CARDIOXANE 500 mg POWDER FOR SOLUTION FOR INFUSION

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before receiving Cardioxane

You should also know that:

• Your doctor may perform tests before and during treatment with this medicine to check how you respond to treatment and monitor the function of some organs, such as the heart, kidneys, or liver.
• Your doctor may perform blood tests during treatment with Cardioxane to monitor the function of your bone marrow. If you are receiving high-dose cancer treatment (e.g., chemotherapy or radiation) and are also being treated with high-dose Cardioxane, your bone marrow function may decrease. This can affect the production of red blood cells, white blood cells, and platelets.
• Cardioxane may increase the risk of developing leukemia (blood cancer).
• During treatment with Cardioxane, women who can become pregnant and men must use effective contraceptive methods. Women and men should continue to use them for at least six months after finishing treatment with Cardioxane (see also “Pregnancy and breast-feeding”).
• The combination of Cardioxane with the cancer treatment you are receiving may increase the risk of blood clots.
• IfCardioxanepowder or solution comes into contact with the skin,inform your doctor immediately. You or your doctor should wash the affected area immediately with plenty of water.

Children and adolescents

The long-term benefit/risk relationship of the medicine in children and adolescents is not yet clear. Your doctor will inform you of the benefit/risk relationship of this medicine.

Elderly patients (over 65 years old)

Your doctor may adjust your treatment with this medicine according to your state of health (in case of heart, liver, or kidney problems).

Other medicines and Cardioxane

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

Do not take other medicines without informing your doctor, as there may be interactions between Cardioxane and other medicines:

• Vaccines: you should not use this medicine if you are going to be given the yellow fever vaccine, and it is not recommended to use Cardioxane if you are going to be given a vaccine that contains live virus particles.
• Phenytoin, a treatment for seizures.
• Cyclosporin or tacrolimus (both treatments reduce the body's immune system and are used to prevent organ rejection after an organ transplant).
• Myelosuppressive medicines (reduce the production of red blood cells, white blood cells, or platelets).

Pregnancy and breast-feeding

• You should not be given Cardioxane if you are pregnant or planning to become pregnant, unless your doctor considers it necessary.
• Women who can become pregnant and men must use effective contraceptive methods during treatment with Cardioxane and for at least six months after finishing treatment with Cardioxane.
• Stop breast-feeding while being treated with this medicine.

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

Driving and using machines

Fatigue has been reported with Cardioxane treatment. Therefore, if you feel drowsy, do not drive or use machinery.

3. How Cardioxane is administered

How you will be givenCardioxane

This medicine is prepared and administered by a doctor or other healthcare professional. Your doctor will decide what dose you should be given.

• Cardioxane is administered as a drip (infusion) into a vein over approximately 15 minutes.
• Administration will start about 30 minutes before the administration of your cancer treatment (doxorubicin and/or epirubicin).

If you think you have been given too muchCardioxane

If you are given too much Cardioxane, inform your doctor or nurse immediately. You may experience some of the side effects listed in section 4, “Possible side effects”.

4. Possible side effects

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

Some side effects can be serious and need immediate medical attention:

Very common(may affect more than 1 in 10 patients):

• Common infections, fever, sore throat, bruising, and unexpected bleeding (signs of blood disorders such as low red blood cell count, low white blood cell count, low platelet count, and low granulocyte count. However, blood cell counts may return to normal after each treatment cycle)

Common(may affect up to 1 in 10 patients):

• Swelling and redness in a vein

Uncommon(may affect up to 1 in 100 patients):

• Leukemia (blood cancer)
• Sudden loss of consciousness
• Swelling and pain in a part of the body that may be caused by blood clots in the vein
• Swelling of the tissue in the legs

The following adverse reactions have been reported in a few patients during treatment with Cardioxane:

• Allergic reactions including itching, rash, swelling of the face/throat, wheezing, difficulty breathing, changes in consciousness, low blood pressure
• Sudden difficulty breathing, coughing up blood, and chest pain (signs of blood clots in the lungs)

If you experience any of the above side effects, informyour doctor or go to the nearest emergency department immediately.

Other side effects include:

Very common(may affect more than 1 in 10 patients):

• Hair loss
• Vomiting, mouth sores, nausea
• Weakness

Common(may affect up to 1 in 10 patients):

Uncommon(may affect up to 1 in 100 patients)

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet.

You can also report side effects directly through the Spanish Medicines Agency's online platform: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Cardioxane

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

• Do not store above 25°C. Store in the original packaging to protect from light.
• Do not use this medicine after the expiry date stated on the packaging after EXP.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Container Contents and Additional Information

Composition ofCardioxane

• The active ingredient is dexrazoxane (as dexrazoxane hydrochloride).
• Each vial contains 500 mg of dexrazoxane. Cardioxane does not contain any other components.

Appearance ofCardioxaneand Container Contents

Cardioxane is a white to off-white powder for solution for infusion, available in packs of one vial and packs of four vials. Only certain pack sizes may be marketed.

Marketing Authorization Holder

CNX Therapeutics Ireland Limited

5th Floor Rear

Connaught House

1 Burlington Road

Dublin 4

Dublin, Ireland

Manufacturer

Cenexi Laboratoires Thissen S.A.

Rue de la Papyrée 2-4-6

1420 Braine-l’Alleud

Belgium

Date of Last Revision of this Leaflet:22/08/2017.

Detailed and up-to-date 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 INFORMATIONIS INTENDED ONLY FORHEALTHCARE PROFESSIONALS

Cardioxane500mg powder for solution for infusion

Dexrazoxane

DOSAGE AND ADMINISTRATION

Cardioxane is administered by short intravenous infusion (15 minutes), approximately 30 minutes before the administration of the anthracycline, with a dose equal to 10 times the doxorubicin equivalent and 10 times the epirubicin equivalent dose.

Therefore, it is recommended to administer Cardioxane at a dose of 500 mg/m2 when using the usual doxorubicin dosing regimen of 50 mg/m2, or at a dose of 600 mg/m2 when using the usual epirubicin dosing regimen of 60 mg/m2.

Pediatric Population

The safety and efficacy of this medicinal product in children from 0 to 18 years have not been established.

Cardioxane is contraindicated in children from 0 to 18 years who are scheduled to receive a cumulative dose less than 300 mg/m2 of doxorubicin or the cumulative equivalent dose of another anthracycline.

Renal Impairment

In patients with moderate to severe renal impairment (creatinine clearance <40ml>

Hepatic Impairment

The dose ratio should be maintained; i.e., if the dose of anthracycline is reduced, the dose of dexrazoxane should be reduced accordingly.

Elderly Patients (over 65 years)

The dose may be adjusted during treatment with Cardioxane according to the patient's health status (in case of heart, liver, or kidney problems).

In case of overdose, symptomatic treatment should be applied.

INSTRUCTIONS FOR USE

Recommendations for Safe Handling

Prescribers should consult national or recognized guidelines on the handling of cytotoxic agents when using Cardioxane. Reconstitution should only be carried out by trained personnel in a designated area for cytotoxics. Pregnant women should not handle the preparation.

It is recommended to use gloves and other protective clothing to avoid skin contact. Skin reactions have been described after contact with Cardioxane. In case Cardioxane comes into direct contact with the skin or mucous membranes, the affected area should be washed immediately with plenty of water.

Preparation for Intravenous Administration

Reconstitution of Cardioxane

For reconstitution, the contents of each vial should be dissolved in 25 ml of water for injectable preparations. The vial contents dissolve in a few minutes with gentle agitation. The resulting solution has a pH of approximately 1.6. This solution should be further diluted before administration to the patient.

Dilution of Cardioxane

To avoid the risk of thrombophlebitis at the injection site, Cardioxane should be diluted before infusion with one of the solutions mentioned in Table 1. The final volume should be proportional to the number of Cardioxane vials used and the amount of infusion solution for dilution, which can range from 25 ml to 100 ml per vial.

The following table (Table 1) summarizes the final volume and approximate pH of the reconstituted and diluted product from one vial and four vials of Cardioxane. The minimum and maximum volumes of infusion solution to be used per vial are indicated in Table 1.

Table 1. Reconstitution and Dilution of Cardioxane Vials

• The sodium lactate 11.2% should be diluted with a factor of 6 to achieve a concentration of 0.16M.

It is normally recommended, to increase the pH of the solution, to use larger dilution volumes (with a maximum of 100 ml of additional infusion liquid per 25 ml of reconstituted Cardioxane). Smaller volumes (with a minimum of 25 ml of additional infusion liquid per 25 ml of reconstituted Cardioxane) may be used if necessary, depending on the patient's hemodynamic status.

The reconstituted and diluted Cardioxane solution is for single use. Once the product has been diluted, it should be used immediately or within the next four hours, provided it is stored at a temperature between 2°C and 8°C and protected from light.

In cases where the solution and its container allow, parenteral drugs should be inspected visually for particulate matter or precipitate. Cardioxane usually appears as a colorless to yellow solution immediately after reconstitution, although some color variability may be observed over time, which does not indicate loss of activity as long as the product has been stored according to the recommendations. However, it is recommended to discard the product if it is not colorless or yellow immediately after reconstitution.

Incompatibilities

Cardioxane should not be mixed with other products except for the dilution solutions mentioned above.

Storage

Do not use Cardioxane after the expiry date stated on the container.

Before Opening

Do not store above 25°C. Store in the original packaging to protect from light.

After Reconstitution and Dilution

The diluted Cardioxane solution is physically and chemically stable for 4 hours at 25°C.

From a microbiological point of view, the freshly prepared infusion solution should be used immediately. Otherwise, the responsibility for the storage time and conditions of the product before administration lies with the user and, in any case, should not exceed 4 hours at a temperature between 2°C and 8°C (in the refrigerator), with protection from light.

Disposal

Disposal of the used medicinal product and materials that have come into contact with it should be carried out in accordance with local regulations. Care and caution should be taken when disposing of items used to reconstitute and dilute Cardioxane.