25°C) and at 2-8 °C.
After dilution to a concentration of 0.05 mg/ml, the diluted solution must be used immediately.
From a microbiological standpoint, the medicine should be used immediately. If not used immediately,
the in-use storage times and conditions prior to use are the responsibility of the user. The storage
times for the diluted product generally do not exceed 24 hours at 2-8 °C, unless the dilution was carried out under controlled and validated aseptic conditions.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Doxorubicina Teva contains

• The active substance is doxorubicin hydrochloride. Each ml of concentrate for infusion solution contains 2 mg of doxorubicin hydrochloride. Each 5 ml vial contains 10 mg of doxorubicin hydrochloride. Each 10 ml vial contains 20 mg of doxorubicin hydrochloride. Each 25 ml vial contains 50 mg of doxorubicin hydrochloride. Each 100 ml vial contains 200 mg of doxorubicin hydrochloride.
• The excipients are sodium chloride, hydrochloric acid (E507), sodium hydroxide (E524) and water for injections.

Description of the appearance of Doxorubicina Teva and package contents
Doxorubicina Teva 2 mg/ml concentrate for infusion solution is a clear red solution. The solution is supplied in colourless glass vials closed with a chlorobutyl rubber stopper and an aluminium seal covered by a coloured disc. Doxorubicina Teva 2 mg/ml is available in 5 ml, 10 ml, 25 ml and 100 ml vials. Each pack contains one injection vial.
It is possible that not all pack sizes are marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Teva Italia S.r.l. – Piazzale Luigi Cadorna, 4 – 20123 Milano
Manufacturer
Pharmachemie B.V., Swensweg 5, 2031 GA Haarlem, The Netherlands

The following information is intended exclusively for physicians or healthcare professionals

Incompatibilities
Doxorubicin is incompatible with heparin, aminophylline, cephalothin, dexamethasone, fluorouracil and hydrocortisone.
Doxorubicin must be diluted only with sodium chloride 9 mg/ml (0.9%) solution for infusion or with glucose 50 mg/ml (5%) solution for infusion.

Handling and disposal precautions
Care must be taken when handling Doxorubicin Teva solution. Any contact with the solution should be avoided. During preparation, strict aseptic technique must be used; protective measures should include the use of gloves, mask, safety goggles and protective clothing. Use of a vertical laminar airflow cabinet (LAF) is recommended.
Personnel must be trained in proper handling techniques for cytotoxic drugs. Pregnant personnel must be excluded from handling this drug.
In case of contact of Doxorubicin Teva with skin or mucous membranes, the affected area must be thoroughly washed with water and soap. In case of contact with the eyes, rinse with water or sterile physiological solution, then consult an ophthalmologist.
After use, vials and materials used for injection, including gloves, must be destroyed in accordance with regulations for cytotoxic agents. Unused medicine and waste materials derived from this medicine must be disposed of in compliance with local regulations.
Spills or leaks of the drug should be inactivated using a 1% or higher sodium hypochlorite solution, or more simply with a phosphate buffer (pH > 8) until the solution is eliminated. All materials used for cleaning must be disposed of as indicated above.

Dosage and administration
Treatment with doxorubicin must be initiated by a physician or after consultation with a physician experienced in cytotoxic therapy. Patients must be closely and frequently monitored during treatment.
Doxorubicin must NOT be administered by intramuscular, subcutaneous, oral or intrathecal routes.
Intravenous (i.v.) administration of doxorubicin must be performed with extreme caution; it is advisable to administer the drug via infusion through a freely running i.v. line of physiological saline or 5% glucose over 3–5 minutes. This method minimizes the risk of thrombosis and perivenous extravasation, which may lead to severe cellulitis, blistering and tissue necrosis. Doxorubicin may be administered intravenously as a bolus over a few minutes, as a short infusion over up to one hour, or as a continuous infusion for up to 96 hours. Direct intravenous injection is not recommended due to the risk of extravasation, which may occur even when adequate blood return is confirmed by aspiration.
Doxorubicin may be diluted within a concentration range of 0.05 mg/ml to 0.5 mg/ml in sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion, using non-PVC infusion bags.

Intravenous administration
The dose is usually calculated based on body surface area (mg/m²). The dosage regimen for doxorubicin may vary depending on the indication (solid tumors or acute leukemia) and on its use within a specific treatment regimen (as monotherapy or in combination with other cytotoxic agents, or as part of multidisciplinary procedures including a combination of chemotherapy, surgery, radiotherapy and hormonal therapy).

Monotherapy
The recommended dose is 60–75 mg/m² of body surface area administered intravenously as a single dose or divided over 2–3 consecutive days, given intravenously every 21 days. Dosage and regimens may be adjusted according to protocol. For precise dosing information, refer to current protocols.

Combination therapy
If Doxorubicin Teva is administered in combination with other cytostatic agents, the dose should be reduced to 30–60 mg/m² every 3–4 weeks.

Maximum cumulative dose
To avoid cardiomyopathy, the total cumulative lifetime dose of doxorubicin (including use with related drugs such as daunorubicin) should not exceed 450–550 mg/m² of body surface area. Extreme caution is required when exceeding a cumulative dose of 400 mg/m² in patients with prior mediastinal irradiation, previous or concomitant treatment with potentially cardiotoxic agents, or in high-risk patients (i.e., patients with arterial hypertension for more than 5 years, prior coronary, valvular or myocardial cardiac damage, or aged over 70 years). Cardiac function in these patients must be monitored.

Special populations

Immunosuppressed patients
The dose should be reduced in case of immunosuppression; an alternative regimen is 15–20 mg/m² of body surface area weekly.

Patients with impaired hepatic function
In case of impaired hepatic function, the dose should be reduced according to the following scheme.

Patients with impaired renal function
In patients with renal insufficiency (GFR less than 10 ml/min), only 75% of the planned dose should be administered.

Patients at risk of heart failure
For patients at increased risk of cardiotoxicity, treatment with a continuous 24-hour infusion of a single dose should be considered instead of bolus injection. This approach may reduce the frequency of cardiotoxicity without compromising therapeutic efficacy. In these patients, left ventricular ejection fraction must be measured before each cycle.

Patients with limited bone marrow reserve unrelated to bone marrow involvement by disease
Doses may be reduced in patients previously treated with myelosuppressive agents. The bone marrow reserve in these patients may be inadequate.

Elderly patients
The dose may be reduced in elderly patients.

Paediatric population
Due to the significant risk of doxorubicin-induced cardiotoxicity in childhood, specific maximum cumulative dose limits based on patient age must be applied. Generally, in children (under 12 years of age), the maximum cumulative dose is 300 mg/m², while in adolescents (over 12 years of age), the maximum cumulative dose is set at 450 mg/m². Maximum cumulative doses for neonates have not yet been defined, but lower tolerance is expected.

In children, the dose should be reduced due to their higher risk of cardiotoxicity, particularly delayed effects. Myelosuppression should be anticipated, with nadir occurring 10–14 days after the start of treatment. Refer to established treatment protocols and specialist literature.

Obese patients
A reduced initial dose or prolonged dosing interval may be considered in obese patients.

Intravesical administration:
Doxorubicina Teva may be administered by intravesical instillation for the treatment of superficial bladder carcinoma and to prevent recurrence after transurethral resection (T.U.R.). The recommended dose for intravesical treatment of superficial bladder carcinoma is 30–50 mg in 25–50 ml of physiological saline solution for instillation. The optimal concentration is approximately 1 mg/ml. The solution should remain in the bladder for 1–2 hours. During this time, the patient should be rotated 90° every 15 minutes. To avoid unwanted dilution with urine, patients should be instructed not to drink any fluids during the 12 hours preceding instillation (this should reduce urine production to approximately 50 ml/h). Instillations may be repeated at intervals ranging from 1 week to 1 month, depending on whether the treatment is therapeutic or prophylactic.

Note: Doxorubicina Teva cannot be substituted with a liposomal formulation of doxorubicin hydrochloride.

Treatment monitoring
Before or during treatment with doxorubicin, the following monitoring tests are recommended (the frequency of testing depends on the patient's general condition, dose administered, and concomitant medications):

• Chest X-rays and ECG
• Regular monitoring of cardiac function (LVEF measurement, e.g., by ECG, echocardiography, or radionuclide ventriculography)
• Examination of the oral cavity and pharynx to detect mucosal changes
• Blood tests: hematocrit, platelets, white blood cell count, SGPT, SGOT, LDH, bilirubin, uric acid, AST, ALT, ALP

Left ventricular function monitoring
An assessment of left ventricular ejection fraction (LVEF) should be performed using echocardiography or radionuclide ventriculography to optimize the patient's cardiac status. This evaluation should be carried out before starting treatment and after each cumulative dose of approximately 100 mg/m².

Storage conditions after dilution
Chemical and physical in-use stability has been demonstrated for 7 days when diluted to a concentration of 0.5 mg/ml in sodium chloride 9 mg/ml (0.9%) solution for infusion or in glucose 50 mg/ml (5%) solution for infusion, protected from light and stored at room temperature (15–25°C) or at 2–8°C.

When diluted to a concentration of 0.05 mg/ml, the diluted solution must be used immediately.

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

Disposal
Disposal procedures involving water must take into account the cytotoxic nature of this substance.