Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 have been reported with Cubicin. If an allergic reaction to Cubicin occurs, discontinue use and institute appropriate therapy.
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.
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.
Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay.
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).
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 (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.
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).
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:
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).
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. 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 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).
An adjustment of Cubicin dose interval is needed for 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.
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).
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 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.
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).
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.
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.
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).
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.
In clinical studies, 2,011 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. 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, 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, drug rash with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.
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:
Common: 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
Uncommon: Decreased appetite, hyperglycaemia, electrolyte imbalance
Common: Anxiety, insomnia
Common: Dizziness, headache
Uncommon: Paraesthesia, taste disorder, tremor, eye irritation
Not known*: Peripheral neuropathy**
Uncommon: Vertigo
Uncommon: Supraventricular tachycardia, extrasystole
Common: Hypertension, hypotension
Uncommon: Flushes
Not known*: Eosinophilic pneumonia1**, cough
Common: Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension
Uncommon: Dyspepsia, glossitis
Common: 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
Uncommon: Vaginitis
Common: Infusion site reactions, pyrexia, asthenia
Uncommon: Fatigue, pain
* 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.
1 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).
2 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.
3 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.
The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy 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 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.
Cubicin is not physically or chemically compatible with glucose-containing solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
