Drug Class Description
Antibacterials for systemic use, Other antibacterials.

Generic Name
Daptomycin

Drug Description
Cubicin 350 mg powder for concentrate for solution for 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 or water for injections.Cubicin 500 mg powder for concentrate for solution for 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 or water for injections.

Presentation
Powder for concentrate for solution for infusion.A pale yellow to light brown lyophilised powder.

Indications
Cubicin is indicated for the treatment of the following infections in adultsComplicated skin and soft-tissue infections (cSSTI).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. Staphylococcus aureus bacteraemia (SAB) when associated with RIE or with cSSTI.Daptomycin is active against Gram positive bacteria only. 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.

Adult Dosage
PosologycSSTI without concurrent Staphylococcus aureus bacteraemia: The recommended dose is 4 mg/kg administered once every 24 hours for 714 days or until the infection is resolved.cSSTI with concurrent Staphylococcus aureus bacteraemia: The recommended dose is 6 mg/kg administered once every 24 hours. See below for dose adjustments in patients with renal insufficiency. 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 right-sided infective endocarditis due to Staphylococcus aureus: The recommended dose is 6 mg/kg administered once every 24 hours. See below for dose adjustments in patients with renal insufficiency. The duration of therapy should be in accordance with available official recommendations.Renal insufficiencyDaptomycin is eliminated primarily by the kidney.Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in patients with any degree of renal insufficiency (Cr Cl < 80 ml/min) when it is considered that the expected clinical benefit outweighs the potential risk. The response to treatment and renal function should be closely monitored in all patients with some degree of renal insufficiency.Dose adjustments in patients with renal insufficiency by indication and creatinine clearanceIndication for use (1)Creatinine clearance (1)Dose recommendation (1)CommentscSSTI without S. aureus bacteraemia 30 ml/min4 mg/kg once daily< 30 ml/min4 mg/kg every 48 hours(1,2)RIE or cSSTI associated with S. aureus bacteraemia 50 ml/min6 mg/kg once daily(3)(1) The safety and efficacy of the dose interval adjustment has not been clinically eva luated and the recommendation is based on pharmacokinetic modelling data.(2) The same dose adjustments, which are also based solely on modelling are recommended for patients on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the completion of dialysis on dialysis days.(3) There are insufficient data to support a dose recommendation for patients with RIE or cSSTI associated with Staphylococcus aureus bacteraemia who have a creatinine clearance < 50 ml/min. There are no data available to support the efficacy of 4 mg/kg daily in patients with RIE or cSSTI associated with Staphylococcus aureus bacteraemia whose creatinine clearance is between 3049 ml/min or to support the use of 4 mg/kg every 48 hours in such patients whose creatinine clearance is < 30 ml/min.Hepatic insufficiencyNo dose adjustment is necessary when administering Cubicin to patients with mild or moderate hepatic insufficiency (Child-Pugh Class B). No data are available in patients with severe hepatic insufficiency (Child-Pugh Class C). Therefore caution should be exercised if Cubicin is given to such patients.Elderly patientsThe recommended doses should be used in elderly patients except those with severe renal insufficiency. However, there are limited data on the safety and efficacy of daptomycin in patients aged > 65 years and caution should be exercised if Cubicin is given to such patients.Children and adolescents ( < 18 years old)Due to the lack of data on safety and efficacy Cubicin is not recommended for use in children and adolescents ( < 18 years of age).Method of administrationCubicin is given by intravenous infusion (see section 6.6) and administered over a 30 minute period.

Child Dosage
Children and adolescents ( < 18 years old) - Due to the lack of data on safety and efficacy Cubicin is not recommended for use in children and adolescents ( < 18 years of age).

Elderly Dosage
The recommended doses should be used in elderly patients except those with severe renal insufficiency (see above and Special Precautions). However, there are limited data on the safety and efficacy of daptomycin in patients aged> 65 years and caution should be exercised if Cubicin is given to such patients.

Contra Indications
Hypersensitivity to the active substance or excipient.

Special Precautions
If a focus of Staphylococcus aureus 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.It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia.Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 patients.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.Creatine phosphokinase and myopathyIncreases 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 Interactions and Adverse Reactions). 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.• 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.• CPK should be measured more frequently than once weekly in patients who are at higher risk of developing myopathy. These patients include those with severe renal insufficiency (creatinine clearance 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.The use of antibiotics may promote the overgrowth of non-susceptible micro-organisms. If super infection occurs during therapy, appropriate measures should be taken.Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or shortly following treatment.

Interactions
Daptomycin undergoes little to no Cytochrome P450 (CYP450) mediated metabolism. In vitro studies have determined that daptomycin does not inhibit or induce the activities of clinically significant human CYP isoforms (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-related drug interactions are to be expected.There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy. However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these medications at the same time as Cubicin. It is recommended that other medications 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 Special Precautions and Adverse Reactions.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 a particular reagent used in some assays of Prothrombin Time/International Normalised Ratio (PT/INR) have been reported. This interference led to an apparent 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. Pregnancy and lactation No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/fetal development, parturition or postnatal development.Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the potential benefit outweighs the possible risk.It is not known whether daptomycin is excreted in human milk. Therefore, breastfeeding should be discontinued during treatment with Cubicin.

Adverse Reactions
Clinical StudiesIn 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.For subjects who received Cubicin, the adverse reactions that were most frequently reported during therapy plus follow-up were: headache, nausea, vomiting, diarrhoea, fungal infections, rash, infusion site reaction, increased creatine phosphokinase (CPK) and abnormal liver enzymes; alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase.The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to Common = 1/100, 1/1,000, 1/10,000, < 1/1,000, Very rare = 1/10,000:Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Infections and Infestations - Common: Fungal infections, Uncommon: Urinary tract infection.Blood and lymphatic system disorders - Uncommon: Thrombocythaemia, anaemia, eosinophilia.Metabolism and nutrition disorders - Uncommon: Anorexia, hyperglycaemia.Psychiatric disorders - Uncommon: Anxiety, insomnia.Nervous system disorders - Common: Headache, Uncommon: Dizziness, paraesthesiae, taste disorder.Cardiac disorders - Uncommon: Supraventricular tachycardia, extrasystoleVascular disordersUncommon: Flushes, hypertension, hypotensionGastrointestinal disordersCommon: Nausea, vomiting, diarrhoeaUncommon: Constipation, abdominal pain, dyspepsia, glossitisHepatobiliary disordersUncommon: JaundiceSkin and subcutaneous tissue disordersCommon: RashUncommon: Pruritis, urticariaMusculoskeletal, connective tissue and bone disordersUncommon: Myositis, muscle weakness, muscle pain, arthralgiaRenal and urinary disorders Uncommon: Renal insufficiencyReproductive system and breast disordersUncommon: VaginitisGeneral disorders and administration site conditionsCommon: Infusion site reactionsUncommon: Pyrexia, weakness, fatigue, painInvestigationsCommon: Liver function tests abnormal (increased AST, ALT and alkaline phosphatase), increased CPKUncommon: Electrolyte imbalance, increased serum creatinine, increased myoglobin, lactic dehydrogenase (LDH) increasedPost-MarketingAdverse reactions that have been reported Post-Marketing that are not listed above are:Immune system disordersVery rare: Hypersensitivity, manifested by isolated spontaneous reports including, but not limited to; pulmonary eosinophilia, vesicobullous rash with mucous membrane involvement and sensation of oropharyngeal swelling.Very rare: AnaphylaxisVery rare: There have been isolated cases of infusion reactions including the following symptoms: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste.Musculoskeletal, connective tissue and bone disordersVery rare: RhabdomyolysisIsolated cases of rhabdomyolysis have been reported; when clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal insufficiency, or in those receiving concomitant medications known to cause rhabdomyolysis.InvestigationsIn 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 13 toxicity and resolved upon discontinuation of treatment.

Manufacturer
Novartis

Drug Availability
(POM)

Updated
11 August 2009