Daptomycin Equity 500 mg Powder for solution for infusion

Daptomycin Equity is indicated for the following infections in adults:

• Complicated skin and skin structure infections (cSSSI) 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 (bacteraemia), 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 daptomycin, as contained in Daptomycin Equity, 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 daptomycin in patients with Staphylococcus aureus bloodstream infections included limited data from patients with left-sided infective endocarditis; outcomes in these patients were poor.
• Daptomycin Equity is not indicated for the treatment of pneumonia (see section 4.4).

Posology

Dosage and administration pertain to adults 18 years and over.

Complicated Skin and Skin Structure Infections (cSSSI): Daptomycin Equity 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 7-14 days. Daptomycin Equity should not be dosed more frequently than once a day.

Staphylococcus aureus bloodstream infections (Bacteraemia), including Right-Sided Endocarditis: Daptomycin Equity 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 perceived risk of complications in the individual patients. Daptomycin Equity should not be dosed more frequently than once a day.

Special populations

Renal insufficiency: Daptomycin is eliminated primarily by the kidneys. Due to limited clinical experience (see table and footnotes below) Daptomycin Equity should only be used in patients with any degree of renal insufficiency (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) should be monitored closely in all patients with any degree of renal insufficiency (see sections 4.4. and 5.2)

Method of administration

In adults, Daptomycin Equity is given by intravenous infusion and administered over a 30-minute period, or by intravenous injection and administered over a 2-minute period (see section 6.6).

• Hypersensitivity to daptomycin or to any of the excipients listed in section 6.1.

General

Prescribers must adhere to the principles of antibiotic stewardship. The use of antibiotics may promote the selection of non-susceptible organisms. If super-infection occurs during therapy, appropriate measures should be taken. If a focus of infection other than cSSTI or RIE is identified after initiation of Daptomycin Equity 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 have been reported with daptomycin. If an allergic reaction to Daptomycin Equity occurs, discontinue use and institute appropriate therapy.

Pneumonia

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

RIE due to Staphylococcus aureus

The safety and efficacy of Daptomycin Equity in children and adolescents aged below 18 years with right-sided infective endocarditis (RIE) due to Staphylococcus aureus have not been established. The efficacy of Daptomycin Equity in patients with prosthetic valve infections or with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated.

Deep-seated infections

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

Enterococcal infections

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Daptomycin Equity against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of Daptomycin Equity 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).

Clostridium difficile -associated diarrhoea

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

Laboratory test interactions

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

Creatine phosphokinase and myopathy

Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with daptomycin, as contained in Daptomycin Equity (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 daptomycin-treated patients (1,9 %) than in those that received comparators (0,5 %). Therefore, it is recommended that:

• Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.
• CPK should be measured more frequently (e.g. every 2-3 days at least during the first two weeks of treatment) in patients who are at higher risk of developing myopathy. For example, patients with any degree of renal impairment (creatinine clearance < 80 ml/min; see also section 4.2), including those on haemodialysis or CAPD, and patients taking other medicines 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 Equity therapy. This should be taken into account when initiating Daptomycin Equity therapy and, if Daptomycin Equity is given, these patients should be monitored more frequently than once weekly.
• Daptomycin Equity should not be administered to patients who are taking other medicines associated with myopathy.
• Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.
• Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Daptomycin Equity 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 Daptomycin Equity should be investigated and consideration should be given to discontinuation of Daptomycin Equity (see sections 4.8 and 5.3).

Eosinophilic pneumonia

Eosinophilic pneumonia has been reported in patients receiving daptomycin (see section 4.8). In most reported cases associated with daptomycin patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organising pneumonia. The majority of cases occurred after more than 2 weeks of treatment with daptomycin and improved when Daptomycin Equity was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Daptomycin Equity should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products). Daptomycin Equity should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.

Renal impairment

Renal impairment has been reported during treatment with daptomycin. Severe renal impairment may in itself also predispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above). An adjustment of Daptomycin Equity dose interval is needed for adult patients whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Daptomycin Equity should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.

Caution is advised when administering Daptomycin Equity to patients who already have some degree of renal impairment (creatinine clearance < 80 ml/min) before commencing therapy with Daptomycin Equity. Regular monitoring of renal function is advised (see also section 5.2).

In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic medicines, regardless of the patient's pre-existing renal function (see also section 4.5).

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

Obesity

In obese subjects with Body Mass Index (BMI) > 40 kg/m2 but with creatinine clearance > 70 ml/min, the AUC0-u221e daptomycin was significantly increased (mean 42 % higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).

Persisting or relapsing Staphylococcus aureus bloodstream infection.

Patients with persisting or relapsing S.aureus bloodstream infection or poor clinical response should have repeat blood cultures. If a culture is positive for S.aureus, minimum inhibitory concentration (MIC) susceptibility testing of the isolate should be performed using a standardised procedure. Diagnostic evaluation of the patient should be performed 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.

Severe cutaneous adverse reactions (SCARs)

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, Daptomycin Equity 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 Equity, treatment with Daptomycin Equity must not be restarted in this patient at any time.

Tubulointerstitial nephritis (TIN)

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 Daptomycin Equity should undergo medical evaluation. If TIN is suspected, Daptomycin Equity should be discontinued promptly and appropriate therapy and/or measures should be taken.

Paediatric population

Safety and efficacy of Daptomycin Equity in patients under the age of 18 have not been established (see section 4.2).

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 daptomycin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicines alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.

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

Experience with the concomitant administration of daptomycin and warfarin is limited. Studies of daptomycin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving Daptomycin Equity and warfarin should be monitored for the first several days after therapy with Daptomycin Equity is initiated.

There is limited experience regarding concomitant administration of Daptomycin Equity 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 daptomycin. It is recommended that other medicines associated with myopathy should if possible be temporarily discontinued during treatment with Daptomycin Equity 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 as contained in Daptomycin Equity 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 Equity is co-administered with any other medicine known to reduce renal filtration.

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

Daptomycin Equity should not be used during pregnancy because safety has not been established.

Breastfeeding

Safety has not been established and therefore Daptomycin Equity should not be used during breastfeeding.

Fertility

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

Dizziness and vertigo have been reported (see section 4.8). Caution is advised when driving or operating machinery. No studies on the effects on the ability to drive and use machines have been performed.

Summary of 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 rash with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.

Tabulated list of adverse reactions

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

System Organ Class Frequency Adverse Reaction

Infections and infestations Frequent Fungal infections, urinary tract infection, candida infection Less frequent Fungaemia, oral and vaginal candidiasis, osteomyelitis, fungal urinary tract infection Unknown frequency Clostridium difficile -associated diarrhoea**

Blood and lymphatic system disorders Frequent Anaemia Less frequent Thrombocythaemia, eosinophilia, increased international normalised ratio (INR), leucocytosis, prolonged prothrombin time (PT), lymphadenopathy Unknown frequency Thrombocytopaenia

Immune system disorders Unknown frequency Hypersensitivity**, manifested by isolated spontaneous reports including, but not limited to angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), pulmonary eosinophilia, vesicobullous rash with mucous membrane involvement and sensation of oropharyngeal swelling, anaphylaxis**, infusion reactions including the following symptoms: tachycardia, pyrexia, wheezing, rigors, systemic flushing, vertigo, syncope and metallic taste

Metabolism and nutrition disorders Less frequent Decreased appetite, hyperglycaemia, electrolyte imbalance, hypokalaemia, hypomagnesaemia

Psychiatric disorders Less frequent Anxiety, insomnia, hallucination, mental status change

Nervous system disorders Frequent Dizziness, headache Less frequent Paraesthesia, taste disorder, tremor, dyskinesia Unknown frequency Peripheral neuropathy**

Ear and labyrinth disorders Less frequent Vertigo, tinnitus

Eye disorders Less frequent Eye irritation, blurred vision

Cardiac disorders Less frequent Supraventricular tachycardia, extrasystole, atrial flutter, atrial fibrillation, cardiac arrest

Vascular disorders Frequent Hypertension, hypotension Less frequent Flushes

Respiratory, thoracic and mediastinal disorders Less frequent Dyspnoea Unknown frequency Eosinophilic pneumonia 1 **, cough

Gastrointestinal disorders Frequent Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension Less frequent Dyspepsia, glossitis, dry mouth, epigastric discomfort, gingival pain, oral hypoaesthesia, loose stools, stomatitis

Hepato-biliary disorders Frequent Liver function tests abnormal 2 (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)) Less frequent Jaundice

Skin and subcutaneous tissue disorders Frequent Rash, pruritus Less frequent Urticaria, eczema, heat rash, rash vesicular Unknown frequency Acute generalised exanthematous pustulosis (AGEP), medicine reaction with eosinophilia and systemic symptoms (DRESS)**, vesiculobullous rash with or without mucous membrane involvement (SJS or TEN)**

Musculoskeletal and connective tissue disorders Frequent Limb pain, serum creatine phosphokinase (CPK) 2 increased Less frequent Myositis, increased myoglobin, muscular weakness, muscle pain, arthralgia, increased serum lactate dehydrogenase (LDH), muscle cramps, myalgia, back pain Unknown frequency Rhabdomyolysis 3 **

Renal and urinary disorders Less frequent Renal impairment, including renal failure and renal insufficiency, increased serum creatinine, renal failure acute, proteinuria Unknown frequency* Tubulointerstitial nephritis (TIN)**

Reproductive system and breast disorders Less frequent Vaginitis

General disorders and administration site conditions Frequent Infusion site reactions, pyrexia, asthenia Less frequent Fatigue, pain, chest pain, discomfort (not otherwise specified), oedema, jitteriness, rigors, weakness

Investigations Less frequent Increased blood bicarbonate, increased blood phosphorus, increased lactate dehydrogenase (LDH)

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

** See section 4.4.

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). 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).