Consumer medicine information

Cubicin

Daptomycin

BRAND INFORMATION

Brand name

Cubicin

Active ingredient

Daptomycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cubicin.

What is in this leaflet

This leaflet answers some common questions about Cubicin. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will provide.

If you have any concerns about this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Cubicin is used for

What it is used for

Cubicin is used in adults and children (1 to 17 years of age) to treat complicated infections of the skin and the tissues under the skin.

It is also used in adults and children to treat blood infections. It is also used in adults to treat infections of the tissues that line the inside of the heart (including heart valves) - that are caused by Staphylococcus aureus bacteria.

Cubicin will not work against infections that cause pneumonia (a serious infection or inflammation in the lung tissue).

How Cubicin works

Cubicin is an antibiotic that belongs to a group of medicines called cyclic lipopeptides. These antibiotics work by killing the Gram-positive bacteria that are causing your infection.

Ask your doctor if you have any questions about why Cubicin has been prescribed for you. Your doctor may have prescribed it for another purpose.

This medicine is available only with a doctor's prescription.

Cubicin is not addictive.

Before you have Cubicin

When you must not have it

You must not have Cubicin if you are allergic (hypersensitive) to daptomycin, the active ingredient, or to any of the other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Before you are given it

Cubicin should not be administered to children below the age of 1 year due to possible side effects on muscles and nerves that were observed in animal studies.

Tell your doctor if you:

  • are allergic to any other medicines, foods, dyes or preservatives
  • have or have had any kidney problems. Your doctor may need to change the dose of Cubicin
  • are suffering from diarrhoea
  • are pregnant, or intend to become pregnant
    Like most medicines, Cubicin is not recommended in pregnancy. Your doctor will discuss with you the risks and benefits of having Cubicin during pregnancy.
  • are breastfeeding or plan to breastfeed.
    You should not breast-feed your child during your treatment with Cubicin.

Taking other medicines

Tell your doctor if you are taking, or have recently taken, any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and Cubicin may interfere with each other.

Tell your doctor if you are taking:

  • Warfarin (a medicine used to prevent blood clots).
  • Statins or fibrates (medicines used to lower cholesterol)
  • Cyclosporin (a medicine used to help prevent organ transplant rejection or to treat certain problems with the immune system)
  • Non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors, e.g. celecoxib (medicines used to relieve pain, swelling or other symptoms of inflammation)
  • Tobramycin, another antibiotic used to treat various types of bacterial infections.

These medicines may be affected by Cubicin, or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/her before you are given this medicine.

How Cubicin is given

Cubicin will be given to you by a doctor or a nurse as it needs to be given as an injection or infusion into a vein. For adults, the dose will depend on how much you weigh and the type of infection being treated.

For children (1 to 17 years of age), the dose will depend on the age of the patient, how much the child weighs, and the type of infection being treated.

Your doctor will decide on the dose and how long you will receive Cubicin.

If you have kidney problems, you may receive Cubicin less often, e.g. every other day. If you are receiving dialysis, and your next dose of Cubicin is due on a dialysis day, you will usually be given Cubicin after the dialysis session.

How it is given

Adults: Cubicin is given directly into your blood stream by intravenous injection over about 2 minutes or by infusion (drip) over about 30 minutes.

Children ( 7-17 years of age): Cubicin is given directly into the blood stream by infusion (drip) over 30 minutes.

Children (1-6 years of age): Cubicin is given directly into your blood stream by infusion (drip) over 60 minutes.

If you are given too much (overdose)

Since Cubicin is usually given to you in hospital under the supervision of your doctor, it is very unlikely that you will be given too much of the medicine. Your doctor, nurse or pharmacist will be monitoring your progress and checking the medicine that you are given.

Please contact the Poisons Information Centre (telephone 13 11 26, for advice on overdose management.

While you are being given Cubicin

Things you must do

If the symptoms of your infection do not improve, or if they become worse, tell your doctor.

If you develop itching with swelling or skin rash or difficulty breathing while you are being given Cubicin tell your doctor immediately.

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

  • Tender or aching muscles or muscle weakness.
    Your doctor will make sure that you have a blood test and will decide whether or not you should continue Cubicin treatment. The symptoms generally go away within a few days of stopping Cubicin.
  • Any unusual tingling or numbness of the hands or feet, loss of feeling or difficulties in moving.
    Your doctor will decide whether or not you should continue treatment.
  • Diarrhoea, especially if you notice blood.
    Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care. Do not take any diarrhoea medicine without first checking with your doctor.
  • New or worsening fever, cough or difficulty breathing.
    These may be the signs of a rare, but serious lung disorder called eosinophilic pneumonia. If you experience these symptoms, tell your doctor. Your doctor will check the condition of your lungs and will decide whether or not you should continue Cubicin treatment.

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

Your doctor will monitor your kidney function and the health of your muscles more frequently during Cubicin treatment if you have kidney problems.

If you get a sore white mouth or tongue while you are being given Cubicin or soon after stopping it, tell your doctor. Also tell your doctor if you get vaginal itching or discharge. This may mean you have a fungal infection called thrush. Sometimes the use of Cubicin allows fungi to grow and the above symptoms to occur. Cubicin does not work against fungi.

You should tell your doctor that you are being treated with Cubicin if you are about to have a blood clotting test or any other blood tests. It may interfere with the results of some tests.

If you become pregnant soon after being given Cubicin, tell your doctor.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being given Cubicin. It may affect other medicines used during surgery.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given Cubicin.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given Cubicin.

Things you must not do

Do not stop receiving Cubicin because you are feeling better, unless advised by your doctor. If you do not complete the full course prescribed by your doctor, all of the bacteria causing your infection may not be killed. These bacteria may continue to grow and multiply so that your infection may not clear completely or it may return.

Things to be careful of

Be careful driving or operating machinery until you know how Cubicin affects you. Cubicin generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, Cubicin may cause dizziness or tiredness in some people.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are taking Cubicin.

Cubicin helps most people with certain infections, but it may have unwanted side-effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or nurse if you notice any of the following and they worry you:

  • oral thrush (symptoms include a white, furry, sore tongue and mouth)
  • vaginal thrush (symptoms include sore and itchy vagina and/or discharge)
  • inflammation and irritation of the vagina (vaginitis)
  • fungal infections
  • pain, itchiness or redness at the site of administration
  • general pain, weakness or tiredness (fatigue)
  • trembling
  • decreased appetite
  • dizziness
  • spinning sensation (vertigo)
  • headache
  • flushes
  • mild stomach upsets such as indigestion (dyspepsia), feeling sick (nausea), being sick (vomiting) or stomach pain
  • abdominal pain, swelling or bloating
  • flatulence
  • constipation or mild diarrhoea
  • taste disturbance
  • eye irritation
  • difficulty in sleeping (insomnia)
  • pain in the arms or legs, or joint pain
  • anxiety
  • urinary tract infection
  • high or low blood pressure

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

  • anaphylaxis, a sudden life-threatening allergic reaction with the symptoms: sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • difficulty breathing, new or worsening cough, new or worsening fever (these may be the signs of a rare, but serious lung disorder called eosinophilic pneumonia)
  • unexplained muscle pain, tenderness, weakness or cramps
  • tingling, burning or numbness of arms and hands or legs and feet (paraesthesia)
  • loss or difficulty moving the arms and/or legs
  • changes in heart rhythm
  • yellowing of the skin and eyes (jaundice)
  • kidney problems, including kidney failure
  • diarrhoea, especially bloody diarrhoea
  • fainting
  • unusual bleeding in the skin and bruising
  • hypersensitivity reactions (serious allergic reactions) such as:
    - pus filled bumps that can spread over the body, sometimes with a fever
    - shivering or chills
    - flushed appearance
    - blistering rash (vesiculobullous rash)
    - swelling of the face, neck and throat
    - fainting
    - cough.

Hypersensitivity reactions (serious allergic reactions including anaphylaxis, angioedema, drug rash with eosinophilia and systemic symptoms (DRESS) and pulmonary eosinophilia); and a serious lung disorder called eosinophilic pneumonia have been reported in patients given Cubicin.

Tell your doctor if you notice anything else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet.

After you are given Cubicin

Tell your doctor immediately if you develop diarrhoea, especially bloody diarrhoea, after your treatment has stopped. Diarrhoea is a common problem that happens when taking antibiotics. It usually stops when the antibiotic is stopped.

Other medicines of the same class as Cubicin may also cause diarrhoea.

Do not take any diarrhoea medicine without first checking with your doctor.

Storage

It is unlikely you will have to store Cubicin powder at home.

If you do have to store it:

  • Keep it in a refrigerator (2°C to 8°C).
  • Keep the vial in the outer carton in order to protect it from light.
  • Do not store it or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on a window sill.

Heat and dampness can destroy some medicines.

Keep the medicine where children cannot reach it.

Product description

What it looks like

Cubicin comes in a 10 mL glass vial containing a pale yellow to light brown powder.

Ingredients

Each vial contains daptomycin 350 mg or 500 mg as the active ingredient.

It also contains the following inactive ingredient:

  • sodium hydroxide

Cubicin does not contain preservatives or bacteriostatic agents.

Sponsor

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A
26 Talavera Road
Macquarie Park, NSW 2113

Date of preparation

This leaflet was prepared in April 2020.

Australian Registration Numbers:

AUST R 143574 (350 mg vial)

AUST R 143586 (500 mg vial)

® = Registered trademark

Based on PI dated 14 April 2020.

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Cubicin

Active ingredient

Daptomycin

Schedule

S4

 

1 Name of Medicine

Daptomycin.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

103060-53-3.

2 Qualitative and Quantitative Composition

Cubicin 350 mg powder for injection.
Cubicin 500 mg powder for injection.
Daptomycin is the active ingredient in Cubicin. It is a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus.
Active ingredient: daptomycin.
Chemical names: N-decanoly-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl- L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo- 3-methyl-L-glutamyl-3-anthraniloyl-L-alanine epsilon1-lactone.
Molecular weight: 1620.67.
Molecular formula: C72H101N17O26.
Cubicin is supplied in a single-dose 10 mL vial, as a sterile, preservative-free, pale yellow to light brown, lyophilised cake or powder containing 350 mg or 500 mg of daptomycin for intravenous (IV) use following reconstitution with 0.9% sodium chloride injection.
Daptomycin has a high aqueous solubility (> 1 g/mL).
The only inactive ingredient is sodium hydroxide, which is used in minimal quantities for pH adjustment.

3 Pharmaceutical Form

Powder for injection.
Sterile, preservative-free, pale yellow to light brown, lyophilised cake or powder.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Daptomycin is an antibacterial agent of a new class of antibiotics, the cyclic lipopeptides. Daptomycin is a natural product that has clinical utility in the treatment of infections caused by aerobic Gram positive bacteria. Daptomycin retains potency against antibiotic resistant Gram positive bacteria, including isolates resistant to methicillin, vancomycin, and linezolid.

Mechanism of action.

The mechanism of action of daptomycin is distinct from that of any other antibiotic. Daptomycin binds to bacterial membranes and causes a rapid depolarisation of membrane potential in both growing and stationary phase cells. This loss of membrane potential causes inhibition of protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.

Resistance.

The mechanism of daptomycin resistance is not fully understood. There are no known transferable elements that confer resistance to daptomycin.
There is no cross resistance due to resistance mechanisms that are specific for another class of antibiotics.
As documented with other antibiotics when used in patients with difficult to treat infections and/or for prolonged periods, emergent decreases in susceptibility have been observed in both S. aureus and enterococcal isolates following Cubicin therapy.

PK/PD relationship.

Daptomycin exhibits rapid, concentration dependent bactericidal activity against sensitive Gram positive organisms in vitro.
Based on animal models of infection, the antimicrobial activity of daptomycin appears to correlate with the AUC/MIC (area under the concentration time curve/minimum inhibitory concentration) ratio for certain pathogens, including S. aureus. The principal pharmacokinetic/pharmacodynamics parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with Cubicin.

Clinical trials.

Complicated skin and skin structure infections (cSSSI).

Skin and skin structure infections are defined as infections of the epidermis, dermis or subcutaneous tissue, and have highly diverse aetiologies and clinical manifestations. The complicated category includes deep soft tissue infections which require significant medical intervention, and abnormal skin or wound infections, which typically occur in compromised patients and may require surgical intervention.

Adults with cSSSI.

Adult patients with clinically documented cSSSI (Table 3) were enrolled in two randomised, multinational, multicentre, investigator blinded studies comparing daptomycin (4 mg/kg IV q24h) with either vancomycin (1 g IV q12h) or an antistaphylococcal semisynthetic penicillin (i.e. nafcillin, oxacillin, cloxacillin or flucloxacillin; 4 to 12 g IV per day). In these trials cSSSIs included wound infections, major abscesses, severe carbunculosis, infected ulcers and infections in the presence of a complicating factor, such as infections involving deep soft tissue, fascia or muscle, and infections in immunosuppressed patients (e.g. HIV infection, chronic systemic steroids, diabetes mellitus).
Patients known to have bacteraemia at baseline were excluded. Patients with creatinine clearance (ClCr) between 30 and 70 mL/min were to receive a lower dose of daptomycin as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of daptomycin adjusted. In study DAP-SST-9801 (9801), 16% of the ITT patients treated with daptomycin had their regimen adjusted for renal function. In study DAP-SST-9901 (9901), only 2% had their regimen adjusted. Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated.
Study 9801 was conducted primarily in the United States and South Africa, whilst study 9901 was conducted outside of the US, including 5 sites in Australia. Both studies were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 patients treated with daptomycin and 558 treated with comparator in the two studies. The majority (89.7%) of patients received IV medication exclusively.
The efficacy endpoints in both studies were the clinical success rates in the intent to treat (ITT) population and in the clinically evaluable (CE) population. The ITT population included all enrolled subjects who had a complicated skin and soft tissue infection and received at least one dose of study medication. The CE population consisted of all subjects in the ITT population who met specific predefined criteria such that the clinical outcome of their infection could be inferred to reflect the effect of the study drug.
In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with daptomycin and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76.0% (158/208) in patients treated with daptomycin and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with daptomycin and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with daptomycin and 90.4% (226/250) in patients treated with comparator drugs.
The success rates by pathogen for microbiologically evaluable patients are presented in Table 4.
Overall clinical efficacy results are provided in Tables 5 and 6 in terms of the sponsor defined primary clinical efficacy parameters at the test of cure visit (7-12 days after cessation of antibiotic treatment) for MITT and CE populations.

Paediatric patients (1 to 17 years of age) with cSSSI.

The safety and efficacy of daptomycin was evaluated in paediatric patients 1 to 17 years of age (DAP-PEDS-07-03) with cSSSI caused by Gram positive pathogens. Patients were enrolled in a stepwise approach into well-defined age groups and given age dependent doses once daily 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 (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 age dependent doses of IV 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 (see Table 7).
The overall therapeutic response rate also was similar for the daptomycin and SOC treatment arms for infections caused by MRSA, MSSA and Streptococcus pyogenes (Table 8, ME population); response rates were > 94% for both treatment arms across these common pathogens.

S. aureus bacteraemia/endocarditis.

Adults with S. aureus bacteraemia/endocarditis.

The efficacy of daptomycin in the treatment of patients with S. aureus bacteraemia (SAB) was demonstrated in a randomised, controlled, multinational, multicentre open label study. In this study, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either daptomycin (6 mg/kg IV q24h) or standard of care (antistaphylococcal semisynthetic penicillin 2 g IV q4h (nafcillin, oxacillin, cloxacillin or flucloxacillin) or vancomycin 1 g IV q12h, both with initial gentamicin 1 mg/kg IV every 8 hours for first 4 days). Of the patients in the comparator group, 93% received initial gentamicin for a median of 4 days compared with 1 patient (< 1%) in the daptomycin group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance < 30 mL/min, shock unresponsive to treatment for 4 hours and pneumonia were excluded.
Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (possible, definite, or not endocarditis). Echocardiography, including a transoesophageal echocardiogram (TEE), was performed within 5 days following study enrolment. The choice of comparator agent was based on the oxacillin susceptibility of the S. aureus isolate. The duration of study treatment was based on the investigator's clinical diagnosis. Final diagnoses and outcome assessments at test of cure (6 weeks after the last treatment dose) were made by a treatment blinded adjudication committee, using protocol specified clinical definitions and a composite primary efficacy endpoint (clinical and microbiological success) at the test of cure visit.
A total of 246 patients ≥ 18 years of age (124 daptomycin, 122 comparator) with S. aureus bacteraemia were randomized from 48 centres in the US and Europe. In the ITT population, 120 patients received daptomycin and 115 received comparator (62 antistaphylococcal semisynthetic penicillin and 53 vancomycin). Thirty five patients treated with antistaphylococcal semisynthetic penicillins received vancomycin initially for 1 to 3 days, pending final susceptibility results for the S. aureus isolates. The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25%) in the daptomycin group and 37/115 (32%) in the comparator group were ≥ 65 years of age. Of the 235 ITT patients, there were 141 (60%) males and 156 (66%) Caucasians across the two treatment groups. In addition, 176 (75%) of the ITT population had systemic inflammatory response syndrome (SIRS) and 85 (36%) had surgical procedures within 30 days of onset of the S. aureus bacteraemia. Eighty-nine patients (38%) had bacteraemia caused by MRSA. Entry diagnosis was based on the modified Duke criteria and included 37 (16%) definite, 144 (61%) possible and 54 (23%) not endocarditis. Of the 37 patients with an entry diagnosis of definite endocarditis, all (100%) had a final diagnosis of infective endocarditis and of the 144 patients with an entry diagnosis of possible endocarditis, 15 (10%) had a final diagnosis of infective endocarditis as assessed by the adjudication committee. Of the 54 patients with an entry diagnosis of not endocarditis, 1 (2%) had a final diagnosis of infective endocarditis as assessed by the adjudication committee.
There were 182 patients with bacteraemia and 53 patients with infective endocarditis as assessed by the adjudication committee in the ITT population, including 35 with right sided and 18 with left sided endocarditis. The 182 patients with bacteraemia included 121 with complicated and 61 with uncomplicated S. aureus bacteraemia.
Complicated bacteraemia was defined as S. aureus isolated from blood cultures obtained on at least 2 different calendar days and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria. Uncomplicated bacteraemia was defined as S. aureus isolated from blood culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection of prosthetic material and classification of the patient as not having endocarditis according to the modified Duke criteria. The definition of right sided endocarditis (RIE) used in the clinical trial was definite or possible endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Complicated RIE included patients who were not intravenous drug users, had a positive blood culture for MRSA, serum creatinine ≥ 2.5 mg/dL or evidence of extrapulmonary sites of infection. Patients who were intravenous drug users, had a positive blood culture for MSSA, serum creatinine < 2.5 mg/dL and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE.
The co-primary efficacy endpoints in the study were the adjudication committee success rates at the test of cure visit (6 weeks after the last treatment dose) in the ITT and per protocol (PP) populations. The overall adjudication committee success rates in the ITT population were 44.2% (53/120) in patients treated with daptomycin and 41.7% (48/115) in patients treated with comparator (difference = 2.4% (95% CI 10.2, 15.1)). The success rates in the PP population were 54.4% (43/79) in patients treated with daptomycin and 53.3% (32/60) in patients treated with comparator (difference = 1.1% (95% CI 15.6, 17.8)).
Adjudication committee success rates are shown in Table 9.
Eighteen (18/120) patients in the daptomycin arm and 19/116 patients in the comparator arm died during the study. These include 3/28 daptomycin treated and 8/26 comparator treated patients with endocarditis, as well as 15/92 daptomycin treated and 11/90 comparator treated patients with bacteraemia. Among patients with persisting or relapsing S. aureus infections, 8/19 daptomycin treated and 7/11 comparator treated patients died.
Overall, there was no difference in time to clearance of S. aureus bacteraemia between daptomycin and comparator. The median time to clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days.
Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the adjudication committee in 19/120 (15.8%) daptomycin treated patients (12 with MRSA and 7 with MSSA) and 11/115 (9.6%) comparator treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with antistaphylococcal semisynthetic penicillin). Among all failures, 6 daptomycin treated patients and 1 vancomycin treated patient developed increasing MICs for daptomycin (reduced susceptibility) by central laboratory testing on or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep seated infection and did not receive necessary surgical intervention (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric patients (1 to 17 years of age) with S. aureus bacteraemia.

The paediatric S. aureus bacteraemia study was designed as a prospective multi-centre, randomised, comparative trial to treat paediatric patients aged 1 to 17 years with bacteraemia. Patients known to have any of the following conditions at baseline were excluded:
presence of shock or hypotension unresponsive to fluids or vasopressors for ≥ 4 hours;
renal insufficiency in terms of estimated creatinine clearance rate (ClCr) 50 mL/min/1.73 m2;
history of clinically significant muscular disease, for example, creatine phosphokinase (CPK) elevation ≥ 10 X ULN (upper limit of normal) without symptoms or ≥ 5 X ULN with symptoms such as myalgia, muscle stiffness, muscle weakness;
suspected or confirmed S. aureus empyema, meningitis, endocarditis or pneumonia.
Patients were enrolled in a stepwise approach into three age groups and given age-dependent doses of Cubicin once daily for up to 42 days. The different age groups and doses evaluated were as follows:
age group 1 (n=14): 12-17 years treated with Cubicin dosed at 7 mg/kg once daily;
age group 2 (n=19): 7-11 years treated with Cubicin dosed at 9 mg/kg once daily;
age group 3 (n=22); 2-6 years treated with Cubicin dosed at 12 mg/kg once daily.
No patients 1 to < 2 years of age were enrolled.
Patients were randomised 2:1 to receive Cubicin or a standard of care comparator, which included intravenous therapy with vancomycin, semi-synthetic penicillin, first generation cephalosporin or clindamycin. Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required).
The primary objective of Study DAP-PEDBAC-11-02 was to assess the safety of intravenous daptomycin versus SOC antibiotics. Efficacy outcomes included: Clinical outcome based on the blinded Evaluator's assessment of clinical response (success [cure, improved], failure, or non-evaluable) at the TOC visit (see Table 10); and Microbiological response (success, failure, or non-evaluable) based on evaluation of Baseline infecting pathogen at TOC (see Table 11).
Of the 82 subjects randomised in the study, 81 subjects were treated with Cubicin or comparator and included in the safety population, and 73 had a proven S. aureus bacteraemia at Baseline. Of these, 51 subjects were randomised to the Cubicin group and 22 subjects were randomised to the comparator group. The mean duration of IV therapy was 12 days with a range of 1 to 44 days. Forty-eight subjects switched to oral therapy, and the mean duration of oral therapy was 21 days. The clinical success rates determined at 7 to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (45/51) for Cubicin and 77% (17/22) for comparator.
The microbiological outcome at TOC for the daptomycin and SOC treatment arms for infections caused by MRSA and MSSA are presented in Table 11.

5.2 Pharmacokinetic Properties

The mean (SD) pharmacokinetic parameters of daptomycin at steady state following IV administration of 4 to 12 mg/kg q24h to healthy young adults are summarised in Table 12.
Daptomycin pharmacokinetics were generally linear (dose proportional) and time independent at Cubicin doses of 4 to 12 mg/kg q24h. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following administration of 4, 6, 8, 10 and 12 mg/kg q24h in healthy adults were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9) and 13.7 (5.2) microgram/mL, respectively.

Distribution.

Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration independent manner. The overall mean binding ranged from 90 to 93%.
In clinical studies, mean serum protein binding in adult subjects with ClCr ≥ 30 mL/min was comparable to that observed in healthy adult subjects with normal renal function. However, there was a trend toward decreasing serum protein binding among adult subjects with ClCr < 30 mL/min (87.6%), including those receiving haemodialysis (85.9%) and continuous ambulatory peritoneal dialysis (CAPD) (83.5%). The protein binding of daptomycin in adult subjects with hepatic impairment (Child-Pugh B) was similar to that in healthy adult subjects.
The volume of distribution at steady state (Vss) of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose.

Metabolism.

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 drugs metabolised by the P450 system.
In 5 healthy young adults after infusion of radiolabelled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. In a separate study, no metabolites were observed in plasma on day 1 following administration of daptomycin at 6 mg/kg to subjects. Inactive metabolites have been detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.

Excretion.

Daptomycin is excreted primarily by the kidney. Concomitant administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin.
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 of 5 healthy adult subjects using radiolabelled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations) and 5.7% of the administered dose was recovered from faeces (collected for up to 9 days) based on total radioactivity.
Because renal excretion is the primary route of elimination, dosage adjustment is necessary in patients with severe renal impairment (ClCr < 30 mL/min) (see Section 4.2 Dose and Method of Administration).

Special patient groups.

Elderly.

The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (≥ 75 years of age) and 11 healthy young adult controls (18 to 30 years of age). Following administration of a single 4 mg/kg IV dose, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-∞ was approximately 58% higher in elderly subjects compared with young healthy adult subjects. There were no differences in Cmax. No dosage adjustment is warranted for elderly patients with normal renal function.

Paediatric.

The pharmacokinetics of daptomycin after a single 4 mg/kg dose of Cubicin were evaluated in three groups of paediatric patients with Gram positive infections. The pharmacokinetic profile in adolescents, 12-17 years of age, showed reduced exposure. In the two younger age groups (7 to 11 years and 2 to 6 years), total clearance was higher compared with that in adolescents, resulting in lower exposure (AUC and Cmax) and elimination half-life. As the adolescent exposure is less than adults it is possible that inadequate exposure may occur with the 4 mg/kg dose that is not the recommended dose in these two groups.
A separate study was conducted to evaluate the pharmacokinetics of daptomycin after a single 8 mg/kg or 10 mg/kg dose of Cubicin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to 6 years, inclusive, with proven or suspected Gram positive infection who were receiving standard antibacterial therapy.
The mean exposure (AUC0-∞) was approximately 429 and 550 microgram.hr/mL after the administration of 8 and 10 mg/kg single doses, respectively, similar to the exposure seen in adults at the 4 mg/kg dose at steady state (495 microgram.hr/mL). The pharmacokinetics of daptomycin appears to be linear in the dose range studied. The half life, clearance and volume of distribution were similar at both dose levels.
A phase 4 study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with cSSSI caused by Gram positive pathogens. Patients were enrolled into 4 age groups (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Intravenous daptomycin doses of 5 to 10 mg/kg were administered and 256 children received daptomycin, from which pharmacokinetic sampling was performed on 45 children from across the age groups.
Daptomycin pharmacokinetic parameters following the administration of multiple doses, are provided in Table 13. Daptomycin exposure (AUCss and Cmax,ss) was similar across the different age groups after dose adjustment based on body weight and age.
A study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years of age, inclusive) with S. aureus bacteraemia. Patients were enrolled into 3 age groups (see Clinical trials), and intravenous doses of 7 to 12 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUCss and Cmax,ss) was similar across different age groups after dose adjustment based on body weight and age (Table 14).
No patients 1 to < 2 years of age were enrolled in the study. Simulation using a population pharmacokinetic model demonstrated that the AUCss 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.

The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (body mass index (BMI) 25 to 39.9 kg/m2) and 6 extremely obese (BMI ≥ 40 kg/m2) subjects and controls matched for age, sex and renal function. Following administration of a single 4 mg/kg IV dose based on total bodyweight, the plasma clearance of daptomycin normalised to total bodyweight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects compared with non-obese controls. The AUC0-∞ of daptomycin was approximately 30% higher in moderately obese and 31% higher in extremely obese subjects compared with nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No dosage adjustment of daptomycin is warranted in obese subjects.

Gender.

No clinically significant gender related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when administering daptomycin.

Renal impairment.

Population derived pharmacokinetic parameters were determined for infected adult patients (complicated skin and skin structure infections and S. aureus bacteraemia) and non-infected adult subjects with varying degrees of renal function (Table 15). Plasma clearance (CLT), elimination half-life (t1/2) and volume of distribution at steady state (Vss) were similar in patients with complicated skin and skin structure infections compared with those with S. aureus bacteraemia. Following the administration of daptomycin 4 mg/kg q24h, the mean CLT was 9%, 22% and 46% lower among subjects and patients with mild (ClCr 50-80 mL/min), moderate (ClCr 30-50 mL/min) and severe (ClCr < 30 mL/min) renal impairment, respectively, than in those with normal renal function (ClCr > 80 mL/min). The mean steady-state systemic exposure (AUC), t1/2 and Vss increased with decreasing renal function, although the mean AUC was not markedly different for patients with ClCr 30-80 mL/min compared with those with normal renal function. The mean AUC for patients with ClCr < 30 mL/min and for patients on haemodialysis (dosed postdialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. Following the administration of daptomycin 4 mg/kg q24h, the mean Cmax ranged from 60 to 70 microgram/mL in patients with ClCr ≥ 30 mL/min, while the mean Cmax for patients with ClCr < 30 mL/min ranged from 41 to 58 microgram/mL. The mean Cmax ranged from 80 to 114 microgram/mL in patients with mild to moderate renal impairment and was similar to that of patients with normal renal function after the administration of daptomycin 6 mg/kg q24h. In patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently. Daptomycin should be administered following the completion of haemodialysis on haemodialysis days (see Section 4.2 Dose and Method of Administration for recommended dosage regimens).

Hepatic impairment.

The pharmacokinetics of daptomycin were evaluated in 10 subjects with moderate hepatic impairment (Child-Pugh class B) and compared with healthy volunteers (N = 9) matched for gender, age, and weight. The pharmacokinetics of daptomycin was not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when administering daptomycin to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh class C) has not been evaluated.

5.3 Preclinical Safety Data

Genotoxicity.

Daptomycin was not mutagenic or clastogenic in a battery of in vivo and in vitro genotoxicity tests comprising mutation in bacteria and mammalian cells, chromosomal aberrations and DNA damage in mammalian cells, a bone marrow micronucleus assay in mice and a sister chromatid exchange assay in Chinese hamsters.

Carcinogenicity.

Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of daptomycin.

4 Clinical Particulars

4.1 Therapeutic Indications

Daptomycin is active against Gram positive bacteria only. In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, daptomycin should be coadministered with appropriate antibacterial agent(s).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Daptomycin is not indicated for the treatment of pneumonia.

Adult patients (≥ 18 years of age).

Complicated skin and skin structure infections.

Cubicin is indicated for the treatment of adults (≥ 18 years of age) with complicated skin and skin structure infections (cSSSI) who require parenteral therapy and who have intolerance to alternative agents (especially penicillin allergy) or who have failed on other therapy, and when caused by organisms known to be susceptible to daptomycin.

Staphylococcus aureus bloodstream infections (bacteraemia).

Cubicin is indicated in adults (≥ 18 years of age) for Staphylococcus aureus bloodstream infections (bacteraemia), including right-sided native valve infective endocarditis (RIE), caused by methicillin-susceptible and methicillin-resistant isolates.
The efficacy of daptomycin in patients with prosthetic heart valves or in left-sided endocarditis due to Staphylococcus aureus has not been demonstrated. In the setting of Staphylococcus aureus bacteraemia (SAB), if a focus of infection is diagnosed as left-sided endocarditis after Cubicin therapy has been initiated, then consideration should be given to instituting alternative antibacterial therapy (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric patients (1 to 17 years of age).

Daptomycin is not indicated for treatment of patients less than 1 year of age (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Daptomycin has not been studied in treatment of infective endocarditis in children (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use).

Complicated skin and skin structure infections.

Cubicin is indicated for the treatment of patients aged 1 to 17 years with complicated skin and skin structure infections (cSSSI) who require parenteral therapy and who have intolerance to alternative agents (especially penicillin allergy) or who have failed on other therapy, and when caused by organisms known to be susceptible to daptomycin.

Staphylococcus aureus bloodstream infections (bacteraemia).

Cubicin is indicated in paediatric patients (1 to 17 years of age) with Staphylococcus aureus bacteraemia not due to pneumonia, caused by daptomycin-susceptible isolates. Empiric treatment should be reviewed based on the results of susceptibility testing. Prescribing should be in accordance with nationally or locally-endorsed guidelines for the treatment of Staphylococcus aureus bacteraemia.

4.3 Contraindications

Cubicin is contraindicated in patients with known hypersensitivity to daptomycin or to the excipient.

4.4 Special Warnings and Precautions for Use

General.

Although daptomycin is indicated in adults for the treatment of right sided endocarditis caused by Staphylococcus aureus, its efficacy in patients with left sided infective endocarditis has not been demonstrated in controlled clinical trials. Therefore, use of daptomycin in left sided endocarditis caused by S. aureus is not recommended and consideration should be given to instituting alternative antibacterial therapy.

Anaphylaxis/hypersensitivity reactions.

Anaphylaxis/hypersensitivity reactions have been reported with nearly all antibacterial agents including Cubicin. If an allergic reaction to Cubicin occurs, discontinue the medicine and institute appropriate therapy.

Pneumonia.

Daptomycin is not indicated for the treatment of pneumonia. It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of community acquired pneumonia (inhalational or airborne), due to binding to pulmonary surfactant and consequent inactivation (see Section 4.1 Therapeutic Indications).

Eosinophilic pneumonia.

Eosinophilic pneumonia has been reported in patients receiving Cubicin (see Section 4.8 Adverse Effects (Undesirable Effects)). In reported cases associated with Cubicin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organising pneumonia. In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting Cubicin and improved when Cubicin 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 Cubicin should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other drugs), and Cubicin should be discontinued immediately. Treatment with systemic steroids is recommended.

Drug reaction with eosinophilia and systemic symptoms (DRESS) and tubulointerstitial nephritis (TIN).

DRESS and TIN have been reported in post-marketing experience with daptomycin. Patients who develop fever, skin rash, peripheral eosinophilia and/or new or worsening renal impairment or other organ impairment while receiving Cubicin should undergo medical evaluation. If DRESS and/or TIN are suspected, Cubicin should be discontinued promptly and appropriate treatment instituted.

Skeletal muscle effects.

Increases in plasma creatine phosphokinase (CPK) levels associated with muscular pains, weakness and/or rhabdomyolysis have been reported during therapy with Cubicin (see Section 4.8 Adverse Effects (Undesirable Effects)).
In a phase 1 study in adults examining doses up to 12 mg/kg q24h of daptomycin for 14 days, no skeletal muscle effects or CPK elevations were observed.
In the two phase 3 cSSSI trials of daptomycin in adults at a dose of 4 mg/kg, elevations in CPK were reported as adverse events in 15/534 (2.8%) daptomycin-treated patients compared with 10/558 (1.8%) comparator treated patients. In only one of these two trials an elevation in CPK > 500 was detected in association with a musculoskeletal event; these findings were reported in two patients, one in each treatment group.
In the S. aureus bacteraemia/endocarditis trial in adults, at a daptomycin dose of 6 mg/kg, elevations in CPK were reported as clinical adverse events in 8/120 (6.7%) daptomycin treated patients compared with 1/116 (< 1%) comparator treated patients. In patients with normal CPK at baseline, 25.0% in the daptomycin group and 12.5% in the comparator group had CPK ≥ ULN during therapy or up to 3 days post-treatment. Eighteen (75.0%) of the 24 daptomycin patients with CPK ≥ ULN at baseline had CPK return to the normal range during treatment. A total of 11 daptomycin patients had treatment emergent elevations in CPK to > 500 U/L, including 3 patients with CPK ≥ ULN at baseline. Of these 11 patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor which may have contributed to these laboratory findings. Three of these 11 daptomycin patients had an elevation in CPK > 500 U/L with an associated musculoskeletal or asthenia event, 2 of whom had an alternative aetiology for these events.
Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy such as muscle pain or weakness, particularly of the distal extremities. Plasma CPK levels should be monitored at baseline and at regular intervals (at least once weekly) during therapy in all patients. In addition, transaminase levels should be monitored in patients who are at increased risk for drug induced myopathies or hepatotoxicity. Patients with unexplained elevations of CPK or unexplained muscle pain, tenderness or weakness should be monitored more frequently than once weekly. CPK should be measured more frequently than once weekly in patients who are at higher risk of developing myopathy. These patients include those with severe renal impairment (creatinine clearance < 30 mL/min) and patients taking other medications known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and cyclosporin).
It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal (ULN) 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.
During postmarketing surveillance very rare isolated cases of rhabdomyolysis in patients receiving daptomycin have been reported; when clinical information on the patients was available, approximately 50% of the cases occurred in patients with pre-existing renal impairment or in those receiving concomitant medications known to cause rhabdomyolysis. It is recommended that other medications associated with myopathy should, if possible, be temporarily discontinued during treatment with daptomycin unless the benefits of concomitant administration outweigh the risk.
Daptomycin should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation > 1,000 U/L (~ 5 x ULN) or in patients without reported symptoms who have marked elevations in CPK > 2,000 U/L (≥ 10 x ULN). In addition, consideration should be given to temporarily suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, in patients receiving daptomycin.
In studies of clinically relevant duration (14-28 days), skeletal muscle effects associated with daptomycin were observed in adult rats and dogs with no changes in cardiac or smooth muscle. The lowest observed effect level (LOEL) for myopathy in adult rats and dogs occurred at exposure levels of 0.8 to 2.3-fold the mean AUC in patients with normal renal function following 30 minute continuous infusion dosing of 6 mg/kg. Skeletal muscle effects were characterized by degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No fibrosis or rhabdomyolysis was observed up to the highest doses tested in rats and dogs (approximately 9 and 5 times the human AUC at 6 mg/kg/day, respectively). All muscle effects, including microscopic changes, were fully reversible in rats within 30 days and in dogs within 2 months following cessation of dosing.

Peripheral nerve effects.

Physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving Cubicin (see Section 4.8 Adverse Effects (Undesirable Effects)). Paediatric patients below the age of one year should not be given Cubicin due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs.
In a phase 1 study in adults examining doses up to 12 mg/kg q24h of daptomycin for 14 days, no evidence of nerve conduction deficits or symptoms of peripheral neuropathy was observed. In a small number of patients in phase 1 and phase 2 studies at doses up to 6 mg/kg, administration of daptomycin was associated with decreases in nerve conduction velocity and with adverse events (e.g. paraesthesias, Bell's palsy) possibly reflective of peripheral or cranial neuropathy. However, nerve conduction deficits were also detected in a similar number of comparator subjects in these studies.
In phase 3 cSSSI and community acquired pneumonia (CAP) studies in adults, 7/989 (0.7%) daptomycin treated patients and 7/1,018 (0.7%) comparator treated patients experienced paraesthesias. New or worsening peripheral neuropathy was not diagnosed in any of these patients. In the S. aureus bacteraemia/endocarditis trial in adults, a total of 11/120 (9.2%) patients in the daptomycin group and 2/120 (1.7%) patients in the comparator group were identified who had experienced adverse events associated with the peripheral nervous system. All of the events were classified as mild to moderate in severity; most were of short duration and resolved during continued treatment with daptomycin or were likely due to an alternative aetiology.
In adult rats and dogs, effects of daptomycin on peripheral and/or spinal nerve (characterised by axonal degeneration and frequently accompanied in dogs by functional changes in nerve conduction and/or loss of reflexes, decreased pain perception, tremor and motor incoordination) were observed at doses higher than those associated with skeletal myopathy. Reversal of both the microscopic and functional effects was almost complete within 6 months postdose. Exposure margins for peripheral nerve effects in rats and dogs are 8-fold and 6-fold, respectively based on comparison of Cmax values at the no observed effect level (NOEL) with the Cmax achieved with 30 minute continuous infusion dosing of 6 mg/kg once daily in patients with normal renal function. Therefore, physicians should be alert to the possibility of signs and symptoms of neuropathy in patients receiving daptomycin.
Neonatal dogs were more sensitive to the nerve and muscle effects of daptomycin than adult or juvenile dogs. Effects of daptomycin were assessed in neonatal dogs following once daily IV administration for 28 consecutive days from postnatal days (PND) 4 through 31 at nominal dosage levels of 10 [no observed adverse effect level (NOAEL)], 25, 50 and 50/75 mg/kg/day.
At dose levels of 50 and 75 mg/kg/day with associated Cmax and AUCinf values of ≥ 321 microgram/mL and ≥ 1,470 microgram.h/mL, respectively, marked clinical signs of twitching, muscle rigidity in the limbs, and impaired use of limbs were observed. Resulting decreases in bodyweights and overall body condition at dose ≥ 50 mg/kg/day necessitated early discontinuation by PND19. At the dose level of 25 mg/kg/day associated Cmax and AUCinf values of 147 microgram/mL and 717 microgram.h/mL, respectively, mild clinical signs of twitching and one incidence of muscle rigidity were observed without any effects on bodyweight and were reversible over a 28 days recovery period. These data indicate a limited margin between doses associated with mild versus marked adverse clinical signs. Histopathological assessment did not reveal any daptomycin related changes in the peripheral and central nervous system tissue, as well as in the skeletal muscle and tissue assessed, at any dose level. No adverse clinical signs for these target organs of toxicity were observed in the dogs that received daptomycin at 10 mg/kg/day, the NOAEL, with associated Cmax and AUCinf values of 62 microgram/mL and 247 microgram.h/mL, respectively.

Nonsusceptible organisms.

The use of antibiotics may promote the selection of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.
Prescribing daptomycin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.
Patients with deep seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay so as not to compromise successful therapy.
There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin 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.
As documented with other antibiotics when used in patients with difficult to treat infections and/or for prolonged periods, emergent decreases in susceptibility have been observed in a limited number of enterococcal isolates following daptomycin therapy. Failures with daptomycin in the treatment of enterococcal bloodstream infections have been reported.
Resistance or lack of susceptibility needs to be monitored during therapy.

Antibiotic associated colitis.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including daptomycin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of any antibacterial agent.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicated that a toxin produced by Clostridium difficile is a primary cause of "antibiotic associated colitis".
If a diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against C. difficile.

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 Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).

Persisting or relapsing S. aureus infection.

Patients with persisting or relapsing S. aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for S. aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci of infection. Appropriate surgical intervention (e.g. debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibiotic regimen may be required.
Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the adjudication committee in 19/120 (15.8%) daptomycin treated patients (12 with MRSA and 7 with MSSA) and 11/115 (9.6%) comparator treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with antistaphylococcal semisynthetic penicillin). Among all failures, 6 daptomycin treated patients and 1 vancomycin treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing on or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep seated infection and did not receive necessary surgical intervention (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Use in renal impairment.

Renal impairment has been reported during treatment with Cubicin. Severe renal impairment may in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of the development of myopathy or neuropathy (see above).
In adult patients with renal impairment, both renal function and CPK should be monitored more frequently than once a week.

Use in the elderly.

Of the 534 patients treated with daptomycin in phase 3 controlled clinical trials of cSSSI, 27.0% were 65 years of age or older and 12.4% were 75 years of age or older. Of the 120 patients treated with daptomycin in the phase 3 controlled clinical trial of S. aureus bacteraemia/endocarditis, 25.0% were 65 years of age or older and 15.8% were 75 years of age or older. In phase 3 clinical studies of cSSSI and S. aureus bacteraemia/endocarditis, lower clinical success rates were seen in patients ≥ 65 years of age compared with those < 65 years of age. In addition, treatment emergent adverse events were more common in patients ≥ 65 years old than in patients < 65 years of age.

Paediatric use.

Cubicin should not be administered to paediatric patients below the age of one year 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.
Use in paediatric patients with renal impairment had not been studied and no dosage recommendations have been formulated.
Use in treatment of pneumonia is contraindicated.
Use in the following conditions has not been studied: infective endocarditis (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Effects on laboratory tests.

Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant concentration dependent false prolongation of prothrombin time (PT) and elevation of the international normalised ratio (INR) when certain recombinant thromboplastin reagents are used in the assay. The possibility of an erroneously elevated PT/INR result may be minimized by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin concentrations may be present at trough to cause interaction.
If confronted with an abnormally high PT/INR result in a patient being treated with Cubicin, it is recommended that clinicians:
1. Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next Cubicin dose (i.e. at trough concentration). If the PT/INR value drawn at trough remains substantially elevated over what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method.
2. Evaluate for other causes of abnormally elevated PT/INR results.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Daptomycin undergoes little or no Cytochrome P450 (CYP450) mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolised by the CYP450 system.
Cubicin was studied in adult human drug-drug interaction studies with aztreonam, tobramycin, warfarin, simvastatin, and probenecid.

Warfarin.

Concomitant administration of daptomycin (6 mg/kg q24h for 5 days) and warfarin (25 mg single oral dose) had no significant effect on the pharmacokinetics of either drug and the INR was not significantly altered. As experience with the concomitant administration of daptomycin and warfarin is limited, anticoagulant activity in patients receiving daptomycin and warfarin should be monitored for the first several days after initiating therapy with daptomycin (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).

Other anticoagulants.

Studies of Cubicin with anticoagulants, other than warfarin, have not been conducted.

HMG-CoA reductase inhibitors.

Inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of CPK. There were no reports of skeletal myopathy in a placebo controlled phase 1 trial in which 10 healthy subjects on stable simvastatin therapy were treated concurrently with daptomycin (4 mg/kg q24h) for 14 days. In the phase 3 S. aureus bacteraemia/endocarditis trial, 5/22 daptomycin treated patients who received prior or concomitant therapy with an HMG-CoA reductase inhibitor developed CPK elevations > 500 U/L. Experience with coadministration of HMG-CoA reductase inhibitors and daptomycin in patients is limited; therefore, consideration should be given to temporarily suspending use of HMG-CoA reductase inhibitors in patients receiving daptomycin (see Section 4.8 Adverse Effects (Undesirable Effects)).

Aztreonam, tobramycin and probenecid.

Cubicin was studied in human drug/drug interaction studies with aztreonam, tobramycin and probenecid.

Aztreonam.

The pharmacokinetics of daptomycin were not significantly altered by aztreonam. Daptomycin had no effect on the bioavailability of aztreonam.

Probenecid.

Daptomycin had no effect on the pharmacokinetics of probenecid, and nor did probenecid alter the pharmacokinetics of daptomycin.

Tobramycin.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of Cubicin is unknown. Caution is warranted when daptomycin is coadministered with tobramycin.

Interactions with other antibiotics.

In vitro studies have investigated daptomycin interactions with other antibiotics. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibiotics, and rifampin have been shown against some isolates of staphylococci (including some methicillin resistant isolates) and enterococci (including some vancomycin resistant isolates). The clinical significance of these in vitro studies is unclear.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Daptomycin did not affect the fertility or reproductive performance of male and female rats when administered intravenously at doses up to 150 mg/kg/day, which is approximately 9 times the estimated human exposure level based upon AUCs.
(Category B1)
Embryo/foetal development studies performed in rats and rabbits at doses of up to 75 mg/kg, approximately 2 and 4 times the recommended 6 mg/kg human dose, respectively, on a body surface area basis, have revealed no evidence of harm to the foetus due to daptomycin. There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, Cubicin should be used during pregnancy only if the potential benefit outweighs the possible risk.
In a single case study, Cubicin was 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 microgram/mL, which is a low concentration. Women should be instructed to avoid breastfeeding while receiving Cubicin.

4.8 Adverse Effects (Undesirable Effects)

During clinical trials of Cubicin, the following adverse drug reactions were reported during therapy and during follow-up. The adverse drug reactions are organized by system organ class, and the frequency categories for these adverse drug reactions are reported below as follows:
Very common: ≥ 1/10 (≥ 10%); common: ≥ 1/100 and < 1/10 (≥ 1% and < 10%); uncommon: ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1%); rare: ≥ 1/10,000 and < 1/1000 (≥ 0.01% and < 0.1%); very rare: < 1/10,000 (< 0.01%).

Infections and infestations.

Common: fungal infection, urinary tract infection, candida infection. Uncommon: fungemia.

Blood and lymphatic system disorders.

Common: anaemia. Uncommon: eosinophilia, thrombocytosis, leukocytosis.

Metabolism and nutrition disorders.

Uncommon: decreased appetite, hyperglycaemia, electrolyte imbalance.

Psychiatric disorders.

Common: anxiety, insomnia.

Nervous system disorders.

Common: dizziness, headache. Uncommon: paraesthesia, taste disorder, tremor, eye irritation.

Ear and labyrinth disorders.

Uncommon: vertigo.

Cardiac disorders.

Uncommon: supraventricular arrhythmia.

Vascular disorders.

Common: hypertension, hypotension. Uncommon: flushing.

Gastrointestinal disorders.

Common: gastrointestinal and abdominal pain, constipation, diarrhoea, nausea, vomiting, flatulence, bloating and distension. Uncommon: dyspepsia.

Hepatobiliary disorders.

Rare: jaundice.

Skin and subcutaneous tissue disorders.

Common: rash, pruritus. Uncommon: urticaria.

Musculoskeletal, connective tissue and bone disorders.

Common: limb pain. Uncommon: arthralgia, muscle pain, muscular weakness, muscle cramps.

Renal and urinary disorders.

Uncommon: renal impairment including renal failure and renal insufficiency.

Reproductive system and breast disorders.

Uncommon: vaginitis.

General disorders and administration site conditions.

Common: infusion site reaction, pyrexia, asthenia. Uncommon: fatigue, chills.

Investigations.

Common: blood creatine phosphokinase (CPK) increased, liver function test abnormal (increased ALT, AST, or ALP). Uncommon: blood lactate dehydrogenase (LDH) increased, blood creatinine increased, International Normalised Ratio (INR) increased. Rare: prothrombin time (PT) prolonged.

Postmarketing.

The following adverse drug reactions, not listed above, have been reported during worldwide postmarketing experience:

Blood and lymphatic system disorders.

Thrombocytopenia.

Immune system disorders.

Hypersensitivity reactions (see Section 4.4 Special Warnings and Precautions for Use) including, but not limited to: anaphylaxis, angioedema, drug reaction with eosinophilia and systemic symptoms (DRESS) and pulmonary eosinophilia.

Musculoskeletal, connective tissue and bone disorders.

Rhabdomyolysis (see Section 4.4 Special Warnings and Precautions for Use).

Nervous system disorders.

Peripheral neuropathy (see Section 4.4 Special Warnings and Precautions for Use).

Renal and urinary disorders.

Tubulointerstitial nephritis (TIN).

Infections and infestations.

Clostridium difficile associated diarrhoea (see Section 4.4 Special Warnings and Precautions for Use).

Investigations.

Myoglobin increased, platelet count decreased.

Skin and subcutaneous tissue disorders.

Vesiculobullous rash, with or without mucous membrane involvement, acute generalised exanthematous pustulosis.

Respiratory, thoracic and mediastinal disorders.

Eosinophilic pneumonia (see Section 4.4 Special Warnings and Precautions for Use), organising pneumonia, cough.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Adults.

Cubicin in 0.9% sodium chloride is administered either by injection over a 2 minute period or infusion over a 30 minute period. Do not dose Cubicin more frequently than once a day. Measure creatinine phosphokinase levels at baseline and at regular intervals (at least weekly (see Section 4.4 Special Warnings and Precautions for Use)).

For complicated skin and skin structure infections (CSSSI).

Cubicin 4 mg/kg once daily for 7-14 days or until the infection is resolved.

For bacteraemia or right sided endocarditis caused by S. aureus (SAB/RIE).

Cubicin 6 mg/kg is administered once daily for 2-6 weeks depending on the diagnosis.
For dosage in paediatric patients see Special populations.

Special populations.

Patients with renal impairment.

Because daptomycin is eliminated primarily by the kidneys, a dosage adjustment is recommended for adult patients with creatinine clearance (ClCr) < 30 mL/min, including adult patients receiving haemodialysis or continuous ambulatory peritoneal dialysis.

Adult patients with creatinine clearance ≥ 30 mL/min.

No dose adjustment is required in patients whose creatinine clearance is ≥ 30 mL/min. Response to treatment and renal function should be closely monitored in all patients with renal insufficiency.

Adult patients with creatinine clearance < 30 mL/min.

The dosing interval should be lengthened to a single dose once every 48 hours for these patients. Alternatively, patients on haemodialysis can be dosed three times per week after haemodialysis. Clinical response to treatment and renal function should be closely monitored in these patients.
The same dose adjustment and advice is recommended for adult patients on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, daptomycin should be administered following the completion of haemodialysis on haemodialysis days.
In adult patients with renal impairment, monitor both renal function and CPK more frequently than once weekly.
The dosage regimen for Cubicin in paediatric patients with renal impairment has not been established. There is currently no dosing guidance/recommendation for paediatric patients with renal impairment.

Patients with hepatic impairment.

No dosage adjustment is warranted when administering Cubicin to patients with mild or moderate hepatic impairment (Child-Pugh class B). The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh class C) have not been evaluated.

Elderly patients.

Elderly patients have been treated with the same dose as patients aged 18-65. No adjustment of Cubicin dosage is warranted for elderly patients with ClCr ≥ 30 mL/min.

Paediatric patients (1 to 17 years of age).

Complicated skin and skin structure infections.

Cubicin is administered intravenously in 0.9% sodium chloride once every 24 hours up to 14 days, by infusion over a 30 minute period or a 60 minute period. Do not dose Cubicin more frequently than once a day, and measure creatine phosphokinase (CPK) levels at baseline and at regular intervals (at least weekly) (see Section 4.4 Special Warnings and Precautions for Use).
Unlike in adults, Cubicin should not be administered by injection over a two (2) minute period in paediatric patients.
The recommended dosage regimens based on age adjustment for paediatric patients with cSSSI are shown in Table 1.
Paediatric patients below the age of one year should not be given Cubicin due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see Section 4.4 Special Warnings and Precautions for Use).

Staphylococcus aureus bloodstream infections (bacteraemia).

The recommended dosage regimens based on age for paediatric patients with S. aureus bloodstream infections (bacteraemia) are shown in Table 2. Cubicin should be administered intravenously in 0.9% sodium chloride injection once every 24 hours. For duration of therapy, please see Table 2.

Instructions for use and handling.

Cubicin is supplied in single dose vials, each containing 500 mg or 350 mg daptomycin as a sterilised lyophilised powder. The contents of a Cubicin vial are reconstituted, using aseptic technique, to 50 mg/mL as follows:

Note.

To minimise foaming, avoid vigorous agitation or shaking of the vial during or after reconstitution.
1. Remove the polypropylene flip off cap from the Cubicin vial to expose the central portion of the rubber stopper.
2. Wipe top of rubber stopper with 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.
3. Slowly transfer 7 mL of 0.9% sodium chloride injection (for 350 mg vials) or 10 mL of 0.9% sodium chloride injection (for 500 mg vial) through the centre of the rubber stopper into the Cubicin vial using a bevelled sterile transfer needle that is 21 gauge or smaller diameter, or a needleless device, pointing the transfer needle toward the wall of the vial.
4. Ensure that the entire Cubicin product is wetted by gently rotating the vial.
5. Allow the product to stand undisturbed for 10 minutes.
6. Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.
7. Slowly remove reconstituted liquid (50 mg daptomycin/mL) from the vial using a bevelled sterile needle 21 gauge or smaller in diameter.

Adults.

Intravenous injection over a period of 2 minutes.

For IV injection over a period of 2 minutes in adult patients, reconstituted Cubicin is administered at a concentration of 50 mg/mL.

Intravenous injection over a period of 30 minutes.

For IV infusion over a period of 30 minutes in adult patients, reconstituted Cubicin (concentration of 50 mg/mL) is further diluted, using aseptic technique, with 0.9% sodium chloride.

Paediatric patients (1 to 17 years of age).

Intravenous infusion over a period of 30 or 60 minutes.

For IV infusion over a period of 30 minutes in paediatric patients, reconstituted Cubicin (concentration of 50 mg/mL) is further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection. The infusion rate should be maintained at 1.67 mL/min over the 30 minute period.
For IV infusion over a period of 60 minutes in paediatric patients, reconstituted Cubicin (concentration of 50 mg/mL) is further diluted, using aseptic technique, into an IV infusion bag containing 25 mL of 0.9% sodium chloride injection. The infusion rate should be maintained at 0.42 mL/min over the 60 minute period.
Unlike in adults, Cubicin should not be administered by injection over a two minute period in paediatric patients (see Section 4.2 Dose and Method of Administration, Paediatric patients (1 to 17 years of age)).
Prior to injection, the reconstituted product should contain no visible particulate matter.
Cubicin contains no preservative or bacteriostatic agent. Aseptic technique must be used in preparation of final IV solution.

Compatible intravenous solutions.

Cubicin is compatible with 0.9% sodium chloride injection and lactated Ringer's injection.

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, Cubicin is presumed to be unlikely to produce an effect on the ability to drive or use machinery.

4.9 Overdose

In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by haemodialysis (approximately 15% of the administered dose is removed over 4 hours) or by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Cubicin is not compatible with glucose-containing diluents, including dextrose. Because only limited data are available on the compatibility of Cubicin with other IV substances, additives and other medications should not be added to Cubicin single-dose vials or infusion bags or infused simultaneously through the same IV line (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If the same IV line is used for sequential infusion of different drugs, flush the line with a compatible intravenous solution before and after infusion with Cubicin.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

Stability after reconstitution and dilution.

In the vial.

Chemical and physical in-use stability of the reconstituted solution in the vial has been demonstrated for 12 hours at room temperature or up to 48 hours if stored under refrigeration (2°C to 8°C).

In the infusion bag.

Chemical and physical in-use stability of the diluted solution in the infusion bag has been established for 12 hours at room temperature or 48 hours if stored under refrigeration (2°C to 8°C).
However, to reduce microbiological hazard, the reconstituted solution and the diluted solution should be used as soon as practicable after reconstitution and after dilution. If storage of the reconstituted or further diluted solution is necessary, solutions should be stored under refrigeration at 2°C to 8°C for a combined time (vial and infusion bag) of no more than 24 hours.
Because only limited data are available on the compatibility of Cubicin with other IV substances, additives or other medications should not be added to Cubicin single-use vials or infused simultaneously through the same IV line. If the same IV line is used for sequential infusion of several different drugs, the line should be flushed with a compatible infusion solution before and after infusion with Cubicin.

6.4 Special Precautions for Storage

Store in original packages at refrigerated temperatures of between 2°C to 8°C; avoid excessive heat.

6.5 Nature and Contents of Container

Cubicin is supplied in single-dose vials containing 350 mg or 500 mg daptomycin as a sterile, lyophilised powder. Single-dose 10 mL capacity vial: package of 1.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes