Daptomycin Amarox 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  thedecision  to  use  daptomycin  should  take   into   account   the antibacterial susceptibility of the organism and should bebased 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 inbacteraemia should be associated with RIE or with cSSTI, while in paediatric patients, use in bacteraemia should beassociated with cSSTI.

Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gram negativeand/or certain types of  anaerobic  bacteria  are  suspected, Daptomycin Amarox should be co-administered with appropriateantibacterial agent(s).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Clinical studies in patients employed infusion of daptomycin over at least 30 minutes. There is no clinical experience inpatients with the administration of daptomycin as an injection over 2 minutes. This mode of administration was onlystudied in healthy subjects. However, when compared with the same doses given as intravenous infusions over 30minutes there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (seealso sections 4.8 and 5.2).

Posology Adults

-  cSSTI without concurrent SAB: Daptomycin Amarox 4 mg/kg is administered once every 24 hours for 7-14 days or until theinfection is resolved (see section 5.1).

-   cSSTI with concurrent SAB: Daptomycin Amarox 6 mg/kg is administered once every 24 hours. See below for dose adjustments inpatients with renal impairment. The duration of therapy may need to

be longer than 14 days in accordance with theperceived risk of complications in the individual patient.

-   Known or suspected RIE due to Staphylococcus aureus: Daptomycin Amarox 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The

duration of therapy should be in accordance withavailable official recommendations. Daptomycin Amarox is administered intravenously in 0.9 % sodium chloride (see section 6.6). Daptomycin Amarox should not be used morefrequently than once a day.

Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least weekly) duringtreatment (see section 4.4).

Renal impairment

Daptomycin is eliminated primarily by the kidney.

 

Due to limited clinical experience (see table and footnotes below) Daptomycin  Amarox  should  only be used in adult patients withany degree of renal impairment (CrCl < 80 ml/min) when it is considered that the expected clinical benefit outweighsthe potential risk.  The  response  to  treatment, renal function and creatine phosphokinase (CPK) levels should be closelymonitored in all patients

 

with any degree of renal impairment (see also sections 4.4 and 5.2). The dosage regimen for Daptomycin Amarox in paediatric patients with renal impairment has not been established. Dose adjustments in adult patients with renal impairment by indication and creatinine clearance

Indication for use	Creatinine clearance	Dose recommendation	Comments
cSSTI without SAB	≥ 30 ml/min	4 mg/kg once daily	See section 5.1
	< 30 ml/min	4 mg/kg every 48 hours	(1, 2)
RIE         or               cSSTI associated with SAB	≥ 30 ml/min	6 mg/kg once daily	See section 5.1
	< 30 ml/min	6 mg/kg every 48 hours	(1, 2)
cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia   (1)  The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see sections 4.4 and 5.2). (2)   The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK modelling results, are recommended for adult patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible,  Daptomycin  Amarox  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 Amarox 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-PughClass C). Therefore caution should be exercised if Daptomycin Amarox is given to such patients.

Elderly patients

 

The recommended doses should be used in elderly patients except those with severe renal impairment (see above andsection 4.4).

Paediatric population (1 to 17 years of age)

The recommended dosage regimens for paediatric patients based on age and indication are shown below.

Age Group	Indication
	cSSTI without SAB		cSSTI associated with SAB
	Dosage Regimen	Duration              of Therapy	Dosage Regimen	Duration                  of Therapy
12 to 17 years	5 mg/kg once every 24 hours infused over 30 minutes	Up     to          14 days	7 mg/kg once every 24 hours infused over 30 minutes	(1)
7 to 11 years	7 mg/kg once every 24 hours infused over 30 minutes		9 mg/kg once every 24 hours infused over 30 minutes
2 to 6 years	9 mg/kg once every 24 hours infused over 60 minutes		12 mg/kg once every 24 hours infused over 60 minutes
1 to < 2 years	10 mg/kg once every 24 hours infused over 60		12 mg/kg once every 24 hours infused over 60

 

 

	minutes		minutes
cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia;   (1) Minimum duration of Daptomycin Amarox for paediatric SAB should be in accordance with the perceived risk of complications in the individual patient.   The duration of Daptomycin Amarox 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 Amarox was 12 days, with a range of 1 to 44 days. The duration of therapy should be in accordance with available official recommendations.

Daptomycin Amarox is administered intravenously in 0.9 % sodium chloride (see section 6.6).

Daptomycin Amarox should not be used morefrequently 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 Amarox due to the risk of potential effects onmuscular, 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 Amarox is given by intravenous  infusion  (see  section  6.6)  and administered over a 30-minute period or byintravenous injection (see section 6.6) and administered over a 2-minute period.

In paediatric patients aged 7 to 17 years, Daptomycin Amarox is given by intravenous infusion over a 30-minute period (see section6.6). In paediatric patients aged 1 to 6 years, Daptomycin Amarox is given by intravenous infusion over a 60-minute period (seesection 6.6).

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

General

If a focus of infection other than cSSTI or RIE is identified  after  initiation  of  Daptomycin Amarox therapy consideration should begiven to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of thespecific type of infection(s) present.

Anaphylaxis/hypersensitivity reactions

Anaphylaxis/hypersensitivity reactions have been reported with Daptomycin Amarox. If an allergic reaction to Daptomycin Amarox occurs, discontinue use and institute appropriate therapy.

Pneumonia

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

RIE due to Staphylococcus aureus

Clinical data on the use of Daptomycin Amarox to treat RIE due to Staphylococcus aureus are limited to 19 adult patients (see“Clinical efficacy in adults” in section  5.1).  The  safety  and efficacy of Daptomycin Amarox in children and adolescents aged below18 years with right-sided infective endocarditis (RIE) due to Staphylococcus aureus have not been established.

The efficacy of Daptomycin Amarox 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 ofprosthetic 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 Amarox against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, doseregimens 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 associatedwith 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 occursduring therapy, appropriate measures should be taken.

Clostridioides difficile-associated diarrhoea

Clostridioides difficile-associated diarrhoea (CDAD)  has  been  reported  with  Daptomycin Amarox (see section 4.8). If CDAD issuspected or confirmed, Daptomycin Amarox 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 observedwhen 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 Amarox (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to > 5x Upper Limit ofNormal (ULN) without muscle symptoms occurred more commonly in Daptomycin Amarox-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) inpatients 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, fibratesand 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 Amarox should not be administered to patients who are taking other medicinal products associated with myopathyunless 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 levelsmonitored every 2 days. Daptomycin Amarox should be discontinued in the presence of unexplained muscle symptoms if the CPKlevel 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 Amarox 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 Amarox due to the risk of potential effects onmuscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonataldogs (see section 5.3).

Eosinophilic pneumonia

Eosinophilic pneumonia has been  reported  in  patients  receiving  Daptomycin Amarox  (see section 4.8). In most reported cases associated  with  Daptomycin Amarox,  patients  developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffusepulmonary infiltrates or organising pneumonia. The majority of cases occurred after more than 2 weeks of treatment with Daptomycin Amarox and improved when Daptomycin Amarox 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 Amarox should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude othercauses (e.g. bacterial infection, fungal infection, parasites, other medicinal products).

 

Daptomycin Amarox should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms(DRESS) and vesiculobullous rash with or without mucous membrane involvement (Stevens-Johnson Syndrome (SJS)or Toxic Epidermal Necrolysis (TEN)), which could be life- threatening or fatal, have been reported with daptomycin (seesection 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skinreactions, and be closely monitored. If signs and symptoms suggestive of these  reactions  appear,  Daptomycin Amarox should be discontinued immediately and  an alternative treatment should  be considered.  If the patient has developed a severecutaneous adverse reaction with the use of daptomycin,

treatment with daptomycin must not be restarted in thispatient at any time. Tubulointerstitial nephritis

Tubulointerstitial nephritis (TIN) has been reported in post-marketing experience with daptomycin. Patients who developfever, rash, eosinophilia and/or new or worsening renal impairment while receiving Daptomycin Amarox should undergo medicalevaluation. If  TIN  is  suspected, Daptomycin Amarox should be discontinued promptly and appropriate therapy and/or measuresshould be taken.

Renal impairment

Renal impairment has been reported during treatment with Daptomycin Amarox. 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 Amarox dose interval  is  needed  for  adult  patients whose  creatinine clearance is < 30 ml/min (seesections 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 Amarox 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 Amarox to patients who already have some degree of renal impairment(creatinine clearance < 80 ml/min) before commencing therapy with

  Daptomycin Amarox.                                                                                                              

 

Regular monitoring of renal function isadvised (see also section 5.2).

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

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

Obesity

In obese subjects with Body Mass Index (BMI) > 40 kg/m but with creatinine clearance > 70 ml/min, the AUC 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).

Sodium

This medicine contains sodium that has to be taken into consideration by patients on a controlled sodium diet.

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 Amarox  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 thepharmacokinetics 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 co-administrationby intravenous infusion over a 30-minute period using a Daptomycin Amarox dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Daptomycin Amarox is unknown.

Caution is warranted when Daptomycin Amarox is co-administered with tobramycin. Experience with the concomitant administration of Daptomycin Amarox and warfarin is limited.

 

Studies of Daptomycin Amarox with anticoagulants other than  warfarin  have  not  been conducted. Anticoagulant activity in patients receiving Daptomycin Amarox and warfarin should be monitored for the first several days after therapy with Daptomycin Amarox 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 casesof rhabdomyolysis occurred in adult patients taking one of these medicinal products at the same time as Daptomycin Amarox. It is recommended that other medicinal                    products    associated   with                                    myopathy should         if                                    possible    be

temporarily discontinued during treatment with Daptomycin Amarox unless the benefits of concomitant administration outweigh the  risk.  If  co-administrationcannot  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 apharmacodynamic 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 someassays of prothrombin time/international normalised ratio (PT/INR) have been reported. This interference led to a falseprolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients takingdaptomycin, 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 plasmaconcentrations of daptomycin (see section 4.4).

Pregnancy

No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmfuleffects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

 

 

Daptomycin Amarox should not be used during pregnancy unless clearly necessary i.e., only if the expected benefit outweighs thepossible risk.

 

Breast-feeding

 

In a single human case study, Daptomycin Amarox was intravenously administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 μg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when Daptomycin Amarox is administered to nursing women.

 

 

Fertility

 

No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effectswith respect to fertility (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed.

On the basis of reported adverse drug reactions, Daptomycin Amarox is presumed to be unlikely to produce an effect on the abilityto drive or use machinery.

Summary of the safety profile

 

In clinical  studies,  2,011  adult  subjects  received  Daptomycin Amarox.  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 6 mg/kg, of whom 304 were patients and

156 were healthy volunteers. In paediatric studies, 372 patients received Daptomycin Amarox, of whom 61 received a single dose and 311 received a therapeutic regimen for cSSTI or SAB (daily doses ranged from 4 mg/kgto 12 mg/kg).

 

Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to themedicinal product) were reported at similar frequencies for Daptomycin Amarox 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), aspartateaminotransferase (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, eosinophilicpneumonia (occasionally presenting as organising  pneumonia),  drug  reaction  with eosinophilia and systemicsymptoms (DRESS), angioedema and rhabdomyolysis.

Tabulated list of adverse reactions

 

The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding tovery common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000);very rare (< 1/10,000); not known (cannot be estimated from the available data):

 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

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

System organ class	Frequency	Adverse reactions
Infections and infestations	Common:	Fungal infection	infections,	urinary	tract	infection,	candida
	Uncommon:	Fungaemia

 

 

			Not known*:	Clostridioides difficile-associated diarrhoea**
Blood    and disorders	lymphatic	system	Common:	Anaemia
			Uncommon:	Thrombocythaemia,        eosinophilia,                                         international normalised ratio (INR) increased, leukocytosis
			Rare:	Prothrombin time (PT) prolonged
			Not known*:	Thrombocytopaenia
Immune system disorders			Not known*:	Hypersensitivity**, manifested by isolated spontaneous reports including, but not limited to angioedema, pulmonary eosinophilia, sensation of oropharyngeal swelling, anaphylaxis**, infusion reactions including the following symptoms: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste
Metabolism disorders	and	nutrition	Uncommon:	Decreased imbalance	appetite,	hyperglycaemia,	electrolyte
Psychiatric disorders			Common:	Anxiety, insomnia
Nervous system disorders			Common:	Dizziness, headache
			Uncommon:	Paraesthesia, taste disorder, tremor, eye irritation
			Not known*:	Peripheral neuropathy**
Ear and labyrinth disorders			Uncommon:	Vertigo
Cardiac disorders			Uncommon:	Supraventricular tachycardia, extrasystole

 

 

Vascular disorders		Common:	Hypertension, hypotension
		Uncommon:	Flushes
Respiratory,                    thoracic mediastinal disorders	and	Not known*:	Eosinophilic pneumonia1**, cough
Gastrointestinal disorders		Common:	Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension
		Uncommon:	Dyspepsia, glossitis
Hepatobiliary disorders		Common:	Liver function tests abnormal2 (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP))
		Rare:	Jaundice
Skin and subcutaneous disorders	tissue	Common:	Rash, pruritus
		Uncommon:	Urticaria
		Not known*:	Acute generalised exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS)**, vesiculobullous rash with or without mucous membrane involvement (SJS or TEN)**
Musculoskeletal and connective tissue disorders		Common:	Limb       pain, (CPK)2 increased	serum	creatine	phosphokinase
		Uncommon:	Myositis, increased myoglobin, muscular weakness, muscle pain, arthralgia, serum lactate dehydrogenase

 

 

		(LDH) increased, muscle cramps
	Not known*:	Rhabdomyolysis3 **
Renal and urinary disorders	Uncommon:	Renal impairment, including renal failure and renal insufficiency, serum creatinine increased
	Not known*:	Tubulointerstitial nephritis (TIN)**
Reproductive system and breast disorders	Uncommon:	Vaginitis
General                       disorders                    and administration site conditions	Common:	Infusion site reactions, pyrexia, asthenia
	Uncommon:	Fatigue, pain

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

** See section 4.4.

 

1 While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the reporting rate of spontaneous reports is very low (< 1/10,000).

2 In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3 toxicity and resolved upon discontinuation of treatment.

3 When clinical information on the patients was available to make a judgement, approximately 50 % of the cases occurred in patients with pre-existing renal impairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.

 

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy adult volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.

Reporting of suspected adverse reactions

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below)

•  Saudi Arabia:

 

 

 

o Other GCC States:

Please contact the relevant competent authority.

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 % ofthe administered dose is removed over 48 hours).

Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code: J01XX09

 

Mechanism of action

Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only. The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes of both growing andstationary phase cells causing depolarisation and leading to a rapid inhibition of protein, DNA, and RNA synthesis. Thisresults in bacterial cell death with negligible cell lysis.

PK/PD relationship

Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive organisms in vitro andin in vivo animal models. In animal models AUC/MIC and Cmax/MIC correlate with efficacy and predicted bacterial kill invivo at single doses equivalent to human adult doses of 4 mg/kg and 6 mg/kg once daily.

Mechanisms of resistance

Strains with decreased susceptibility to daptomycin have been reported especially during the treatment of patients withdifficult-to-treat infections and/or following administration for prolonged periods. In particular, there have been reports oftreatment 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 susceptibilityor frank resistance to daptomycin during therapy.

The mechanism(s) of daptomycin resistance is (are) not fully understood. Breakpoints

Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S. pneumoniae) are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.

Susceptibility

The prevalence of resistance may vary geographically and over time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

 

 

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 Amarox 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 Amarox.

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 Amarox met the criteria for  RIE. Of these 19 patients 11 were infected with methicillin-susceptible and 8 with methicillin- resistant Staphylococcus aureus. The success rates in RIE patients are shown in the table below.

 

 

Population	Daptomycin	Comparator	Differences in Success
	n/N (%)	n/N (%)	Rates (95 % CI)
ITT (intention to treat) Population
RIE	8/19 (42.1 %)	7/16 (43.8 %)	-1.6 % (-34.6, 31.3)
PP (per protocol) Population
RIE	6/12 (50.0 %)	4/8 (50.0 %)	0.0 % (-44.7, 44.7)

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in 19/120 (15.8 %) patients treated with Daptomycin Amarox, 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 Amarox 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 5 mg/kg or standard-of-care comparator (SOC);

•  Age group 2 (n=113): 7 to 11 years treated with daptomycin dosed at 7 mg/kg or SOC;

•  Age group 3 (n=125): 2 to 6 years treated with daptomycin dosed at 9 mg/kg or SOC;

•  Age group 4 (n=45): 1 to < 2 years treated with daptomycin dosed at 10 mg/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
	Daptomycin n/N (%)	Comparator n/N (%)	% difference
Intent-to-treat	227/257 (88.3 %)	114/132 (86.4 %)	2.0
Modified intent-to-treat	186/210 (88.6 %)	92/105 (87.6 %)	0.9
Clinically evaluable	204/207 (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):

 

Pathogen	Overall Successa rate in Paediatric cSSTI n/N (%)
	Daptomycin	Comparator
Methicillin-susceptible Staphylococcus aureus (MSSA)	68/69 (99 %)	28/29 (97 %)
Methicillin-resistant Staphylococcus aureus (MRSA)	63/66 (96 %)	34/34 (100 %)
Streptococcus pyogenes	17/18 (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 randomised 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 7 mg/kg or SOC comparator;

•  Age group 2 (n=28): 7 to 11 years treated with daptomycin dosed at 9 mg/kg or SOC;

•  Age group 3 (n=32): 1 to 6 years treated with daptomycin dosed at 12 mg/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
	Daptomycin n/N (%)	Comparator n/N (%)	% difference
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).

Pathogen

Microbiological Success rate in Paediatric

 

 

	SAB n/N (%)
	Daptomycin	Comparator
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 %)

Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/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 6 mg/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 wasindependent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetratethe 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 adultvolunteers and adult patients treated with daptomycin, protein binding averaged about 90 % including subjects withrenal impairment.

Biotransformation

In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with humanhepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that

 

daptomycin will inhibit or induce the metabolismof medicinal products metabolised by the P450 system.

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

Elimination

Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and daptomycin has noeffect 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/hr/kg and its renalclearance is 4 to 7 ml/hr/kg.

In a mass balance study using radiolabelled material, 78 % of the administered dose was recovered from the urinebased 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 4 mg/kg intravenous dose of Daptomycin Amarox over a 30- minute period, the mean totalclearance of daptomycin was approximately 35 % lower and the   mean AUC

was approximately 58 % higher inelderly subjects (≥ 75 years of age) compared with those in healthy young subjects (18 to 30 years of age). There wereno differences in Cmax. The differences noted are most likely due to the normal reduction in renal function observed inthe 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 4 mg/kg dose of Daptomycin Amarox, total clearance normalised by weight and elimination half-life of daptomycin inadolescents (12-17 years of age) with Gram-positive infection were similar to adults. After a single 4 mg/kg dose of Daptomycin Amarox, total clearance of daptomycin in children 7-11 years of age with Gram-positive infection was  higher  than inadolescents, whereas  elimination half-life  was shorter.  After  a single 4, 8, or 10 mg/kg dose of Daptomycin Amarox, total clearanceand 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 6 mg/kg dose of Daptomycin Amarox, the clearanceand elimination half-life of daptomycin in children 13-24 months of age were similar to children 2-6  years of age whoreceived a single 4-10 mg/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 inpaediatric patients (1 to 17 years old, inclusive) with cSSTI caused by Gram-positive pathogens. Daptomycin pharmacokinetics in patients in this study are summarised 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 Range	12-17 years (N=6)	7-11 years (N=2)a	2-6 years (N=7)	1     to     <2       years (N=30)b
Dose Infusion Time	5 mg/kg 30 minutes	7 mg/kg 30 minutes	9 mg/kg 60 minutes	10 mg/kg 60 minutes
AUC0-24hr	387 (81)	438	439 (102)	466

 

 

(μg×hr/ml)
Cmax (μg/ml)	62.4 (10.4)	64.9, 74.4	81.9 (21.6)	79.2
Apparent t1/2 (hr)	5.3 (1.6)	4.6	3.8 (0.3)	5.04
CL/wt (ml/hr/kg)	13.3 (2.9)	16.0	21.4 (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 summarised 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 6 mg/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 Range	12-17 years (N=13)	7-11 years (N=19)	1 to 6 years (N=19)*
Dose Infusion Time	7 mg/kg 30 minutes	9 mg/kg 30 minutes	12 mg/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 12 mg/kg once daily would be comparable to that in adult patients receiving 6 mg/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 4 mg/kg or 6 mg/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 6 mg/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 6 mg/kg dose to HD and CAPD adult patients the daptomycin AUC was approximately 1.3-fold higher than that observed after a second 6 mg/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 Amarox 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 4 mg/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.

Daptomycin administration was associated with minimal to  mild  degenerative/regenerative changes in skeletal musclein 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  6  mg/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 6 mg/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 associatedwith skeletal muscle toxicity.

In neonatal dogs, daptomycin caused marked clinical signs of twitching, muscle rigidity in the limbs, and impaired useof limbs, which resulted in decreases in body weight and overall body condition at doses ≥ 50 mg/kg/day and necessitated early discontinuation of treatment in these dose groups. At lower dose levels (25 mg/kg/day), mild andreversible clinical signs of twitching and one incidence of muscle rigidity were observed without any effects on bodyweight. 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 oflactating animals has not been studied.

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

Sodium Hydroxide and water for injection

Daptomycin for injection is not physically or chemically compatible with glucose-containing solutions. This medicinal product must notbe mixed with other medicinal products except those mentioned in section 6.6.

24 Months In-Use Storage Conditions for Daptomycin for Injection Once Reconstituted in Acceptable Intravenous Diluents Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration between 2° and 8°C (36° and 46°F). The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours if stored under refrigeration. The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration. Compatible Intravenous Solutions Daptomycin for injection is compatible with 0.9% sodium chloride injection and lactated Ringer’s injection.

Store in a refrigerator between 2°C and 8°C.

Reconstitution data

Daptomycin for Injection is compatible with 0.9% sodium chloride injection and lactated Ringer's injection.

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

Vial pack

Preparation and Administration of Daptomycin for Injection 350mg/vial

There are different formulations of daptomycin that have differences concerning storage and

 

reconstitution. Carefully follow the reconstitution and storage procedures in labeling.

 

 

Reconstitution of Daptomycin for Injection Vial

Daptomycin for injection is supplied in single-dose vials, each containing 350 mg daptomycin as a sterile, lyophilized powder. The contents of a daptomycin for injection vial should be reconstituted, using aseptic technique, to 50 mg per mL as follows:

1.    To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.

2.  Remove the polypropylene flip-off cap from the daptomycin for injection vial to expose the central portion of the rubber stopper.

3.  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.

4.   Slowly transfer 7 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the daptomycin for injection vial, pointing the transfer needle toward the wall of the vial. It is recommended that a beveled sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device is used, pointing the transfer needle toward the wall of the vial.

5.  Ensure that all of the daptomycin for injection powder is wetted by gently rotating the vial.

i.  Allow the wetted product to stand undisturbed for 10 minutes.

ii..Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.

Preparation and Administration of Daptomycin for Injection 500mg/vial

There are different formulations of daptomycin that have differences concerning storage and reconstitution. Carefully follow the reconstitution and storage procedures in labeling.

Reconstitution of Daptomycin for Injection Vial

Daptomycin for injection is supplied in single-dose vials, each containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a daptomycin for injection vial should be reconstituted, using aseptic technique, to 50 mg per mL as follows:

1.    To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.

 

2.  Remove the polypropylene flip-off cap from the daptomycin for injection vial to expose the central portion of the rubber stopper.

3.  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.

4.  Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the daptomycin for injection vial, pointing the transfer needle toward the wall of the vial. It is recommended that a beveled sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device is used, pointing the transfer needle toward the wall of the vial.

5.  Ensure that all of the daptomycin for injection powder is wetted by gently rotating the vial.

i.  Allow the wetted product to stand undisturbed for 10 minutes.

ii..Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.

Administration Instructions

Parenteral drug products should be inspected visually for particulate matter prior to administration. Slowly remove reconstituted liquid (50 mg daptomycin per mL) from the vial using a beveled sterile needle that is 21 gauge or smaller in diameter. Administer as an intravenous injection or infusion as described below:

Adults

Intravenous Injection over a period of 2 minutes

•  For intravenous (IV) injection over a period of 2 minutes in adult patients only: Administer the appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg per mL). Intravenous Infusion over a period of 30 minutes

•  For intravenous (IV) infusion over a period of 30 minutes in adult patients: The appropriate volume of the reconstituted daptomycin for injection (concentration of 50 mg per mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection.

No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution. Do not exceed the In-Use storage conditions of the reconstituted and diluted solutions of daptomycin for injection described below. Discard unused portions of

 

daptomycin for injection.