Dapicub 500 mg Powder for solution for infusion

DAPICUB is indicated for the following infections in adults:

• Complicated skin and skin structure infections (cSSTI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus dysgalactiae subsp equisimilis. Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms.
• Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis (SAB/RIE) caused by methicillin-susceptible and methicillin-resistant isolates. Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms.
• The efficacy of DAPICUB in patient with left-sided infective endocarditis and in patients with artificial valve endocarditis due to Staphylococcus aureus has not been demonstrated. Data of DAPICUB in patient with Staphylococcus aureus bloodstream infections with left-sided infective endocarditis is limited and the outcomes for those patients were poor.
• DAPICUB is not indicated for the treatment of pneumonia (see section 4.4).

Posology

Dosage and administration for adults, 18 years and older

Complicated skin and skin structure infections (cSSTI)

DAPICUB 4 mg/kg is administered once every 24 hours for 7 to 14 days. DAPICUB should not be used more frequently than once a day.

Staphylococcus aureus bloodstream infections (bacteremia), including right-sided infective endocarditis (SAB/RIE)

DAPICUB 6 mg/kg is administered once every 24 hours for 2 to 6 weeks. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient. DAPICUB should not be used more frequently than once a day.

Special populations

Renal insufficiency

Daptomycin is eliminated primarily by the kidney. Due to limited clinical experience (see table and footnotes below) DAPICUB 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).

Method of administration

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

• Hypersensitivity to daptomycin or to any of the excipients (see section 6.1).

Non-susceptible micro-organisms

The use of antibiotics may promote the overgrowth of non-susceptible micro-organisms. If super-infection occurs during therapy, appropriate measures should be taken.

Clostridium difficile-associated diarrhoea (CDAD)

CDAD has been reported with the use of DAPICUB and may range in severity from mild diarrhoea to fatal colitis (see section 4.8). If CDAD is suspected or confirmed, DAPICUB may need to be discontinued and appropriate treatment instituted as clinically indicated.

Pneumonia

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

Eosinophilic pneumonia

Eosinophilic pneumonia has been reported in patients receiving DAPICUB (see section 4.8). In most reported cases associated with DAPICUB, 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 DAPICUB and improved when DAPICUB 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 DAPICUB should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, and other medicines). DAPICUB should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.

Renal impairment

Renal impairment has been reported during treatment with DAPICUB. Severe renal impairment may in itself also predispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see below). An adjustment of DAPICUB 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. DAPICUB 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 DAPICUB to patients who already have some degree of renal impairment (creatinine clearance < 80 ml/min) before commencing therapy with DAPICUB. Regular monitoring of renal function is advised (see also section 5.2).

General

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

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

There is limited experience regarding concomitant administration of daptomycin with other medicines 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 medicines at the same time as DAPICUB. It is recommended that other medicines associated with myopathy should if possible be temporarily discontinued during treatment with DAPICUB 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, and 4.8).

Pregnancy and Breastfeeding

Safety in pregnancy and breastfeeding has not been established.

Fertility

No data is available on fertility.

It is unlikely that DAPICUB has an influence on the ability to drive and use machines, however, adverse reactions, such as dizziness has been reported during treatment, patients should ensure that they do not engage in the above activities until they are aware of the measure to which DAPICUB affects them (see section 4.8).

a. Summary of the safety profile

The most frequently reported adverse reactions are: Fungal infections, urinary tract infection, candida infection, anemia, 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.

In the event of overdose, supportive care is advised. DAPICUB is slowly cleared from the body by hemodialysis (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).