Dabucor 350 mg/500 mg Solution

DABUCOR is indicated for the following infections in adults:

• Complicated skin and skin structure infections (cSSSI) caused by susceptable isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates), Sreptococcus pyogenes, Streptococcus agalactiae and Streptococcus dysgalactiae subsp.equismilis. Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms.
• Staphylococcus aureus bloodstream infections (bacteraemia), including those with right-sided infective endocarditis (SAB/RIE), caused by methcillin-susceptable and methicllin-resistant isolates. Combination therapy may be clinically indiacted if the document or presumed pathogens including Gram-negative or anaerobicorganisms.

The efficacy of DABUCOR in patients with left-sided infective endocarditis and in patients with artificial valve endocarditis due to Staphylococcus aureus has not been demonstrated. The clinical trial of DABUCOR in patients with Staphylococcus aureus blood stream infections included limited data from patients with left-sided infective endocarditis, outcomes in these patients were poor. DABUCOR is not indicated for the treatment of pneumonia (also see section 4.4).

Posology

Dosage and administration pertain to adults 18 years and over

Complicated Skin and Skin Structure Infections (cSSSI): DABUCOR 4 mg/kg should be administered once daily over a 30-minute period by IV infusion in 0.9 % sodium chloride injection once every 24 hours for 7 u2013 14 days. DABUCOR should not be dosed more frequently than once a day.

Staphylococcus aureus bloodstream infections (Bacteraemia), including Right-Sided Endocarditis: DABUCOR 6 mg/kg should be administered once daily over a 30-minute period by IV infusion in 0.9 % sodium chloride injection once every 24 hours for a minimum of 2-6 weeks. The duration of treatment may be longer than 14 days in accordance with the perceive risk of complications in the individual patients. DABUCOR should not be dosed 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) DABUCOR should only be used in patients with any degree of renal insufficiency (cr Cl u02c2 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) should be monitored closely in all patients with any degree of renal insufficiency (see section 4.4).

Hepatic insufficiency

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

Obesity

No dosage adjustment of DABUCOR is warranted in moderately obsess (Body Mass Index (BMI)) 25-39,9 kg/m2 patients.

Elderly patients

No dosage adjustments are warranted for elderly with normal renal function.

Children and adolescents (u02c2 18 years old)

Safety and efficacy of DABUCOR in patients under the age of 18 have not been established.

Method of administration

DABUCOR is indicated for parenteral use only. For instructions on reconstitution and dilution of DABUCOR before administration, see section 6.6.

DABUCOR is contraindicated in patients with known hypersensitivity to daptomycin or to any of the ingredients of DABUCOR listed in section 6.1.

General

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

Anaphylaxis/hypersensitivity reactions

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

Pneumonia

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

RIE due to Staphylococcus aureus

Clinical data on the use of DABUCOR to treat right-sided infective endocarditis (RIE) due to Staphylococcus aureus are limited to 19 adult patients (see u201cClinical efficacy in adultsu201d in section 5.1).

The safety and efficacy of DABUCOR in children and adolescents aged below 18years with right-sided infective endocarditis (RIE) due to Staphylococcus aureus have not been established.

The efficacy of DABUCOR in patients with prosthetic valve infections or with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated.

Deep-seated infections

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

Enterococcal infections

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

Non-susceptible micro-organisms

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

Clostridioides difficile -associated diarrhoea

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

Drug/laboratory test interactions

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

Creatine phosphokinase and myopathy

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

• Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.
• CPK should be measured more frequently (e.g. every 2-3 days at least during the first two weeks of treatment) inpatients who are at higher risk of developing myopathy. For example, patients with any degree of renal impairment (creatinine clearance < 80 ml/min; see also section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).
• It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be at increased risk of further increases during daptomycin therapy. This should be taken into account when initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently than once weekly.
• DABUCOR should not be administered to patients who are taking other medicines associated with myopathy unless it is considered that the benefit to the patient outweighs the risk.
• Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.
• Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. DABUCOR should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.

Peripheral neuropathy

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

Paediatric population

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

Eosinophilic pneumonia

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

Severe cutaneous adverse reactions

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

Tubulointerstitial nephritis

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

Renal impairment

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

CYP P450 enzymes

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.

Interaction studies for DABUCOR were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin.

Aztreonam

The pharmacokinetics of daptomycin were not significantly altered by aztreonam.

Tobramycin

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

Warfarin

Experience with the concomitant administration of DABUCOR and warfarin is limited. Studies of DABUCOR with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving DABUCOR and warfarin should be monitored for the first several days after therapy with DABUCOR is initiated. 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 DABUCOR. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with DABUCOR unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy (see sections 4.4, 4.8 and 5.3).

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

Laboratory test interactions

During post u2013 marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported. This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin (see section 4.4).

Pregnancy

Safety in pregnancy has not been established.

Breast-feeding

Safety in lactation has not been established.

Fertility

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

No studies on the effects on the ability to drive and use machines have been performed. However, adverse reactions such as headache, insomnia and dizziness have been reported (see section 4.8), therefore patients experiencing these adverse reactions should not drive or use machines.

a. Summary of the safety profile

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

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

b. Tabulated list of adverse reactions

Table 1 below contains adverse reactions associated with daptomycin treatment

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).