DAPTOMYCIN HIKMA 500 mg POWDER FOR SOLUTION FOR INJECTION AND INFUSION

2. What you need to know before you are given Daptomicina Hikma

You should not be given Daptomicina Hikma

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, inform your doctor or nurse. If you think you may be allergic, consult your doctor or nurse.

Warnings and precautions

Consult your doctor or nurse before starting treatment with daptomycin:

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

If any of the above cases apply to you, inform your doctor or nurse before receiving daptomycin.

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

• Severe allergic reactions have been observed in patients treated with almost all antibacterial agents, including daptomycin. The symptoms may include 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 daptomycin. The symptoms that occur with these skin diseases may include:
• • onset of fever or worsening of it,
  • red spots on the skin, 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 ulcers in the mouth or genitals.
• Severe kidney problems have been reported with the use of daptomycin. The symptoms may include fever and rash.
• Any type of tingling or numbness in the hands or feet, loss of sensitivity, or unusual movement difficulties. If this happens, inform your doctor, who will decide whether or not to continue treatment.
• Diarrhea, especially if you notice the presence of blood or mucus in your stool or if the diarrhea becomes severe or prolonged.
• Onset of fever or worsening of it, cough, or difficulty breathing. These may 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 to continue treatment with daptomycin.

Daptomycin may interfere with laboratory tests that measure the 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 daptomycin. Inform your doctor that you are being treated with daptomycin.

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

Children and adolescents

Daptomycin should not be administered to children under one year of age, as animal studies have shown that this age group may experience severe adverse effects.

Use in elderly patients

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

Other medicines and Daptomicina Hikma

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 is possible that the risk of muscle side effects may increase if you take any of these medicines (and others that may affect the muscles) during treatment with daptomycin. Your doctor may decide not to administer daptomycin or temporarily interrupt treatment with the other medicine.
• Pain-relieving medicines called non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors (e.g., celecoxib). These may interfere with the elimination of daptomycin by the kidneys.
• Oral anticoagulants (e.g., warfarin), which are medicines that prevent blood clotting. It may be necessary for your doctor to monitor your blood clotting times.

Pregnancy and breastfeeding

Daptomycin is not usually given to pregnant women. If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

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

Driving and using machines

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

Daptomicina Hikma contains sodium

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

3. How Daptomicina Hikma is given

Daptomicina will be administered 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 administered 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 functioning correctly.

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

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

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

The following are described 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 daptomycin. These severe allergic reactions require immediate medical attention. Inform your doctor or nurse immediately if you have any of the following symptoms:

• Chest pain or pressure,
• Rash or hives, sometimes affecting the mouth and genitals
• Swelling around the throat,
• Fast or weak pulse,
• Difficulty breathing,
• Fever,
• Chills or shivering,
• Flushing,
• Dizziness,
• Fainting,
• Metallic taste.

Consult 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 daptomycin are:A rare but potentially serious lung condition called eosinophilic pneumonia, mostly after more than 2 weeks of treatment. The symptoms may include difficulty breathing, onset of cough or worsening of it, or onset of fever or worsening of it.
• Severe skin diseases. The symptoms may include:
• • onset of fever or worsening of it,
  • red spots on the skin, 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 ulcers in the mouth or genitals.
• A severe kidney problem. The symptoms may include fever and rash.

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

The following are described the most frequently reported side effects:

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

• Fungal infections, such as thrush,
• Urinary tract infection,
• Decrease in the number of red blood cells (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 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 described other side effects that may occur after treatment with daptomycin:

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

• Blood disorders (e.g., increased platelet count, which may increase the tendency to develop blood clots, or increased number of certain types of white blood cells),
• Decreased appetite,
• Numbness or tingling in the hands or feet, altered sense of taste,
• Tremors,
• Changes in heart rhythm, flushing,
• Indigestion (dyspepsia), tongue inflammation,
• Itchy rash,
• Muscle pain, cramps, or weakness, muscle inflammation (myositis), joint pain,
• Kidney problems,
• Vaginal inflammation and irritation,
• Generalized pain or weakness, fatigue (fatigue),
• 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 more easily, gum bleeding, or nosebleeds.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if it is possible that they are not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Daptomicina Hikma

• 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 and label after EXP. The expiry date refers to the last day of the month shown.
• Store in a refrigerator (between 2 °C and 8 °C).

After reconstitution:

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 at 2 °C – 8 °C.

After dilution:

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

For intravenous infusion over 30 minutes, the combined storage time (reconstituted solution in the vial and diluted solution in infusion bags; see section 6) at 25 °C should not exceed 12 hours (or 24 hours at 2 °C - 8 °C).

For intravenous injection over 2 minutes, the storage time of the reconstituted solution in the vial (see section 6) at 25 °C should not exceed 12 hours (or 48 hours at 2 °C - 8 °C).

However, from a microbiological point of view, the product should be used immediately. This product does not contain any preservative or bacteriostatic agent. If not used immediately, the in-use storage times are the responsibility of the user and would normally not be longer than 24 hours at 2 °C-8 °C, unless the reconstitution/dilution has been carried out under controlled and validated aseptic conditions.

Do not use Daptomicina Hikma if you notice any change in the appearance of the product (signs of moisture or presence of particles with a different color in the powder, or presence of particles, turbidity, or precipitate when reconstituting the solution).

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

6. Contents of the pack and other information

Composition of Daptomicina Hikma

• The active substance is daptomycin. One vial of powder contains 500 mg of daptomycin. One ml contains 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
• The other ingredient is sodium hydroxide (for pH adjustment).

Appearance of the Product and Container Contents

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

Hikma Daptomycin is available in packs containing 1 vial or 5 vials.

Only some pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Hikma Pharmaceuticals (Portugal) S.A.

Estrada do Rio da Mó, 8, 8A and 8B, Fervença

2705-906 Terrugem SNT

Portugal

Manufacturer

Medichem, S.A.

Narcis Monturiol 41A

08970 Sant Joan Despí (Barcelona)

Spain

Or

Hikma Italia S.p.A.

Viale Certosa, 10

27100 Pavia

Italy

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

Hikma Spain, S.L.U.

Calle Anabel Segura nº11, Edificio A, planta 1ª, oficina 2

28108 - Alcobendas, Madrid

Spain

This medicine is authorized in the Member States of the European Economic Area under the following names:

Date of the last revision of this leaflet: December 2023.

Other sources of information

Detailed information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS): http://www.aemps.gob.es/

The following information is intended exclusively for healthcare professionals

Important: Consult the Summary of Product Characteristics before prescribing this medicine.

Instructions for use and handling

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 by injection over 2 minutes in pediatric patients. Pediatric patients from 7 to 17 years old should receive daptomycin as an infusion over 30 minutes. In pediatric patients under 7 years old who receive a dose of 9-12 mg/kg, daptomycin should be administered over 60 minutes. Preparation of the infusion solution requires an additional dilution step, as detailed below:

Daptomycin Hikma administered as intravenous infusion over 30 or 60 minutes

By reconstituting the lyophilized product with 10 ml of sodium chloride 9 mg/ml (0.9%) injection solution, a concentration of 50 mg/ml of daptomycin for infusion can be obtained.

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

To prepare daptomycin for intravenous infusion, follow these instructions:

For reconstitution or dilution of the daptomycin lyophilized product, an aseptic technique must be used.

For reconstitution:

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

For dilution:

1. Slowly withdraw the appropriate reconstituted liquid (50 mg daptomycin/ml) from the vial using a new sterile needle of 21 gauge or smaller, inverting the vial to allow the solution to drain towards the stopper. With a syringe, insert the needle into the inverted vial. Keeping the vial inverted, place the tip of the needle at the bottom of the vial solution 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 all the 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 sodium chloride 9 mg/ml (0.9%).
4. The reconstituted and diluted solution should be infused intravenously over 30 or 60 minutes.

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

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

The stability of the diluted solution in infusion bags is 12 hours at 25 °C or 24 hours if stored refrigerated at 2 °C – 8 °C.

Daptomycin Hikma administered as a 2-minute intravenous injection (only for adult patients)

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

Reconstituting the lyophilized product with 10 ml of sodium chloride 9 mg/ml (0.9%) injection solution yields a concentration of 50 mg/ml of daptomycin for injection.

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

To prepare daptomycin for intravenous injection, follow these instructions:

An aseptic technique must be used at all times to reconstitute the daptomycin lyophilized product.

1. Remove the flip-off polypropylene cap to expose the central part of the rubber stopper. Clean the top of the rubber stopper with a cotton swab with alcohol or another antiseptic solution and let it dry. After cleaning, do not touch the rubber stopper or allow it to come into contact with any other surface. Withdraw 10 ml of sodium chloride 9 mg/ml (0.9%) injection solution into a syringe using a sterile transfer needle of 21 gauge or smaller, or a needleless device, then slowly inject it into the vial through the center of the rubber stopper, aiming the needle towards the vial wall.
2. The vial should be gently rotated to ensure that the product is completely moistened, and then left to stand for 10 minutes.
3. Finally, the vial should be gently rotated/shaken for a few minutes until a transparent reconstituted solution is obtained. Vigorous agitation/movement should be avoided to prevent foam formation in the product.
4. The reconstituted solution should be carefully inspected before use to ensure that the product is dissolved and to verify the absence of particles in suspension. The color of the reconstituted daptomycin solution may vary from pale yellow to light brown.
5. Slowly withdraw the reconstituted liquid (50 mg of daptomycin/ml) from the vial using a sterile needle of 21 gauge or smaller.
6. Invert the vial to allow the solution to drain towards the stopper. With a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, place the tip of the needle at the bottom of the vial solution 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 all the 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. Then, the reconstituted and diluted solution should be administered intravenously slowly over 2 minutes.

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

However, from a microbiological point of view, the product should be used immediately. If not used immediately, the in-use storage times are the responsibility of the user and normally should not exceed 24 hours at 2 °C - 8 °C, unless the reconstitution/dilution has been carried out under controlled and validated aseptic conditions.

This medicine should not be mixed with other medicines except those mentioned above.

The vials of Daptomycin Hikma are for single use. Any unused remainder of the vial should be discarded.