CUPRIPEN 250mg capsules medication leaflet

Cubicin 350 mg powder for solution for injection or infusion

Cubicin 500 mg powder for solution for injection or infusion

Cubicin 350 mg powder for solution for injection or infusion

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.

Cubicin 500 mg powder for solution for injection or infusion

Each vial contains 500 mg daptomycin.

One ml provides 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml(0.9 %) solution.

For the full list of excipients, see section 6.1.

Powder for solution for injection or infusion

A pale yellow to light brown lyophilised cake or powder.

Cubicin 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-tissueinfections (cSSTI).

- Adult patients with right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It isrecommended that the decision to use daptomycin should take into account the antibacterialsusceptibility 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 inpaediatric 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, Cubicin should beco-administered with appropriate antibacterial agent(s).

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

Clinical studies in patients employed infusion of daptomycin over at least 30 minutes. There is noclinical 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 thesame doses given as intravenous infusions over 30 minutes there were no clinically importantdifferences in the pharmacokinetics and safety profile of daptomycin (see sections 4.8 and 5.2).

- cSSTI without concurrent SAB: Cubicin 4 mg/kg is administered once every 24 hours for7-14 days or until the infection is resolved (see section 5.1).

- cSSTI with concurrent SAB: Cubicin 6 mg/kg is administered once every 24 hours. See belowfor dose adjustments in patients with renal impairment. The duration of therapy may need to belonger than 14 days in accordance with the perceived risk of complications in the individualpatient.

- Known or suspected RIE due to Staphylococcus aureus: Cubicin 6 mg/kg is administered onceevery 24 hours. See below for dose adjustments in patients with renal impairment. The durationof therapy should be in accordance with available official recommendations.

Cubicin is administered intravenously in 0.9 % sodium chloride (see section 6.6). Cubicin should notbe used more frequently than once a day.

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

Daptomycin is eliminated primarily by the kidney.

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

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

Indication for use Creatinine clearance Dose recommendation CommentscSSTI without SAB4 mg/kg once daily See section 5.1 30 ml/min< 30 ml/min 4 mg/kg every 48 hours (1, 2)

RIE or cSSTIassociated with 6 mg/kg once daily See section 5.1

SAB  30 ml/min6 mg/kg every 48 hours (1, 2)< 30 ml/mincSSTI = 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 controlledclinical trials and the recommendation is based on pharmacokinetic studies and modelling results (seesections 4.4 and 5.2).(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PKmodelling results, are recommended for adult patients on haemodialysis (HD) or continuousambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered followingthe completion of dialysis on dialysis days (see section 5.2).

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

Indication

Age Group cSSTI without SAB cSSTI associated with SAB

Duration of Duration of

Dosage Regimen Therapy Dosage Regimen Therapy5 mg/kg once every 7 mg/kg once every12 to 1724 hours infused over 24 hours infused overyears30 minutes 30 minutes7 mg/kg once every 9 mg/kg once every7 to 1124 hours infused over 24 hours infused overyears30 minutes 30 minutes

Up to 14 days (1)9 mg/kg once every 12 mg/kg once every2 to 6 years 24 hours infused over 24 hours infused over60 minutes 60 minutes10 mg/kg once every 12 mg/kg once every1 to < 224 hours infused over 24 hours infused overyears60 minutes 60 minutescSSTI = 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 riskof complications in the individual patient. The duration of Cubicin may need to be longer than 14 daysin accordance with the perceived risk of complications in the individual patient. In the paediatric SABstudy, the mean duration of IV Cubicin was 12 days, with a range of 1 to 44 days. The duration oftherapy should be in accordance with available official recommendations.

Cubicin is administered intravenously in 0.9 % sodium chloride (see section 6.6). Cubicin should notbe used more frequently than once a day.

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

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

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

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

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

If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin therapyconsideration should be given to instituting alternative antibacterial therapy that has beendemonstrated to be efficacious in the treatment of the specific type of infection(s) present.

Anaphylaxis/hypersensitivity reactions

Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to

Cubicin occurs, discontinue use and institute appropriate therapy.

It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia.

Cubicin is therefore not indicated for the treatment of pneumonia.

RIE due to Staphylococcus aureus

Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 adultpatients (see “Clinical efficacy in adults” in section 5.1). The safety and efficacy of Cubicin inchildren and adolescents aged below 18 years with right-sided infective endocarditis (RIE) due to

Staphylococcus aureus have not been established.

The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infectiveendocarditis 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 clinicalefficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and

Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for thetreatment of enterococcal infections, with or without bacteraemia, have not been identified. Failureswith daptomycin in the treatment of enterococcal infections that were mostly accompanied bybacteraemia have been reported. In some instances treatment failure has been associated with theselection 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 micro-organisms. Ifsuperinfection occurs during therapy, appropriate measures should be taken.

Clostridioides difficile-associated diarrhoea

Clostridioides difficile-associated diarrhoea (CDAD) has been reported with Cubicin (see section 4.8).

If CDAD is suspected or confirmed, Cubicin may need to be discontinued and appropriate treatmentinstituted 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 (seesection 4.5).

Creatine phosphokinase and myopathy

Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscularpains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reportedduring therapy with Cubicin (see sections 4.5, pct. 4.8 and 5.3). In clinical studies, marked increases inplasma CPK to > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred morecommonly in Cubicin-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 twoweeks 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; seesection 4.2), including those on haemodialysis or CAPD, and patients taking other medicinalproducts known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibratesand ciclosporin).

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

* Cubicin should not be administered to patients who are taking other medicinal productsassociated with myopathy unless it is considered that the benefit to the patient outweighs therisk.

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

* Any patient that develops unexplained muscle pain, tenderness, weakness or cramps shouldhave CPK levels monitored every 2 days. Cubicin should be discontinued in the presence ofunexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit ofnormal.

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapywith Cubicin should be investigated and consideration should be given to discontinuation ofdaptomycin (see sections 4.8 and 5.3).

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

Eosinophilic pneumonia

Eosinophilic pneumonia has been reported in patients receiving Cubicin (see section 4.8). In mostreported cases associated with Cubicin, patients developed fever, dyspnoea with hypoxic respiratoryinsufficiency, and diffuse pulmonary infiltrates or organising pneumonia. The majority of casesoccurred after more than 2 weeks of treatment with Cubicin and improved when Cubicin wasdiscontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Cubicinshould undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, toexclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products).

Cubicin should be discontinued immediately and treatment with systemic steroids should be initiatedwhen appropriate.

Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemicsymptoms (DRESS) and vesiculobullous rash with or without mucous membrane involvement(Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN)), which could belife-threatening or fatal, have been reported with daptomycin (see section 4.8). At the time ofprescription, patients should be advised of the signs and symptoms of severe skin reactions, and beclosely monitored. If signs and symptoms suggestive of these reactions appear, Cubicin should bediscontinued immediately and an alternative treatment should be considered. If the patient hasdeveloped a severe cutaneous adverse reaction with the use of daptomycin, treatment with daptomycinmust 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 whilereceiving Cubicin should undergo medical evaluation. If TIN is suspected, Cubicin should bediscontinued promptly and appropriate therapy and/or measures should be taken.

Renal impairment has been reported during treatment with Cubicin. Severe renal impairment may initself also pre-dispose to elevations in daptomycin levels which may increase the risk of developmentof myopathy (see above).

An adjustment of Cubicin 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 havenot been evaluated in controlled clinical trials and the recommendation is mainly based onpharmacokinetic modelling data. Cubicin should only be used in such patients when it is consideredthat the expected clinical benefit outweighs the potential risk.

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

In addition, regular monitoring of renal function is advised during concomitant administration ofpotentially nephrotoxic agents, regardless of the patient’s pre-existing renal function (see section 4.5).

The dosage regimen for Cubicin 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-obesematched controls. There is limited information on the safety and efficacy of daptomycin in the veryobese and so caution is recommended. However, there is currently no evidence that a dose reduction isrequired (see section 5.2).

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

Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikelythat daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450system.

Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid.

Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinalproducts alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were notsignificantly altered by aztreonam.

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

Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of Cubicinwith anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patientsreceiving Cubicin and warfarin should be monitored for the first several days after therapy with

Cubicin is initiated.

There is limited experience regarding concomitant administration of daptomycin with other medicinalproducts that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases ofmarked rises in CPK levels and cases of rhabdomyolysis occurred in adult patients taking one of thesemedicinal products at the same time as Cubicin. It is recommended that other medicinal productsassociated with myopathy should if possible be temporarily discontinued during treatment with

Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administrationcannot be avoided, CPK levels should be measured more frequently than once weekly and patientsshould be closely monitored for any signs or symptoms that might represent myopathy. Seesections 4.4, pct. 4.8 and 5.3.

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

During post-marketing surveillance, cases of interference between daptomycin and particular reagentsused 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 abnormalitiesof PT/INR are observed in patients taking daptomycin, consideration should be given to a possible invitro interaction with the laboratory test. The possibility of erroneous results may be minimised bydrawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin(see section 4.4).

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

Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the expected benefitoutweighs the possible risk.

In a single human case study, Cubicin was intravenously administered daily for 28 days to a nursingmother at a dose of 500 mg/day, and samples of the patient’s breast milk were collected over a24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was0.045 µg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feedingshould be discontinued when Cubicin is administered to nursing women.

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

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

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

In clinical studies, 2,011 adult subjects received Cubicin. Within these trials, 1,221 subjects received adaily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjectsreceived a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. Inpaediatric studies, 372 patients received Cubicin, of whom 61 received a single dose and 311 receiveda therapeutic regimen for cSSTI or SAB (daily doses ranged from 4 mg/kg to 12 mg/kg). Adversereactions (i.e. considered by the investigator to be possibly, probably, or definitely related to themedicinal product) were reported at similar frequencies for Cubicin 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 (increasedalanine 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 witheosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.

The following adverse reactions were reported during therapy and during follow-up with frequenciescorresponding 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 fromthe available data):

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

Table 1 Adverse reactions from clinical studies and post-marketing reports

System organ class Frequency Adverse reactions

Infections and infestations Common: Fungal infections, urinary tract infection, candidainfection

Uncommon: Fungaemia

Not known*: Clostridioides difficile-associated diarrhoea**

Blood and lymphatic system Common: Anaemiadisorders Uncommon: Thrombocythaemia, eosinophilia, internationalnormalised ratio (INR) increased, leukocytosis

Rare: Prothrombin time (PT) prolonged

Not known*: Thrombocytopaenia

Immune system disorders Not known*: Hypersensitivity**, manifested by isolatedspontaneous reports including, but not limited toangioedema, pulmonary eosinophilia, sensation oforopharyngeal swelling, anaphylaxis**, infusionreactions including the following symptoms:tachycardia, wheezing, pyrexia, rigors, systemicflushing, vertigo, syncope and metallic taste

Metabolism and nutrition Uncommon: Decreased appetite, hyperglycaemia, electrolytedisorders imbalance

Psychiatric disorders Common: Anxiety, insomnia

System organ class Frequency Adverse reactions

Nervous system disorders Common: Dizziness, headache

Uncommon: Paraesthesia, taste disorder, tremor, eye irritation

Not known*: Peripheral neuropathy**

Ear and labyrinth disorders Uncommon: Vertigo

Cardiac disorders Uncommon: Supraventricular tachycardia, extrasystole

Vascular disorders Common: Hypertension, hypotension

Uncommon: Flushes

Respiratory, thoracic and Not known*: Eosinophilic pneumonia1**, coughmediastinal disorders

Gastrointestinal disorders Common: Gastrointestinal and abdominal pain, nausea,vomiting, constipation, diarrhoea, flatulence, bloatingand distension

Uncommon: Dyspepsia, glossitis

Hepatobiliary disorders Common: Liver function tests abnormal2 (increased alanineaminotransferase (ALT), aspartate aminotransferase(AST) or alkaline phosphatase (ALP))

Rare: Jaundice

Skin and subcutaneous tissue Common: Rash, pruritusdisorders Uncommon: Urticaria

Not known*: Acute generalised exanthematous pustulosis (AGEP),drug reaction with eosinophilia and systemicsymptoms (DRESS)**, vesiculobullous rash with orwithout mucous membrane involvement (SJS or

TEN)**

Musculoskeletal and Common: Limb pain, serum creatine phosphokinase (CPK)2connective tissue disorders increased

Uncommon: Myositis, increased myoglobin, muscular weakness,muscle pain, arthralgia, serum lactate dehydrogenase(LDH) increased, muscle cramps

Not known*: Rhabdomyolysis3 **

Renal and urinary disorders Uncommon: Renal impairment, including renal failure and renalinsufficiency, serum creatinine increased

Not known*: Tubulointerstitial nephritis (TIN)**

Reproductive system and Uncommon: Vaginitisbreast disorders

General disorders and Common: Infusion site reactions, pyrexia, astheniaadministration site conditions Uncommon: Fatigue, pain

* Based on post-marketing reports. Since these reactions are reported voluntarily from apopulation of uncertain size, it is not possible to reliably estimate their frequency which istherefore categorised as not known.

** See section 4.4.1 While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown,to date the reporting rate of spontaneous reports is very low (< 1/10,000).2 In some cases of myopathy involving raised CPK and muscle symptoms, the patients alsopresented with elevated transaminases. These transaminase increases were likely to be related tothe skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3 toxicityand resolved upon discontinuation of treatment.

3 When clinical information on the patients was available to make a judgement, approximately50 % of the cases occurred in patients with pre-existing renal impairment, or in those receivingconcomitant medicinal products known to cause rhabdomyolysis.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code:

J01XX09

Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.

The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes ofboth growing and stationary phase cells causing depolarisation and leading to a rapid inhibition ofprotein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.

PK/PD relationship

Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positiveorganisms in vitro and in in vivo animal models. In animal models AUC/MIC and Cmax/MIC correlatewith efficacy and predicted bacterial kill in vivo at single doses equivalent to human adult doses of4 mg/kg and 6 mg/kg once daily.

Mechanisms of resistance

Strains with decreased susceptibility to daptomycin have been reported especially during the treatmentof patients with difficult-to-treat infections and/or following administration for prolonged periods. Inparticular, there have been reports of treatment failures in patients infected with Staphylococcusaureus, Enterococcus faecalis or Enterococcus faecium, including bacteraemic patients, that havebeen associated with the selection of organisms with reduced susceptibility or frank resistance todaptomycin during therapy.

The mechanism(s) of daptomycin resistance is (are) not fully understood.

Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on

Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S.

pneumoniae) are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.

Susceptibility

The prevalence of resistance may vary geographically and over time for selected species and localinformation on resistance is desirable, particularly when treating severe infections. As necessary,expert advice should be sought when the local prevalence of resistance is such that the utility of theagent in at least some types of infections is questionable.

Commonly Susceptible Species

Staphylococcus aureus *

Staphylococcus haemolyticus

Coagulase negative staphylococci

Streptococcus agalactiae*

Streptococcus dysgalactiae subsp equisimilis*

Streptococcus pyogenes*

Group G streptococci

Clostridium perfringens

Peptostreptococcus spp

Gram negative organisms

* denotes species against which it is considered that activity has been satisfactorily demonstrated inclinical studies.

In two adult clinical trials in complicated skin and soft tissues infections, 36 % of patients treated with

Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most commontype of infection treated was wound infection (38 % of patients), while 21 % had major abscesses.

These limitations of the patients population treated should be taken into account when deciding to use

Cubicin.

In a randomised controlled open-label study in 235 adult patients with Staphylococcus aureusbacteraemia (i.e. at least one positive blood culture of Staphylococcus aureus prior to receiving thefirst dose) 19 of 120 patients treated with Cubicin met the criteria for RIE. Of these 19 patients 11were infected with methicillin-susceptible and 8 with methicillin-resistant Staphylococcus aureus. Thesuccess rates in RIE patients are shown in the table below.

Differences in

Population Daptomycin Comparator

Successn/N (%) n/N (%) Rates (95 % CI)

ITT (intention to treat) Population

RIE 8/19 (42.1 %) 7/16 (43.8 %) -1.6 % (-34.6, 31.3)

PP (per protocol) Population

RIE 6/12 (50.0 %) 4/8 (50.0 %) 0.0 % (-44.7, 44.7)

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in19/120 (15.8 %) patients treated with Cubicin, 9/53 (16.7 %) patients treated with vancomycin and2/62 (3.2 %) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among thesefailures six patients treated with Cubicin and one patient treated with vancomycin were infected with

Staphylococcus aureus that developed increasing MICs of daptomycin on or following therapy (see“Mechanisms of resistance” above). Most patients who failed due to persisting or relapsing

Staphylococcus aureus infection had deep-seated infection and did not receive necessary surgicalintervention.

Clinical efficacy in paediatric patients

The safety and efficacy of daptomycin was evaluated in paediatric patients aged 1 to 17 years (Study

DAP-PEDS-07-03) with cSSTI caused by Gram positive pathogens. Patients were enrolled in astepwise approach into well-defined age groups and given age-dependent doses once daily for up to14 days, as follows:

* Age group 1 (n=113): 12 to 17 years treated with daptomycin dosed at 5 mg/kg or standard-of-care comparator (SOC);

* Age group 2 (n=113): 7 to 11 years treated with daptomycin dosed at 7 mg/kg or SOC;

* Age group 3 (n=125): 2 to 6 years treated with daptomycin dosed at 9 mg/kg or SOC;

* Age group 4 (n=45): 1 to < 2 years treated with daptomycin dosed at 10 mg/kg or SOC.

The primary objective of Study DAP-PEDS-07-03 was to assess the safety of treatment. Secondaryobjectives included an assessment of efficacy of age-dependent doses of intravenous daptomycin incomparison with standard-of-care therapy. The key efficacy endpoint was the sponsor-defined clinicaloutcome at test-of-cure (TOC), which was defined by a blinded medical director. A total of389 subjects were treated in the study, including 256 subjects who received daptomycin and133 subjects who received standard-of-care. In all populations the clinical success rates werecomparable between the daptomycin and SOC treatment arms, supporting the primary efficacyanalysis in the ITT population.

Summary of sponsor-defined clinical outcome at TOC:

Clinical Success in Paediatric cSSTI

Daptomycin Comparatorn/N (%) n/N (%) % difference

Intent-to-treat 227/257 (88.3 %) 114/132 (86.4 %) 2.0

Modified intent-to-treat 186/210 (88.6 %) 92/105 (87.6 %) 0.9

Clinically evaluable 204/207 (98.6 %) 99/99 (100 %) -1.5

Microbiologically evaluable (ME) 164/167 (98.2 %) 78/78 (100 %) -1.8

The overall therapeutic response rate also was similar for the daptomycin and SOC treatment arms forinfections caused by MRSA, MSSA and Streptococcus pyogenes (see table below; ME population);response rates were > 94 % for both treatment arms across these common pathogens.

Summary of overall therapeutic response by type of baseline pathogen (ME population):

Overall Successa rate in Paediatric cSSTI

Pathogen n/N (%)

Daptomycin Comparator

Methicillin-susceptible Staphylococcus aureus (MSSA) 68/69 (99 %) 28/29 (97 %)

Methicillin-resistant Staphylococcus aureus (MRSA) 63/66 (96 %) 34/34 (100 %)

Streptococcus pyogenes 17/18 (94 %) 5/5 (100 %)a Subjects achieving clinical success (Clinical Response of “Cure” or “Improved”) and microbiologicalsuccess (pathogen-level response of “Eradicated” or “Presumed Eradicated”) are classified as overalltherapeutic success.

The safety and efficacy of daptomycin was evaluated in paediatric patients aged 1 to 17 years (Study

DAP-PEDBAC-11-02) with bacteraemia caused by Staphylococcus aureus. Patients were randomisedin a 2:1 ratio into the following age groups and given age-dependent doses once daily for up to42 days, as follows:

* Age group 1 (n=21): 12 to 17 years treated with daptomycin dosed at 7 mg/kg or SOCcomparator;

* Age group 2 (n=28): 7 to 11 years treated with daptomycin dosed at 9 mg/kg or SOC;

* Age group 3 (n=32): 1 to 6 years treated with daptomycin dosed at 12 mg/kg or SOC;

The primary objective of Study DAP-PEDBAC-11-02 was to assess the safety of intravenousdaptomycin versus SOC antibiotics. Secondary objectives included: Clinical outcome based on theblinded Evaluator’s assessment of clinical response (success [cure, improved], failure, or non-evaluable) at the TOC Visit; and Microbiological response (success, failure, or non-evaluable) basedon evaluation of Baseline infecting pathogen at TOC.

A total of 81 subjects were treated in the study, including 55 subjects who received daptomycin and26 subjects who received standard-of-care. No patients 1 to <2 years of age were enrolled in the study.

In all populations the clinical success rates were comparable in the daptomycin versus the SOCtreatment arm.

Summary of Blinded Evaluator defined clinical outcome at TOC:

Clinical Success in Paediatric SAB

Daptomycin Comparatorn/N (%) n/N (%) % difference

Modified intent-to-treat (MITT) 46/52 (88.5 %) 19/24 (79.2 %) 9.3 %

Microbiologically modifiedintent-to-treat (mMITT) 45/51 (88.2 %) 17/22 (77.3 %) 11.0 %

Clinically evaluable (CE) 36/40 (90.0 %) 9/12 (75.0 %) 15.0 %

The microbiological outcome at TOC for the daptomycin and SOC treatment arms for infectionscaused by MRSA and MSSA are presented in the table below (mMITT population).

Microbiological Success rate in Paediatric

SAB

Pathogen n/N (%)

Daptomycin Comparator

Methicillin-susceptible Staphylococcus aureus (MSSA) 43/44 (97.7 %) 19/19 (100.0 %)

Methicillin-resistant Staphylococcus aureus (MRSA) 6/7 (85.7 %) 3/3 (100.0 %)

Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kgadministered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthyadult volunteers. Steady-state concentrations are achieved by the third daily dose.

Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportionalpharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUCand Cmax) was demonstrated in healthy adult subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous injection.

Animal studies showed that daptomycin is not absorbed to any significant extent after oraladministration.

The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycinappears to only minimally penetrate the blood-brain barrier and the placental barrier following singleand multiple doses.

Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. Inhealthy adult volunteers and adult patients treated with daptomycin, protein binding averaged about90 % including subjects with renal impairment.

In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies withhuman hepatocytes indicate that daptomycin does not inhibit or induce the activities of the followinghuman cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely thatdaptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450system.

After infusion of 14C-daptomycin in healthy adults, the plasma radioactivity was similar to theconcentration determined by microbiological assay. Inactive metabolites were detected in urine, asdetermined by the difference in total radioactive concentrations and microbiologically activeconcentrations. In a separate study, no metabolites were observed in plasma, and minor amounts ofthree oxidative metabolites and one unidentified compound were detected in urine. The site ofmetabolism has not been identified.

Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid anddaptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no activetubular secretion of daptomycin.

Following intravenous administration, plasma clearance of daptomycin is approximately 7 to9 ml/hr/kg and its renal clearance is 4 to 7 ml/hr/kg.

In a mass balance study using radiolabelled material, 78 % of the administered dose was recoveredfrom the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin wasapproximately 50 % of the dose. About 5 % of the administered radiolabel was excreted in the faeces.

Following administration of a single 4 mg/kg intravenous dose of Cubicin over a 30-minute period, themean total clearance of daptomycin was approximately 35 % lower and the mean AUC0-∞ wasapproximately 58 % higher in elderly subjects (≥ 75 years of age) compared with those in healthyyoung subjects (18 to 30 years of age). There were no differences in Cmax. The differences noted aremost likely due to the normal reduction in renal function observed in the geriatric population.

No dose adjustment is necessary based on age alone. However, renal function should be assessed andthe dose should be reduced if there is evidence of severe renal impairment.

Children and adolescents (1 to 17 years of age)

The pharmacokinetics of daptomycin in paediatric subjects was evaluated in 3 single-dosepharmacokinetic studies. After a single 4 mg/kg dose of Cubicin, total clearance normalised by weightand elimination half-life of daptomycin in adolescents (12-17 years of age) with Gram-positiveinfection were similar to adults. After a single 4 mg/kg dose of Cubicin, total clearance of daptomycinin children 7-11 years of age with Gram-positive infection was higher than in adolescents, whereaselimination half-life was shorter. After a single 4, 8, or 10 mg/kg dose of Cubicin, total clearance andelimination half-life of daptomycin in children 2-6 years of age were similar at different doses; totalclearance was higher and elimination half-life was shorter than in adolescents. After a single 6 mg/kgdose of Cubicin, the clearance and elimination half-life of daptomycin in children 13-24 months of agewere similar to children 2-6 years of age who received a single 4-10 mg/kg dose. The results of thesestudies show that exposures (AUC) in paediatric patients across all doses are generally lower thanthose in adults at comparable doses.

Paediatric patients with cSSTI

A Phase 4 study (DAP-PEDS-07-03) was conducted to assess safety, efficacy, and pharmacokineticsof daptomycin in paediatric patients (1 to 17 years old, inclusive) with cSSTI caused by Gram-positivepathogens. Daptomycin pharmacokinetics in patients in this study are summarised in Table 2.

Following administration of multiple doses, daptomycin exposure was similar across different agegroups after dose adjustment based on body weight and age. Plasma exposures achieved with thesedoses were consistent with those achieved in the adult cSSTI study (following 4 mg/kg once daily inadults).

Table 2 Mean (Standard Deviation) of Daptomycin Pharmacokinetics in Paediatric cSSTI

Patients (1 to 17 Years of Age) in Study DAP-PEDS-07-03a 1 to <2 years

Age Range 12-17 years (N=6) 7-11 years (N=2) 2-6 years (N=7)(N=30)b

Dose 5 mg/kg 7 mg/kg 9 mg/kg 10 mg/kg

Infusion Time 30 minutes 30 minutes 60 minutes 60 minutes

AUC0-24hr387 (81) 438 439 (102) 466(g×hr/ml)

Cmax (g/ml) 62.4 (10.4) 64.9, 74.4 81.9 (21.6) 79.2

Apparent t1/2 (hr) 5.3 (1.6) 4.6 3.8 (0.3) 5.04

CL/wt (ml/hr/kg) 13.3 (2.9) 16.0 21.4 (5.0) 21.5

Pharmacokinetic parameter values estimated by noncompartmental analysisaIndividual values reported as only two patients in this age group provided pharmacokinetic samples to enablepharmacokinetic analysis; AUC, apparent t1/2 and CL/wt could be determined for only one of the two patientsbPharmacokinetic analysis conducted on the pooled pharmacokinetic profile with mean concentrations across subjects at eachtime point

Paediatric patients with SAB

A Phase 4 study (DAP-PEDBAC-11-02) was conducted to assess safety, efficacy, andpharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with SAB.

Daptomycin pharmacokinetics inpatients in this study are summarised in Table 3. Followingadministration of multiple doses, daptomycin exposure was similar across different age groups afterdose adjustment based on body weight and age. Plasma exposures achieved with these doses wereconsistent with those achieved in the adult SAB study (following 6 mg/kg once daily in adults).

Table 3 Mean (Standard Deviation) of Daptomycin Pharmacokinetics in Paediatric SAB

Patients (1 to 17 Years of Age) in Study DAP-PEDBAC-11-02

Age Range 12-17 years (N=13) 7-11 years (N=19) 1 to 6 years (N=19)*

Dose 7 mg/kg 9 mg/kg 12 mg/kg

Infusion Time 30 minutes 30 minutes 60 minutes

AUC0-24hr656 (334) 579 (116) 620 (109)(g×hr/ml)

Cmax (g/ml) 104 (35.5) 104 (14.5) 106 (12.8)

Apparent t1/2 (hr) 7.5 (2.3) 6.0 (0.8) 5.1 (0.6)

CL/wt (ml/hr/kg) 12.4 (3.9) 15.9 (2.8) 19.9 (3.4)

Pharmacokinetic parameter values estimated using a model-based approach with sparsely collected pharmacokinetic samplesfrom individual patients in the study.

*Mean (Standard Deviation) calculated for patients 2 to 6 years of age, since no patients 1 to <2 years of age were enrolled inthe study. Simulation using a population pharmacokinetic model demonstrated that the AUCss (area under the concentration-time curve at steady state) of daptomycin in paediatric patients 1 to <2 years of age receiving 12 mg/kg once daily would becomparable to that in adult patients receiving 6 mg/kg once daily.

Obesity

Relative to non-obese subjects daptomycin systemic exposure measured by AUC was about 28 %higher in moderately obese subjects (Body Mass Index of 25-40 kg/m2) and 42 % higher in extremelyobese subjects (Body Mass Index of > 40 kg/m2). However, no dose adjustment is considered to benecessary based on obesity alone.

No clinically significant gender-related differences in daptomycin pharmacokinetics have beenobserved.

No clinically significant differences in daptomycin pharmacokinetics have been observed in Black or

Japanese subjects relative to Caucasian subjects.

Following administration of a single 4 mg/kg or 6 mg/kg intravenous dose of daptomycin over a30-minute period to adult subjects with various degrees of renal impairment, total daptomycinclearance (CL) decreased and systemic exposure (AUC) increased as renal function (creatinineclearance) decreased.

Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day afteradministration of a 6 mg/kg dose to adult patients on HD or CAPD was 2-fold higher than thatobserved in adult patients with normal renal function who received the same dose. On the second dayafter administration of a 6 mg/kg dose to HD and CAPD adult patients the daptomycin AUC wasapproximately 1.3-fold higher than that observed after a second 6 mg/kg dose in adult patients withnormal renal function. On this basis, it is recommended that adult patients on HD or CAPD receivedaptomycin once every 48 hours at the dose recommended for the type of infection being treated (seesection 4.2).

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

The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic impairment(Child-Pugh B classification of hepatic impairment) compared with healthy volunteers matched forgender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary whenadministering daptomycin in patients with moderate hepatic impairment. The pharmacokinetics ofdaptomycin in patients with severe hepatic impairment (Child-Pugh C classification) have not beenevaluated.

Daptomycin administration was associated with minimal to mild degenerative/regenerative changes inskeletal muscle in the rat and dog. Microscopic changes in skeletal muscle were minimal(approximately 0.05 % of myofibres affected) and at the higher doses were accompanied by elevationsin CPK. No fibrosis or rhabdomyolysis was observed. Depending on the study duration, all muscleeffects, including microscopic changes, were fully reversible within 1-3 months following cessation ofdosing. No functional or pathological changes in smooth or cardiac muscle were observed.

The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levelsof 0.8 to 2.3-fold the human therapeutic levels at 6 mg/kg (30-minute intravenous infusion) forpatients with normal renal function. As the pharmacokinetics (see section 5.2) is comparable, thesafety margins for both methods of administration are very similar.

A study in dogs demonstrated that skeletal myopathy was reduced upon once daily administration ascompared to fractionated dosing at same total daily dose, suggesting that myopathic effects in animalswere primarily related to time between doses.

Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscleeffects in adult rats and dogs, and were primarily related to plasma Cmax. Peripheral nerve changeswere characterised by minimal to slight axonal degeneration and were frequently accompanied byfunctional changes. Reversal of both the microscopic and functional effects was complete within6 months post-dose. Safety margins for peripheral nerve effects in rats and dogs are 8- and 6-fold,respectively, based on comparison of Cmax values at the No Observed Effect Level (NOEL) with the

Cmax achieved on dosing with 30-minute intravenous infusion of 6 mg/kg once daily in patients withnormal renal function.

The findings of in vitro and some in vivo studies designed to investigate the mechanism of daptomycinmyotoxicity indicate that the plasma membrane of differentiated spontaneously contracting musclecells is the target of toxicity. The specific cell surface component directly targeted has not beenidentified. Mitochondrial loss/damage was also observed; however the role and significance of thisfinding in the overall pathology are unknown. This finding was not associated with an effect onmuscle contraction.

In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions ascompared to skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doseslower than those associated with skeletal muscle toxicity.

In neonatal dogs, daptomycin caused marked clinical signs of twitching, muscle rigidity in the limbs,and impaired use of limbs, which resulted in decreases in body weight and overall body condition atdoses ≥ 50 mg/kg/day and necessitated early discontinuation of treatment in these dose groups. Atlower dose levels (25 mg/kg/day), mild and reversible clinical signs of twitching and one incidence ofmuscle rigidity were observed without any effects on body weight. There was no histopathologicalcorrelation in the peripheral and central nervous system tissue, or in the skeletal muscle, at any doselevel, and the mechanism and clinical relevance for the adverse clinical signs are therefore unknown.

Reproductive toxicity testing showed no evidence of effects on fertility, embryofoetal, or postnataldevelopment. However, daptomycin can cross the placenta in pregnant rats (see section 5.2). Excretionof daptomycin into milk of lactating animals has not been studied.

Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic orclastogenic in a battery of in vivo and in vitro genotoxicity tests.

Sodium hydroxide

Cubicin is not physically or chemically compatible with glucose-containing solutions. This medicinalproduct must not be mixed with other medicinal products except those mentioned in section 6.6.

3 years

After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial hasbeen demonstrated for 12 hours at 25 °C and up to 48 hours at 2 °C - 8 °C. Chemical and physicalstability 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 anddiluted 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 (seesection 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. Nopreservative or bacteriostatic agent is present in this product. If not used immediately, in-use storagetimes 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 after reconstitution and after reconstitution and dilution of the medicinalproduct 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 withyellow 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 blueplastic flip off caps.

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

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

Cubicin given as 30 or 60-minute intravenous infusion

A 50 mg/ml concentration of Cubicin 350 mg powder for infusion is obtained by reconstituting thelyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection.

A 50 mg/ml concentration of Cubicin 500 mg powder for infusion is obtained by reconstituting thelyophilised 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 productwill appear clear and may have a few small bubbles or foam around the edge of the vial.

Cubicin 350 mg powder for solution for injection or infusion

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

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

For Reconstitution:1. The polypropylene flip off cap should be removed to expose the central portions of the rubberstopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution andallow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any othersurface. Draw 7 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection into a syringeusing 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 needletowards the wall of the vial.

2. The vial should be gently rotated to ensure complete wetting of the product and then allowed tostand for 10 minutes.

3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clearreconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of theproduct.

4. The reconstituted solution should be checked carefully to ensure that the product is in solutionand 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 %) (typicalvolume 50 ml).

For Dilution:1. Slowly remove the appropriate reconstituted liquid (50 mg daptomycin/ml) from the vial using anew sterile needle that is 21 gauge or smaller in diameter by inverting the vial in order to allowthe solution to drain towards the stopper. Using a syringe, insert the needle into the invertedvial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in thevial when drawing the solution into the syringe. Before removing the needle from the vial, pullthe plunger all the way back to the end of the syringe barrel in order to remove the requiredsolution 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 or60 minutes as directed in section 4.2.

Cubicin 500 mg powder for solution for injection or infusion

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

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

For Reconstitution:1. The polypropylene flip off cap should be removed to expose the central portions of the rubberstopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution andallow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any othersurface. Draw 10 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection into a syringeusing 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 needletowards the wall of the vial.

2. The vial should be gently rotated to ensure complete wetting of the product and then allowed tostand for 10 minutes.

3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clearreconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of theproduct.

4. The reconstituted solution should be checked carefully to ensure that the product is in solutionand 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 %) (typicalvolume 50 ml).

For Dilution:1. Slowly remove the appropriate reconstituted liquid (50 mg daptomycin/ml) from the vial using anew sterile needle that is 21 gauge or smaller in diameter by inverting the vial in order to allowthe solution to drain towards the stopper. Using a syringe, insert the needle into the invertedvial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in thevial when drawing the solution into the syringe. Before removing the needle from the vial, pullthe plunger all the way back to the end of the syringe barrel in order to remove the requiredsolution 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 or60 minutes as directed in section 4.2.

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

Cubicin given as 2-minute intravenous injection (adult patients only)

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

A 50 mg/ml concentration of Cubicin 350 mg powder for injection is obtained by reconstituting thelyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection.

A 50 mg/ml concentration of Cubicin 500 mg powder for injection is obtained by reconstituting thelyophilised 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 productwill appear clear and may have a few small bubbles or foam around the edge of the vial.

Cubicin 350 mg powder for solution for injection or infusion

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 rubberstopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution andallow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any othersurface. Draw 7 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection into a syringeusing 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 needletowards the wall of the vial.

2. The vial should be gently rotated to ensure complete wetting of the product and then allowed tostand for 10 minutes.

3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clearreconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of theproduct.

4. The reconstituted solution should be checked carefully to ensure that the product is in solutionand visually inspected for the absence of particulates prior to use. Reconstituted solutions of

Cubicin range in colour from pale yellow to light brown.

5. Slowly remove the reconstituted liquid (50 mg daptomycin/ml) from the vial using a sterileneedle 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 thevery bottom of the solution in the vial when drawing the solution into the syringe. Beforeremoving the needle from the vial, pull the plunger all the way back to the end of the syringebarrel 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 asdirected in section 4.2.

Cubicin 500 mg powder for solution for injection or infusion

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 rubberstopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution andallow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any othersurface. Draw 10 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection into a syringeusing 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 needletowards the wall of the vial.

2. The vial should be gently rotated to ensure complete wetting of the product and then allowed tostand for 10 minutes.

3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clearreconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of theproduct.

4. The reconstituted solution should be checked carefully to ensure that the product is in solutionand visually inspected for the absence of particulates prior to use. Reconstituted solutions of

Cubicin range in colour from pale yellow to light brown.

5. Slowly remove the reconstituted liquid (50 mg daptomycin/ml) from the vial using a sterileneedle 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 thevery bottom of the solution in the vial when drawing the solution into the syringe. Beforeremoving the needle from the vial, pull the plunger all the way back to the end of the syringebarrel 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 asdirected 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 (seesection 6.3).

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

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

Cubicin 350 mg powder for solution for injection or infusion

EU/1/05/328/001

EU/1/05/328/003

Cubicin 500 mg powder for solution for injection or infusion

EU/1/05/328/002

EU/1/05/328/004

Date of first authorisation: 19 January 2006

Date of latest renewal: 29 November 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu