CUBICIN Powder for concentrate for solution for injection or infusion Ref.[2700] Active ingredients: Daptomycin

Clinical studies in patients employed infusion of daptomycin over 30 minutes. There is no clinical experience in patients with the administration of daptomycin as an injection over 2 minutes. This mode of administration was only studied in healthy subjects. However, when compared with the same doses given as intravenous infusions over 30 minutes there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).

Posology

• cSSTI without concurrent Staphylococcus aureus bacteraemia: Cubicin 4 mg/kg is administered once every 24 hours for 7-14 days or until the infection is resolved (see section 5.1).
• cSSTI with concurrent Staphylococcus aureus bacteraemia: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient.
• Known or suspected right-sided infective endocarditis due to Staphylococcus aureus: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy should be in accordance with available official recommendations.

Cubicin is administered intravenously in 0.9% sodium chloride (see section 6.6). Cubicin should not be used more frequently than once a day.

Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least weekly) during treatment (see section 4.4).

Renal impairment

Daptomycin is eliminated primarily by the kidney.

Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in patients with any degree of renal impairment (CrCl <80 ml/min) when it is considered that the expected clinical benefit outweighs the potential risk. The response to treatment, renal function and creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of renal impairment (see also sections 4.4 and 5.2). The dosage regimen for Cubicin in paediatric patients with renal impairment has not been established.

Dose adjustments in patients with renal impairment by indication and creatinine clearance:

cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia
(1) The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see sections 4.4 and 5.2).
(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK modelling results, are recommended for patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the completion of dialysis on dialysis days (see section 5.2).

Hepatic impairment

No dose adjustment is necessary when administering Cubicin to patients with mild or moderate hepatic impairment (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic impairment (Child-Pugh Class C). Therefore caution should be exercised if Cubicin is given to such patients.

Elderly patients

The recommended doses should be used in elderly patients except those with severe renal impairment (see above and section 4.4).

Paediatric patients (1 to 17 years of age)

The recommended dosage regimens for paediatric patients based on age and indication are shown below.

cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia;
¹ Minimum duration of Cubicin for paediatric SAB should be in accordance with the perceived risk of complications in the individual patient. The duration of Cubicin may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient. In the paediatric SAB study, the mean duration of IV Cubicin was 12 days, with a range of 1 to 44 days. The duration of therapy should be in accordance with available official recommendations.

Cubicin is administered intravenously in 0.9% sodium chloride (see section 6.6). Cubicin should not be used more frequently than once a day.

Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least weekly) during treatment (see section 4.4).

Paediatric patients below the age of one year should not be given Cubicin due to the risk of potential effects on muscular, neuromuscular and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see section 5.3).

Method of administration

In adults, Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period or by intravenous injection (see section 6.6) and administered over a 2-minute period.

In paediatric patients aged 7 to 17 years, Cubicin is given by intravenous infusion over a 30-minute period (see section 6.6). In paediatric patients aged 1 to 6 years, Cubicin is given by intravenous infusion over a 60-minute period (see section 6.6).

In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by haemodialysis (approximately 15% of the administered dose is removed over 4 hours) or by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours).

Shelf life: 3 years.

After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial has been demonstrated for 12 hours at 25°C and up to 48 hours at 2°C–8°C. Chemical and physical stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours at 2°C–8°C.

For the 30-minute intravenous infusion, the combined storage time (reconstituted solution in vial and diluted solution in infusion bag; see section 6.6) at 25°C must not exceed 12 hours (or 24 at 2°C–8°C).

For the 2-minute intravenous injection, the storage time of the reconstituted solution in the vial (see section 6.6) at 25°C must not exceed 12 hours (or 48 at 2°C–8°C).

However, from a microbiological point of view the product should be used immediately. No preservative or bacteriostatic agent is present in this product. If not used immediately, in-use storage times are the responsibility of the user and would not normally be longer than 24 hours at 2°C–8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C–8°C).

For storage conditions of the reconstituted or reconstituted and diluted medicinal product see section 6.3.

Cubicin 350 mg powder for solution for injection or infusion: Single use 10 ml type I clear glass vials with type I rubber stoppers and aluminium closures with yellow plastic flip off caps.

Cubicin 500 mg powder for solution for injection or infusion Single use 10 ml type I clear glass vials with type I rubber stoppers and aluminium closures with blue plastic flip off caps.

Available in packs containing 1 vial or 5 vials. Not all pack sizes may be marketed.

Daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over 2 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional dilution step as detailed below.

Cubicin 350mg powder for solution for injection or infusion

Cubicin given as 30-minute intravenous infusion

A 50 mg/ml concentration of Cubicin for infusion is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous infusion, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.

1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.
5. The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical volume 50 ml).
6. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
7. Replace needle with a new needle for the intravenous infusion.
8. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9. The reconstituted and diluted solution should then be infused intravenously over 30 minutes as directed in section 4.2.

The following have been shown to be compatible when added to Cubicin containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.

Cubicin given as 2-minute intravenous injection

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

A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous injection, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.

1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.
5. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
6. Replace needle with a new needle for the intravenous injection.
7. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
8. The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.

Cubicin vials are for single-use only.

From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Cubicin 500mg powder for solution for injection or infusion

Cubicin given as 30-minute intravenous infusion

A 50 mg/ml concentration of Cubicin for infusion is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous infusion, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.

1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.
5. The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical volume 50 ml).
6. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
7. Replace needle with a new needle for the intravenous infusion.
8. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9. The reconstituted and diluted solution should then be infused intravenously over 30 minutes as directed in section 4.2.

The following have been shown to be compatible when added to Cubicin containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.

Cubicin given as 2-minute intravenous injection

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

A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

To prepare Cubicin for intravenous injection, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.

1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.
5. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
6. Replace needle with a new needle for the intravenous injection.
7. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
8. The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.

Cubicin vials are for single-use only.

From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.