CANCIDAS 50 mg powder for concentrate for solution forinfusion

CANCIDAS is an antifungal medicine that interferes with the production of a component (glucan polysaccharide) of the fungal cell wall that is necessary if the fungus is to continue living and growing. Fungal cells exposed to CANCIDAS have incomplete or defective cell walls, making them fragile and unable to grow.

CANCIDAS may have been prescribed to treat a serious fungal infection called invasive candidiasis. The infection is caused by fungal (yeast) cells called Candida. These yeast cells are normally found in the digestive tract, and do not cause an infection unless they enter the bloodstream (in which case the infection is referred to as candidaemia) or other tissues or organs, such as the lining of the abdomen (peritonitis), the heart, the kidneys, the liver, bones, muscles, joints, spleen, or eyes. Persons at high risk for invasive candidiasis include surgical patients and those whose immune systems are deficient. Fever and chills that do not respond to antibacterial therapy are the most common symptoms of this type of infection.

Alternatively, your doctor may have prescribed CANCIDAS to treat a fungal infection in your nose, nasal sinuses, or lungs because other antifungal treatments have not been working as well as expected or because the other antifungal treatments are causing side effects. This infection is caused by organisms called Aspergillus. Aspergillus fungal infections begin in the respiratory system (in the nose, sinuses, or lungs) because the spores of the fungus are found in the air we breathe every day. This infection is named invasive aspergillosis. It is possible for the fungus to spread to other tissues and organs. In most healthy individuals, the natural ability to fight disease destroys the spores and removes them from the body. Some medical conditions lower the body?s resistance to diseases. Also, certain medicines prescribed for patients who are organ or bone marrow recipients lower the body?s resistance to diseases. These are the patients who are most likely to develop an Aspergillus infection.

Persistent fever due to infection may occur following chemotherapy or medical conditions that lower the body?s resistance to disease by lowering counts of certain white blood cells. If the fever is not reduced by treatment with an antibiotic, your doctor may suspect that you have a fungal infection and prescribe CANCIDAS to treat it.

Do not take CANCIDAS

• if you are hypersensitive (allergic) to caspofungin or any of the other ingredients of CANCIDAS.

Take special care with CANCIDAS

• if you have had or now have liver problems. Some patients with liver problems may require a dosage adjustment.
• if you are taking cyclosporin, a medicine to help prevent organ transplant rejection or to treat certain problems with your immune system. Your physician may order additional blood tests during your treatment.
• if you have any allergies.

Tell your doctor about any medical conditions you have or have had.

Children and Adolescents

CANCIDAS has been approved for use in children and adolescents for all the infection types described above. The dose used in paediatric patients may differ from the dose used in adult patients.

Taking other medicines

Your physician will determine if any adjustments should be made to other medicines you may be taking. If you are receiving cyclosporine, your physician may order additional blood tests during your treatment.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. It is particularly important for your doctor to know if you are taking certain anti-HIV medicines (including efavirenz or nevirapine), the antiseizure (epilepsy) medicines phenytoin and carbamazepine, the steroid dexamethasone, the antibiotic rifampicin, and the immunosuppressant tacrolimus.

Pregnancy and breastfeeding

CANCIDAS has not been studied in pregnant women, and should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Women receiving CANCIDAS should not breast-feed.
Ask your doctor for advice before taking any medicine.

Driving and using machines

There is no information to suggest that CANCIDAS affects your ability to drive or operate machinery.

Important information about some of the ingredients of CANCIDAS

CANCIDAS contains sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

CANCIDAS will always be prepared and given to you by a doctor or another healthcare professional.

CANCIDAS should be administered once daily by slow intravenous infusion over approximately 1 hour.

Your physician will determine the duration of your treatment and how much CANCIDAS you will receive each day. He will monitor your response and condition. The dose will not need to be adjusted according to your age or if you are suffering from renal impairment. If you weigh more than 80 kg, a dose adjustment may be required.

If you take more CANCIDAS than you should

Your doctor will monitor your response and condition to determine what CANCIDAS treatment is needed. However, if you are concerned that you may have been given too much CANCIDAS, contact your doctor or another healthcare professional immediately.

If you miss/forget to take a dose of CANCIDAS

Your doctor will monitor your response and condition to determine what CANCIDAS treatment is needed. However, if you are concerned that you may have missed a dose, contact your doctor or another healthcare professional immediately.

If you stop taking CANCIDAS

There are no known withdrawal symptoms.

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

The following terms are used to describe how often side effects have been reported.

Very common (occurring in at least 1 in 10 patients treated)
Common (occurring in at least 1 of 100 and less than 1 of 10 patients treated)
Uncommon (occurring in at least 1of 1,000 and less than 1 of 100 patients treated) Rare (occurring in at least 1 of 10,000 and less than 1 of 1,000 patients treated)
Not known (cannot be estimated from the available data)

Adults 18 years of age or older:

Blood and lymphatic system disorders:

Uncommon: alterations in some laboratory blood tests (including decrease in red blood cell count)

Metabolism and nutrition disorders:

Common: low potassium levels in the blood
Uncommon: increase in amount of body fluid, loss of appetite, imbalance of salt in the body, low magnesium levels in the blood, high sugar level in the blood, low calcium level in the blood, increase in acid level in the blood

Psychiatric disorders:

Uncommon: nervousness, disorientation, inability to sleep

Nervous system disorders:

Common: headache
Uncommon: dizziness, taste disturbance, tingling or numbness, sleepiness, shaking, decreased feeling or sensitivity (especially in the skin)

Eye disorders:

Uncommon: yellowing of the whites of the eyes, blurred vision, swollen eyelid, increase in tears

Cardiac disorders:

Uncommon: sensation of fast or irregular heart beats, rapid heart beat, irregular heart beat, abnormal heart rhythm, heart failure

Vascular disorders:

Common: inflammation of vein
Uncommon: swelling and redness along a vein which is extremely tender when touched, flushing, hot flush, high blood pressure, low blood pressure

Respiratory, thoracic and mediastinal disorders:

Common: shortness of breath
Uncommon: blocked nose, pain in throat area, fast breathing rate, tightening of the bands of muscle around the airways resulting in wheezing or coughing, cough, shortness of breath that awakens the patient during sleep, shortage of oxygen in the body, crackling sounds in the lungs, wheezing

Gastrointestinal disorders:

Common: nausea, vomiting, diarrhoea
Uncommon: belly pain, upper belly pain, dry mouth, indigestion, stomach discomfort, bloating, swelling due to build-up of fluid around the belly, constipation, difficulty swallowing, passing gas

Hepatobiliary disorders:

Common: alterations in some laboratory blood tests (including increased values of some liver tests) Uncommon: decreased flow of bile, enlarged liver, yellowing of the skin and/or whites of the eyes, chemical-driven liver damage, liver disorder

Skin and subcutaneous tissue disorders:Common: rash, itching, excessive sweating, skin redness
Uncommon: red often itchy spots on the limbs and sometimes on the face and the rest of the body, rash of varying appearance, hives, generalised itching, abnormal skin tissue

Musculoskeletal and connective tissue disorders:Common: joint pain
Uncommon: back pain, pain in limb, bone pain, muscular weakness, muscle pain

Renal and urinary disorders:

Uncommon: loss of kidney function, sudden loss of kidney function

General disorders and administration site conditions:

Common: fever, chills, itching at the injection site
Uncommon: pain, catheter site pain, fatigue, injection site complaints (redness, hard lump, pain, swelling, irritation, rash, hives), inflammation of vein at injection site, swelling in limbs, tenderness, chest discomfort, chest pain, swelling of the face, feeling of body temperature change, generally feeling unwell, swelling

Investigations:

Common: alterations in some laboratory blood tests (including increased values of some kidney tests)

Children and adolescents (12 months to 17 years of age):

Nervous system disorders:

Common: headache

Cardiac disorders:

Common: rapid heart beat

Vascular disorders:

Common: flushing, low blood pressure

Hepatobiliary disorders:Common: alterations in some laboratory blood tests (increased values of some liver tests)

Skin and subcutaneous tissue disorders:Common: rash, itching

General disorders and administration site conditions:

Very common: fever
Common: chills, catheter site pain

Investigations:

Common: alterations in some laboratory blood tests

Possible histamine-mediated symptoms have been reported including reports of rash, swelling of the face and/or lips, and/or throat, itching, sensation of warmth, or trouble breathing.

Life-threatening allergic reactions that might include difficulty breathing with wheezing or worsening of an existing rash have also been reported rarely during administration of CANCIDAS. Other side effects may also occur rarely, and as with any prescription medicine, some side effects may be serious. Ask your doctor for more information.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Keep out of the reach and sight of children.

Do not use CANCIDAS after the expiry date which is stated on the carton and the vial. The first 2 numbers indicate the month; the next 4 numbers indicate the year. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C to 8°C).

Reconstituted CANCIDAS should be used immediately because it does not contain any preservatives to prevent bacterial contamination. Only a trained health care professional who has read the complete directions (please see below ?Instructions of how to reconstitute and dilute CANCIDAS?) can properly prepare this medicine for use.

What CANCIDAS contains

The active substance of CANCIDAS is caspofungin (as acetate).
The other ingredients are: sucrose, mannitol, glacial acetic acid, and sodium hydroxide.

What CANCIDAS looks like and contents of the pack
CANCIDAS is a sterile, white to off-white, freeze-dried compact powder.

Each pack contains one vial containing 50 mg Caspofungin (as acetate).

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder Merck Sharp Dohme Limited Hertford Road, Hoddesdon Hertfordshire EN11 9BU United Kingdom Product Manufacturer Merck Sharp Dohme B. V. Waarderweg 39, Postbus 581 2003 PC Haarlem The Netherlands

or

Laboratories Merck Sharp & Dohme- Chibret Route de Marsat-RIOM
63963 Clermont-Ferrand Cedex 9
France

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

BelgiqueBelgiëBelgien Merck Sharp Dohme B.V. TélTel 32 0 800 38693 MSDBelgiuminfomerck.com LuxembourgLuxemburg Merck Sharp Dohme B.V. Tél 32 0 800 38693 MSDBelgiuminfomerck.com

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This leaflet was last approved in

The following information is intended for medical or healthcare professionals only:

Instructions of how to reconstitute and dilute CANCIDAS:

Reconstitution of CANCIDAS

DO NOT USE ANY DILUENTS CONTAINING GLUCOSE as CANCIDAS is not stable in diluents containing glucose. DO NOT MIX OR CO-INFUSE CANCIDAS WITH ANY OTHER MEDICINES, as there are no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medicinal products. Visually inspect the infusion solution for particulate matter or discolouration.

INSTRUCTIONS FOR USE IN ADULT PATIENTS

Step 1 Reconstitution of conventional vials

To reconstitute the powder bring the vial to room temperature and aseptically add 10.5 ml of water for injections. The concentrations of the reconstituted vials will be 5.2 mg/ml.

The white to off-white compact lyophilised powder will dissolve completely. Mix gently until a clear solution is obtained. Reconstituted solutions should be visually inspected for particulate matter or discolouration. This reconstituted solution may be stored for up to 24 hours at or below 25°C.

Step 2 Addition of Reconstituted CANCIDAS to patient infusion solution

Diluents for the final solution for infusion are: sodium chloride solution for injection, or lactated Ringer?s solution. The solution for infusion is prepared by aseptically adding the appropriate amount of reconstituted concentrate (as shown in the table below) to a 250 ml infusion bag or bottle. Reduced volume infusions in 100 ml may be used, when medically necessary, for 50 mg or 35 mg daily doses. Do not use if the solution is cloudy or has precipitated. This infusion solution must be used within 24 hours if stored at or below 25°C, or within 48 hours if stored refrigerated at 2 to 8°C. Chemical and physical in-use stability of the diluted solution in sterile lactated Ringer?s solution and sodium chloride solution 9 mg/ml (0.9 %), 4.5 mg/ml (0.45 %), and 2.25 mg/ml (0.225 %) for infusion has been demonstrated for 24 hours at 25°C and for 48 hours at 2 to 8°C. From a microbiological point of view, the solution must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.

PREPARATION OF THE SOLUTION FOR INFUSION IN ADULTS

DOSE Standard preparation reconstituted CANCIDAS added to 250 ml final concentration Volume of recon- stituted CANCIDAS for transfer to intravenous bag or bottle Reduced volume infusion reconstituted CANCIDAS added to 100 ml final concentration 50 mg 10 ml 0.19 mgml - 50 mg at reduced volume 10 ml - 0.45 mgml 7 ml 0.14 mgml - 35 mg for moderate hepatic insufficiency from one 50 mg vial 7 ml - 0.33 mgml 35 mg for moderate hepatic insufficiency from one 50 mg vial at reduced volume 10.5 ml should be used for reconstitution of all vials

INSTRUCTIONS FOR USE IN PAEDIATRIC PATIENTS

Calculation of Body Surface Area (BSA) for paediatric dosing Before preparation of infusion, calculate the body surface area (BSA) of the patient using the following formula: (Mosteller3 Formula)

3 Mosteller RD Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 2231717 1098 letter

Preparation of the 70 mg/m2infusion for paediatric patients >3 months of age (using a 50-mg vial)

1. Determine the actual loading dose to be used in the paediatric patient by using the patient's BSA (as calculated above) and the following equation: BSA (m 2) X 70 mg/m 2 = Loading Dose The maximum loading dose on Day 1 should not exceed 70 mg regardless of the patient's calculated dose.

2. Equilibrate the refrigerated vial of CANCIDAS to room temperature.

3. Aseptically add 10.5 ml of 0.9 % Sodium Chloride Injection, Sterile Water for Injection or Bacteriostatic Water for Injection with methylparaben and propylparaben. a This reconstituted solution may be stored for up to one hour at ?25°C (?77°F). b This will give a final caspofungin concentration in the vial of 5.2 mg/ml.

4. Remove the volume of drug equal to the calculated loading dose (Step 1) from the vial. Aseptically transfer this volume (ml) c of reconstituted CANCIDAS to an IV bag (or bottle) containing 250 ml of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection, or Lactated Ringers Injection. Alternatively, the volume (ml) c of reconstituted CANCIDAS can be added to a reduced volume of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection or Lactated Ringers Injection, not to exceed a final concentration of 0.5 mg/ml. This infusion solution must be used within 24 hours if stored at ?25°C (?77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F).

Preparation of the 50 mg/m2infusion for paediatric patients >3 months of age (using a 50-mg vial)

1. Determine the actual daily maintenance dose to be used in the paediatric patient by using the patient's BSA (as calculated above) and the following equation: BSA (m 2) X 50 mg/m 2 = Daily Maintenance Dose The daily maintenance dose should not exceed 70 mg regardless of the patient's calculated dose.

2. Equilibrate the refrigerated vial of CANCIDAS to room temperature.

3. Aseptically add 10.5 ml of 0.9 % Sodium Chloride Injection, Sterile Water for Injection or Bacteriostatic Water for Injection with methylparaben and propylparaben. a This reconstituted solution may be stored for up to one hour at ?25°C (?77°F). b This will give a final caspofungin concentration in the vial of 5.2 mg/ml.

4. Remove the volume of drug equal to the calculated daily maintenance dose (Step 1) from the vial. Aseptically transfer this volume (ml) c of reconstituted CANCIDAS to an IV bag (or bottle) containing 250 ml of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection, or Lactated Ringers Injection. Alternatively, the volume (ml) c of reconstituted CANCIDAS can be added to a reduced volume of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection or Lactated Ringers Injection, not to exceed a final concentration of 0.5 mg/ml. This infusion solution must be used within 24 hours if stored at ?25°C (?77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F).

Preparation notes:

a The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained.

b Visually inspect the reconstituted solution for particulate matter or discoloration during reconstitution and prior to infusion. Do not use if the solution is cloudy or has precipitated.

c CANCIDAS is formulated to provide the full labeled vial dose (50 mg) when 10 ml is withdrawn from the vial.