`
`ANNEX I
`
`SUMMARY OF PRODUCT CHARACTERISTICS
`
`1
`
`Amneal v. Cubist
`IPR2020-00193
`Cubist Ex. 2001
`
`

`

`1.
`
`NAME OF THE MEDICINAL PRODUCT
`
`
`Cubicin 350 mg powder for solution for injection or infusion
`Cubicin 500 mg powder for solution for injection or infusion
`
`2.
`
`QUALITATIVE AND QUANTITATIVE COMPOSITION
`
`Cubicin 350 mg powder for solution for injection or infusion
`Each vial contains 350 mg daptomycin.
`One ml provides 50 mg of daptomycin after reconstitution with 7 ml of sodium chloride 9 mg/ml
`(0.9%) solution.
`
`Cubicin 500 mg powder for solution for injection or infusion
`Each vial contains 500 mg daptomycin.
`One ml provides 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml
`(0.9%) solution.
`
`For the full list of excipients, see section 6.1.
`
`3.
`
`PHARMACEUTICAL FORM
`
`Powder for solution for injection or infusion
`A pale yellow to light brown lyophilised cake or powder.
`
`4.
`
`CLINICAL PARTICULARS
`
`4.1 Therapeutic indications
`
`-
`
`Cubicin is indicated for the treatment of the following infections (see sections 4.4 and 5.1).
`-
`Adult and paediatric (1 to 17 years of age) patients with complicated skin and soft-tissue
`infections (cSSTI).
`Adult patients with right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It is
`recommended that the decision to use daptomycin should take into account the antibacterial
`susceptibility of the organism and should be based on expert advice. See sections 4.4 and 5.1.
`Adult and paediatric (1 to 17 years of age) patients with Staphylococcus aureus bacteraemia
`(SAB). In adults, use in bacteraemia should be associated with RIE or with cSSTI, while in
`paediatric patients, use in bacteraemia should be associated with cSSTI.
`
`-
`
`Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where
`Gram negative and/or certain types of anaerobic bacteria are suspected, Cubicin should be co-
`administered with appropriate antibacterial agent(s).
`
`Consideration should be given to official guidance on the appropriate use of antibacterial agents.
`
`4.2
`
`Posology and method of administration
`
`Clinical studies in patients employed infusion of daptomycin over at least 30 minutes. There is no
`clinical experience in patients with the administration of daptomycin as an injection over 2 minutes.
`This mode of administration was only studied in healthy subjects. However, when compared with the
`same doses given as intravenous infusions over 30 minutes there were no clinically important
`differences in the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).
`
`2
`
`

`

`Posology
`
`Adults
`-
`
`-
`
`-
`
`cSSTI without concurrent SAB: Cubicin 4 mg/kg is administered once every 24 hours for
`7-14 days or until the infection is resolved (see section 5.1).
`cSSTI with concurrent SAB: Cubicin 6 mg/kg is administered once every 24 hours. See below
`for dose adjustments in patients with renal impairment. The duration of therapy may need to be
`longer than 14 days in accordance with the perceived risk of complications in the individual
`patient.
`Known or suspected RIE due to Staphylococcus aureus: Cubicin 6 mg/kg is administered once
`every 24 hours. See below for dose adjustments in patients with renal impairment. The duration
`of therapy should be in accordance with available official recommendations.
`
`Cubicin is administered intravenously in 0.9% sodium chloride (see section 6.6). Cubicin should not
`be used more frequently than once a day.
`
`Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least
`weekly) during treatment (see section 4.4).
`
`Renal impairment
`Daptomycin is eliminated primarily by the kidney.
`
`Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in
`adult patients with any degree of renal impairment (CrCl < 80 ml/min) when it is considered that the
`expected clinical benefit outweighs the potential risk. The response to treatment, renal function and
`creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of
`renal impairment (see also sections 4.4 and 5.2). The dosage regimen for Cubicin in paediatric
`patients with renal impairment has not been established.
`
`Dose adjustments in adult patients with renal impairment by indication and creatinine clearance
`
`Indication for use
`cSSTI without SAB
`
`Creatinine clearance
`
`Dose recommendation
`
`Comments
`
` 30 ml/min
`
`4 mg/kg once daily
`
`See section 5.1
`
`RIE or cSSTI
`associated with
`SAB
`
`< 30 ml/min
`
`4 mg/kg every 48 hours
`
`(1, 2)
`
` 30 ml/min
`
`6 mg/kg once daily
`
`See section 5.1
`
`< 30 ml/min
`
`6 mg/kg every 48 hours
`
`(1, 2)
`
`cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia
`(1) The safety and efficacy of the dose interval adjustment have not been evaluated in controlled
`clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see
`sections 4.4 and 5.2).
`(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK
`modelling results, are recommended for adult patients on haemodialysis (HD) or continuous
`ambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered
`following the completion of dialysis on dialysis days (see section 5.2).
`
`3
`
`

`

`Hepatic impairment
`No dose adjustment is necessary when administering Cubicin to patients with mild or moderate
`
`hepatic impairment (Child-Pugh Class B) (see section 5.2). No data are available in patients with
`severe hepatic impairment (Child-Pugh Class C). Therefore caution should be exercised if Cubicin is
`given to such patients.
`
`Elderly patients
`The recommended doses should be used in elderly patients except those with severe renal impairment
`(see above and section 4.4).
`
`Paediatric patients (1 to 17 years of age)
`The recommended dosage regimens for paediatric patients based on age and indication are shown
`below.
`
`Indication
`
`cSSTI without SAB
`Duration of
`Therapy
`
`cSSTI associated with SAB
`Duration of
`Therapy
`
`Up to 14 Days
`
`(1)
`
`Age group
`
`12 to 17
`years
`
`7 to 11
`years
`
`2 to 6 years
`
`Dosage Regimen
`Dosage Regimen
`7 mg/kg once every
`5 mg/kg once every
`24 hours infused over
`24 hours infused over
`30 minutes
`30 minutes
`9 mg/kg once every
`7 mg/kg once every
`24 hours infused over
`24 hours infused over
`30 minutes
`30 minutes
`12 mg/kg once every
`9 mg/kg once every
`24 hours infused over
`24 hours infused over
`60 minutes
`60 minutes
`12 mg/kg once every
`10 mg/kg once every
`1 to < 2
`24 hours infused over
`24 hours infused over
`years
`60 minutes
`60 minutes
`cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia;
`(1) Minimum duration of Cubicin for paediatric SAB should be in accordance with the perceived risk
`of complications in the individual patient. The duration of Cubicin may need to be longer than 14
`days in accordance with the perceived risk of complications in the individual patient. In the paediatric
`SAB study, the mean duration of IV Cubicin was 12 days, with a range of 1 to 44 days. The duration
`of therapy should be in accordance with available official recommendations.
`
`Cubicin is administered intravenously in 0.9 % sodium chloride (see section 6.6). Cubicin should not
`be used more frequently than once a day.
`
`Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least
`weekly) during treatment (see section 4.4).
`
`Paediatric patients below the age of one year should not be given 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 5.3).
`
`Method of administration
`In adults, Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-
`minute period or by intravenous injection (see section 6.6) and administered over a 2-minute period.
`
`In paediatric patients aged 7 to 17 years, Cubicin is given by intravenous infusion over a 30-minute
`period (see section 6.6). In paediatric patients aged 1 to 6 years, Cubicin is given by intravenous
`infusion over a 60-minute period (see section 6.6).
`
`4
`
`

`

`4.3 Contraindications
`
`Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
`
`4.4
`
`Special warnings and precautions for use
`
`General
`If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin 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 Cubicin. If an allergic reaction to
`Cubicin occurs, discontinue use and institute appropriate therapy.
`
`Pneumonia
`It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of
`pneumonia. Cubicin is therefore not indicated for the treatment of pneumonia.
`
`RIE due to Staphylococcus aureus
`Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 adult
`patients (see “Information from clinical trials” in section 5.1). The safety and efficacy of Cubicin 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 Cubicin 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 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. Failures
`with daptomycin in the treatment of enterococcal infections that were mostly accompanied by
`bacteraemia have been reported. In some instances treatment failure has been associated with the
`selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).
`
`Non-susceptible micro-organisms
`The use of antibacterials may promote the overgrowth of non-susceptible micro-organisms. If
`superinfection occurs during therapy, appropriate measures should be taken.
`
`Clostridium difficile-associated diarrhoea
`Clostridium difficile-associated diarrhoea (CDAD) has been reported with Cubicin (see section 4.8).
`If CDAD is suspected or confirmed, Cubicin 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).
`
`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 Cubicin (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 Cubicin-treated patients (1.9%) than in those that received comparators (0.5%).
`Therefore, it is recommended that:
`Plasma CPK should be measured at baseline and at regular intervals (at least once weekly)
`
`during therapy in all patients.
`CPK should be measured more frequently (e.g. every 2-3 days at least during the first two
`weeks of treatment) in patients who are at higher risk of developing myopathy. For example,
`patients with any degree of renal impairment (creatinine clearance < 80 ml/min; see also
`section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal
`products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates
`and ciclosporin).
`It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at
`baseline may be at increased risk of further increases during daptomycin therapy. This should
`be taken into account when initiating daptomycin therapy and, if daptomycin is given, these
`patients should be monitored more frequently than once weekly.
`Cubicin should not be administered to patients who are taking other medicinal products
`associated with myopathy unless it is considered that the benefit to the patient outweighs the
`risk.
`Patients should be reviewed regularly while on therapy for any signs or symptoms that might
`represent myopathy.
`Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should
`have CPK levels monitored every 2 days. Cubicin 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 Cubicin 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 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 5.3).
`
`Eosinophilic pneumonia
`Eosinophilic pneumonia has been reported in patients receiving Cubicin (see section 4.8). In most
`reported cases associated with Cubicin, 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 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 medicinal products).
`Cubicin should be discontinued immediately and treatment with systemic steroids should be initiated
`when appropriate.
`
`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 development
`of myopathy (see above).
`
`6
`
`

`

`An adjustment of Cubicin 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. Cubicin 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 Cubicin to patients who already have some degree of renal
`impairment (creatinine clearance < 80 ml/min) before commencing therapy with Cubicin. Regular
`monitoring of renal function is advised (see also section 5.2).
`
`In addition, regular monitoring of renal function is advised during concomitant administration of
`potentially nephrotoxic agents, regardless of the patient’s pre-existing renal function (see also
`section 4.5).
`
`The dosage regimen for Cubicin 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-∞ 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).
`
`4.5
`
`Interaction with other medicinal products and other forms of interaction
`
`Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely
`that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450
`system.
`
`Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid.
`Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal
`products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not
`significantly altered by aztreonam.
`
`Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during
`coadministration by intravenous infusion over a 30-minute period using a Cubicin dose of 2 mg/kg,
`the changes were not statistically significant. The interaction between daptomycin and tobramycin
`with an approved dose of Cubicin is unknown. Caution is warranted when Cubicin is co-administered
`with tobramycin.
`
`Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of
`Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in
`patients receiving Cubicin and warfarin should be monitored for the first several days after therapy
`with Cubicin is initiated.
`
`There is limited experience regarding concomitant administration of daptomycin with other medicinal
`products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of
`marked rises in CPK levels and cases of rhabdomyolysis occurred in adult patients taking one of these
`medicinal products at the same time as Cubicin. It is recommended that other medicinal products
`associated with myopathy should if possible be temporarily discontinued during treatment with
`Cubicin 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.
`
`7
`
`

`

`Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-
`administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2
`
`inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-
`administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-
`administered with any other medicinal product known to reduce renal filtration.
`
`During post–marketing surveillance, cases of interference between daptomycin and particular reagents
`used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported.
`This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities
`of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in
`vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by
`drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin
`(see section 4.4).
`
`4.6
`
`Fertility, pregnancy and lactation
`
`Pregnancy
`No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or
`indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or
`postnatal development (see section 5.3).
`
`Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the expected benefit
`outweighs the possible risk.
`
`Breast-feeding
`In a single human case study, Cubicin was intravenously administered daily for 28 days to a nursing
`mother at a dose of 500 mg/day, and samples of the patient’s breast milk were collected over a 24-
`hour period on day 27. The highest measured concentration of daptomycin in the breast milk was
`0.045 mcg/ml, which is a low concentration. Therefore, until more experience is gained, breast-
`feeding should be discontinued when Cubicin is administered to nursing women.
`
`Fertility
`No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or
`indirect harmful effects with respect to fertility (see section 5.3).
`
`4.7 Effects on ability to drive and use machines
`
`No studies on the effects on the ability to drive and use machines have been performed.
`
`On the basis of reported adverse drug reactions, Cubicin is presumed to be unlikely to produce an
`effect on the ability to drive or use machinery.
`
`4.8 Undesirable effects
`
`Summary of the safety profile
`In clinical studies, 2,011 adult subjects received Cubicin. Within these trials, 1,221 subjects received
`a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects
`received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. In
`paediatric studies, 372 patients received Cubicin, of whom 61 received a single dose and 311 received
`a therapeutic regimen for cSSTI or SAB (daily doses ranged from 4 mg/kg to 12 mg/kg). Adverse
`reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the
`medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.
`
`The most frequently reported adverse reactions (frequency common (≥ 1/100 to < 1/10)) are:
`Fungal infections, urinary tract infection, candida infection, anaemia, anxiety, insomnia, dizziness,
`headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting,
`
`8
`
`

`

`constipation, diarrhoea, flatulence, bloating and distension, liver function tests abnormal (increased
`alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)),
`
`rash, pruritus, limb pain, serum creatine phosphokinase (CPK) increased, infusion site reactions,
`pyrexia, asthenia.
`
`Less frequently reported, but more serious, adverse reactions include hypersensitivity reactions,
`eosinophilic pneumonia (occasionally presenting as organising pneumonia), drug rash with
`eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.
`
`Tabulated list of adverse reactions
`The following adverse reactions were reported during therapy and during follow-up with frequencies
`corresponding to very common ( 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to
`< 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from
`the available data):
`
`Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
`
`Table 1
`
`Adverse reactions from clinical studies and post-marketing reports
`
`System organ class
`Infections and infestations
`
`Blood and lymphatic system
`disorders
`
`Immune system disorders
`
`Metabolism and nutrition
`disorders
`Psychiatric disorders
`Nervous system disorders
`
`Ear and labyrinth disorders
`Cardiac disorders
`Vascular disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Frequency
`Common:
`
`Adverse reactions
`Fungal infections, urinary tract infection, candida
`infection
`Uncommon:
`Fungaemia
`Not known*: Clostridium difficile-associated diarrhoea**
`Common:
`Anaemia
`Uncommon:
`Thrombocythaemia, eosinophilia, international
`normalised ratio (INR) increased, leukocytosis
`Rare:
`Prothrombin time (PT) prolonged
`Not known*:
`Thrombocytopaenia
`Not known*: 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, wheezing, pyrexia, rigors, systemic
`flushing, vertigo, syncope and metallic taste
`Decreased appetite, hyperglycaemia, electrolyte
`imbalance
`Anxiety, insomnia
`Dizziness, headache
`Paraesthesia, taste disorder, tremor, eye irritation
`Peripheral neuropathy**
`Vertigo
`Supraventricular tachycardia, extrasystole
`Hypertension, hypotension
`Flushes
`Eosinophilic pneumonia1**, cough
`
`Uncommon:
`
`Common:
`Common:
`Uncommon:
`Not known*:
`Uncommon:
`Uncommon:
`Common:
`Uncommon:
`Not known*:
`
`9
`
`

`

`Common:
`
`Uncommon:
`Common:
`
`Gastrointestinal disorders
`
`
`Hepatobiliary disorders
`
`Skin and subcutaneous tissue
`disorders
`
`Musculoskeletal and
`connective tissue disorders
`
`Renal and urinary disorders
`
`Gastrointestinal and abdominal pain, nausea,
`vomiting, constipation, diarrhoea, flatulence,
`bloating and distension
`Dyspepsia, glossitis
`Liver function tests abnormal2 (increased alanine
`aminotransferase (ALT), aspartate aminotransferase
`(AST) or alkaline phosphatase (ALP))
`Rare:
`Jaundice
`Common:
`Rash, pruritus
`Uncommon:
`Urticaria
`Not known*: Acute generalised exanthematous pustulosis
`Common:
`Limb pain, serum creatine phosphokinase (CPK)2
`increased
`Uncommon: Myositis, increased myoglobin, muscular weakness,
`muscle pain, arthralgia, serum lactate dehydrogenase
`(LDH) increased, muscle cramps
`Not known*: Rhabdomyolysis3 **
`Uncommon:
`Renal impairment, including renal failure and renal
`insufficiency, serum creatinine increased
`Vaginitis
`
`Uncommon:
`
`Reproductive system and
`breast disorders
`Common:
`Infusion site reactions, pyrexia, asthenia
`General disorders and
`Uncommon:
`Fatigue, pain
`administration site conditions
`*
`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.
`While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown,
`to date the reporting rate of spontaneous reports is very low (< 1/10,000).
`In some cases of myopathy involving raised CPK and muscle symptoms, the patients also
`presented with elevated transaminases. These transaminase increases were likely to be related
`to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3
`toxicity and resolved upon discontinuation of treatment.
`When clinical information on the patients was available to make a judgement, approximately
`50% of the cases occurred in patients with pre-existing renal impairment, or in those receiving
`concomitant medicinal products known to cause rhabdomyolysis.
`
`**
`1
`
`2
`
`3
`
`The safety data for the administration of daptomycin via 2-minute intravenous injection are derived
`from two pharmacokinetic studies in healthy adult volunteers. Based on these study results, both
`methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute
`intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in
`local tolerability or in the nature and frequency of adverse reactions.
`
`Reporting of suspected adverse reactions
`Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
`allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
`professionals are asked to report any suspected adverse reactions via the national reporting system
`listed in Appendix V.
`
`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).
`
`10
`
`

`

`5.
`
`
`
`PHARMACOLOGICAL PROPERTIES
`
`5.1
`
`Pharmacodynamic properties
`
`Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code:
`J01XX09
`
`Mechanism of action
`Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.
`
`The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes
`of both growing and stationary phase cells causing depolarisation and leading to a rapid inhibition of
`protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.
`
`PK/PD relationship
`Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive
`organisms in vitro and in in vivo animal models. In animal models AUC/MIC and Cmax/MIC correlate
`with efficacy and predicted bacterial kill in vivo at single doses equivalent to human adult doses of
`4 mg/kg and 6 mg/kg once daily.
`
`Mechanisms of resistance
`Strains with decreased susceptibility to daptomycin have been reported especially during the
`treatment of patients with difficult-to-treat infections and/or following administration for prolonged
`periods. In particular, there have been reports of treatment failures in patients infected with
`Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium, including bacteraemic
`patients, that have been associated with the selection of organisms with reduced susceptibility or frank
`resistance to daptomycin during therapy.
`
`The mechanism(s) of daptomycin resistance is (are) not fully understood.
`
`Breakpoints
`Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on
`Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S.
`pneumoniae) are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.
`
`Susceptibility
`The prevalence of resistance may vary geographically and over time for selected species and local
`information on resistance is desirable, particularly when treating severe infections. As necessary,
`expert advice should be sought when the local prevalence of resistance is such that the utility of the
`agent in at least some types of infections is questionable.
`
`11
`
`

`

`Commonly Susceptible Species
`Staphylococcus aureus *
`
`Staphylococcus haemolyticus
`Coagulase negative staphylococci
`Streptococcus agalactiae*
`Streptococcus dysgalactiae subsp equisimilis*
`Streptococcus pyogenes*
`Group G streptococci
`Clostridium perfringens
`Peptostreptococcus spp
`Inherently resistant organisms
`Gram negative organisms
`* denotes species against which it is considered that activity has been satisfactorily demonstrated in
`clinical studies.
`
`Clinical efficacy in adults
`In two adult clinical trials in complicated skin and soft tissues infections, 36% of patients treated with
`Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most common
`type of infection treated was wound infection (38% of patients), while 21% had major abscesses.
`These limitations of the patients population treated should be taken into account when deciding to use
`Cubicin.
`
`In a randomised controlled open-label study in 235 adult patients with Staphylococcus aureus
`bacteraemia (i.e. at least one positive blood culture of Staphylococcus aureus prior to receiving the
`first dose) 19 of 120 patients treated with Cubicin met the criteria for RIE. Of these 19 patients 11
`were infected with methicillin-susceptible and 8 with methicillin-resistant Staphylococcus aureus.
`The success rates in RIE patients are shown in the table below.
`
`Population
`
`ITT (intention to treat) Population
`RIE
`PP (per protocol) Population
`RIE
`
`Daptomycin
`n/N (%)
`
`Comparator
`n/N (%)
`
`Differences in
`Success
`Rates (95% CI)
`
`8/19 (42.1%)
`
`7/16 (43.8%)
`
`-1.6% (-34.6, 31.3)
`
`6/12 (50.0%)
`
`4/8 (50.0%)
`
`0.0% (-44.7, 44.7)
`
`Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in
`19/120 (15.8%) patients treated with Cubicin, 9/53 (16.7%) patients treated with vancomycin and
`2/62 (3.2%) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among these
`failures six patients treated with Cubicin and one patient treated with vancomycin were infected with
`Staphylococcus aureus that developed increasing MICs of daptomycin on or following therapy (see
`“Mechanisms of resistance” above). Most patients who failed due to persisting or relapsing
`Staphylococcus aureus infection had deep-seated infection and did not receive necessary