Daptomycin for Injection or Infusion 350mg

  1. Name of the medicinal product

Daptomycin 350mg powder for solution for injection or infusion Taj Pharma
Daptomycin 500mg powder for solution for injection or infusion Taj Pharma

  1. Qualitative and quantitative composition

Daptomycin 350mg powder for solution for injection or infusion

Each vial contains 350mg daptomycin.

One ml provides 50mg of daptomycin after reconstitution with 7 ml of sodium chloride 9mg/ml (0.9%) solution.

Daptomycin 500mg powder for solution for injection or infusion

Each vial contains 500mg daptomycin.

One ml provides 50mg of daptomycin after reconstitution with 10 ml of sodium chloride 9mg/ml (0.9%) solution.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Powder for solution for injection or infusion

A pale yellow to light brown lyophilised cake or powder.

  1. Clinical particulars

4.1 Therapeutic indications

Daptomycin 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, Daptomycin 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).

Posology

Adults

– cSSTI without concurrent SAB: Daptomycin 4mg/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: Daptomycin 6mg/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: Daptomycin 6mg/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.

Daptomycin is administered intravenously in 0.9% sodium chloride (see section 6.6). Daptomycin 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) Daptomycin 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 Daptomycin 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 useCreatinine clearanceDose recommendationComments
cSSTI without SAB≥ 30 ml/min4mg/kg once dailySee section 5.1
< 30 ml/min4mg/kg every 48 hours(1, 2)
RIE or cSSTI associated with SAB≥ 30 ml/min6mg/kg once dailySee section 5.1
< 30 ml/min6mg/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, Daptomycin should be administered following the completion of dialysis on dialysis days (see section 5.2).

Hepatic impairment

No dose adjustment is necessary when administering Daptomycin 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 Daptomycin 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.

Age groupIndication
cSSTI without SABcSSTI associated with SAB
Dosage RegimenDuration of TherapyDosage RegimenDuration of Therapy
12 to 17 years5mg/kg once every 24 hours infused over 30 minutesUp to 14 Days7mg/kg once every 24 hours infused over 30 minutes(1)
7 to 11 years7mg/kg once every 24 hours infused over 30 minutes9mg/kg once every 24 hours infused over 30 minutes
2 to 6 years9mg/kg once every 24 hours infused over 60 minutes12mg/kg once every 24 hours infused over 60 minutes
1 to < 2 years10mg/kg once every 24 hours infused over 60 minutes12mg/kg once every 24 hours infused over 60 minutes
cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia;

(1) Minimum duration of Daptomycin for paediatric SAB should be in accordance with the perceived risk of complications in the individual patient. The duration of Daptomycin 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 Daptomycin was 12 days, with a range of 1 to 44 days. The duration of therapy should be in accordance with available official recommendations.

Daptomycin is administered intravenously in 0.9 % sodium chloride (see section 6.6). Daptomycin 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 Daptomycin 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, Daptomycin 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, Daptomycin is given by intravenous infusion over a 30-minute period (see section 6.6). In paediatric patients aged 1 to 6 years, Daptomycin is given by intravenous infusion over a 60-minute period (see section 6.6).

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 Daptomycin 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 Daptomycin. If an allergic reaction to Daptomycin 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 is therefore not indicated for the treatment of pneumonia.

RIE due to Staphylococcus aureus

Clinical data on the use of Daptomycin 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 Daptomycin 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 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 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 Daptomycin (see section 4.8). If CDAD is suspected or confirmed, Daptomycin 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 Daptomycin (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 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.
  • Daptomycin 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. Daptomycin 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 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 Daptomycin 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 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 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 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 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 pre-dispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).

An adjustment of Daptomycin 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 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 to patients who already have some degree of renal impairment (creatinine clearance < 80 ml/min) before commencing therapy with Daptomycin. 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 Daptomycin 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 Daptomycin 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 Daptomycin dose of 2mg/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 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 and warfarin should be monitored for the first several days after therapy with Daptomycin 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 Daptomycin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with Daptomycin 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).

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).

Daptomycin 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, Daptomycin was intravenously administered daily for 28 days to a nursing mother at a dose of 500mg/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 Daptomycin 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, Daptomycin 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 Daptomycin. Within these trials, 1,221 subjects received a daily dose of 4mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6mg/kg, of whom 304 were patients and 156 were healthy volunteers. In paediatric studies, 372 patients received Daptomycin, of whom 61 received a single dose and 311 received a therapeutic regimen for cSSTI or SAB (daily doses ranged from 4mg/kg to 12mg/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 Daptomycin 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 (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 classFrequencyAdverse reactions
Infections and infestationsCommon:Fungal infections, urinary tract infection, candida infection
Uncommon:Fungaemia
Not known*:Clostridium difficile-associated diarrhoea**
Blood and lymphatic system disordersCommon:Anaemia
Uncommon:Thrombocythaemia, eosinophilia, international normalised ratio (INR) increased, leukocytosis
Rare:Prothrombin time (PT) prolonged
Not known*:Thrombocytopaenia
Immune system disordersNot 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
Metabolism and nutrition disordersUncommon:Decreased appetite, hyperglycaemia, electrolyte imbalance
Psychiatric disordersCommon:Anxiety, insomnia
Nervous system disordersCommon:Dizziness, headache
Uncommon:Paraesthesia, taste disorder, tremor, eye irritation
Not known*:Peripheral neuropathy**
Ear and labyrinth disordersUncommon:Vertigo
Cardiac disordersUncommon:Supraventricular tachycardia, extrasystole
Vascular disordersCommon:Hypertension, hypotension
Uncommon:Flushes
Respiratory, thoracic and mediastinal disordersNot known*:Eosinophilic pneumonia1**, cough
Gastrointestinal disordersCommon:Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension
Uncommon:Dyspepsia, glossitis
Hepatobiliary disordersCommon:Liver function tests abnormal2 (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP))
Rare:Jaundice
Skin and subcutaneous tissue disordersCommon:Rash, pruritus
Uncommon:Urticaria
Not known*:Acute generalised exanthematous pustulosis
Musculoskeletal and connective tissue disordersCommon: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*:Rhabdomyolysis**
Renal and urinary disordersUncommon:Renal impairment, including renal failure and renal insufficiency, serum creatinine increased
Reproductive system and breast disordersUncommon:Vaginitis
General disorders and administration site conditionsCommon: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.

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.

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.

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).

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials.

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 4mg/kg and 6mg/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 ≤ 1mg/l and Resistant > 1mg/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.

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 Daptomycin 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 Daptomycin.

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 Daptomycin 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.

PopulationDaptomycinComparatorDifferences in Success
n/N (%)n/N (%)Rates (95% CI)
ITT (intention to treat) Population
RIE8/19 (42.1%)7/16 (43.8%)-1.6% (-34.6, 31.3)
PP (per protocol) Population
RIE6/12 (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 Daptomycin, 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 Daptomycin 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 surgical intervention.

Clinical efficacy in paediatric patients

The safety and efficacy of daptomycin was evaluated in paediatric patients aged 1 to 17 years (Study DAP-PEDS-07-03) with cSSTI caused by Gram positive pathogens. Patients were enrolled in a stepwise approach into well-defined age groups and given age-dependent doses once daily for up to 14 days, as follows:

  • Age group 1 (n=113): 12 to 17 years treated with daptomycin dosed at 5mg/kg or standard-of-care comparator (SOC);
  • Age group 2 (n=113): 7 to 11 years treated with daptomycin dosed at 7mg/kg or SOC;
  • Age group 3 (n=125): 2 to 6 years treated with daptomycin dosed at 9mg/kg or SOC;
  • Age group 4 (n=45): 1 to < 2 years treated with daptomycin dosed at 10mg/kg or SOC.

The primary objective of Study DAP-PEDS-07-03 was to assess the safety of treatment. Secondary objectives included an assessment of efficacy of age-dependent doses of intravenous daptomycin in comparison with standard-of-care therapy. The key efficacy endpoint was the sponsor-defined clinical outcome at test-of-cure (TOC), which was defined by a blinded medical director. A total of 389 subjects were treated in the study, including 256 subjects who received daptomycin and 133 subjects who received standard-of-care. In all populations the clinical success rates were comparable between the daptomycin and SOC treatment arms, supporting the primary efficacy analysis in the ITT population.

Summary of sponsor-defined clinical outcome at TOC:

 

Clinical Success in Paediatric cSSTI% difference
Daptomycin

n/N (%)

Comparator

n/N (%)

Intent-to-treat227/257 (88.3%)114/132 (86.4%)2.0
Modified intent-to-treat186/210 (88.6%)92/105 (87.6%)0.9
Clinically evaluable204/207 (98.6%)99/99 (100%)-1.5
Microbiologically evaluable (ME)164/167 (98.2%)78/78 (100%)-1.8

The overall therapeutic response rate also was similar for the daptomycin and SOC treatment arms for infections caused by MRSA, MSSA and Streptococcus pyogenes (see table below; ME population); response rates were > 94% for both treatment arms across these common pathogens.

Summary of overall therapeutic response by type of baseline pathogen (ME population):

PathogenOverall Successa rate in Paediatric cSSTI

n/N (%)

DaptomycinComparator
Methicillin-susceptible Staphylococcus aureus (MSSA)68/69 (99%)28/29 (97%)
Methicillin-resistant Staphylococcus aureus (MRSA)63/66 (96%)34/34 (100%)
Streptococcus pyogenes17/18 (94%)5/5 (100%)

a Subjects achieving clinical success (Clinical Response of “Cure” or “Improved”) and microbiological success (pathogen–level response of “Eradicated” or “Presumed Eradicated”) are classified as overall therapeutic success.

The safety and efficacy of daptomycin was evaluated in paediatric patients aged 1 to 17 years (Study DAP-PEDBAC-11-02) with bacteraemia caused by Staphylococcus aureus. Patients were randomized in a 2:1 ratio into the following age groups and given age-dependent doses once daily for up to 42 days, as follows:

  • Age group 1 (n=21): 12 to 17 years treated with daptomycin dosed at 7mg/kg or SOC comparator;
  • Age group 2 (n=28): 7 to 11 years treated with daptomycin dosed at 9mg/kg or SOC;
  • Age group 3 (n=32): 1 to 6 years treated with daptomycin dosed at 12mg/kg or SOC;

The primary objective of Study DAP-PEDBAC-11-02 was to assess the safety of intravenous daptomycin versus SOC antibiotics. Secondary objectives included: Clinical outcome based on the blinded Evaluator’s assessment of clinical response (success [cure, improved], failure, or non-evaluable) at the TOC Visit; and Microbiological response (success, failure, or non-evaluable) based on evaluation of Baseline infecting pathogen at TOC.

A total of 81 subjects were treated in the study, including 55 subjects who received daptomycin and 26 subjects who received standard-of-care. No patients 1 to <2 years of age were enrolled in the study. In all populations the clinical success rates were comparable in the daptomycin versus the SOC treatment arm.

Summary of Blinded Evaluator defined clinical outcome at TOC:

Clinical Success in Paediatric SAB% difference
Daptomycin

n/N (%)

Comparator

n/N (%)

Modified intent-to-treat (MITT)46/52 (88.5%)19/24 (79.2%)9.3%
Microbiologically modified intent-to-treat (mMITT)45/51 (88.2%)17/22 (77.3%)11.0%
Clinically evaluable (CE)36/40 (90.0%)9/12 (75.0%)15.0%

The microbiological outcome at TOC for the daptomycin and SOC treatment arms for infections caused by MRSA and MSSA are presented in the table below (mMITT population).

PathogenMicrobiological Success rate in Paediatric SAB

n/N (%)

DaptomycinComparator
Methicillin-susceptible Staphylococcus aureus (MSSA)43/44 (97.7%)19/19 (100.0%)
Methicillin-resistant Staphylococcus aureus (MRSA)6/7 (85.7%)3/3 (100.0%)

5.2 Pharmacokinetic properties

Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12mg/kg administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy adult volunteers. Steady-state concentrations are achieved by the third daily dose.

Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6mg/kg. Comparable exposure (AUC and Cmax) was demonstrated in healthy adult subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous injection.

Animal studies showed that daptomycin is not absorbed to any significant extent after oral administration.

Distribution

The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetrate the blood-brain barrier and the placental barrier following single and multiple doses.

Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy adult volunteers and adult patients treated with daptomycin, protein binding averaged about 90% including subjects with renal impairment.

Biotransformation

In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

After infusion of 14C-daptomycin in healthy adults, the plasma radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.

Elimination

Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin.

Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 ml/h/kg and its renal clearance is 4 to 7 ml/h/kg.

In a mass balance study using radiolabelled material, 78% of the administered dose was recovered from the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin was approximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.

Special populations

Elderly

Following administration of a single 4mg/kg intravenous dose of Daptomycin over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-∞ was approximately 58% higher in elderly subjects (≥ 75 years of age) compared with those in healthy young subjects (18 to 30 years of age). There were no differences in Cmax. The differences noted are most likely due to the normal reduction in renal function observed in the geriatric population.

No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should be reduced if there is evidence of severe renal impairment.

Children and adolescents (1 to 17 years of age)

The pharmacokinetics of daptomycin in paediatric subjects was evaluated in 3 single-dose pharmacokinetic studies. After a single 4mg/kg dose of Daptomycin, total clearance normalized by weight and elimination half-life of daptomycin in adolescents (12-17 years of age) with Gram-positive infection were similar to adults. After a single 4mg/kg dose of Daptomycin, total clearance of daptomycin in children 7-11 years of age with Gram-positive infection was higher than in adolescents, whereas elimination half-life was shorter. After a single 4, 8, or 10mg/kg dose of Daptomycin, total clearance and elimination half-life of daptomycin in children 2-6 years of age were similar at different doses; total clearance was higher and elimination half-life was shorter than in adolescents. After a single 6mg/kg dose of Daptomycin, the clearance and elimination half-life of daptomycin in children 13-24 months of age were similar to children 2-6 years of age who received a single 4-10mg/kg dose. The results of these studies show that exposures (AUC) in paediatric patients across all doses are generally lower than those in adults at comparable doses.

Paediatric patients with cSSTI

A Phase 4 study (DAP-PEDS-07-03) was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with cSSTI caused by Gram-positive pathogens. Daptomycin pharmacokinetics in patients in this study are summarized in Table 2. Following administration of multiple doses, daptomycin exposure was similar across different age groups after dose adjustment based on body weight and age. Plasma exposures achieved with these doses were consistent with those achieved in the adult cSSTI study (following 4mg/kg once daily in adults).

Table 2 Mean (Standard Deviation) of Daptomycin Pharmacokinetics in Paediatric cSSTI Patients (1 to 17 Years of Age) in Study DAP-PEDS-07-03

Age Range12-17 years (N=6)7-11 years (N=2)a2-6 years (N=7)1 to <2 years (N=30)b
Dose

Infusion Time

5mg/kg

30 minutes

7mg/kg

30 minutes

9mg/kg

60 minutes

10mg/kg

60 minutes

AUC0-24hr (μg×hr/ml)387 (81)438439 (102)466
Cmax (μg/ml)62.4 (10.4)64.9, 74.481.9 (21.6)79.2
Apparent t1/2 (hr)5.3 (1.6)4.63.8 (0.3)5.04
CL/wt (ml/hr/kg)13.3 (2.9)16.021.4 (5.0)21.5

Pharmacokinetic parameter values estimated by noncompartmental analysis

aIndividual values reported as only two patients in this age group provided pharmacokinetic samples to enable pharmacokinetic analysis; AUC, apparent t1/2 and CL/wt could be determined for only one of the two patients

bPharmacokinetic analysis conducted on the pooled pharmacokinetic profile with mean concentrations across subjects at each time point

Paediatric patients with SAB

A Phase 4 study (DAP-PEDBAC-11-02) was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with SAB. Daptomycin pharmacokinetics inpatients in this study are summarized in Table 3. Following administration of multiple doses, daptomycin exposure was similar across different age groups after dose adjustment based on body weight and age. Plasma exposures achieved with these doses were consistent with those achieved in the adult SAB study (following 6mg/kg once daily in adults).

Table 3 Mean (Standard Deviation) of Daptomycin Pharmacokinetics in Paediatric SAB Patients (1 to 17 Years of Age) in Study DAP-PEDBAC-11-02

Age Range12-17 years (N=13)7-11 years (N=19)1 to 6 years (N=19)*
Dose

Infusion Time

7mg/kg

30 minutes

9mg/kg

30 minutes

12mg/kg

60 minutes

AUC0-24hr (μg×hr/ml)656 (334)579 (116)620 (109)
Cmax (μg/ml)104 (35.5)104 (14.5)106 (12.8)
Apparent t1/2 (hr)7.5 (2.3)6.0 (0.8)5.1 (0.6)
CL/wt (ml/hr/kg)12.4 (3.9)15.9 (2.8)19.9 (3.4)

Pharmacokinetic parameter values estimated using a model-based approach with sparsely collected pharmacokinetic samples from individual patients in the study.

*Mean (Standard Deviation) calculated for patients 2 to 6 years of age, since no patients 1 to <2 years of age were enrolled in the study. Simulation using a population pharmacokinetic model demonstrated that the AUCss (area under the concentration-time curve at steady state) of daptomycin in paediatric patients 1 to <2 years of age receiving 12mg/kg once daily would be comparable to that in adult patients receiving 6mg/kg once daily.

Obesity

Relative to non-obese subjects daptomycin systemic exposure measured by AUC was about 28% higher in moderately obese subjects (Body Mass Index of 25-40 kg/m2) and 42% higher in extremely obese subjects (Body Mass Index of > 40 kg/m2). However, no dose adjustment is considered to be necessary based on obesity alone.

Gender

No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.

Renal impairment

Following administration of a single 4mg/kg or 6mg/kg intravenous dose of daptomycin over a 30-minute period to adult subjects with various degrees of renal impairment, total daptomycin clearance (CL) decreased and systemic exposure (AUC) increased as renal function (creatinine clearance) decreased.

Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after administration of a 6mg/kg dose to adult patients on HD or CAPD was 2-fold higher than that observed in adult patients with normal renal function who received the same dose. On the second day after administration of a 6mg/kg dose to HD and CAPD adult patients the daptomycin AUC was approximately 1.3-fold higher than that observed after a second 6mg/kg dose in adult patients with normal renal function. On this basis, it is recommended that adult patients on HD or CAPD receive daptomycin once every 48 hours at the dose recommended for the type of infection being treated (see section 4.2).

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

Hepatic impairment

The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic impairment (Child-Pugh B classification of hepatic impairment) compared with healthy volunteers matched for gender, age and weight following a single 4mg/kg dose. No dosage adjustment is necessary when administering daptomycin in patients with moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh C classification) have not been evaluated.

5.3 Preclinical safety data

Daptomycin administration was associated with minimal to mild degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopic changes in skeletal muscle were minimal (approximately 0.05% of myofibres affected) and at the higher doses were accompanied by elevations in CPK. No fibrosis or rhabdomyolysis was observed. Depending on the study duration, all muscle effects, including microscopic changes, were fully reversible within 1-3 months following cessation of dosing. No functional or pathological changes in smooth or cardiac muscle were observed.

The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels of 0.8 to 2.3-fold the human therapeutic levels at 6mg/kg (30-minute intravenous infusion) for patients with normal renal function. As the pharmacokinetics (see section 5.2) is comparable, the safety margins for both methods of administration are very similar.

A study in dogs demonstrated that skeletal myopathy was reduced upon once daily administration as compared to fractionated dosing at same total daily dose, suggesting that myopathic effects in animals were primarily related to time between doses.

Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscle effects in adult rats and dogs, and were primarily related to plasma Cmax. Peripheral nerve changes were characterised by minimal to slight axonal degeneration and were frequently accompanied by functional changes. Reversal of both the microscopic and functional effects was complete within 6 months post-dose. Safety margins for peripheral nerve effects in rats and dogs are 8- and 6-fold, respectively, based on comparison of Cmax values at the No Observed Effect Level (NOEL) with the Cmax achieved on dosing with 30-minute intravenous infusion of 6mg/kg once daily in patients with normal renal function.

The findings of in vitro and some in vivo studies designed to investigate the mechanism of daptomycin myotoxicity indicate that the plasma membrane of differentiated spontaneously contracting muscle cells is the target of toxicity. The specific cell surface component directly targeted has not been identified. Mitochondrial loss/damage was also observed; however the role and significance of this finding in the overall pathology are unknown. This finding was not associated with an effect on muscle contraction.

In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions as compared to skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doses lower than those associated with skeletal muscle toxicity.

In neonatal dogs, daptomycin caused marked clinical signs of twitching, muscle rigidity in the limbs, and impaired use of limbs, which resulted in decreases in body weight and overall body condition at doses ≥50mg/kg/day and necessitated early discontinuation of treatment in these dose groups. At lower dose levels (25mg/kg/day), mild and reversible clinical signs of twitching and one incidence of muscle rigidity were observed without any effects on body weight. There was no histopathological correlation in the peripheral and central nervous system tissue, or in the skeletal muscle, at any dose level, and the mechanism and clinical relevance for the adverse clinical signs are therefore unknown.

Reproductive toxicity testing showed no evidence of effects on fertility, embryofoetal, or postnatal development. However, daptomycin can cross the placenta in pregnant rats (see section 5.2). Excretion of daptomycin into milk of lactating animals has not been studied.

Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic or clastogenic in a battery of in vivo and in vitro genotoxicity tests.

  1. Pharmaceutical particulars

6.1 List of excipients

Sodium hydroxide

6.2 Incompatibilities

Daptomycin 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.

6.3 Shelf life

3 years

After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial has been demonstrated for 12 hours at 25°C and up to 48 hours at 2°C – 8°C. Chemical and physical stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours at 2°C – 8°C.

For the 30-minute intravenous infusion, the combined storage time (reconstituted solution in vial and diluted solution in infusion bag; see section 6.6) at 25°C must not exceed 12 hours (or 24 at 2°C – 8°C).

For the 2-minute intravenous injection, the storage time of the reconstituted solution in the vial (see section 6.6) at 25°C must not exceed 12 hours (or 48 at 2°C – 8°C).

However, from a microbiological point of view the product should be used immediately. No preservative or bacteriostatic agent is present in this product. If not used immediately, in-use storage times are the responsibility of the user and would not normally be longer than 24 hours at 2°C – 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

For storage conditions after reconstitution and after reconstitution and dilution of the medicinal product see section 6.3.

6.5 Nature and contents of container

Daptomycin 350mg powder for solution for injection or infusion

Single use 10 ml type I clear glass vials with type I rubber stoppers and aluminium closures with yellow plastic flip off caps.

Daptomycin 500mg powder for solution for injection or infusion

Single use 10 ml type I clear glass vials with type I rubber stoppers and aluminium closures with blue plastic flip off caps.

Available in packs containing 1 vial or 5 vials. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

In adults, daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over 2 minutes. Daptomycin should not be administered as a 2-minute injection to paediatric patients. Paediatric patients 7 to 17 years old should receive daptomycin infused over 30 minutes. In paediatric patients under 7 years old receiving a 9-12mg/kg dose, daptomycin should be administered over 60 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional dilution step as detailed below.

Daptomycin given as 30 or 60-minute intravenous infusion

A 50mg/ml concentration of Daptomycin 350mg powder for infusion is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9mg/ml (0.9%) solution for injection.

A 50mg/ml concentration of Daptomycin 500mg powder for infusion is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9mg/ml (0.9%) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

Daptomycin 350mg powder for solution for injection or infusion

To prepare Daptomycin for intravenous infusion, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute or dilute lyophilised Daptomycin.

For Reconstitution:

  1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 7 ml of sodium chloride 9mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
  2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
  3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
  4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin range in colour from pale yellow to light brown.
  5. The reconstituted solution should then be diluted with sodium chloride 9mg/ml (0.9%) (typical volume 50 ml).

For Dilution:

  1. Slowly remove the appropriate reconstituted liquid (50mg daptomycin/ml) from the vial using a new sterile needle that is 21 gauge or smaller in diameter by inverting the vial in order to allow the solution to drain towards the stopper. Using a syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove the required solution from the inverted vial.
  2. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
  3. Transfer the required reconstituted dose into 50 ml sodium chloride 9mg/ml (0.9%).
  4. The reconstituted and diluted solution should then be infused intravenously over 30 or 60 minutes as directed in section 4.2.

Daptomycin 500mg powder for solution for injection or infusion

To prepare Daptomycin for intravenous infusion, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute or dilute lyophilised Daptomycin.

For Reconstitution:

  1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 10 ml of sodium chloride 9mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
  2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
  3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
  4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin range in colour from pale yellow to light brown.
  5. The reconstituted solution should then be diluted with sodium chloride 9mg/ml (0.9%) (typical volume 50 ml).

For Dilution:

  1. Slowly remove the appropriate reconstituted liquid (50mg daptomycin/ml) from the vial using a new sterile needle that is 21 gauge or smaller in diameter by inverting the vial in order to allow the solution to drain towards the stopper. Using a syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove the required solution from the inverted vial.
  2. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
  3. Transfer the required reconstituted dose into 50 ml sodium chloride 9mg/ml (0.9%).
  4. The reconstituted and diluted solution should then be infused intravenously over 30 or 60 minutes as directed in section 4.2.

The following have been shown to be compatible when added to Daptomycin containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.

Daptomycin given as 2-minute intravenous injection (adult patients only)

Water should not be used for reconstitution of Daptomycin for intravenous injection. Daptomycin should only be reconstituted with sodium chloride 9mg/ml (0.9%).

A 50mg/ml concentration of Daptomycin 350mg powder for injection is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9mg/ml (0.9%) solution for injection.

A 50mg/ml concentration of Daptomycin 500mg powder for injection is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9mg/ml (0.9%) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.

Daptomycin 350mg powder for solution for injection or infusion

To prepare Daptomycin for intravenous injection, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Daptomycin.

  1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 7 ml of sodium chloride 9mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
  2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
  3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
  4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin range in colour from pale yellow to light brown.
  5. Slowly remove the reconstituted liquid (50mg daptomycin/ml) from the vial using a sterile needle that is 21 gauge or smaller in diameter.
  6. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
  7. Replace needle with a new needle for the intravenous injection.
  8. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
  9. The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.

Daptomycin 500mg powder for solution for injection or infusion

To prepare Daptomycin for intravenous injection, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Daptomycin.

  1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 10 ml of sodium chloride 9mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
  2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
  3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
  4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin range in colour from pale yellow to light brown.
  5. Slowly remove the reconstituted liquid (50mg daptomycin/ml) from the vial using a sterile needle that is 21 gauge or smaller in diameter.
  6. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
  7. Replace needle with a new needle for the intravenous injection.
  8. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
  9. The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.

Daptomycin vials are for single-use only.

From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

  1. Manufactured in India by:
    TAJ PHARMACEUTICALS LTD.
    Mumbai, India
    Unit No. 214.Old Bake House,
    Maharashtra chambers of Commerce Lane,
    Fort, Mumbai – 400001
    at:Gujarat, INDIA.
    Customer Service and Product Inquiries:
    1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
    Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
    E-mail: tajgroup@tajpharma.com

 

Daptomycin for injection or infusion 350mg, 500mg

Package leaflet: Information for the patient

Daptomycin 350mg, 500mg powder for solution for injection or infusion Taj Pharma

daptomycin

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or nurse.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Daptomycin is and what it is used for
    2. What you need to know before you are given Daptomycin
    3. How Daptomycin is given
    4. Possible side effects
    5. How to store Daptomycin
    6. Contents of the pack and other information
  2. What Daptomycin is and what it is used for

The active substance in Daptomycin powder for solution for injection or infusion is daptomycin. Daptomycin is an antibacterial that can stop the growth of certain bacteria. Daptomycin is used in adults and in children and adolescents (age from 1 to 17 years) to treat infections of the skin and the tissues below the skin. It is also used to treat infections in the blood when associated with skin infection.

Daptomycin is also used in adults to treat infections in the tissues that line the inside of the heart (including heart valves) which are caused by a type of bacteria called Staphylococcus aureus. It is also used to treat infections in the blood caused by the same type of bacteria when associated with heart infection.

Depending on the type of infection(s) that you have, your doctor may also prescribe other antibacterials while you are receiving treatment with Daptomycin.

  1. What you need to know before you are given Daptomycin

You should not be given Daptomycin

If you are allergic to daptomycin or to sodium hydroxide or to any of the other ingredients of this medicine (listed in section 6).

If this applies to you, tell your doctor or nurse. If you think you may be allergic, ask your doctor or nurse for advice.

Warnings and precautions

Talk to your doctor or nurse before you are given Daptomycin.

  • If you have, or have previously had kidney problems. Your doctor may need to change the dose of Daptomycin (see section 3 of this leaflet).
  • Occasionally, patients receiving Daptomycin may develop tender or aching muscles or muscle weakness (see section 4 of this leaflet for more information). If this happens tell your doctor. Your doctor will make sure you have a blood test and will advise whether or not to continue with Daptomycin. The symptoms generally go away within a few days of stopping Daptomycin.
  • If you are very overweight. There is a possibility that your blood levels of Daptomycin could be higher than those found in persons of average weight and you may need careful monitoring in case of side effects.

If any of these applies to you, tell your doctor or nurse before you are given Daptomycin.

Tell your doctor straight away if you develop any of the following symptoms:

  • Serious, acute allergic reactions have been observed in patients treated with nearly all antibacterial agents, including Daptomycin. Tell a doctor or a nurse straight away if you experience symptoms suggestive of allergic reaction, such as wheezing, difficulty breathing, swelling of the face, neck and throat, rashes and hives, fever (see section 4 of this leaflet for more information).
  • Any unusual tingling or numbness of the hands or feet, loss of feeling or difficulties with movements. If this happens, tell your doctor who will decide whether you should continue the treatment.
  • Diarrhoea, especially if you notice blood or mucus, or if diarrhoea becomes severe or persistent.
  • New or worsening fever, cough or difficulty breathing. These may be signs of a rare but serious lung disorder called eosinophilic pneumonia. Your doctor will check the condition of your lungs and decide whether or not you should continue Daptomycin treatment.

Daptomycin may interfere with laboratory tests that measure how well your blood is clotting. The results can suggest poor blood clotting when, in fact, there is no problem. Therefore it is important that your doctor takes into account that you are receiving Daptomycin. Please inform your doctor that you are on treatment with Daptomycin.

Your doctor will perform blood tests to monitor the health of your muscles both before you start treatment and frequently during treatment with Daptomycin.

Children and adolescents

Daptomycin should not be administered to children below one year of age as studies in animals have indicated that this age group may experience severe side effects.

Use in elderly

People over the age of 65 can be given the same dose as other adults, provided their kidneys are working well.

Other medicines and Daptomycin

Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines.

It is particularly important that you mention the following:

  • Medicines called statins or fibrates (to lower cholesterol) or ciclosporin (a medicinal product used in transplantation to prevent organ rejection or for other conditions, e.g. rheumatoid arthritis or atopic dermatitis). It is possible that the risk of side effects affecting the muscles may be higher when any of these medicines (and some others that can affect muscles) is taken during treatment with Daptomycin. Your doctor may decide not to give you Daptomycin or to stop the other medicine for a while.
  • Pain killing medicines called non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors (e.g. celecoxib). These could interfere with the effects of Daptomycin in the kidney.
  • Oral anti-coagulants (e.g. warfarin), which are medicines that prevent blood from clotting. It may be necessary for your doctor to monitor your blood clotting times.

Pregnancy and breast-feeding

Daptomycin is not usually given to pregnant women. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before you are given this medicine.

Do not breast-feed if you are receiving Daptomycin, because it may pass into your breast milk and could affect the baby.

Driving and using machines

Daptomycin has no known effects on the ability to drive or use machines.

  1. How Daptomycin is given

Daptomycin will usually be given to you by a doctor or a nurse.

Adults (18 years of age and above)

The dose will depend on how much you weigh and the type of infection being treated. The usual dose for adults is 4mg for every kilogram (kg) of body weight once daily for skin infections or 6mg for every kg of body weight once daily for a heart infection or a blood infection associated with skin or heart infection. In adult patients, this dose is given directly into your blood stream (into a vein), either as an infusion lasting about 30 minutes or as an injection lasting about 2 minutes. The same dose is recommended in people aged over 65 years provided their kidneys are working well.

If your kidneys do not work well, you may receive Daptomycin less often, e.g. once every other day. If you are receiving dialysis, and your next dose of Daptomycin is due on a dialysis day, you will be usually given Daptomycin after the dialysis session.

Children and adolescents (1 to 17 years of age)

The dose for children and adolescents (1 to 17 years of age) will depend on the age of patient and the type of infection being treated. This dose is given directly into the blood stream (into a vein), as an infusion lasting about 30-60 minutes.

A course of treatment usually lasts for 1 to 2 weeks for skin infections. For blood or heart infections and skin infections your doctor will decide how long you should be treated.

Detailed instructions for use and handling are given at the end of the leaflet.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The most serious side effects are described below:

Very rare serious side effects (may affect up to 1 in 10,000 people)

A hypersensitivity reaction (serious allergic reaction including anaphylaxis, angioedema, drug rash with eosinophilia and systemic symptoms (DRESS)) has been reported, in some cases during administration of Daptomycin. This serious allergic reaction needs immediate medical attention. Tell your doctor or nurse straight away if you experience any of the following symptoms:

  • Chest pain or tightness,
  • Rash with blistering, sometimes affecting the mouth and genitals,
  • Swelling around throat,
  • Rapid or weak pulse,
  • Wheezing,
  • Fever,
  • Shivering or trembling,
  • Hot flushes,
  • Dizziness,
  • Fainting,
  • Metallic taste.

Tell your doctor straight away if you experience unexplained muscle pain, tenderness, or weakness. In very rare cases (reported in less than 1 in every 10,000 patients), muscle problems can be serious, including muscle breakdown (rhabdomyolysis), which can result in kidney damage.

Serious side effects with frequency not known (frequency cannot be estimated from the available data)

A rare but potentially serious lung disorder called eosinophilic pneumonia has been reported in patients given Daptomycin, mostly after more than 2 weeks of treatment. The symptoms can include difficulty breathing, new or worsening cough, or new or worsening fever. If you experience these symptoms, tell your doctor or nurse straight away.

If you experience raised or fluid-filled skin spots over a large area of your body, tell your doctor or nurse straight away.

The most frequently reported side effects are described below:

Common side effects (may affect up to 1 in 10 people)

  • Fungal infections such as thrush,
  • Urinary tract infection,
  • Decreased number of red blood cells (anaemia),
  • Dizziness, anxiety, difficulty in sleeping,
  • Headache,
  • Fever, weakness (asthenia),
  • High or low blood pressure,
  • Constipation, abdominal pain,
  • Diarrhoea, feeling sick (nausea) or being sick (vomiting),
  • Flatulence,
  • Abdominal swelling or bloating,
  • Skin rash or itching,
  • Pain, itchiness or redness at the site of infusion,
  • Pain in arms or legs,
  • Blood testing showing higher levels of liver enzymes or creatine phosphokinase (CPK).

Other side effects which may occur following Daptomycin treatment are described below:

Uncommon side effects (may affect up to 1 in 100 people)

  • Blood disorders (e.g. increased number of small blood particles called platelets, which may increase the tendency for blood clotting, or higher levels of certain types of white blood cells),
  • Decreased appetite,
  • Tingling or numbness of the hands or feet, taste disturbance,
  • Trembling,
  • Changes in heart rhythm, flushes,
  • Indigestion (dyspepsia), inflammation of the tongue,
  • Itchy rash of skin,
  • Muscle pain, cramping, or weakness, inflammation of the muscles (myositis), joint pain,
  • Kidney problems,
  • Inflammation and irritation of the vagina,
  • General pain or weakness, tiredness (fatigue),
  • Blood test showing increased levels of blood sugar, serum creatinine, myoglobin, or lactate dehydrogenase (LDH), prolonged blood clotting time or imbalance of salts,
  • Itchy eyes.

Rare side effects (may affect up to 1 in 1,000 people)

  • Yellowing of the skin and eyes,
  • Prothrombin time prolonged.

Frequency not known (frequency cannot be estimated from the available data)

Antibacterial-associated colitis, including pseudomembranous colitis (severe or persistent diarrhoea containing blood and/or mucus, associated with abdominal pain or fever), easy bruising, bleeding gums, or nosebleeds.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

  1. How to store Daptomycin
  • Keep this medicine out of the sight and reach of children.
  • Do not use this medicine after the expiry date which is stated on the carton and label after EXP. The expiry date refers to the last day of the month.
  • Store in a refrigerator (2°C – 8°C).
  1. Contents of the pack and other information

What Daptomycin contains

  • The active substance is daptomycin. One vial of powder contains 500mg daptomycin.
  • The other ingredient is sodium hydroxide.

What Daptomycin looks like and contents of the pack

Daptomycin powder for solution for injection or infusion in a glass vial. It is mixed with a solvent to form a liquid before it is administered.

Daptomycin is available in packs containing 1 vial or 5 vials.

  1. Manufactured in India by:
    TAJ PHARMACEUTICALS LTD.
    Mumbai, India
    Unit No. 214.Old Bake House,
    Maharashtra chambers of Commerce Lane,
    Fort, Mumbai – 400001
    at:Gujarat, INDIA.
    Customer Service and Product Inquiries:
    1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
    Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
    E-mail: tajgroup@tajpharma.com