Doxorubicin Hikma

PACKAGE LEAFLET

Package leaflet: Information for the user

Doxorubicina Hikma

2 mg/ml
Concentrate for solution for infusion
Doxorubicin hydrochloride
Generic Medicine
Please read this entire leaflet carefully before using this medicine
because it contains important information for you.

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

Contents of this leaflet:

1. What Doxorubicina Hikma is and what it is used for
2. What you need to know before using Doxorubicina Hikma
3. How to use Doxorubicina Hikma
4. Possible side effects
5. How to store Doxorubicina Hikma
6. Package contents and other information

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

Doxorubicina Hikma belongs to a group of anticancer (antitumour) medicines known as anthracyclines. Doxorubicin damages tumour (cancerous) cells and prevents their growth.

Doxorubicina Hikma is used to treat:

• lung cancer (small cell lung carcinoma)
• certain bladder cancers (locally advanced or metastatic). It is also used intravesically (into the bladder) for early-stage (superficial) bladder cancer to prevent recurrence of bladder cancer after surgical intervention.
• bone cancer (osteosarcoma), administered before and after surgery
• breast cancer
• certain types of blood cancer (acute lymphocytic leukaemia or myeloblastic leukaemia)
• lymphatic tissue cancer (Hodgkin's and non-Hodgkin's lymphoma)
• bone marrow cancer (multiple myeloma)
• thyroid cancers (advanced papillary/follicular thyroid carcinoma, anaplastic thyroid carcinoma)
• soft tissue tumours (advanced soft tissue sarcoma in adults)
• recurrent ovarian cancer
• cancer of the uterine lining (advanced or recurrent endometrial carcinoma)
• a specific type of childhood kidney tumour (Wilms' tumour)
• a childhood nervous tissue tumour (advanced neuroblastoma).

Doxorubicina Hikma may also be used in combination with other anticancer medicines.
As Doxorubicina Hikma is an anticancer medicine, it will be administered in a specialised unit and under the supervision of a physician 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 need to know before using Doxorubicina Hikma

Do not use Doxorubicina Hikma:

• if you are allergic to doxorubicin or to any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to medicines belonging to the class of anthracyclines or anthracenediones.
• if you are breastfeeding.

Please speak with your doctor if you are in any of the situations described above.
Warnings and precautions
Talk to your doctor or nurse before using Doxorubicina Hikma.
Depending on the route of administration, Doxorubicina Hikma will NOT be administered to you in the following situations:

Intravenous use (into a vein):

• you have been informed, following previous anticancer therapy, that you had persistent reduction in blood cell production (poorly functioning bone marrow – myelosuppression)
• you developed severe inflammation or ulcers in the mouth (stomatitis) after previous anticancer therapy
• you have had certain heart problems (severe heart rhythm disturbances, reduced heart function, (previous) heart attack, heart inflammation). These problems may arise rapidly and have a short but severe course.
• tendency to easy bleeding
• you suffer from any type of systemic infections
• your liver is not functioning properly
• you have previously received doxorubicin or other anthracyclines up to the maximum cumulative dose.

Intravesical use (into the bladder):

• if you have a tumour growing into the wall of the bladder
• if you have a urinary tract infection
• if you have inflammation of the bladder
• if you have blood in your urine (haematuria)
• if you have difficulties with catheter use (a tube inserted into the bladder to drain urine).

Exercise particular caution with Doxorubicina Hikma and inform your doctor before treatment if:

• you are elderly
• you have had bone marrow damage
• you have previously received radiation therapy to the chest cavity (mediastinum)
• you have been treated with similar antitumour agents (other anthracyclines)
• you have or have ever had heart problems.

Please speak with your doctor if any of the above situations apply to you.
Important information about Doxorubicina Hikma

• Doxorubicin may cause infertility, which may be permanent, in both men and women.
• If you experience 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 start treatment in another vein and carefully monitor the affected area.
• If you have previously been treated with doxorubicin and have become pregnant (even up to 20 years ago), your doctor will monitor your heart function, even if you have not had heart problems in the past.
• Your urine may appear reddish during treatment with Doxorubicina Hikma.
• During treatment with Doxorubicina Hikma, 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, who will provide appropriate treatment.
• Vaccinations are not recommended during treatment with Doxorubicina Hikma. You should also avoid contact with people who have recently been vaccinated with the polio vaccine.

Before and during treatment with Doxorubicina Hikma, your doctor will:

• check your blood count before each treatment cycle, as doxorubicin treatment may 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, interrupt, or delay treatment.

• check your lungs and chest to ensure your lungs are functioning properly during treatment.

• perform an electrocardiogram (ECG), a test that records heart activity, before starting doxorubicin treatment and throughout treatment, as doxorubicin may cause inflammation of the heart muscle (cardiomyopathy). This is particularly important if you have had heart disease, are over 70 or under 15 years of age, have previously been treated with doxorubicin (or other related medicines in the anthracycline group), or have received radiation therapy to 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 a prior history of heart disease.
  In general, 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 heart function.

• monitor your blood uric acid levels and ensure you drink sufficient fluids, as doxorubicin may increase uric acid levels in the blood (hyperuricaemia).

• regularly check your mouth and throat during treatment, as doxorubicin may cause changes in the lining of the mouth and throat.

• monitor kidney function. Dose reduction may be necessary.

• monitor liver function (through blood tests). Dose reduction may be required if liver function is reduced.

• 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 Hikma.

Other medicines and Doxorubicina Hikma
Inform your doctor if you are taking, have recently taken, or might take any other medicines. In particular, 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 affecting heart function (such as calcium antagonists).
• 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 events.
• you have been treated with medicines affecting 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), or antiretroviral drugs (for AIDS). This may cause bone marrow damage, leading to reduced blood cell counts.
• 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 Hikma.
• 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 events (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 may cause increased uric acid levels in the blood.
• you are taking digoxin (for heart conditions), as the effect of digoxin may decrease.
• you are taking antiepileptic medicines such as phenytoin, carbamazepine, or valproate, as the effect of these medicines may decrease.
• 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.

Pregnancy and breastfeeding
If you are a woman, you must avoid pregnancy during treatment with doxorubicin and for 6 months after treatment ends.
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. If you are considering fathering a child after treatment, consult your doctor. Since doxorubicin may cause permanent infertility, it is advisable to discuss the possibility of sperm freezing before starting treatment (cryopreservation or cryostorage).
Doxorubicin is not recommended during pregnancy.
Breastfeeding must be discontinued during treatment with Doxorubicina Hikma.
Ask your doctor or pharmacist for advice before taking any medicine.
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 Hikma contains sodium
This medicine contains 3.54 mg (< 1 mmol) of sodium per ml of concentrate. These values should be taken into account for patients on a controlled sodium diet.

3. How to use Doxorubicina Hikma

Doxorubicin must be administered to you only under the supervision of a physician experienced in antitumor therapy.
Your doctor may perform certain tests, such as blood tests, ECG, etc., before starting treatment or during treatment to determine the appropriate dose of Doxorubicina Hikma to administer.
Doxorubicin will be administered into a vein through intravenous infusion, or into the bladder.
Preparation and administration of the medicine 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, and your general medical condition. It will also depend on any other treatments you may have received for your tumor.
Your doctor will calculate your body surface area in square meters (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 kidney or liver problems
If you have severe impairment of kidney or liver function, a dose reduction may be necessary.

If you are given more Doxorubicina Hikma than you should
Since the medicine is administered by a doctor, it is unlikely that you will receive an overdose.
However, if you have any concerns, inform your doctor or nurse immediately.
Effects of an overdose of Doxorubicina Hikma may include: inflammation of the stomach and intestines (particularly the lining), heart problems, and severe damage to the bone marrow (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 involves 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 you experience heart problems, you must be evaluated by a specialist (cardiologist).
Accidental extravasation (leakage outside the vein) can cause serious adverse effects, including tissue death (necrosis) and inflammation of the vein with blood clot formation.
A burning sensation at the infusion site may indicate extravasation; therefore, inform your doctor immediately if you suspect that extravasation has occurred.

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 everybody gets them.
Contact your doctor or nurse immediately if you experience:

• An allergic reaction causing swelling of the lips, face or neck making it very difficult to breathe; skin rash or hives, anaphylactic shock (a severe drop in blood pressure, paleness, restlessness, weak pulse, loss of consciousness).
• Severe symptoms of nausea, vomiting and inflammation of the lining of the mouth or nose.

These side effects are very serious, but rare. They may require urgent medical treatment.
Some of these side effects may be very severe and require careful patient monitoring. Some side effects depend on the rate of administration and the dose.
Bone marrow damage is an example of such effects and may be very serious, although it is usually temporary. Common symptoms of bone marrow damage include fever, infections, blood poisoning, shock (severe drop in blood pressure, paleness, restlessness, rapid and weak pulse, moist skin, decreased level of consciousness) due to blood poisoning (septic shock), bleeding, lack of oxygen in tissues (tissue hypoxia), and tissue death.
Accidental administration outside the vein (extravasation) may cause severe skin inflammation (cellulitis), blistering, inflammation of the vein with formation of a blood clot (thrombophlebitis), inflammation of the lymph glands characterised by painful red streaks under the skin surface (lymphangitis), and localised tissue death which may require surgical intervention (including skin grafting).

The following side effects have been reported with the frequencies indicated below:
Very common: affects more than 1 in 10 people
Common: affects 1 to 10 in 100 people
Uncommon: affects 1 to 10 in 1,000 people
Rare: affects 1 to 10 in 10,000 people
Very rare: affects less than 1 in 10,000 people
Not known: frequency cannot be estimated from the available data

Very common

• Nausea, vomiting, abdominal pain, gastrointestinal problems, diarrhoea.
• Inflammation of mucous membranes, e.g. of the mouth or oesophagus.
• Hair loss (reversible).
• Flushing (reddening of the skin), skin sensitivity to artificial or natural light (photosensitivity).
• Red colouration of urine.
• Bone marrow damage (myelosuppression) with reduction in the number of white blood cells and platelets, increasing the likelihood of infection and the risk of bleeding or bruising.
• 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 (over 60 years of age), or if the patient has high blood pressure.

Effects may occur immediately after treatment or may manifest several years after treatment.

• Fever.
• Anaemia (a reduction in red blood cells which may make the skin pale and cause weakness or shortness of breath).
• Inflammation of the lining 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.

Common

• 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.
• Bleeding problems (haemorrhage).
• Loss of appetite (anorexia).
• Allergic reactions at sites previously treated with radiotherapy (so-called radiation recall reaction).
• Itching.

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

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

Uncommon

• Doxorubicin, when used in combination with other anticancer medicines, may cause certain types of blood cancer (leukaemia). These cancers may become apparent within 1–7 years.
• Blood poisoning (sepsis/septicaemia).
• Bleeding from the stomach or intestine, abdominal pain, ulcers and tissue cell death (necrosis) in the large intestine with bleeding and infections, particularly in the large intestine. This may occur when doxorubicin is used together with cytarabine (an anticancer medicine).
• Loss of water (dehydration).

Rare

• Skin rash (exanthema), hives.
• Discolouration (pigmentation) of the skin and nails, nail separation (onycholysis).
• Tremor, dizziness.
• Reactions at the injection site, including itching, skin 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).

Very rare

• Heart rhythm disorders (non-specific changes in the ECG trace).
• Isolated cases of potentially fatal heart rhythm irregularities (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).
• Blockage of a blood vessel due to a blood clot.
• 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.
• Tissue damage, particularly in hands and feet, causing redness, swelling, blistering, tingling or burning sensation due to infiltration of the medicine into tissues (palmar-plantar erythrodysesthesia syndrome).
• 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).
• Hot flushes of the face.

Not known

• Shortness of breath due to spasm of the airway muscles (bronchospasm).
• Temporary increase in liver enzymes.
• Severe liver damage which may occasionally lead to permanent damage of normal liver tissue (cirrhosis).
• Inflammation of the eyelid surfaces, outer layer of the eye or cornea (conjunctivitis/keratitis), increased tear production.
• Severe pain and swelling of the joints.
• Radiation damage (to skin, lungs, throat, oesophagus, stomach and intestinal lining, heart) that is already healing but may reappear with doxorubicin treatment.
• Patches of thick, scaly or crusted skin (actinic keratosis).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system at:
http://www.agenziafarmaco.gov.it/it/responsabili .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Doxorubicina Hikma

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after
EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2–8°C). Keep the vial in the outer packaging to
protect the medicine from light.
Do not use this medicine if you notice that the solution is not clear, red and free from
particles.
Any unused medicine or waste material derived from it must be disposed of according to
local legal requirements. Observe the guidelines for handling cytotoxic agents.

6. Package contents and other information

What Doxorubicina Hikma contains

• The active substance is doxorubicin hydrochloride.
• The other components are sodium chloride, hydrochloric acid and water for injections.

Each vial contains 2 mg/ml of doxorubicin hydrochloride.
Description of the appearance of Doxorubicina Hikma and contents of the pack
Doxorubicina Hikma 2 mg/ml concentrate for solution for infusion is a clear red solution.
Doxorubicina Hikma is supplied in amber glass vials with a rubber stopper and sealed with an aluminium flip-off cap.
Pack sizes:
1 x 5 ml
1 x 25 ml
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Hikma Farmacêutica (Portugal) S.A.
Estrada do Rio da Mó, nº8, 8A, 8B
Fervença
2705-906 Terrugem SNT
Portugal
Manufacturer
Thymoorgan Pharmazie GmbH
Schiffgraben 23
38690 Goslar
Germany
This medicinal product is authorised in the Member States of the European Economic Area under the following names:
Italy Doxorubicina Hikma, 2 mg/ml, concentrate for solution for infusion
Netherlands Doxorubicine HCl Hikma 2 mg/ml, concentraat voor oplossing voor infusie
Portugal Doxorubicina Hikma, 2 mg/ml, concentrado para solução para perfusão

The following information is intended exclusively for healthcare professionals:

• Expiry date

Unopened vials: 18 months
Opened vials: The product should be used immediately after opening the vial.
Prepared infusion solutions:
Chemical and physical stability during use has been demonstrated in 0.9% sodium chloride injection solution and in 5% dextrose injection solution for up to 7 days at 2–8°C and 25°C when prepared in glass containers protected from light.
From a microbiological standpoint, the product should be used immediately. If not used immediately, storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2°C–8°C, unless dilution has been carried out under controlled and validated aseptic conditions.

• Special precautions for disposal and handling

Doxorubicin is a potent cytotoxic agent that must be prescribed, prepared, and administered only by healthcare professionals experienced in the safe handling of such preparations. The following guidelines must be followed when handling, preparing, and using doxorubicin.

Preparation

1. Personnel must be trained in proper handling techniques.
2. Pregnant personnel must be excluded from handling this drug.
3. Personnel handling doxorubicin must wear protective clothing: goggles, gowns, disposable gloves, and masks.
4. All items used for administration and cleaning, including gloves, must be placed in high-risk waste disposal bags suitable for high-temperature incineration (700°C).
5. All cleaning materials must be disposed of as indicated above.
6. Always wash hands after removing gloves.

Contamination

1. In case of skin or mucous membrane contact, thoroughly wash the affected area with soap and water or with sodium bicarbonate solution. In any case, do not scrub the skin with a brush. A mild cream may be used to soothe skin irritation.
2. In case of eye contact, hold the eyelid open and rinse the affected eye with copious amounts of water for at least 15 minutes or with 9 mg/ml (0.9%) sodium chloride solution for injection. Then seek immediate medical evaluation by a specialist or ophthalmologist.
3. In case of spillage or leakage, treat with a 1% sodium hypochlorite solution or, more simply, with phosphate buffer (pH > 8) until the solution is decolorized. Use a cloth/sponge kept in an appropriate area. Rinse twice with water. Place all cloths into a plastic bag, seal it, and prepare for incineration.

Administration:
Doxorubicin for intravenous use must be administered carefully. It is recommended to administer the medicinal product through a freely flowing line with sodium chloride 9 mg/ml (0.9%) or dextrose 50 mg/ml (5%) over 3 to 5 minutes. This method, together with flushing the vein after administration, 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 1 hour, or as a continuous infusion (via a central catheter) 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 observed upon aspiration with a needle.
Doxorubicin must not be administered by intramuscular, subcutaneous, oral, or intrathecal routes.

Disposal
For single use only. Unused medicine or materials used for dilution and administration must be destroyed according to standard hospital procedures applicable to cytotoxic agents, in compliance with current regulations regarding the disposal of hazardous waste.
Medicines must not be disposed of via wastewater or household waste. This will help protect the environment.