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

Daptomycin Noridem 350 mg Powder for solution for injection/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.

Excipient with known effect:

Each vial of 350 mg contains approximately 1.45 – 4.83 mg sodium.

For the full list of excipients, see section 6.1.

Powder for solution for injection/infusion

A pale yellow to light brown lyophilised cake or powder.

4.1 Therapeutic indications

Daptomycin Noridem 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 Noridem 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 Noridem 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 Noridem 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 Noridem 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.

1.

Daptomycin Noridem is administered intravenously in 0.9% sodium chloride (see section 6.6). Daptomycin Noridem 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.

Hepatic impairment

No dose adjustment is necessary when administering Daptomycin Noridem 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 Noridem 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.

cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia;

(1) Minimum duration of Daptomycin Noridem for paediatric SAB should be in accordance with the perceived risk of complications in the individual patient. The duration of Daptomycin Noridem 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 Noridem is administered intravenously in 0.9 % sodium chloride (see section 6.6). Daptomycin Noridem 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 Noridem 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 Noridem 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 Noridem is given by intravenous infusion over a 30-minute period (see section 6.6). In paediatric patients aged 1 to 6 years,Daptomycin Noridem is given by intravenous infusion over a 60-minute period (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 Noridem 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 Noridem 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 Noridem 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 “Information from clinical trials” 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 left-sided 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 micro-organisms. 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 Noridem 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 Noridem 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 Noridem should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.

2.

Peripheral neuropathy

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with Daptomycin Noridem 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 Noridem 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 Noridem 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 Noridemshould be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.

Renal impairment

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

An adjustment of Daptomycin Noridem 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 Noridem 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 Noridem to patients who already have some degree of renal impairment (creatinine clearance < 80 mL/min) before commencing therapy with Daptomycin Noridem. 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 pre-existing 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-OO 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).

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. 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 coadministration 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 Noridem is unknown. Caution is warranted when Daptomycin Noridem is co-administered with tobramycin.

Experience with the concomitant 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 Noridem and warfarin should be monitored for the first several days after therapy with Daptomycin Noridem is initiated.

There is limited experience regarding concomitant 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 Noridem unless the benefits of concomitant administration outweigh the risk. If co-administration 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 coadministration 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 coadministration due to additive renal effects. Therefore, caution is advised when daptomycin is coadministered 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 Noridem should not be used during pregnancy unless clearly necessary i.e., only if the expected benefit outweighs the possible risk.

Breastfeeding

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 Noridem 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 rash 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.

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

* Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore 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 also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1–3 toxicity and resolved upon discontinuation of treatment.

3 When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with preexisting renal impairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.

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 Website: 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

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

J01XX09

Mechanism of action

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 of both growing and stationary phase cells causing depolarisation and leading to a rapid inhibition of protein, 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 positive organisms in vitro and in in vivo animal models. In animal models AUC/MIC and Cmax/MIC correlate with efficacy and predicted bacterial kill in vivo at single doses equivalent to human adult doses of 4 mg/kg and 6 mg/kg once daily.

Mechanisms of resistance

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

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

Breakpoints

The MIC breakpoints according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), version10.0, January 01, 2020 are displayed in the following table:________­________________________­______________

Susceptibility

The prevalence of resistance may vary geographically and over time for selected species and local information 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 the agent in at least some types of infections is questionable.

Staphylococcus aureus 1 2

Staphylococcus haemolyticus

Coagulase negative staphylococci

Streptococcus agalactiae 2

Streptococcus dysgalactiae subsp equisimilis 2

Streptococcus pyogenes 2

Group G streptococci

Clostridium perfringens

Peptostreptococcus spp

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in 19/120 (15.8%) patients treated with daptomycin, 9/53 (16.7%) patients treated with vancomycin and 2/62 (3.2%) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among these failures six patients treated with daptomycin 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 surgical intervention.

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 a stepwise approach into well-defined age groups and given age-dependent doses once daily for up to 14 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. Secondary objectives included an assessment of efficacy of agedependent doses of intravenous daptomycin in comparison with standard-of-care therapy. The key efficacy endpoint was the sponsor-defined clinical outcome at test-of-cure (TOC), which was defined by a blinded medical director.

A total of 389 subjects were treated in the study, including 256 subjects who received daptomycin and 133 subjects who received standard-of-care. In all populations the clinical success rates were comparable between the daptomycin and SOC treatment arms, supporting the primary efficacy analysis in the ITT population.

Summary of sponsor-defined clinical outcome at TOC:_________­____________

Clinical Success in Paediatric cSSTI

The overall therapeutic response rate also was similar for the daptomycin and SOC treatment arms for infections 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):________­________________________­________________________­___________

a Subjects achieving clinical success (Clinical Response of “Cure” or “Improved”) and

microbiological success (pathogen-level response of “Eradicated” or “Presumed Eradicated”) are classified as overall therapeutic 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 randomized in a 2:1 ratio into the following age groups and given age-dependent doses once daily for up to 42 days, as follows:

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

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 intravenous daptomycin versus SOC antibiotics. Secondary objectives included: Clinical outcome based on the blinded 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) based on evaluation of Baseline infecting pathogen at TOC.

A total of 81 subjects were treated in the study, including 55 subjects who received daptomycin and 26 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 SOC treatment arm.

Summary of Blinded Evaluator defined clinical outcome at TOC:

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

5.2 Pharmacokinetic properties

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

Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and 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 oral administration.

Distribution

The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetrate the blood-brain barrier and the placental barrier following single and multiple doses.

Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy adult volunteers and adult patients treated with daptomycin, protein binding averaged about 90% including subjects with renal impairment.

Biotransformation

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

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

Elimination

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

Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 mL/h/kg and its renal clearance is 4 to 7 mL/h/kg.

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

Special populations

Elderly

Following administration of a single 4 mg/kg intravenous dose of daptomycin over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-oo was approximately 58% higher in elderly subjects (> 75 years of age) compared with those in healthy young subjects (18 to 30 years of age). There were no differences in Cmax. The differences noted are most 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 and the dose should be reduced if there is evidence of severe renal impairment.

Children and adolescents (1 to 17years of age)

The pharmacokinetics of daptomycin in paediatric subjects was evaluated in 3 single-dose pharmacokinetic studies. After a single 4 mg/kg dose of daptomycin, total clearance normalized by weight and elimination half-life of daptomycin in adolescents (12–17 years of age) with Gram-positive infection were similar to adults. After a single 4 mg/kg dose of daptomycin, total clearance of daptomycin in children 7–11 years of age with Gram-positive infection was higher than in adolescents, whereas elimination half-life was shorter. After a single 4, 8, or 10 mg/kg dose of daptomycin, total clearance and elimination half-life of daptomycin in children 2–6 years of age were similar at different doses; total clearance was higher and elimination half-life was shorter than in adolescents. After a single 6 mg/kg dose of daptomycin, the clearance and elimination half-life of daptomycin in children 13–24 months of age were similar to children 2–6 years of age who received a single 4–10 mg/kg dose. The results of these studies show that exposures (AUC) in paediatric patients across all doses are generally lower than those in adults at comparable doses.

Paediatric patients with cSSTI

A Phase 4 study (DAP-PEDS-07–03) was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with cSSTI caused by Gram positive pathogens. Daptomycin pharmacokinetics in patients in this study are summarized in Table 2.Following administration of multiple doses, daptomycin exposure was similar across different age groups after dose adjustment based on body weight and age. Plasma exposures achieved with these doses were consistent with those achieved in the adult cSSTI study (following 4 mg/kg once daily in adults).

Table 2 Mean (Standard Deviation) of daptomycin Pharmacokinetics

in Paediatric cSSTI Patients (1 to 17 Years of Age) in Study DAP-PEDS-07–03

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

Paediatric patients with SAB

A Phase 4 study (DAP-PEDBAC-11–02) was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with SAB. Daptomycin pharmacokinetics inpatients in this study are summarized in Table 3. Following administration of multiple doses, daptomycin exposure was similar across different age groups after dose adjustment based on body weight and age. Plasma exposures achieved with these doses were consistent 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

Pharmacokinetic parameter values estimated using a model-based approach with sparsely collected pharmacokinetic samples from 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 in the study. Simulation using a population pharmacokinetic model demonstrated that the AUCss (area under the concentrationtime curve at steady state) of daptomycin in paediatric patients 1 to <2 years of age receiving 12 mg/kg once daily would be comparable 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 extremely obese subjects (Body Mass Index of > 40 kg/m2). However, no dose adjustment is considered to be necessary based on obesity alone.

Gender

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

Renal impairment

Following administration of a single 4 mg/kg or 6 mg/kg intravenous dose of daptomycin over a 30– minute period to adult subjects with various degrees of renal impairment, total daptomycin clearance (CL) decreased and systemic exposure (AUC) increased as renal function (creatinine clearance) decreased.

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

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

Hepatic impairment

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 for gender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary when administering daptomycin in patients with moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh C classification) have not been evaluated.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

Daptomycin Noridem 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 ± 2 °C and up to 48 hours at 5 ± 3 °C.

After dilution:

Chemical and physical in-use stability of the diluted solution in infusion bags is established for 12 hours at 25 ± 2 °C or 24 hours at 5 ± 3 °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 ± 2 °C must not exceed 12 hours (or 24 hours 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 ± 2 °C must not exceed 12 hours (or 48 hours at 2 °C – 8 °C).

However, from a microbiological point of view the product should be used immediately. No

preservative or bacteriostatic agent is present in this product. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C – 8 °C, unless reconstitution/di­lution has taken place in controlled and validated aseptic conditions.

After admixture:

Chemical and physical in-use stability of the admixtures is established for 2 hours at 25 ± 2°C.

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C).For storage conditions after reconstitution / dilution of the medicinal product see section 6.3.

6.5 Nature and contents of container

Single use 10 mL type I clear glass vials with bromobutyl rubber stoppers and yellow aluminium caps having a plastic flip off cover.

Available in packs containing 1, 5, 10 or 50 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 Noridem given as 30 or 60-minute intravenous infusion

A 50 mg/mL concentration of Daptomycin Noridem 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 5 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 Noridem for intravenous infusion, please adhere to the following instructions:

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

For Reconstitution:

1. The plastic 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 center 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 Noridem range in colour from pale yellow to light brown.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 Noridem containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.

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

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

A 50 mg/mL concentration of Daptomycin Noridem 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 5 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 Noridem for intravenous injection, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Daptomycin Noridem.

1. The plastic 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 center 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 Noridem 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 Noridem 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

Noridem Enterprises Limited

Evagorou & Makariou,

Mitsi Building 3, Office 115,

Nicosia 1065, Cyprus

8 MARKETING AUTHORISATION NUMBER(S)

PL 24598/0065

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

01/07/2020