CUBICIN 350 mg POWDER FOR INJECTABLE SOLUTION AND FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Cubicin 350mg powder for solution for injection and infusion

daptomycin

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

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What Cubicin is and what it is used for
2. What you need to know before you are given Cubicin
3. How Cubicin is given
4. Possible side effects
5. Storing Cubicin
6. Contents of the pack and other information

1. What Cubicin is and what it is used for

The active substance in Cubicin powder for solution for injection and infusion is daptomycin. Daptomycin is an antibacterial agent capable of stopping the growth of certain bacteria. Cubicin is used in adults and in children and adolescents (aged 1 to 17 years) to treat infections of the skin and soft tissues. It is also used to treat infections in the blood when associated with a skin infection.

Cubicin is also used in adults to treat infections of the tissues that line the inside of the heart (including heart valves), caused by a type of bacteria called Staphylococcus aureus.It is also used to treat infections in the blood caused by the same type of bacteria when associated with a heart infection.

Depending on the type of infection(s) you have, your doctor may also prescribe other antibacterial agents while you are being treated with Cubicin.

2. What you need to know before you are given Cubicin

You must not be given Cubicin

If you are allergic to daptomycin or sodium hydroxide or any of the other ingredients of this medicine (listed in section 6).

If this is the case, tell your doctor or nurse. If you think you may be allergic, ask your doctor or nurse.

Warnings and precautions

Tell your doctor or nurse before you are given Cubicin:

• If you have or have ever had kidney problems. Your doctor may need to change the dose of Cubicin (see section 3 of this leaflet).
• Occasionally, patients who receive Cubicin may develop increased sensitivity, pain, or muscle weakness (see section 4 of this leaflet for more information). Tell your doctor if this happens. Your doctor will make sure you have a blood test and advise whether or not you should continue using Cubicin. The symptoms usually go away within a few days after stopping treatment with Cubicin.
• If you have ever had a severe skin rash or skin peeling, blisters, and/or sores in the mouth, or severe kidney problems after taking daptomycin.
• If you are significantly overweight, there is a possibility that your blood levels of Cubicin may be higher than those found in people of average weight, and you may need closer monitoring for side effects.

If any of the above applies to you, tell your doctor or nurse before you are given Cubicin.

Tell your doctor or nurse immediatelyif you develop any of the following symptoms:

• Severe and serious allergic reactions have been observed in patients treated with almost all antibacterial agents, including Cubicin. Symptoms can include wheezing, difficulty breathing, swelling of the face, neck, and throat, skin rash, and hives, or fever.
• Severe skin diseases have been reported with the use of Cubicin. The symptoms that occur with these skin diseases can include:

• onset of fever or worsening of fever,
• red spots on the skin that are raised or filled with fluid, which can start in the armpits or in areas of the chest or groin and can spread over a large area of the body,
• blisters or sores in the mouth or genitals.

• Severe kidney problems have been reported with the use of Cubicin. Symptoms can include fever and rash.
• Any type of tingling or numbness in the hands or feet, loss of sensation, or unusual movement difficulties. If this happens, tell your doctor, who will decide whether you should continue treatment.
• Diarrhea, especially if you notice blood or mucus in your stool or if the diarrhea becomes severe or lasts a long time.
• Onset of fever or worsening of fever, cough, or difficulty breathing. These can be signs of a rare but serious lung problem called eosinophilic pneumonia. Your doctor will check the condition of your lungs and decide whether or not you should continue treatment with Cubicin.

Cubicin may interfere with laboratory tests that measure your blood's ability to clot. The results may appear to suggest poor clotting, even if there is no actual problem. Therefore, it is essential that your doctor is aware that you are receiving Cubicin. Tell your doctor that you are being treated with Cubicin.

Your doctor will perform blood tests to monitor the health of your muscles before you start treatment and frequently during treatment with Cubicin.

Children and adolescents

Cubicin must not be given to children under 1 year of age. Animal studies have shown that this age group may experience severe side effects.

Use in elderly patients

Patient over 65 years of age may receive the same dose as other adults, provided their kidneys are working correctly.

Other medicines and Cubicin

Tell your doctor or nurse if you are using, have recently used, or might use any other medicines.

It is particularly important that you mention the following:

• Medicines called statins or fibrates (to lower cholesterol) or cyclosporin (a medicine used in transplants to prevent organ rejection or for other conditions, e.g., rheumatoid arthritis or atopic dermatitis). It may increase the risk of muscle side effects if you take any of these medicines (and others that may affect muscles) during treatment with Cubicin. Your doctor may decide not to give you Cubicin or temporarily stop treatment with the other medicine.
• Pain-relieving medicines called non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors (e.g., celecoxib). They may interfere with the elimination of Cubicin by the kidneys.
• Oral anticoagulants (e.g., warfarin), which are medicines that prevent blood clotting. Your doctor may need to monitor your blood clotting times.

Pregnancy and breastfeeding

Cubicin is not normally given to pregnant women. If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, ask your doctor or pharmacist for advice before using this medicine.

You must not breastfeed if you are receiving Cubicin, as it may pass into breast milk and affect the baby.

Driving and using machines

Cubicin has no known effects on the ability to drive or use machines.

Cubicin contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per dose; it is essentially "sodium-free".

3. How Cubicin is given

Cubicin will be given to you by your doctor or nurse.

Adults (18 years of age and older)

The dose will depend on your weight and the type of infection being treated. The usual dose for adults is 4 mg per kilogram of body weight once a day for skin infections or 6 mg per kilogram of body weight once a day for heart or blood infections associated with skin infections. In adult patients, this dose is given directly into your bloodstream (into a vein), either as an infusion that lasts about 30 minutes or as an injection that lasts about 2 minutes. The same dose is recommended for people over 65 years of age, provided their kidneys are working correctly.

If your kidneys do not work well, you may receive Cubicin less frequently, e.g., every other day. If you are on dialysis and your next dose of Cubicin is due on a dialysis day, you will normally receive Cubicin after the dialysis session.

Children and adolescents (1 to 17 years of age)

The recommended doses in children and adolescents (1 to 17 years) will depend on the patient's age and the type of infection being treated. This dose is given directly into the bloodstream (into a vein), as an infusion that lasts about 30-60 minutes.

A complete treatment for skin infections usually lasts between 1 and 2 weeks. Your doctor will decide the duration of your treatment for blood or heart infections and for skin infections.

Detailed instructions for use and handling are provided at the end of the leaflet.

4. Possible side effects

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

The following are the most serious side effects:

Serious side effects with frequency not known(cannot be estimated from the available data)

• Some cases of hypersensitivity reactions (severe allergic reactions, including anaphylaxis and angioedema) have been reported during the administration of Cubicin. These severe allergic reactions require immediate medical attention. Tell your doctor or nurse immediately if you have any of the following symptoms:

• Chest pain or pressure,
• Rash or hives,
• Swelling around the throat,
• Fast or weak pulse,
• Wheezing,
• Fever,
• Chills or shivering,
• Flushing,
• Dizziness,
• Fainting,
• Metallic taste.

• Tell your doctor immediately if you have pain, increased sensitivity, or muscle weakness of unknown origin. Muscle problems can be severe, including muscle breakdown (rhabdomyolysis), which can cause kidney damage.

Other side effects that have been reported with the use of Cubicin are:

• A rare but potentially serious lung condition called eosinophilic pneumonia, mostly after more than 2 weeks of treatment. Symptoms can include difficulty breathing, onset of cough or worsening of cough, or onset of fever or worsening of fever.
• Severe skin diseases. The symptoms can include:
• onset of fever or worsening of fever,
• red spots on the skin that are raised or filled with fluid, which can start in the armpits or in areas of the chest or groin and can spread over a large area of the body,
• blisters or sores in the mouth or genitals.
• A severe kidney problem. Symptoms can include fever and rash.

If you experience these symptoms, tell your doctor or nurse immediately. Your doctor will perform additional tests to establish a diagnosis.

The following are the most common side effects:

Common side effects(may affect up to 1 in 10 patients)

• Fungal infections, such as thrush (mouth ulcers),
• Urinary tract infection,
• Decrease in red blood cell count (anemia),
• Dizziness, anxiety, difficulty sleeping,
• Headache,
• Fever, weakness (asthenia),
• High or low blood pressure,
• Constipation, abdominal pain,
• Diarrhea, nausea or vomiting,
• Flatulence,
• Abdominal swelling or abdominal distension,
• Skin rash or itching,
• Pain, itching, or redness at the infusion site,
• Pain in arms or legs,
• High levels of liver enzymes or creatine phosphokinase (CPK) in blood tests.

The following are other side effects that may occur with Cubicin:

Uncommon side effects(may affect up to 1 in 100 patients)

Blood disorders (e.g., increased platelet count, which can increase the tendency to develop blood clots, or increased white blood cell count),

• Decreased appetite,
• Numbness or tingling in hands or feet, altered sense of taste,
• Tremors,
• Changes in heart rhythm, flushing,
• Indigestion (dyspepsia), tongue inflammation,
• Itchy rash,
• Pain, cramps, or muscle weakness, muscle inflammation (myositis), joint pain,
• Kidney problems,
• Vaginal inflammation and irritation,
• Generalized pain or weakness, fatigue (tiredness),
• High blood sugar, serum creatinine, myoglobin, or lactate dehydrogenase (LDH), prolonged blood clotting time, or electrolyte imbalance, in blood tests,
• Itchy eyes.

Rare side effects(may affect up to 1 in 1,000 patients)

• Yellowing of the skin and eyes (jaundice),
• Prolonged prothrombin time.

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

Antibiotic-associated colitis, including pseudomembranous colitis (severe or persistent diarrhea containing blood and/or mucus, associated with abdominal pain or fever), bruising easily, bleeding gums, or nosebleeds.

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 national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storing Cubicin

• 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 carton after CAD and on the label after EXP. The expiry date is the last day of the month shown.
• Store in a refrigerator (2°C - 8°C).

6. Container Contents and Additional Information

Cubicin Composition

• The active ingredient is daptomycin. A vial of powder contains 350 mg of daptomycin.
• The other component is sodium hydroxide.

Product Appearance and Container Contents

Cubicin powder for solution for injection and infusion is presented in a glass vial as a pale yellow to light brown powder or cake. It is mixed with a solvent to form a solution before administration.

Cubicin is presented in packs containing 1 vial or 5 vials.

Marketing Authorization Holder

Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, Netherlands

Manufacturer

FAREVA Mirabel, Route de Marsat, Riom, 63963, Clermont-Ferrand Cedex 9, France

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet:<{MM/AAAA}><{month AAAA}>.

Detailed information on this medicinal product is available on the European Medicines Agency website: https://www.ema.europa.eu

This information is intended only for healthcare professionals:

Important: Please consult the Summary of Product Characteristics or Package Leaflet before prescribing.

Instructions for Use and Handling

350 mg presentation:

In adults, daptomycin can be administered intravenously as an infusion over 30 minutes or as an injection over 2 minutes. Unlike adults, daptomycin should not be administered to pediatric patients as an injection over 2 minutes. Pediatric patients 7 to 17 years of age should receive daptomycin as an infusion over 30 minutes. Pediatric patients under 7 years of age who receive doses of 9-12 mg/kg should be administered daptomycin as an infusion over 60 minutes. Preparation of the infusion solution requires an additional dilution step, as described below.

Cubicin administered as an intravenous infusion over 30 or 60 minutes

Reconstituting the lyophilized product with 7 ml of an injectable solution containing 9 mg/ml of sodium chloride (0.9%) yields a concentration of 50 mg/ml of Cubicin for infusion.

The lyophilized product takes approximately 15 minutes to dissolve. The fully reconstituted product has a transparent appearance and may present some small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous infusion, follow these instructions:

For reconstitution or dilution of Cubicin lyophilized product, aseptic technique should be used throughout the process.

For reconstitution:

1. The polypropylene "flip-off" cap should be removed to expose the central part of the rubber stopper. Clean the top of the rubber stopper with an alcohol swab or other antiseptic solution and let it dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw up 7 ml of an injectable solution containing 9 mg/ml of sodium chloride (0.9%) into a syringe using a sterile transfer needle of 21 gauge or smaller, or a needleless device, and slowly inject it through the center of the rubber stopper into the vial, aiming the needle towards the vial wall.
2. The vial should be gently rotated to ensure that the product is completely wetted, and then left to stand for 10 minutes.
3. Finally, the vial should be gently rotated/shaken for a few minutes until a clear reconstituted solution is obtained. Avoid vigorous agitation to prevent foam formation.
4. The reconstituted solution should be carefully inspected before use to ensure that the substance is dissolved and to verify the absence of particles in suspension. The color of the reconstituted Cubicin solution may vary from pale yellow to light brown.
5. The reconstituted solution should then be diluted with 9 mg/ml of sodium chloride (0.9%) (typical volume of 50 ml).

For dilution:

1. Slowly withdraw the reconstituted liquid (50 mg daptomycin/ml) from the vial using a new sterile needle of 21 gauge or smaller, inverting the vial so that the solution falls towards the stopper. Using a syringe, insert the needle into the inverted vial. Keeping the vial inverted, place the tip of the needle at the lowest point of the liquid while withdrawing the solution into the syringe. Before removing the needle from the vial, pull the plunger back to the end of the syringe cylinder to withdraw the required solution from the inverted vial.
2. Expel air, large bubbles, and any excess solution to obtain the required dose.
3. Transfer the required reconstituted dose to 50 ml of 9 mg/ml of sodium chloride (0.9%).
4. The reconstituted and diluted solution should be infused intravenously over 30 or 60 minutes.

Cubicin is not physically or chemically compatible with solutions containing glucose. The following drugs have been shown to be compatible when added to infusion solutions containing Cubicin: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin, and lidocaine.

The combined storage time (reconstituted solution in the vial and diluted solution in infusion bags) at 25°C should not exceed 12 hours (24 hours if refrigerated).

The stability of the diluted solution in infusion bags has been established for 12 hours at 25°C or 24 hours if refrigerated at 2°C – 8°C.

Cubicin administered as an intravenous injection over 2 minutes (only for adult patients)

Water should not be used for the reconstitution of Cubicin for intravenous injection. Cubicin should be reconstituted only with 9 mg/ml of sodium chloride (0.9%).

Reconstituting the lyophilized product with 7 ml of an injectable solution containing 9 mg/ml of sodium chloride (0.9%) yields a concentration of 50 mg/ml of Cubicin for injection.

The lyophilized product takes approximately 15 minutes to dissolve. The fully reconstituted product has a transparent appearance and may present some small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous injection, follow these instructions:

For reconstitution of Cubicin lyophilized product, aseptic technique should be used throughout the process.

1. The polypropylene "flip-off" cap should be removed to expose the central part of the rubber stopper. Clean the top of the rubber stopper with an alcohol swab or other antiseptic solution and let it dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw up 7 ml of an injectable solution containing 9 mg/ml of sodium chloride (0.9%) into a syringe using a sterile transfer needle of 21 gauge or smaller, or a needleless device, and slowly inject it through the center of the rubber stopper into the vial, aiming the needle towards the vial wall.
2. The vial should be gently rotated to ensure that the product is completely wetted, and then left to stand for 10 minutes.
3. Finally, the vial should be gently rotated/shaken for a few minutes until a clear reconstituted solution is obtained. Avoid vigorous agitation to prevent foam formation.
4. The reconstituted solution should be carefully inspected before use to ensure that the substance is dissolved and to verify the absence of particles in suspension. The color of the reconstituted Cubicin solution may vary from pale yellow to light brown.
5. Slowly withdraw the reconstituted liquid (50 mg daptomycin/ml) from the vial using a sterile needle of 21 gauge or smaller.
6. Invert the vial so that the solution falls towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, place the tip of the needle at the lowest point of the liquid while withdrawing the solution into the syringe. Before removing the needle from the vial, pull the plunger back to the end of the syringe cylinder to withdraw the entire solution from the inverted vial.
7. Replace the needle with a new one for intravenous injection.
8. Expel air, large bubbles, and any excess solution to obtain the required dose.
9. The reconstituted solution should be slowly injected intravenously over 2 minutes.

The physical and chemical stability during use of the reconstituted solution in the vial has been demonstrated for 12 hours at 25°C and up to a maximum of 48 hours if refrigerated (2°C – 8°C).

However, from a microbiological point of view, the product should be used immediately. If not used immediately, the storage time during use is the responsibility of the user and normally should not exceed 24 hours at 2°C – 8°C, unless the reconstitution/dissolution has taken place in controlled and validated aseptic conditions.

This medicinal product should not be mixed with other medicinal products except those mentioned above.

Cubicin vials are for single use only. Any unused portion of the vial should be discarded.