- Approval Id
- f05d52a78fb4d8e4
- Drug Approval Emc Name
- Dalbavancin 500 mg powder for concentrate for solution for infusion
- Drug Name
- Dalbavancin 500 mg powder for concentrate for solution for infusion
- Company Address
- First Floor, Andrews House, College Road, Guildford, Surrey, GU1 4QB, UK
- Company Website
- https://www.zentiva.co.uk/contact/mi-form
- Company Medical Info Direct Line
- +44 (0)800 090 2408
- Company Medical Info Email
- [email protected]
- Company Customer Care Direct Line
- +44 (0)844 8793 188
- Atc Code
- J01XA04
- Legal Category
- Prescription only medicine
- Authorisation Holder
- 7. Marketing authorisation holder Zentiva Pharma UK Limited, 12 New Fetter Lane, London, EC4A 1JP, United Kingdom
- Authorisation Number
- 8. Marketing authorisation number(s) PL 17780/1349
- Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 10/10/2025
- Instruction Authorisation Holder
- 7. Marketing authorisation holder Zentiva Pharma UK Limited, 12 New Fetter Lane, London, EC4A 1JP, United Kingdom
- Instruction Authorisation Number
- 8. Marketing authorisation number(s) PL 17780/1349
- Instruction Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 10/10/2025
- Instruction Composition
- 2. Qualitative and quantitative composition Each vial contains dalbavancin hydrochloride equivalent to 500 mg dalbavancin. After reconstitution each ml contains 20 mg dalbavancin. The diluted solution for infusion must have a final concentration of 1 to 5 mg/ml dalbavancin (see section 6.6). For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- 3. Pharmaceutical form Powder for concentrate for solution for infusion. White to off-white to pale yellow powder or cake.
- Instruction Clinical Particulars
- 4. Clinical particulars 4.1 Therapeutic indications Dalbavancin is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults and paediatric patients aged 3 months and older (see sections 4.4 and
- Instruction Pharmacology
- 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antibacterials for systemic use, glycopeptide antibacterials, ATC code: J01XA04. Mechanism of action Dalbavancin is a bactericidal lipoglycopeptide. Its mechanism of action in susceptible Gram-positive bacteria involves interruption of cell wall synthesis by binding to the terminal D-alanyl-D-alanine of the stem peptide in nascent cell wall peptidoglycan, preventing cross-linking (transpeptidation and transglycosylation) of disaccharide subunits resulting in bacterial cell death. Mechanism of resistance All Gram-negative bacteria are inherently resistant to dalbavancin. Resistance to dalbavancin in Staphylococcus spp. and Enterococcus spp. is mediated by VanA, a genotype that results in modification of the target peptide in nascent cell wall. Based on in vitro studies the activity of dalbavancin is not affected by other classes of vancomycin resistance genes. Dalbavancin MICs are higher for vancomycin-intermediate staphylococci (VISA) than for fully vancomycin susceptible strains. If the isolates with higher dalbavancin MICs represent stable phenotypes and are correlated with resistance to the other glycopeptides, then the likely mechanism would be an increase in the number of glycopeptide targets in nascent peptidoglycan. Cross-resistance between dalbavancin and other classes of antibiotics was not seen in in vitro studies. Methicillin resistance has no impact on dalbavancin activity. Interactions with other antibacterial agents In in vitro studies, no antagonism has been observed between dalbavancin and other commonly used antibiotics (i.e. cefepime, ceftazidime, ceftriaxone, imipenem, meropenem, amikacin, aztreonam, ciprofloxacin, piperacillin/tazobactam and trimethoprim/sulfamethoxazole), when tested against 12 species of Gram-negative pathogens (see section 4.5). Susceptibility testing breakpoints Minimum inhibitory concentration (MIC) breakpoints determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are listed here: • Staphylococcus spp.: Susceptible ≤ 0.125 mg/l; Resistant > 0.125 mg/l, • Beta-haemolytic streptococci of Groups A, B, C, G: Susceptible ≤ 0.125 mg/l; Resistant > 0.125 mg/l, • Viridans group streptococci (Streptococcus anginosus group only): Susceptible ≤ 0.125 mg/l; Resistant > 0.125 mg/l PK/PD relationship Bactericidal activity against staphylococci in vitro is time-dependent at serum concentrations of dalbavancin similar to those obtained at the recommended dose in humans. In vivo PK/PD relationship of dalbavancin for S. aureus was investigated using a neutropenic model of animal infection. This showed that the antibacterial activity of dalbavancin appears to best correlate with the ratio of area under the unbound plasma concentration-time curve to minimal inhibitory concentration (fAUC/MIC). Clinical efficacy against specific pathogens Efficacy has been demonstrated in clinical studies against the pathogens listed for ABSSSI that were susceptible to dalbavancin in vitro: • Staphylococcus aureus, • Streptococcus pyogenes, • Streptococcus agalactiae, • Streptococcus dysgalactiae, • Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus). Antibacterial activity against other relevant pathogens Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to dalbavancin in the absence of acquired mechanisms of resistance: • Group G streptococci • Clostridium perfringens • Peptostreptococcus spp. Paediatric population Dalbavancin has been evaluated in paediatric patients aged from birth to < 18 years with ABSSSI in one Phase 3 open-label, randomised, comparator controlled clinical trial. The study included 168 patients treated with dalbavancin (90 patients treated with a single dose of dalbavancin and 78 patients, all of them aged 3 months and older, treated with a two-dose regimen of dalbavancin) and 30 patients treated with comparator. The primary objective was to assess the safety and tolerability of Dalbavancin and secondary objectives included assessment of efficacy and pharmacokinetics. Efficacy was a descriptive endpoint. Clinical cure rate at TOC (mITT) was 95.1 % (78/82) in the Dalbavancin single-dose arm, 97.3 % (72/74) in the Dalbavancin two-dose arm and 100 % (30/30) in the comparator arm. The Licensing Authority has deferred the obligation to submit the results of studies with Dalbavancin in one or more subsets of the paediatric population in ABSSSI (see sections 4.2 and 5.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetics of dalbavancin have been characterised in healthy subjects, patients, and special populations. Systemic exposures to dalbavancin are dose proportional following single doses over a range of 140 to 1120 mg, indicating linear pharmacokinetics of dalbavancin. No accumulation of dalbavancin was observed following multiple intravenous infusions administered once-weekly for up to 8 weeks (1,000 mg on Day 1, followed by up to 7 weekly 500 mg doses) in healthy adults. The mean terminal elimination half-life (t1/2) was 372 (range 333 to 405) hours. The pharmacokinetics of dalbavancin are best described using a three-compartment model (α and β distributional phases followed by a terminal elimination phase). Thus, the distributional half-life (t1/2β), which constitutes most of the clinically-relevant concentration-time profile, ranged from 5 to 7 days and is consistent with once-weekly dosing. Estimated pharmacokinetic parameters of dalbavancin following the two-dose regimen and the single-dose regimen, respectively, are shown in Table 2 below. Table 2. Mean (SD) dalbavancin pharmacokinetic parameters for adults using population PK analysis1 Parameter Two-dose regimen2 Single-dose regimen3 Cmax (mg/L) Day 1: 281 (52) Day 8: 141 (26) Day 1: 411 (86) AUC0-Day14 (mg•h/L) 18100 (4600) 20300 (5300) CL (L/h) 0.048 (0.0086) 0.049 (0.0096) 1 Source: DAL-MS-01. 2 1,000 mg on Day 1 + 500 mg on Day 8; Study DUR001-303 subjects with evaluable PK sample. 3 1,500 mg; Study DUR001-303 subjects with evaluable PK sample. The dalbavancin plasma concentration-time following the two-dose and the single-dose regimens, respectively, are shown in Figure 1. Figure 1. Dalbavancin Plasma Concentrations versus time in a typical adult ABSSSI patient (simulation using population pharmacokinetic model) for both the single and the two-dose regimens. Distribution Clearance and volume of distribution at steady state are comparable between healthy subjects and patients with infections. The volume of distribution at steady state was similar to the volume of extracellular fluid. Dalbavancin is reversibly bound to human plasma proteins, primarily to albumin. The plasma protein binding of dalbavancin is 93 % and is not altered as a function of drug concentration, renal insufficiency, or hepatic insufficiency. Following a single intravenous dose of 1,000 mg in healthy volunteers AUC in skin blister fluid amounted (bound and unbound dalbavancin) to approximately 60 % of the plasma AUC at day 7 post-dose. Biotransformation Metabolites have not been observed in significant amounts in human plasma. The metabolites hydroxy-dalbavancin and mannosyl aglycone have been detected in urine (< 25 % of administered dose). The metabolic pathways responsible for producing these metabolites have not been identified; however, due to the relatively minor contribution of metabolism to the overall elimination of dalbavancin, drug-drug interactions via inhibition or induction of metabolism of dalbavancin are not anticipated. Hydroxy-dalbavancin and mannosyl aglycone show significantly less antibacterial activity compared to dalbavancin. Elimination Following administration of a single 1,000 mg dose in healthy subjects, an average of 19 % to 33 % of the administered dalbavancin dose was excreted in urine as dalbavancin and 8 % to 12 % as the metabolite hydroxy-dalbavancin. Approximately 20 % of the administered dose was excreted in faeces. Special populations Renal impairment The pharmacokinetics of dalbavancin were evaluated in 28 adult subjects with varying degrees of renal impairment and in 15 matched control subjects with normal renal function. Following a single dose of 500 mg or 1,000 mg dalbavancin, the mean plasma clearance (CLT) was reduced 11 %, 35 %, and 47 % in subjects with mild (CLCR 50 - 79 ml/min), moderate (CLCR 30 – 49 ml/min), and severe (CLCR < 30 ml/min) renal impairment, respectively, compared to subjects with normal renal function. The mean AUC for subjects with creatinine clearance < 30 ml/min was approximately 2 - fold higher. The clinical significance of the decrease in mean plasma CLT, and the associated increase in AUC0-∞ noted in these pharmacokinetic studies of dalbavancin in subjects with severe renal impairment has not been established. Dalbavancin pharmacokinetics in subjects with end-stage renal disease receiving regularly scheduled renal dialysis (3 times/week) were similar to those observed in subjects with mild to moderate renal impairment, and less than 6 % of an administered dose is removed after 3 hours of haemodialysis. For dosing instructions in adult subjects with renal impairment refer to section 4.2. No observed PK data are available in paediatric patients with severe renal impairment. The predicted dalbavancin mean AUC for paediatric subjects with severe renal impairment (CLCR ≤ 30 ml/min/1.73 m2) was approximately 13-30 % higher compared to paediatric patients with normal renal function treated with the same dose, based on population pharmacokinetic modelling. Hepatic impairment The pharmacokinetics of dalbavancin were evaluated in 17 subjects with mild, moderate, or severe hepatic impairment and compared to 9 matched healthy subjects with normal hepatic function. The mean AUC was unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function; however, the mean AUC decreased by 28 % and 31 %, respectively, in subjects with moderate and severe hepatic impairment. The cause and the clinical significance of the decreased exposure in subjects with moderate and severe hepatic function are unknown. For dosing instructions in subjects with hepatic impairment refer to section 4.2. Gender Clinically significant gender-related differences in dalbavancin pharmacokinetics have not been observed in healthy subjects or in patients with infections. No dose adjustment is recommended based on gender. Elderly The pharmacokinetics of dalbavancin were not significantly altered with age; therefore, dose adjustment is not necessary based on age (see section 4.2). The experience with dalbavancin in elderly is limited: 276 patients ≥ 75 years of age were included in the Phase 2/3 clinical studies, of which 173 received dalbavancin. Patients up to 93 years of age have been included in clinical studies. Paediatric population The pharmacokinetics of dalbavancin has been evaluated in 218 individual paediatric patients [4 days to 17 years of age, including a preterm neonate (gestational age 36 weeks; n=1) and term neonates (gestational age 37 to 40 weeks; n=6)] with creatinine clearance 30 ml/min/1.73 m2 and above. There is insufficient information to assess the exposure of dalbavancin in the paediatric patients with creatinine clearance less than 30 ml/min/1.73 m2. The model predicted plasma AUC0-120h of dalbavancin in preterm neonates at birth (gestational age 26 weeks to <37 weeks) was approximately 60 % of that in adult patients. Table 3. Simulated Mean (SD) dalbavancin pharmacokinetic parameters for paediatrics and adults using population PK analysis1 Parameter Preterm Neonate Term Neonate Young Infant Infant Toddler Child Adolescent Adult Age range GA 26-- <37 weeks Birth -1 month 1 month - < 3 month 3 months - <2 years 2 years - < 6 years 6 years - < 12 years 12 years - < 18 years > = 18 years Dose 22.5 mg/kg 22.5 mg/kg 22.5 mg/kg 22.5 mg/kg 22.5 mg/kg 18 mg/kg 18 mg/kg 1500 mg Cmax (mg/L) 231 (89) 306 (130) 306 (130) 307 (130) 304 (130) 259 (130) 251 (130) 425 (130) AUC0-Day120 (mg•h/L) 6620 (2000) 9000 (2900) 9080 (3000) 9490 (3100) 10200 (3200) 8870 (2900) 9060 (3100) 10800 (3200) 1 Source: DAL-MS-02 In all paediatric age groups, the percentage of patients attaining PK/PD targets related to in vivo drug activity were 90 % or higher for MICs up to 0.125 mg/l. 5.3 Preclinical safety data Dalbavancin toxicity has been evaluated after daily intravenous administration for durations of up to 3 months in rats and dogs. Dose-dependent toxicity included serum chemistry and histological evidence of renal and hepatic injury, reduced red blood cell parameters and injection site irritation. In dogs only, infusion reactions characterised by skin swelling and/or redness (not associated with the injection site), mucosal pallor, salivation, vomiting, sedation, and modest declines in blood pressure and increases in heart rate were observed in a dose-dependent manner. These infusion reactions were transient (resolved within 1 hour post-dosing) and were attributed to histamine release. Dalbavancin toxicity profile in juvenile rats was consistent with that previously observed in adult rats at the same dose (mg/kg /day) levels. Reproductive toxicity studies in rats and rabbits showed no evidence of a teratogenic effect. In rats, at exposures approximately 3 times above clinical exposure, there was reduced fertility and an increased incidence of embryo-lethality, reductions in foetal weight and skeletal ossification and increased neonatal mortality. In rabbits, abortion occurred in conjunction with maternal toxicity at exposures below the human therapeutic range. Long-term carcinogenicity studies have not been conducted. Dalbavancin was not mutagenic or clastogenic in a battery of in vitro and in vivo genotoxicity tests.
- Instruction Pharmaceutical Particulars
- 6. Pharmaceutical particulars 6.1 List of excipients Mannitol (E421) Lactose monohydrate Hydrochloric acid 0.1M (for pH-adjustment) Sodium hydroxide 0.1M (for pH-adjustment) 6.2 Incompatibilities Sodium chloride solutions may cause precipitation and must not be used for reconstitution or dilution (see section 6.6). This medicinal product must not be mixed with other medicinal products or intravenous solutions other than those mentioned in section 6.6. 6.3 Shelf life Dry powder: 2 years Chemical and physical in-use stability of Dalbavancin has been demonstrated for both the reconstituted concentrate and for the diluted solution for 48 hours at or below 25 °C. The total in-use stability from reconstitution to administration should not exceed 48 hours. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. Do not freeze. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 50 ml type I clear glass vials for pharmaceutical use, closed with a bromobutyl stopper and sealed with a green flip-off cap. Each pack contains 1 vial. 6.6 Special precautions for disposal and other handling Dalbavancin must be reconstituted with sterile water for injections and subsequently diluted with 50 mg/ml (5 %) glucose solution for infusion. Dalbavancin vials are for single-use only. Instructions for reconstitution and dilution Aseptic technique must be used for reconstitution and dilution of Dalbavancin. 1. The content of each vial must be reconstituted by slowly adding 25 ml of water for injections. 2. Do not shake. To avoid foaming, alternate between gentle swirling and inversion of the vial, until its contents are completely dissolved. The reconstitution time may be up to 5 minutes. 3. The reconstituted concentrate in the vial contains 20 mg/ml dalbavancin. 4. The reconstituted concentrate must be a clear, colourless to yellow solution with no visible particles. 5. The reconstituted concentrate must be further diluted with 50 mg/ml (5 %) glucose solution for infusion. 6. To dilute the reconstituted concentrate, the appropriate volume of the 20 mg / ml concentrate must be transferred from the vial to an intravenous bag or bottle containing 50 mg/ml (5 %) glucose solution for infusion. For example: 25 ml of the concentrate contains 500 mg dalbavancin.
- Instruction Content
- ## Composition
2. Qualitative and quantitative composition Each vial contains dalbavancin hydrochloride equivalent to 500 mg dalbavancin. After reconstitution each ml contains 20 mg dalbavancin. The diluted solution for infusion must have a final concentration of 1 to 5 mg/ml dalbavancin (see section 6.6). For the full list of excipients, see section 6.1.
## Pharmaceutical Form
3. Pharmaceutical form Powder for concentrate for solution for infusion. White to off-white to pale yellow powder or cake.
## Clinical Particulars
4. Clinical particulars 4.1 Therapeutic indications Dalbavancin is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults and paediatric patients aged 3 months and older (see sections 4.4 and
## Pharmacological Properties
5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antibacterials for systemic use, glycopeptide antibacterials, ATC code: J01XA04. Mechanism of action Dalbavancin is a bactericidal lipoglycopeptide. Its mechanism of action in susceptible Gram-positive bacteria involves interruption of cell wall synthesis by binding to the terminal D-alanyl-D-alanine of the stem peptide in nascent cell wall peptidoglycan, preventing cross-linking (transpeptidation and transglycosylation) of disaccharide subunits resulting in bacterial cell death. Mechanism of resistance All Gram-negative bacteria are inherently resistant to dalbavancin. Resistance to dalbavancin in Staphylococcus spp. and Enterococcus spp. is mediated by VanA, a genotype that results in modification of the target peptide in nascent cell wall. Based on in vitro studies the activity of dalbavancin is not affected by other classes of vancomycin resistance genes. Dalbavancin MICs are higher for vancomycin-intermediate staphylococci (VISA) than for fully vancomycin susceptible strains. If the isolates with higher dalbavancin MICs represent stable phenotypes and are correlated with resistance to the other glycopeptides, then the likely mechanism would be an increase in the number of glycopeptide targets in nascent peptidoglycan. Cross-resistance between dalbavancin and other classes of antibiotics was not seen in in vitro studies. Methicillin resistance has no impact on dalbavancin activity. Interactions with other antibacterial agents In in vitro studies, no antagonism has been observed between dalbavancin and other commonly used antibiotics (i.e. cefepime, ceftazidime, ceftriaxone, imipenem, meropenem, amikacin, aztreonam, ciprofloxacin, piperacillin/tazobactam and trimethoprim/sulfamethoxazole), when tested against 12 species of Gram-negative pathogens (see section 4.5). Susceptibility testing breakpoints Minimum inhibitory concentration (MIC) breakpoints determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are listed here: • Staphylococcus spp.: Susceptible ≤ 0.125 mg/l; Resistant > 0.125 mg/l, • Beta-haemolytic streptococci of Groups A, B, C, G: Susceptible ≤ 0.125 mg/l; Resistant > 0.125 mg/l, • Viridans group streptococci (Streptococcus anginosus group only): Susceptible ≤ 0.125 mg/l; Resistant > 0.125 mg/l PK/PD relationship Bactericidal activity against staphylococci in vitro is time-dependent at serum concentrations of dalbavancin similar to those obtained at the recommended dose in humans. In vivo PK/PD relationship of dalbavancin for S. aureus was investigated using a neutropenic model of animal infection. This showed that the antibacterial activity of dalbavancin appears to best correlate with the ratio of area under the unbound plasma concentration-time curve to minimal inhibitory concentration (fAUC/MIC). Clinical efficacy against specific pathogens Efficacy has been demonstrated in clinical studies against the pathogens listed for ABSSSI that were susceptible to dalbavancin in vitro: • Staphylococcus aureus, • Streptococcus pyogenes, • Streptococcus agalactiae, • Streptococcus dysgalactiae, • Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus). Antibacterial activity against other relevant pathogens Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to dalbavancin in the absence of acquired mechanisms of resistance: • Group G streptococci • Clostridium perfringens • Peptostreptococcus spp. Paediatric population Dalbavancin has been evaluated in paediatric patients aged from birth to < 18 years with ABSSSI in one Phase 3 open-label, randomised, comparator controlled clinical trial. The study included 168 patients treated with dalbavancin (90 patients treated with a single dose of dalbavancin and 78 patients, all of them aged 3 months and older, treated with a two-dose regimen of dalbavancin) and 30 patients treated with comparator. The primary objective was to assess the safety and tolerability of Dalbavancin and secondary objectives included assessment of efficacy and pharmacokinetics. Efficacy was a descriptive endpoint. Clinical cure rate at TOC (mITT) was 95.1 % (78/82) in the Dalbavancin single-dose arm, 97.3 % (72/74) in the Dalbavancin two-dose arm and 100 % (30/30) in the comparator arm. The Licensing Authority has deferred the obligation to submit the results of studies with Dalbavancin in one or more subsets of the paediatric population in ABSSSI (see sections 4.2 and 5.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetics of dalbavancin have been characterised in healthy subjects, patients, and special populations. Systemic exposures to dalbavancin are dose proportional following single doses over a range of 140 to 1120 mg, indicating linear pharmacokinetics of dalbavancin. No accumulation of dalbavancin was observed following multiple intravenous infusions administered once-weekly for up to 8 weeks (1,000 mg on Day 1, followed by up to 7 weekly 500 mg doses) in healthy adults. The mean terminal elimination half-life (t1/2) was 372 (range 333 to 405) hours. The pharmacokinetics of dalbavancin are best described using a three-compartment model (α and β distributional phases followed by a terminal elimination phase). Thus, the distributional half-life (t1/2β), which constitutes most of the clinically-relevant concentration-time profile, ranged from 5 to 7 days and is consistent with once-weekly dosing. Estimated pharmacokinetic parameters of dalbavancin following the two-dose regimen and the single-dose regimen, respectively, are shown in Table 2 below. Table 2. Mean (SD) dalbavancin pharmacokinetic parameters for adults using population PK analysis1 Parameter Two-dose regimen2 Single-dose regimen3 Cmax (mg/L) Day 1: 281 (52) Day 8: 141 (26) Day 1: 411 (86) AUC0-Day14 (mg•h/L) 18100 (4600) 20300 (5300) CL (L/h) 0.048 (0.0086) 0.049 (0.0096) 1 Source: DAL-MS-01. 2 1,000 mg on Day 1 + 500 mg on Day 8; Study DUR001-303 subjects with evaluable PK sample. 3 1,500 mg; Study DUR001-303 subjects with evaluable PK sample. The dalbavancin plasma concentration-time following the two-dose and the single-dose regimens, respectively, are shown in Figure 1. Figure 1. Dalbavancin Plasma Concentrations versus time in a typical adult ABSSSI patient (simulation using population pharmacokinetic model) for both the single and the two-dose regimens. Distribution Clearance and volume of distribution at steady state are comparable between healthy subjects and patients with infections. The volume of distribution at steady state was similar to the volume of extracellular fluid. Dalbavancin is reversibly bound to human plasma proteins, primarily to albumin. The plasma protein binding of dalbavancin is 93 % and is not altered as a function of drug concentration, renal insufficiency, or hepatic insufficiency. Following a single intravenous dose of 1,000 mg in healthy volunteers AUC in skin blister fluid amounted (bound and unbound dalbavancin) to approximately 60 % of the plasma AUC at day 7 post-dose. Biotransformation Metabolites have not been observed in significant amounts in human plasma. The metabolites hydroxy-dalbavancin and mannosyl aglycone have been detected in urine (< 25 % of administered dose). The metabolic pathways responsible for producing these metabolites have not been identified; however, due to the relatively minor contribution of metabolism to the overall elimination of dalbavancin, drug-drug interactions via inhibition or induction of metabolism of dalbavancin are not anticipated. Hydroxy-dalbavancin and mannosyl aglycone show significantly less antibacterial activity compared to dalbavancin. Elimination Following administration of a single 1,000 mg dose in healthy subjects, an average of 19 % to 33 % of the administered dalbavancin dose was excreted in urine as dalbavancin and 8 % to 12 % as the metabolite hydroxy-dalbavancin. Approximately 20 % of the administered dose was excreted in faeces. Special populations Renal impairment The pharmacokinetics of dalbavancin were evaluated in 28 adult subjects with varying degrees of renal impairment and in 15 matched control subjects with normal renal function. Following a single dose of 500 mg or 1,000 mg dalbavancin, the mean plasma clearance (CLT) was reduced 11 %, 35 %, and 47 % in subjects with mild (CLCR 50 - 79 ml/min), moderate (CLCR 30 – 49 ml/min), and severe (CLCR < 30 ml/min) renal impairment, respectively, compared to subjects with normal renal function. The mean AUC for subjects with creatinine clearance < 30 ml/min was approximately 2 - fold higher. The clinical significance of the decrease in mean plasma CLT, and the associated increase in AUC0-∞ noted in these pharmacokinetic studies of dalbavancin in subjects with severe renal impairment has not been established. Dalbavancin pharmacokinetics in subjects with end-stage renal disease receiving regularly scheduled renal dialysis (3 times/week) were similar to those observed in subjects with mild to moderate renal impairment, and less than 6 % of an administered dose is removed after 3 hours of haemodialysis. For dosing instructions in adult subjects with renal impairment refer to section 4.2. No observed PK data are available in paediatric patients with severe renal impairment. The predicted dalbavancin mean AUC for paediatric subjects with severe renal impairment (CLCR ≤ 30 ml/min/1.73 m2) was approximately 13-30 % higher compared to paediatric patients with normal renal function treated with the same dose, based on population pharmacokinetic modelling. Hepatic impairment The pharmacokinetics of dalbavancin were evaluated in 17 subjects with mild, moderate, or severe hepatic impairment and compared to 9 matched healthy subjects with normal hepatic function. The mean AUC was unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function; however, the mean AUC decreased by 28 % and 31 %, respectively, in subjects with moderate and severe hepatic impairment. The cause and the clinical significance of the decreased exposure in subjects with moderate and severe hepatic function are unknown. For dosing instructions in subjects with hepatic impairment refer to section 4.2. Gender Clinically significant gender-related differences in dalbavancin pharmacokinetics have not been observed in healthy subjects or in patients with infections. No dose adjustment is recommended based on gender. Elderly The pharmacokinetics of dalbavancin were not significantly altered with age; therefore, dose adjustment is not necessary based on age (see section 4.2). The experience with dalbavancin in elderly is limited: 276 patients ≥ 75 years of age were included in the Phase 2/3 clinical studies, of which 173 received dalbavancin. Patients up to 93 years of age have been included in clinical studies. Paediatric population The pharmacokinetics of dalbavancin has been evaluated in 218 individual paediatric patients [4 days to 17 years of age, including a preterm neonate (gestational age 36 weeks; n=1) and term neonates (gestational age 37 to 40 weeks; n=6)] with creatinine clearance 30 ml/min/1.73 m2 and above. There is insufficient information to assess the exposure of dalbavancin in the paediatric patients with creatinine clearance less than 30 ml/min/1.73 m2. The model predicted plasma AUC0-120h of dalbavancin in preterm neonates at birth (gestational age 26 weeks to <37 weeks) was approximately 60 % of that in adult patients. Table 3. Simulated Mean (SD) dalbavancin pharmacokinetic parameters for paediatrics and adults using population PK analysis1 Parameter Preterm Neonate Term Neonate Young Infant Infant Toddler Child Adolescent Adult Age range GA 26-- <37 weeks Birth -1 month 1 month - < 3 month 3 months - <2 years 2 years - < 6 years 6 years - < 12 years 12 years - < 18 years > = 18 years Dose 22.5 mg/kg 22.5 mg/kg 22.5 mg/kg 22.5 mg/kg 22.5 mg/kg 18 mg/kg 18 mg/kg 1500 mg Cmax (mg/L) 231 (89) 306 (130) 306 (130) 307 (130) 304 (130) 259 (130) 251 (130) 425 (130) AUC0-Day120 (mg•h/L) 6620 (2000) 9000 (2900) 9080 (3000) 9490 (3100) 10200 (3200) 8870 (2900) 9060 (3100) 10800 (3200) 1 Source: DAL-MS-02 In all paediatric age groups, the percentage of patients attaining PK/PD targets related to in vivo drug activity were 90 % or higher for MICs up to 0.125 mg/l. 5.3 Preclinical safety data Dalbavancin toxicity has been evaluated after daily intravenous administration for durations of up to 3 months in rats and dogs. Dose-dependent toxicity included serum chemistry and histological evidence of renal and hepatic injury, reduced red blood cell parameters and injection site irritation. In dogs only, infusion reactions characterised by skin swelling and/or redness (not associated with the injection site), mucosal pallor, salivation, vomiting, sedation, and modest declines in blood pressure and increases in heart rate were observed in a dose-dependent manner. These infusion reactions were transient (resolved within 1 hour post-dosing) and were attributed to histamine release. Dalbavancin toxicity profile in juvenile rats was consistent with that previously observed in adult rats at the same dose (mg/kg /day) levels. Reproductive toxicity studies in rats and rabbits showed no evidence of a teratogenic effect. In rats, at exposures approximately 3 times above clinical exposure, there was reduced fertility and an increased incidence of embryo-lethality, reductions in foetal weight and skeletal ossification and increased neonatal mortality. In rabbits, abortion occurred in conjunction with maternal toxicity at exposures below the human therapeutic range. Long-term carcinogenicity studies have not been conducted. Dalbavancin was not mutagenic or clastogenic in a battery of in vitro and in vivo genotoxicity tests.
## Pharmaceutical Particulars
6. Pharmaceutical particulars 6.1 List of excipients Mannitol (E421) Lactose monohydrate Hydrochloric acid 0.1M (for pH-adjustment) Sodium hydroxide 0.1M (for pH-adjustment) 6.2 Incompatibilities Sodium chloride solutions may cause precipitation and must not be used for reconstitution or dilution (see section 6.6). This medicinal product must not be mixed with other medicinal products or intravenous solutions other than those mentioned in section 6.6. 6.3 Shelf life Dry powder: 2 years Chemical and physical in-use stability of Dalbavancin has been demonstrated for both the reconstituted concentrate and for the diluted solution for 48 hours at or below 25 °C. The total in-use stability from reconstitution to administration should not exceed 48 hours. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. Do not freeze. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 50 ml type I clear glass vials for pharmaceutical use, closed with a bromobutyl stopper and sealed with a green flip-off cap. Each pack contains 1 vial. 6.6 Special precautions for disposal and other handling Dalbavancin must be reconstituted with sterile water for injections and subsequently diluted with 50 mg/ml (5 %) glucose solution for infusion. Dalbavancin vials are for single-use only. Instructions for reconstitution and dilution Aseptic technique must be used for reconstitution and dilution of Dalbavancin. 1. The content of each vial must be reconstituted by slowly adding 25 ml of water for injections. 2. Do not shake. To avoid foaming, alternate between gentle swirling and inversion of the vial, until its contents are completely dissolved. The reconstitution time may be up to 5 minutes. 3. The reconstituted concentrate in the vial contains 20 mg/ml dalbavancin. 4. The reconstituted concentrate must be a clear, colourless to yellow solution with no visible particles. 5. The reconstituted concentrate must be further diluted with 50 mg/ml (5 %) glucose solution for infusion. 6. To dilute the reconstituted concentrate, the appropriate volume of the 20 mg / ml concentrate must be transferred from the vial to an intravenous bag or bottle containing 50 mg/ml (5 %) glucose solution for infusion. For example: 25 ml of the concentrate contains 500 mg dalbavancin.
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