- Approval Id
- 0f5a8c2908dea778
- 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 Name
- Reig Jofre UK Ltd
- Company Address
- Follaton House, Plymouth Road, Totnes, Devon, TQ9 5NE, UK
- Company Website
- //www.reigjofre.com/en
- Company Telephone
- 01803 300401
- Company Medical Info Direct Line
- 0330 1359 434
- Company Medical Info Email
- MedInfoUK@reigjofre.com
- Company Customer Care Direct Line
- 01803 300401
- Atc Code
- J01XA04
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Reig Jofre UK Limited
Follaton House, Plymouth Road, Totnes,
Devon, TQ9 5NE, UK
- Authorisation Number
- PL 44095/0043
- Authorisation Date
- 12/09/2024
- Instruction Authorisation Holder
- Reig Jofre UK Limited
Follaton House, Plymouth Road, Totnes,
Devon, TQ9 5NE, UK
- Instruction Authorisation Number
- PL 44095/0043
- Instruction Authorisation Date
- 12/09/2024
- Instruction Composition
- Each vial contains dalbavancin hydrochloride equivalent to 500 mg dalbavancin.
After reconstitution each ml of the concentrate 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
- Powder for concentrate for solution for infusion (powder for concentrate).
White or off-white to light yellow powder.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Dalbavancin 500 mg powder for concentrate for solution for infusion 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 5.1).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.4.2 Posology and method of administration
\*\*Posology\*\*
\*Adults\*
The recommended dose of dalbavancin is 1,500 mg administered as either a single infusion of 1,500 mg or as 1,000 mg followed one week later by 500 mg (see sections 5.1 and 5.2).
\*Children and adolescents aged from 6 years to less than 18 years\*
The recommended dose of dalbavancin is a single dose of 18 mg/kg (maximum 1,500 mg).
\*Infants and children aged from 3 months to less than 6 years\*
The recommended dose of dalbavancin is a single dose of 22.5 mg/kg (maximum 1,500 mg).
\*\*\*Special populations\*\*\*
\*Elderly\*
No dose adjustment is necessary (see section 5.2).
\*Renal impairment\*
Dose adjustments are not required for adult and paediatric patients with mild or moderate renal impairment (creatinine clearance ≥ 30 to 79 ml/min). Dose adjustments are not required for adult patients receiving regularly scheduled haemodialysis (3 times/week), and dalbavancin may be administered without regard to the timing of haemodialysis.
In adult patients with chronic renal impairment whose creatinine clearance is < 30 ml/min and who are not receiving regularly scheduled haemodialysis, the recommended dose is reduced to either 1,000 mg administered as a single infusion or 750 mg followed one week later by 375 mg (see section 5.2).
There is insufficient information to recommend dosage adjustment for patients younger than 18 years with creatinine clearance less than 30 ml/min/1.73 m2. Currently available information is described in section 5.2, but no recommendation on a posology can be made.
\*Hepatic impairment\*
No dose adjustment of dalbavancin is recommended for patients with mild hepatic impairment (Child-Pugh A). Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment (Child-Pugh B & C) as no data are available to determine appropriate dosing (see sections 5.2).
\*Paediatric population\*
The safety and efficacy of dalbavancin in children aged < 3 months old has not yet been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.
\*\*Method of administration\*\*
Intravenous use.
Dalbavancin 500 mg powder for concentrate for solution for infusion must be reconstituted and then further diluted prior to administration by intravenous infusion over a 30-minute period. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.4.4 Special warnings and precautions for use
\*\*Hypersensitivity reactions\*\*
Dalbavancin should be administered with caution in patients known to be hypersensitive to other glycopeptides since cross-hypersensitivity may occur. If an allergic reaction to dalbavancin occurs, administration should be discontinued and appropriate therapy for the allergic reaction should be instituted.
\*\*\*Clostridioides (formerly Clostridium) difficile-associated diarrhoea\*\*\*
Antibacterial-associated colitis and pseudomembranous colitis have been reported with the use of nearly all antibiotics and may range in severity from mild to life- threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the treatment with dalbavancin (see section 4.8). In such circumstance, the discontinuation of dalbavancin and the use of supportive measures together with the administration of specific treatment for \*Clostridioides\* (formerly \*Clostridium\*) \*difficile\* should be considered. These patients must never be treated with medicinal products that suppress the peristalsis.
\*\*Infusion-related reactions\*\*
Dalbavancin 500 mg powder for concentrate for solution for infusion is to be administered via intravenous infusion, using a total infusion time of 30 minutes to minimise the risk of infusion-related reactions. Rapid intravenous infusions of glycopeptide antibacterial agents can cause reactions including flushing of the upper body, urticaria, pruritus, and/or rash. Stopping or slowing the infusion may result in cessation of these reactions.
\*\*Renal impairment\*\*
Information on the efficacy and safety of dalbavancin in patients with creatinine clearance < 30 ml/min is limited. Based on simulations, dose adjustment is needed for adult patients with chronic renal impairment whose creatinine clearance is < 30 ml/min and who are not receiving regular haemodialysis (see sections 4.2 and 5.2).
There is insufficient information to recommend dosage adjustment for patients younger than 18 years with creatinine clearance less than 30 ml/min/1.73 m2.
\*\*Mixed infections\*\*
In mixed infections in which Gram-negative bacteria are suspected patients should also be treated with an appropriate antibacterial agent(s) against Gram-negative bacteria (see section 5.1).
\*\*Non-susceptible organisms\*\*
The use of antibiotics may promote the overgrowth of non-susceptible micro- organisms. If superinfection occurs during therapy, appropriate measures should be taken.
\*\*Limitations of the clinical data\*\*
There is limited data on safety and efficacy of dalbavancin when administered for more than two doses (one week apart). In the major trials in ABSSSI the types of infections treated were confined to cellulitis/erysipelas, abscesses and wound infections only. There is no experience with dalbavancin in the treatment of severely immunocompromised patients.
\*\*Excipients\*\*
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.4.5 Interaction with other medicinal products and other forms of interaction
Results from an \*in vitro\* receptor screening study do not indicate a likely interaction with other therapeutic targets or a potential for clinically relevant pharmacodynamic interactions (see section 5.1).
Clinical drug-drug interaction studies with dalbavancin have not been conducted.
\*\*Potential for other medicinal products to affect the pharmacokinetics of dalbavancin.\*\*
Dalbavancin is not metabolised by CYP enzymes \*in vitro\*, therefore co-administered CYP inducers or inhibitors are unlikely to influence the pharmacokinetics of dalbavancin.
It is not known if dalbavancin is a substrate for hepatic uptake and efflux transporters.
Co-administration with inhibitors of these transporters may increase the exposure to dalbavancin.
Examples of such transporter inhibitors are boosted protease inhibitors, verapamil, quinidine, itraconazole, clarithromycin and cyclosporine.
\*\*Potential for dalbavancin to affect the pharmacokinetics of other medicinal products.\*\*
The interaction potential of dalbavancin on medicinal products metabolised by CYP enzymes is expected to be low since it is neither an inhibitor nor an inducer of CYP enzymes \*in vitro\*. There are no data on dalbavancin as an inhibitor of CYP2C8.
It is not known if dalbavancin is an inhibitor of transporters. Increased exposure to transporter substrates sensitive for inhibited transporter activity, such as statins and digoxin, cannot be excluded if combined with dalbavancin.4.6 Fertility, pregnancy and lactation
\*\*Pregnancy\*\*
There are no data from the use of dalbavancin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Dalbavancin 500 mg powder for concentrate for solution for infusion is not recommended during pregnancy, unless the potential expected benefit clearly justifies the potential risk to the foetus.
\*\*Breast-feeding\*\*
It is unknown whether dalbavancin is excreted in human milk. However, dalbavancin is excreted in the milk of lactating rats and may be excreted in human breast milk.
Dalbavancin is not well absorbed orally; however, an impact on the gastrointestinal flora or mouth flora of a breast-feeding infant cannot be excluded. A decision must be made whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Dalbavancin 500 mg powder for concentrate for solution for infusion taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
\*\*Fertility\*\*
Studies in animals have shown reduced fertility (see section 5.3). The potential risk for humans is unknown.4.7 Effects on ability to drive and use machines
Dalbavancin may have a minor influence on the ability to drive and use machines, as dizziness has been reported in a small number of patients (see section 4.8).4.8 Undesirable effects
\*\*Summary of the safety profile\*\*
In Phase 2 / 3 clinical studies, 2,473 adult patients received dalbavancin administered as either a single infusion of 1,500 mg or as 1,000 mg followed one week later by 500 mg. The most common adverse reactions occurring in ≥ 1 % of patients treated with dalbavancin were nausea (2.4 %), diarrhoea (1.9 %), and headache (1.3 %) and were generally of mild or moderate severity.
\*\*Tabulated list of adverse reactions (Table 1)\*\*
The following adverse reactions have been identified in Phase 2/3 clinical trials with dalbavancin.
Adverse reactions are classified according to System Organ Class and frequency. Frequency categories are derived according to the following conventions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000).
\*\*Table 1.\*\*
| | | | |
| --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Common\*\* | \*\*Uncommon\*\* | \*\*Rare\*\* |
| \*\*Infections and infestations\*\* | | vulvovaginal mycotic infection, urinary tract infection, fungal infection, \*Clostridioides\* (formerly \*Clostridium\*) \*difficile\* colitis, oral candidiasis | |
| \*\*Blood and lymphatic system disorders\*\* | | anaemia, thrombocytosis, eosinophilia, leucopenia, neutropenia | |
| \*\*Immune system disorders\*\* | | | Anaphylactoid reaction |
| \*\*Metabolism and nutrition disorders\*\* | | decreased appetite | |
| \*\*Psychiatric disorders\*\* | | insomnia | |
| \*\*Nervous system disorders\*\* | headache | dysgeusia, dizziness | |
| \*\*Vascular disorders\*\* | | flushing, phlebitis | |
| \*\*Respiratory, thoracic and mediastinal disorders\*\* | | cough | bronchospasm |
| \*\*Gastrointestinal disorders\*\* | nausea, diarrhoea | constipation, abdominal pain, dyspepsia, abdominal discomfort, vomiting | |
| \*\*Skin and subcutaneous tissue disorders\*\* | | pruritus, urticaria, rash | |
| \*\*Reproductive system and breast disorders\*\* | | vulvovaginal pruritus | |
| \*\*General disorders and administration site conditions\*\* | | infusion-related reactions | |
| \*\*Investigations\*\* | | blood lactate dehydrogenase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood uric acid increased, liver function test abnormal, transaminases increased, blood alkaline phosphatase increased, platelet count increased, body temperature increased, hepatic enzyme increased, gamma-glutamyl transferase increased | |
\*\*Description of selected adverse reactions\*\*
\*Class adverse reactions\*
Ototoxicity has been associated with glycopeptide use (vancomycin and teicoplanin); patients who are receiving concomitant therapy with an ototoxic medicinal product, such as an aminoglycoside, may be at increased risk.
\*Paediatric population\*
The safety of dalbavancin was evaluated in one Phase 3 clinical trial which included 168 paediatric patients from birth to less than 18 years of age with ABSSSI 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). Overall, the safety findings of dalbavancin in these paediatric patients were similar to those observed in adults.
\*\*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 via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
No specific information is available on the treatment of overdose with dalbavancin, as dose-limiting toxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers have been administered single doses of up to 1,500 mg, and cumulative doses up to 4,500 mg over a period of up to 8 weeks, with no signs of toxicity or laboratory results of clinical concern. In Phase 3 studies, patients have been administered single doses of up to 1,500 mg.
Treatment of overdose with dalbavancin should consist of observation and general supportive measures. Although no information is available specifically regarding the use of haemodialysis to treat overdose, it should be noted that in a Phase 1 study in patients with renal impairment, less than 6 % of the recommended dalbavancin dose was removed after 3 hours of haemodialysis.
- Instruction Pharmacology
- 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:
• \*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 (ƒAUC/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 European Medicines Agency 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 months | 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 (110) | 251 (110) | 425 (100) |
| AUC0-120h (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
- 6.1 List of excipients
Mannitol (E421)
Lactose monohydrate
Hydrochloric acid, concentrated (for pH-adjustment)
Sodium hydroxide (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: 30 months
Chemical and physical in-use stability of Dalbavancin 500 mg powder for concentrate for solution for infusion 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 glass vial with a chlorobutyl rubber stopper and aluminium seal with green polypropylene flip top.
Each pack contains 1 vial.6.6 Special precautions for disposal and other handling
Dalbavancin 500 mg powder for concentrate for solution for infusion must be reconstituted with sterile water for injections and subsequently diluted with 50 mg/ml (5 %) glucose solution for infusion.
Dalbavancin 500 mg powder for concentrate for solution for infusion vials are for single-use only.
\*\*Instructions for reconstitution and dilution\*\*
Aseptic technique must be used for reconstitution and dilution of Dalbavancin 500 mg powder for concentrate for solution for infusion.
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.
7. After dilution the solution for infusion must have a final concentration of 1 to 5 mg/ml dalbavancin
8. The solution for infusion must be clear, colourless to yellow solution with no visible particles.
9. If particulate matter or discoloration is identified, the solution must be discarded.
Dalbavancin 500 mg powder for concentrate for solution for infusion must not be mixed with other medicinal products or intravenous solutions. Sodium chloride containing solutions can cause precipitation and should NOT be used for reconstitution or dilution.
The compatibility of reconstituted Dalbavancin 500 mg powder for concentrate for solution for infusion concentrate has only been established with 50 mg/ml (5 %) glucose solution for infusion.
If a common intravenous line is being used to administer other medicinal products in addition to Dalbavancin 500 mg powder for concentrate for solution for infusion, the line should be flushed before and after each Dalbavancin 500 mg powder for concentrate for solution for infusion infusion with 5% glucose solution for infusion.
\*\*Use in the paediatric population\*\*
For paediatric patients, the dose of Dalbavancin 500 mg powder for concentrate for solution for infusion will vary according to the age and weight of the child up to a maximum of 1,500 mg. Transfer the required dose of reconstituted dalbavancin solution, according to the instructions above, based on the child's weight, from the vial to an intravenous bag or bottle containing 50 mg/ml (5 %) glucose solution for infusion. The diluted solution must have a final dalbavancin concentration of 1 to 5 mg/ml.
Table 4 below provides information to prepare an infusion solution with a final concentration of 2 mg/ml or 5 mg/ml (sufficient for most scenarios), to be administered by syringe pump, to achieve a dose of 22.5 mg/kg in paediatric patients from 3 to 12 months of age weighing from 3 to 12 kg.
Alternative concentrations may be prepared, but must have a final concentration range of 1 to 5 mg/ml of dalbavancin. Refer to Table 4 to confirm the calculations. Values shown are approximate. Note that the table is NOT inclusive of all possible calculated doses for every age group but may be utilised to estimate the approximate volume to verify the calculation.
\*\*Table 4\*\*
\*\*Preparation of Dalbavancin 500 mg powder for concentrate for solution for infusion (final infusion concentration 2 mg/ml or 5 mg/ml to be administered by syringe pump) in paediatric patients aged 3 to 12 months (22.5 mg/kg dose)\*\*
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| Patient Weight (kg) | Dose (mg) to achieve 22.5 mg/kg | Volume of reconstituted dalbavancin solution (20 mg/ml) to be withdrawn from vial (ml) | Volume of diluent 50 mg/ml (5 %) glucose solution to add for mixing (ml) | Final dalbavancin infusion solution concentration | Total Volume Dosed by syringe pump (ml) |
| 3 | 67.5 | 10 ml | 90 ml | 2 mg/ml | 33.8 |
| 4 | 90.0 | 45.0 |
| 5 | 112.5 | 56.3 |
| 6 | 135.0 | 67.5 |
| 7 | 157.5 | 78.8 |
| 8 | 180.0 | 90.0 |
| 9 | 202.5 | 20 ml | 60 ml | 5 mg/ml | 40.5 |
| 10 | 225.0 | 45.0 |
| 11 | 247.5 | 49.5 |
| 12 | 270.0 | 54.0 |
\*\*Disposal\*\*
Discard any portion of the reconstituted solution that remains unused.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
Each vial contains dalbavancin hydrochloride equivalent to 500 mg dalbavancin.
After reconstitution each ml of the concentrate 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
Powder for concentrate for solution for infusion (powder for concentrate).
White or off-white to light yellow powder.
## Clinical Particulars
4.1 Therapeutic indications
Dalbavancin 500 mg powder for concentrate for solution for infusion 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 5.1).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.4.2 Posology and method of administration
\*\*Posology\*\*
\*Adults\*
The recommended dose of dalbavancin is 1,500 mg administered as either a single infusion of 1,500 mg or as 1,000 mg followed one week later by 500 mg (see sections 5.1 and 5.2).
\*Children and adolescents aged from 6 years to less than 18 years\*
The recommended dose of dalbavancin is a single dose of 18 mg/kg (maximum 1,500 mg).
\*Infants and children aged from 3 months to less than 6 years\*
The recommended dose of dalbavancin is a single dose of 22.5 mg/kg (maximum 1,500 mg).
\*\*\*Special populations\*\*\*
\*Elderly\*
No dose adjustment is necessary (see section 5.2).
\*Renal impairment\*
Dose adjustments are not required for adult and paediatric patients with mild or moderate renal impairment (creatinine clearance ≥ 30 to 79 ml/min). Dose adjustments are not required for adult patients receiving regularly scheduled haemodialysis (3 times/week), and dalbavancin may be administered without regard to the timing of haemodialysis.
In adult patients with chronic renal impairment whose creatinine clearance is < 30 ml/min and who are not receiving regularly scheduled haemodialysis, the recommended dose is reduced to either 1,000 mg administered as a single infusion or 750 mg followed one week later by 375 mg (see section 5.2).
There is insufficient information to recommend dosage adjustment for patients younger than 18 years with creatinine clearance less than 30 ml/min/1.73 m2. Currently available information is described in section 5.2, but no recommendation on a posology can be made.
\*Hepatic impairment\*
No dose adjustment of dalbavancin is recommended for patients with mild hepatic impairment (Child-Pugh A). Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment (Child-Pugh B & C) as no data are available to determine appropriate dosing (see sections 5.2).
\*Paediatric population\*
The safety and efficacy of dalbavancin in children aged < 3 months old has not yet been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.
\*\*Method of administration\*\*
Intravenous use.
Dalbavancin 500 mg powder for concentrate for solution for infusion must be reconstituted and then further diluted prior to administration by intravenous infusion over a 30-minute period. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.4.4 Special warnings and precautions for use
\*\*Hypersensitivity reactions\*\*
Dalbavancin should be administered with caution in patients known to be hypersensitive to other glycopeptides since cross-hypersensitivity may occur. If an allergic reaction to dalbavancin occurs, administration should be discontinued and appropriate therapy for the allergic reaction should be instituted.
\*\*\*Clostridioides (formerly Clostridium) difficile-associated diarrhoea\*\*\*
Antibacterial-associated colitis and pseudomembranous colitis have been reported with the use of nearly all antibiotics and may range in severity from mild to life- threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the treatment with dalbavancin (see section 4.8). In such circumstance, the discontinuation of dalbavancin and the use of supportive measures together with the administration of specific treatment for \*Clostridioides\* (formerly \*Clostridium\*) \*difficile\* should be considered. These patients must never be treated with medicinal products that suppress the peristalsis.
\*\*Infusion-related reactions\*\*
Dalbavancin 500 mg powder for concentrate for solution for infusion is to be administered via intravenous infusion, using a total infusion time of 30 minutes to minimise the risk of infusion-related reactions. Rapid intravenous infusions of glycopeptide antibacterial agents can cause reactions including flushing of the upper body, urticaria, pruritus, and/or rash. Stopping or slowing the infusion may result in cessation of these reactions.
\*\*Renal impairment\*\*
Information on the efficacy and safety of dalbavancin in patients with creatinine clearance < 30 ml/min is limited. Based on simulations, dose adjustment is needed for adult patients with chronic renal impairment whose creatinine clearance is < 30 ml/min and who are not receiving regular haemodialysis (see sections 4.2 and 5.2).
There is insufficient information to recommend dosage adjustment for patients younger than 18 years with creatinine clearance less than 30 ml/min/1.73 m2.
\*\*Mixed infections\*\*
In mixed infections in which Gram-negative bacteria are suspected patients should also be treated with an appropriate antibacterial agent(s) against Gram-negative bacteria (see section 5.1).
\*\*Non-susceptible organisms\*\*
The use of antibiotics may promote the overgrowth of non-susceptible micro- organisms. If superinfection occurs during therapy, appropriate measures should be taken.
\*\*Limitations of the clinical data\*\*
There is limited data on safety and efficacy of dalbavancin when administered for more than two doses (one week apart). In the major trials in ABSSSI the types of infections treated were confined to cellulitis/erysipelas, abscesses and wound infections only. There is no experience with dalbavancin in the treatment of severely immunocompromised patients.
\*\*Excipients\*\*
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.4.5 Interaction with other medicinal products and other forms of interaction
Results from an \*in vitro\* receptor screening study do not indicate a likely interaction with other therapeutic targets or a potential for clinically relevant pharmacodynamic interactions (see section 5.1).
Clinical drug-drug interaction studies with dalbavancin have not been conducted.
\*\*Potential for other medicinal products to affect the pharmacokinetics of dalbavancin.\*\*
Dalbavancin is not metabolised by CYP enzymes \*in vitro\*, therefore co-administered CYP inducers or inhibitors are unlikely to influence the pharmacokinetics of dalbavancin.
It is not known if dalbavancin is a substrate for hepatic uptake and efflux transporters.
Co-administration with inhibitors of these transporters may increase the exposure to dalbavancin.
Examples of such transporter inhibitors are boosted protease inhibitors, verapamil, quinidine, itraconazole, clarithromycin and cyclosporine.
\*\*Potential for dalbavancin to affect the pharmacokinetics of other medicinal products.\*\*
The interaction potential of dalbavancin on medicinal products metabolised by CYP enzymes is expected to be low since it is neither an inhibitor nor an inducer of CYP enzymes \*in vitro\*. There are no data on dalbavancin as an inhibitor of CYP2C8.
It is not known if dalbavancin is an inhibitor of transporters. Increased exposure to transporter substrates sensitive for inhibited transporter activity, such as statins and digoxin, cannot be excluded if combined with dalbavancin.4.6 Fertility, pregnancy and lactation
\*\*Pregnancy\*\*
There are no data from the use of dalbavancin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Dalbavancin 500 mg powder for concentrate for solution for infusion is not recommended during pregnancy, unless the potential expected benefit clearly justifies the potential risk to the foetus.
\*\*Breast-feeding\*\*
It is unknown whether dalbavancin is excreted in human milk. However, dalbavancin is excreted in the milk of lactating rats and may be excreted in human breast milk.
Dalbavancin is not well absorbed orally; however, an impact on the gastrointestinal flora or mouth flora of a breast-feeding infant cannot be excluded. A decision must be made whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Dalbavancin 500 mg powder for concentrate for solution for infusion taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
\*\*Fertility\*\*
Studies in animals have shown reduced fertility (see section 5.3). The potential risk for humans is unknown.4.7 Effects on ability to drive and use machines
Dalbavancin may have a minor influence on the ability to drive and use machines, as dizziness has been reported in a small number of patients (see section 4.8).4.8 Undesirable effects
\*\*Summary of the safety profile\*\*
In Phase 2 / 3 clinical studies, 2,473 adult patients received dalbavancin administered as either a single infusion of 1,500 mg or as 1,000 mg followed one week later by 500 mg. The most common adverse reactions occurring in ≥ 1 % of patients treated with dalbavancin were nausea (2.4 %), diarrhoea (1.9 %), and headache (1.3 %) and were generally of mild or moderate severity.
\*\*Tabulated list of adverse reactions (Table 1)\*\*
The following adverse reactions have been identified in Phase 2/3 clinical trials with dalbavancin.
Adverse reactions are classified according to System Organ Class and frequency. Frequency categories are derived according to the following conventions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000).
\*\*Table 1.\*\*
| | | | |
| --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Common\*\* | \*\*Uncommon\*\* | \*\*Rare\*\* |
| \*\*Infections and infestations\*\* | | vulvovaginal mycotic infection, urinary tract infection, fungal infection, \*Clostridioides\* (formerly \*Clostridium\*) \*difficile\* colitis, oral candidiasis | |
| \*\*Blood and lymphatic system disorders\*\* | | anaemia, thrombocytosis, eosinophilia, leucopenia, neutropenia | |
| \*\*Immune system disorders\*\* | | | Anaphylactoid reaction |
| \*\*Metabolism and nutrition disorders\*\* | | decreased appetite | |
| \*\*Psychiatric disorders\*\* | | insomnia | |
| \*\*Nervous system disorders\*\* | headache | dysgeusia, dizziness | |
| \*\*Vascular disorders\*\* | | flushing, phlebitis | |
| \*\*Respiratory, thoracic and mediastinal disorders\*\* | | cough | bronchospasm |
| \*\*Gastrointestinal disorders\*\* | nausea, diarrhoea | constipation, abdominal pain, dyspepsia, abdominal discomfort, vomiting | |
| \*\*Skin and subcutaneous tissue disorders\*\* | | pruritus, urticaria, rash | |
| \*\*Reproductive system and breast disorders\*\* | | vulvovaginal pruritus | |
| \*\*General disorders and administration site conditions\*\* | | infusion-related reactions | |
| \*\*Investigations\*\* | | blood lactate dehydrogenase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood uric acid increased, liver function test abnormal, transaminases increased, blood alkaline phosphatase increased, platelet count increased, body temperature increased, hepatic enzyme increased, gamma-glutamyl transferase increased | |
\*\*Description of selected adverse reactions\*\*
\*Class adverse reactions\*
Ototoxicity has been associated with glycopeptide use (vancomycin and teicoplanin); patients who are receiving concomitant therapy with an ototoxic medicinal product, such as an aminoglycoside, may be at increased risk.
\*Paediatric population\*
The safety of dalbavancin was evaluated in one Phase 3 clinical trial which included 168 paediatric patients from birth to less than 18 years of age with ABSSSI 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). Overall, the safety findings of dalbavancin in these paediatric patients were similar to those observed in adults.
\*\*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 via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
No specific information is available on the treatment of overdose with dalbavancin, as dose-limiting toxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers have been administered single doses of up to 1,500 mg, and cumulative doses up to 4,500 mg over a period of up to 8 weeks, with no signs of toxicity or laboratory results of clinical concern. In Phase 3 studies, patients have been administered single doses of up to 1,500 mg.
Treatment of overdose with dalbavancin should consist of observation and general supportive measures. Although no information is available specifically regarding the use of haemodialysis to treat overdose, it should be noted that in a Phase 1 study in patients with renal impairment, less than 6 % of the recommended dalbavancin dose was removed after 3 hours of haemodialysis.
## 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:
• \*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 (ƒAUC/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 European Medicines Agency 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 months | 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 (110) | 251 (110) | 425 (100) |
| AUC0-120h (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
6.1 List of excipients
Mannitol (E421)
Lactose monohydrate
Hydrochloric acid, concentrated (for pH-adjustment)
Sodium hydroxide (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: 30 months
Chemical and physical in-use stability of Dalbavancin 500 mg powder for concentrate for solution for infusion 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 glass vial with a chlorobutyl rubber stopper and aluminium seal with green polypropylene flip top.
Each pack contains 1 vial.6.6 Special precautions for disposal and other handling
Dalbavancin 500 mg powder for concentrate for solution for infusion must be reconstituted with sterile water for injections and subsequently diluted with 50 mg/ml (5 %) glucose solution for infusion.
Dalbavancin 500 mg powder for concentrate for solution for infusion vials are for single-use only.
\*\*Instructions for reconstitution and dilution\*\*
Aseptic technique must be used for reconstitution and dilution of Dalbavancin 500 mg powder for concentrate for solution for infusion.
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.
7. After dilution the solution for infusion must have a final concentration of 1 to 5 mg/ml dalbavancin
8. The solution for infusion must be clear, colourless to yellow solution with no visible particles.
9. If particulate matter or discoloration is identified, the solution must be discarded.
Dalbavancin 500 mg powder for concentrate for solution for infusion must not be mixed with other medicinal products or intravenous solutions. Sodium chloride containing solutions can cause precipitation and should NOT be used for reconstitution or dilution.
The compatibility of reconstituted Dalbavancin 500 mg powder for concentrate for solution for infusion concentrate has only been established with 50 mg/ml (5 %) glucose solution for infusion.
If a common intravenous line is being used to administer other medicinal products in addition to Dalbavancin 500 mg powder for concentrate for solution for infusion, the line should be flushed before and after each Dalbavancin 500 mg powder for concentrate for solution for infusion infusion with 5% glucose solution for infusion.
\*\*Use in the paediatric population\*\*
For paediatric patients, the dose of Dalbavancin 500 mg powder for concentrate for solution for infusion will vary according to the age and weight of the child up to a maximum of 1,500 mg. Transfer the required dose of reconstituted dalbavancin solution, according to the instructions above, based on the child's weight, from the vial to an intravenous bag or bottle containing 50 mg/ml (5 %) glucose solution for infusion. The diluted solution must have a final dalbavancin concentration of 1 to 5 mg/ml.
Table 4 below provides information to prepare an infusion solution with a final concentration of 2 mg/ml or 5 mg/ml (sufficient for most scenarios), to be administered by syringe pump, to achieve a dose of 22.5 mg/kg in paediatric patients from 3 to 12 months of age weighing from 3 to 12 kg.
Alternative concentrations may be prepared, but must have a final concentration range of 1 to 5 mg/ml of dalbavancin. Refer to Table 4 to confirm the calculations. Values shown are approximate. Note that the table is NOT inclusive of all possible calculated doses for every age group but may be utilised to estimate the approximate volume to verify the calculation.
\*\*Table 4\*\*
\*\*Preparation of Dalbavancin 500 mg powder for concentrate for solution for infusion (final infusion concentration 2 mg/ml or 5 mg/ml to be administered by syringe pump) in paediatric patients aged 3 to 12 months (22.5 mg/kg dose)\*\*
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| Patient Weight (kg) | Dose (mg) to achieve 22.5 mg/kg | Volume of reconstituted dalbavancin solution (20 mg/ml) to be withdrawn from vial (ml) | Volume of diluent 50 mg/ml (5 %) glucose solution to add for mixing (ml) | Final dalbavancin infusion solution concentration | Total Volume Dosed by syringe pump (ml) |
| 3 | 67.5 | 10 ml | 90 ml | 2 mg/ml | 33.8 |
| 4 | 90.0 | 45.0 |
| 5 | 112.5 | 56.3 |
| 6 | 135.0 | 67.5 |
| 7 | 157.5 | 78.8 |
| 8 | 180.0 | 90.0 |
| 9 | 202.5 | 20 ml | 60 ml | 5 mg/ml | 40.5 |
| 10 | 225.0 | 45.0 |
| 11 | 247.5 | 49.5 |
| 12 | 270.0 | 54.0 |
\*\*Disposal\*\*
Discard any portion of the reconstituted solution that remains unused.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
