DAPTOMYCIN 350 MG POWDER FOR SOLUTION FOR INJECTION OR INFUSION - summary of medicine characteristics

Daptomycin 350 mg Powder for solution for injection or infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 350 mg daptomycin.

One ml provides 50 mg of daptomycin after reconstitution with 7 ml of sodium chloride 9 mg/ml (0.9%) solution.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection or infusion.

A pale yellow to light brown lyophilised cake or powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Daptomycin is indicated for the treatment of the following infections (see sections 4.4 and 5.1).

– Adult and paediatric (1 to 17 years of age) patients with complicated skin and soft-tissue infections (cSSTI).

– Adult patients with right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It is recommended that the decision to use daptomycin should take into account the antibacterial susceptibility of the organism and should be based on expert advice. See sections 4.4 and 5.1.

– Adult and paediatric (1 to 17 years of age) patients with Staphylococcus aureus bacteraemia (SAB). In adults, use in bacteraemia should be associated with RIE or with cSSTI, while in paediatric patients, use in bacteraemia should be associated with cSSTI.

Daptomycin is active against Gram-positive bacteria only (see section 5.1). In mixed infections where Gram-negative and/or certain types of anaerobic bacteria are suspected, daptomycin should be co-administered with appropriate antibacterial agent(s).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Clinical studies in patients employed infusion of daptomycin over at least 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

Adults

– cSSTI without concurrent SAB: Daptomycin 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 SAB: Daptomycin 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 RIE due to Staphylococcus aureus: Daptomycin 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.

Daptomycin is administered intravenously in 0.9% sodium chloride (see section 6.6). Daptomycin 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) Daptomycin should only be used in adult 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 Daptomycin in paediatric patients with renal impairment has not been established.

Dose adjustments in adult 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 adult patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Daptomycin should be administered following the completion of dialysis on dialysis days (see section 5.2).

H Hepatic impairment

No dose adjustment is necessary when administering Daptomycin 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 Daptomycin 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 population (1 to 17 years of age)

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

Indication: Complicated skin and soft-tissue infections without S. aureus bacteraemia

Indication: Complicated skin and soft-tissue infections associated with S. aureus bacteraemia

~              12 mg/kg once every 24 hours infused over 60

2 to 6 years.

minutes

,     ~        12 mg/kg once every 24 hours infused over 60

1 to < 2 years. s J

minutes

(1) Minimum duration of Daptomycin for paediatric SAB should be in accordance with the perceived risk of complications in the individual patient. The duration of daptomycin 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 Daptomycin was 12 days, with a range of 1 to 44 days. The duration of therapy should be in accordance with available official recommendations.

Daptomycin is administered intravenously in 0.9 % sodium chloride (see section 6.6). Daptomycin 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 Daptomycin 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, Daptomycin 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, Daptomycin is given by intravenous infusion over a 30-minute period (see section 6.6). In paediatric patients aged 1 to 6 years, Daptomycin is given by intravenous infusion over a 60-minute period (see section 6.6).

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

General

If a focus of infection other than cSSTI or RIE is identified after initiation of

Daptomycin therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.

Anaphylaxis/hy­persensitivity reactions

Anaphylaxis/hy­persensitivity reactions have been reported with Daptomycin. If an allergic reaction to Daptomycin occurs, discontinue use and institute appropriate therapy.

Pneumonia

It has been demonstrated in clinical studies that Daptomycin is not effective in the treatment of pneumonia. Daptomycin is therefore not indicated for the treatment of pneumonia.

RIE due to Staphylococcus aureus

Clinical data on the use of Daptomycin to treat RIE due to Staphylococcus aureus are limited to 19 adult patients (see “Clinical efficacy in adults” in section 5.1). The safety and efficacy of Daptomycin in children and adolescents aged below 18 years with right-sided infective endocarditis (RIE) due to Staphylococcus aureus have not been established.

The efficacy of Daptomycin in patients with prosthetic valve infections or with leftsided infective endocarditis due to Staphylococcus aureus has not been demonstrated.

Deep-seated infections

Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay.

Enterococcal infections

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Daptomycin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).

Non-susceptible micro-organisms

The use of antibacterials may promote the overgrowth of non-susceptible microorganisms. If superinfection occurs during therapy, appropriate measures should be taken.

Clostridioides difficile-associated diarrhoea

Clostridioides difficile-associated diarrhoea (CDAD) has been reported with Daptomycin (see section 4.8). If CDAD is suspected or confirmed, Daptomycin may need to be discontinued and appropriate treatment instituted as clinically indicated.

Drug/laboratory test interactions

False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see also section 4.5).

Creatine phosphokinase and myopathy

Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with Daptomycin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to > 5× Upper Limit of Normal (ULN) without muscle symptoms occurred more commonly in Daptomycin -treated patients (1.9%) than in those that received comparators (0.5%). Therefore, it is recommended that:

Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.

CPK should be measured more frequently (e.g. every 2–3 days at least during the first two weeks of treatment) in patients who are at higher risk of developing myopathy. For example, patients with any degree of renal impairment (creatinine clearance < 80 ml/min; see also section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).

It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be at increased risk of further increases during daptomycin therapy. This should be taken into account when initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently than once weekly.

Daptomycin should not be administered to patients who are taking other medicinal products associated with myopathy unless it is considered that the benefit to the patient outweighs the risk.

Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.

Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Daptomycin should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.

Peripheral neuropathy

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with Daptomycin should be investigated and consideration should be given to discontinuation of daptomycin (see sections 4.8 and 5.3).

Paediatric population

Paediatric patients below the age of one year should not be given Daptomycin 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).

Eosinophilic pneumonia

Eosinophilic pneumonia has been reported in patients receiving Daptomycin (see section 4.8). In most reported cases associated with Daptomycin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organising pneumonia. The majority of cases occurred after more than 2 weeks of treatment with Daptomycin and improved when Daptomycin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Daptomycin should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products). Daptomycin should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and vesiculobullous rash with or without mucous membrane involvement (Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN)), which could be life-threatening or fatal, have been reported with daptomycin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. If signs and symptoms suggestive of these reactions appear, Cubicin should be discontinued immediately and an alternative treatment should be considered. If the patient has developed a severe cutaneous adverse reaction with the use of daptomycin, treatment with daptomycin must not be restarted in this patient at any time.

Tubulointerstitial nephritis

Tubulointerstitial nephritis (TIN) has been reported in post-marketing experience with daptomycin. Patients who develop fever, rash, eosinophilia and/or new or worsening renal impairment while receiving Cubicin should undergo medical evaluation. If TIN is suspected, Cubicin should be discontinued promptly and appropriate therapy and/or measures should be taken.

Renal impairment

Renal impairment has been reported during treatment with Daptomycin. Severe renal impairment may in itself also predispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).

An adjustment of Daptomycin dose interval is needed for adult patients whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Daptomycin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.

Caution is advised when administering Daptomycin to patients who already have some degree of renal impairment (creatinine clearance < 80 ml/min) before commencing therapy with Daptomycin. Regular monitoring of renal function is advised (see also section 5.2).

In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents, regardless of the patient's pre­existing renal function (see also section 4.5).

The dosage regimen for Daptomycin in paediatric patients with renal impairment has not been established.

Obesity

In obese subjects with Body Mass Index (BMI) > 40 kg/m2 but with creatinine clearance > 70 ml/min, the AUC0– / daptomycin was significantly increased (mean 42% higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‚sodium-free‘.

4.5 Interaction with other medicinal products and other forms of interaction

Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

Interaction studies for Daptomycin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during co-administration by intravenous infusion over a 30-minute period using a Daptomycin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Daptomycin is unknown. Caution is warranted when Daptomycin is co-administered with tobramycin.

Experience with the co-administration of Daptomycin and warfarin is limited. Studies of Daptomycin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving Daptomycin and warfarin should be monitored for the first several days after therapy with Daptomycin is initiated.

There is limited experience regarding co-administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in adult patients taking one of these medicinal products at the same time as Daptomycin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with Daptomycin unless the benefits of co-administration outweigh the risk. If coadministration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.

Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal filtration.

During post-marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported. This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Daptomycin should not be used during pregnancy unless clearly necessary i.e., only if the expected benefit outweighs the possible risk.

Breast-feeding

In a single human case study, Daptomycin was intravenously administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 mcg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when Daptomycin is administered to nursing women.

Fertility

No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

On the basis of reported adverse drug reactions, Daptomycin is presumed to be unlikely to produce an effect on the ability to drive or use machinery.

4.8 Undesirable effects

Summary of the safety profile

In clinical studies, 2,011 adult subjects received Daptomycin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. In paediatric studies, 372 patients received Daptomycin, of whom 61 received a single dose and 311 received a therapeutic regimen for cSSTI or SAB (daily doses ranged from 4 mg/kg to 12 mg/kg). Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for Daptomycin and comparator regimens.

The most frequently reported adverse reactions (frequency common (> 1/100 to < 1/10)) are:

Fungal infections, urinary tract infection, candida infection, anaemia, anxiety, insomnia, dizziness, headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension, liver function tests abnormal (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)), rash, pruritus, limb pain, serum creatine phosphokinase (CPK) increased, infusion site reactions, pyrexia, asthenia.

Less frequently reported, but more serious, adverse reactions include hypersensitivity reactions, eosinophilic pneumonia (occasionally presenting as organising pneumonia), drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.

Tabulated list of adverse reactions

The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data):

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy adult volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydroxide

6.2 Incompatibilities

Daptomycin is not physically or chemically compatible with glucose-containing solutions.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

2 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.

After dilution: 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.

6.4 Special precautions for storage

Store in a refrigerator (2°C –8°C)

For storage conditions after reconstitution and after reconstitution and dilution of the medicinal product, see section 6.3

6.5 Nature and contents of container

Type I, colourless tubing glass vial with bromobutyl rubber stopper, aluminium closure and transparent flip-off cap.

Pack sizes: 1 vial or 5 vials

Not all pack sizes may be marketed

6.6 Special precautions for disposal

In adults, daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over 2 minutes. Daptomycin should not be administered as a 2-minute injection to paediatric patients. Paediatric patients 7 to 17 years old should receive daptomycin infused over 30 minutes. In paediatric patients under 7 years old receiving a 9–12 mg/kg dose, daptomycin should be administered over 60 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional dilution step as detailed below.

Daptomycin given as 30 or 60-minute intravenous infusion

A 50 mg/ml concentration of Daptomycin 350 mg powder 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 Daptomycin for intravenous infusion, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute or dilute lyophilised Daptomycin.

For Reconstitution:

1. The flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, 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 Daptomycin 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).

For Dilution:

1. Slowly remove the appropriate reconstituted liquid (50 mg daptomycin/ml) from the vial using a new sterile needle that is 21 gauge or smaller in diameter by inverting the vial in order to allow the solution to drain towards the stopper. Using a 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 the required solution from the inverted vial.

2. Expel air, large bubbles, and any excess solution in order to obtain the required dose.

3. Transfer the required reconstituted dose into 50 ml sodium chloride 9 mg/ml (0.9%).

4. The reconstituted and diluted solution should then be infused intravenously over 30 or 60 minutes as directed in section 4.2.

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

Daptomycin given as 2-minute intravenous injection (adult patients only) Water should not be used for reconstitution of Daptomycin for intravenous injection. Daptomycin should only be reconstituted with sodium chloride 9 mg/ml (0.9%).

A 50 mg/ml concentration of Daptomycin 350 mg powder 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 Daptomycin for intravenous injection, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Daptomycin.

1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, 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 Daptomycin range in colour from pale yellow to light brown.

5. Slowly remove the reconstituted liquid (50 mg daptomycin/ml) from the vial using a sterile needle that is 21 gauge or smaller in diameter.

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 injection.

8. Expel air, large bubbles, and any excess solution in order to obtain the required dose.

9. The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.

Daptomycin 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.

7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Limited

Ash Road North

Wrexham

LL13 9UF

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 29831/0723