XYDALBA 500mg powder for concentrate infusion solution medication leaflet

Xydalba 500 mg powder for concentrate for solution for infusion

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 (seesection 6.6).

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to off-white to pale yellow powder.

Xydalba is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) inadults and paediatric patients from birth (see sections 4.4 and 5.1).

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

The recommended dose of dalbavancin is 1 500 mg administered as either a single infusion of1 500 mg or as 1 000 mg followed one week later by 500 mg (see sections 5.1 and 5.2).

The recommended dose of dalbavancin is a single dose based on the age and weight of the patient.

Dose of dalbavancin in paediatric patients

Age range Dose (single dose regimen)

Birth to less than 6 years 22.5 mg/kg (maximum 1 500 mg)6 to less than 18 years 18 mg/kg (maximum 1 500 mg)

No dose adjustment is necessary (see section 5.2).

Dose adjustments are not required for adult and paediatric patients with mild or moderate renalimpairment (creatinine clearance  30 to 79 ml/min). Dose adjustments are not required for adultpatients receiving regularly scheduled haemodialysis (3 times/week), and dalbavancin may beadministered without regard to the timing of haemodialysis.

In adult patients with chronic renal impairment whose creatinine clearance is < 30 ml/min and who arenot receiving regularly scheduled haemodialysis, the recommended dose is reduced to either 1 000 mgadministered 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 3 months to 18 yearswith creatinine clearance less than 30 ml/min/1.73 m2 and for patients < 3 months old with renalimpairment defined as serum creatinine ≥ 2 times the upper limit of normal, or urine output < 0.5mL/kg/h, or requirement for dialysis. Currently available information is described in section 5.2, butno recommendation on a posology can be made.

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 moderateor severe hepatic impairment (Child-Pugh B & C) as no data are available to determine appropriatedosing (see sections 5.2).

Xydalba must be reconstituted and then further diluted prior to administration by intravenous infusionover a 30 - minute period. For instructions on reconstitution and dilution of the medicinal productbefore administration, see section 6.6.

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

Dalbavancin should be administered with caution in patients known to be hypersensitive to otherglycopeptides since cross-hypersensitivity may occur. If an allergic reaction to dalbavancin occurs,administration should be discontinued and appropriate therapy for the allergic reaction should beinstituted.

Clostridioides (formerly Clostridium) difficile-associated diarrhoea

Antibacterial-associated colitis and pseudomembranous colitis have been reported with the use ofnearly all antibiotics and may range in severity from mild to life threatening. Therefore, it is importantto consider this diagnosis in patients who present with diarrhoea during or subsequent to the treatmentwith dalbavancin (see section 4.8). In such circumstance, the discontinuation of dalbavancin and theuse of supportive measures together with the administration of specific treatment for Clostridioides(formerly Clostridium) difficile should be considered. These patients must never be treated withmedicinal products that suppress the peristalsis.

Xydalba is to be administered via intravenous infusion, using a total infusion time of 30 minutes tominimise the risk of infusion-related reactions. Rapid intravenous infusions of glycopeptideantibacterial agents can cause reactions including flushing of the upper body, urticaria, pruritus, and/orrash. Stopping or slowing the infusion may result in cessation of these reactions.

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 withchronic renal impairment whose creatinine clearance is < 30 ml/min and who are not receiving regularhaemodialysis (see sections 4.2 and 5.2). There is insufficient information to recommend dosageadjustment for patients 3 months to 18 years old with creatinine clearance less than 30 ml/min/1.73 m2and for patients < 3 months old with renal impairment defined as serum creatinine ≥ 2 times the upperlimit of normal, or urine output < 0.5 mL/kg/h, or requirement for dialysis.

Mixed infections

In mixed infections in which Gram-negative bacteria are suspected patients should also be treated withan 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. Ifsuperinfection 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 tocellulitis/erysipelas, abscesses and wound infections only. There is no experience with dalbavancin inthe treatment of severely immunocompromised patients.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Results from an in vitro receptor screening study do not indicate a likely interaction with othertherapeutic targets or a potential for clinically relevant pharmacodynamic interactions (seesection 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 orinhibitors 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 isexpected to be low since it is neither an inhibitor nor an inducer of CYP enzymes in vitro. There areno data on dalbavancin as an inhibitor of CYP2C8.

It is not known if dalbavancin is an inhibitor of transporters. Increased exposure to transportersubstrates sensitive for inhibited transporter activity, such as statins and digoxin, cannot be excluded ifcombined with dalbavancin.

There are no data from the use of dalbavancin in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Xydalba is not recommended during pregnancy, unless the potential expected benefit clearly justifiesthe potential risk to the foetus.

It is unknown whether dalbavancin is excreted in human milk. However, dalbavancin is excreted inthe milk of lactating rats and may be excreted in human breast milk. Dalbavancin is not well absorbedorally; however, an impact on the gastrointestinal flora or mouth flora of a breast-feeding infant cannotbe excluded. A decision must be made whether to continue/discontinue breast-feeding or tocontinue/discontinue therapy with Xydalba taking into account the benefit of breast-feeding for thechild and the benefit of therapy for the woman.

Studies in animals have shown reduced fertility (see section 5.3). The potential risk for humans isunknown.

Xydalba may have a minor influence on the ability to drive and use machines, as dizziness has beenreported in a small number of patients (see section 4.8).

In Phase 2/3 clinical studies, 2 473 adult patients received dalbavancin administered as either a singleinfusion of 1 500 mg or as 1 000 mg followed one week later by 500 mg. The most common adversereactions 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. Frequencycategories 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 vulvovaginal mycotic infection,infestations urinary tract infection, fungalinfection, Clostridioides (formerly

Clostridium) difficile colitis, oralcandidiasis

Blood and lymphatic anaemia, thrombocytosis,system disorders eosinophilia, leucopenia,neutropenia

Immune system anaphylactoiddisorders reaction

Metabolism and decreased appetitenutrition disorders

Psychiatric disorders insomnia

Nervous system headache dysgeusia, dizzinessdisorders

Vascular disorders flushing, phlebitis

Respiratory, thoracic cough bronchospasmand mediastinaldisorders

Gastrointestinal nausea, diarrhoea constipation, abdominal pain,disorders dyspepsia, abdominal discomfort,vomiting

Skin and subcutaneous pruritus, urticaria, rashtissue disorders

Reproductive system vulvovaginal pruritusand breast disorders

General disorders and infusion-related reactionsadministration siteconditions

Investigations blood lactate dehydrogenaseincreased, alanine aminotransferaseincreased, aspartateaminotransferase increased, blooduric acid increased, liver functiontest abnormal, transaminasesincreased, blood alkalinephosphatase increased, platelet countincreased, body temperatureincreased, hepatic enzyme increased,gamma-glutamyl transferaseincreased

Class adverse reactions

Ototoxicity has been associated with glycopeptide use (vancomycin and teicoplanin); patients who arereceiving concomitant therapy with an ototoxic medicinal product, such as an aminoglycoside, may beat increased risk.

The safety of dalbavancin was evaluated in one Phase 3 clinical trial which included 169 paediatricpatients from birth to less than 18 years of age with ABSSSI (or suspected or confirmed sepsis if agedless than 3 months old) treated with dalbavancin (91 patients treated with a single dose of dalbavancinand 78 patients, all of them aged 3 months and older, treated with a two-dose regimen of dalbavancin).

Out of these 169 paediatric patients, 58 were adolescents (12 years and older), 49 were children from 6years to less than 12 years, 35 were 2 years to less than 6 years, 17 were aged 3 months to less than 2years, and 10 were under 3 months of age. Additionally, in a Phase 1, open-label, pharmacokinetictrial, a single-dose administration of dalbavancin was evaluated in 8 patients under 3 months of age.

Across these two clinical studies, 18 children were under 3 months of age, including 3 preterm and 5term neonates. Overall, the safety findings of dalbavancin in these paediatric patients were similar tothose observed in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific information is available on the treatment of overdose with dalbavancin, as dose-limitingtoxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers have beenadministered single doses of up to 1 500 mg, and cumulative doses up to 4 500 mg over a period of upto 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 supportivemeasures. Although no information is available specifically regarding the use of haemodialysis to treatoverdose, it should be noted that in a Phase 1 study in patients with renal impairment, less than 6 % ofthe recommended dalbavancin dose was removed after 3 hours of haemodialysis.

Pharmacotherapeutic group: antibacterials for systemic use, glycopeptide antibacterials,

ATC code: J01XA04.

Dalbavancin is a bactericidal lipoglycopeptide.

Its mechanism of action in susceptible Gram-positive bacteria involves interruption of cell wallsynthesis by binding to the terminal D-alanyl-D-alanine of the stem peptide in nascent cell wallpeptidoglycan, preventing cross-linking (transpeptidation and transglycosylation) of disaccharidesubunits resulting in bacterial cell death.

All Gram-negative bacteria are inherently resistant to dalbavancin.

Resistance to dalbavancin in Staphylococcus spp. and Enterococcus spp. is mediated by VanA, agenotype that results in modification of the target peptide in nascent cell wall. Based on in vitrostudies 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 fullyvancomycin susceptible strains. If the isolates with higher dalbavancin MICs represent stablephenotypes and are correlated with resistance to the other glycopeptides, then the likely mechanismwould 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 usedantibiotics (i.e. cefepime, ceftazidime, ceftriaxone, imipenem, meropenem, amikacin, aztreonam,ciprofloxacin, piperacillin/tazobactam and trimethoprim/sulfamethoxazole), when tested against12 species of Gram-negative pathogens (see section 4.5).

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretative criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) fordalbavancin and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

PK/PD relationship

Bactericidal activity against staphylococci in vitro is time-dependent at serum concentrations ofdalbavancin similar to those obtained at the recommended dose in humans. In vivo PK/PD relationshipof dalbavancin for S. aureus was investigated using a neutropenic model of animal infection. Thisshowed that the antibacterial activity of dalbavancin appears to best correlate with the ratio of areaunder 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 weresusceptible 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 studiessuggest that they would be susceptible to dalbavancin in the absence of acquired mechanisms ofresistance:

* Group G streptococci

* Clostridium perfringens

* Peptostreptococcus spp.

Xydalba has been evaluated in paediatric patients aged from birth to < 18 years with ABSSSI orsuspected or confirmed sepsis if aged less than 3 months old in one Phase 3 open-label, randomised,comparator controlled clinical trial. The study included 169 patients treated with dalbavancin (91patients 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. Seven of 10patients aged less than 3 months were enrolled with suspected or confirmed sepsis. The primaryobjective was to assess the safety and tolerability of dalbavancin, and secondary objectives includedassessment of efficacy and pharmacokinetics. Efficacy was a descriptive endpoint. Clinical cure rate at

TOC (mITT) was 95.2% (79/83) in the dalbavancin single-dose arm, 97.3% (72/74) in the dalbavancintwo-dose arm, and 100% (30/30) in the comparator arm.

The pharmacokinetics of dalbavancin have been characterised in healthy subjects, patients, and specialpopulations. Systemic exposures to dalbavancin are dose proportional following single doses over arange of 140 to 1120 mg, indicating linear pharmacokinetics of dalbavancin. No accumulation ofdalbavancin was observed following multiple intravenous infusions administered once-weekly for upto 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 pharmacokineticsof dalbavancin are best described using a three-compartment model (α and β distributional phasesfollowed by a terminal elimination phase). Thus, the distributional half-life (t1/2β), which constitutesmost of the clinically-relevant concentration-time profile, ranged from 5 to 7 days and is consistentwith once-weekly dosing.

Estimated pharmacokinetic parameters of dalbavancin following the two-dose regimen and thesingle-dose regimen, respectively, are shown in Table 2 below.

Table 2.

Mean (SD) dalbavancin pharmacokinetic parameters for adults using population PK analysis

Parameter Two-dose regimen2 Single-dose regimen3

Cmax (mg/L) Day 1: 281 (52) Day 1: 411 (86)

Day 8: 141 (26)

AUC0-Day1418100 (4600) 20300 (5300)(mg*h/L)

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-doseregimens.

400 - Regimen— 1500mg Day 1

- a)

- - 1000mg Day 1 + 500mg Day 8c 300 -c 200 -o> 100 -

To

- ----------------8 115

Time (days)

Clearance and volume of distribution at steady state are comparable between healthy subjects andpatients with infections. The volume of distribution at steady state was similar to the volume ofextracellular 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 drugconcentration, renal insufficiency, or hepatic insufficiency. Following a single intravenous dose of1 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.

Metabolites have not been observed in significant amounts in human plasma. The metaboliteshydroxy-dalbavancin and mannosyl aglycone have been detected in urine (< 25 % of administereddose). 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 ofdalbavancin, drug-drug interactions via inhibition or induction of metabolism of dalbavancin are notanticipated. Hydroxy-dalbavancin and mannosyl aglycone show significantly less antibacterial activitycompared to dalbavancin.

Following administration of a single 1 000 mg dose in healthy subjects, an average of 19 % to 33 % ofthe administered dalbavancin dose was excreted in urine as dalbavancin and 8 % to 12 % as themetabolite hydroxy-dalbavancin. Approximately 20 % of the administered dose was excreted infaeces.

The pharmacokinetics of dalbavancin were evaluated in 28 adult subjects with varying degrees ofrenal impairment and in 15 matched control subjects with normal renal function. Following a singledose 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 notbeen established. Dalbavancin pharmacokinetics in subjects with end-stage renal disease receivingregularly scheduled renal dialysis (3 times/week) were similar to those observed in subjects with mildto moderate renal impairment, and less than 6 % of an administered dose is removed after 3 hours ofhaemodialysis. For dosing instructions in adult subjects with renal impairment refer to section 4.2.

There is insufficient information to recommend dose adjustment for patients 3 months to 18 years withcreatinine clearance less than 30 mL/min/1.73 m2. Patients < 3 months old with renal impairment,defined as serum creatinine ≥ 2 times the upper limit of normal, or urine output < 0.5 mL/kg/h, orrequirement for dialysis, were excluded from the clinical trials. For the 18 paediatric patients < 3months old that were included in the clinical trials, the range of normalised creatinine clearance (basedon Schwartz bedside equation) was 34 to 118 mL/min/1.73 m2. No observed PK data are available inpaediatric patients with severe renal impairment. The predicted dalbavancin mean AUC for paediatricsubjects with severe renal impairment (CLCR ≤ 30 ml/min/1.73 m2) was approximately 13-30 % highercompared to paediatric patients with normal renal function treated with the same dose, based onpopulation pharmacokinetic modelling.

The pharmacokinetics of dalbavancin were evaluated in 17 subjects with mild, moderate, or severehepatic impairment and compared to 9 matched healthy subjects with normal hepatic function. Themean AUC was unchanged in subjects with mild hepatic impairment compared to subjects withnormal hepatic function; however, the mean AUC decreased by 28 % and 31 %, respectively, insubjects with moderate and severe hepatic impairment. The cause and the clinical significance of thedecreased exposure in subjects with moderate and severe hepatic function are unknown. For dosinginstructions in subjects with hepatic impairment refer to section 4.2.

Clinically significant gender-related differences in dalbavancin pharmacokinetics have not beenobserved in healthy subjects or in patients with infections. No dose adjustment is recommended basedon gender.

The pharmacokinetics of dalbavancin were not significantly altered with age; therefore, doseadjustment is not necessary based on age (see section 4.2). The experience with dalbavancin in elderlyis limited: 276 patients ≥ 75 years of age were included in the Phase 2/3 clinical studies, of which 173received dalbavancin. Patients up to 93 years of age have been included in clinical studies.

The pharmacokinetics of dalbavancin has been evaluated in 219 paediatric patients [4 days to 17 yearsof age, including preterm neonates (gestational age 32 to <37 weeks; n=3) and term neonates(gestational age 37 to 40 weeks; n=5)]. The model predicted mean plasma AUC0-120h of dalbavancin inpreterm neonates at birth (gestational age 32 weeks to <37 weeks) was approximately 62% of that inadult patients, whereas the AUC0-120h in older paediatric groups was 84-96% of that in adult patients.

However, in all paediatric age groups, the percentage of patients attaining the PK/PD targets related tothe in vivo drug activity were above 90% for MICs up to 0.5 mg/L.

Table 3.

Simulated Mean (SD) dalbavancin pharmacokinetic parameters for paediatrics and adults usingpopulation PK analysis

Preterm Term Young Infant Toddler Child Adolescent Adult

Parameter

Neonate Neonate Infant1 3 2 years - 6 years 12 years - ≥ 18

GA 26--

Birth -1 month months < 6 - < 12 < 18 years years

Age range <37month - < 3 - <2 years yearsweeksmonths years22.5 22.5 22.5 22.5 18 18 mg/kg 1500

Dose 22.5 mg/kgmg/kg mg/kg mg/kg mg/kg mg/kg mg

Cmax 305 306 303 258 417228 (88) 305 (130) 250 (110)(mg/L) (130) (130) (130) (110) (110)

AUC0-120h 6 480 8 930 9 040 9 470 10 100 8 850 9 030 10 500(mg*h/L) (2 000) (2 900) (3 000) (3 100) (3 300) (2 900) (3 100) (3 100)1 Source: DAL-MS-03.

Dalbavancin toxicity has been evaluated after daily intravenous administration for durations of up to3 months in rats and dogs. Dose-dependent toxicity included serum chemistry and histologicalevidence of renal and hepatic injury, reduced red blood cell parameters and injection site irritation. Indogs only, infusion reactions characterised by skin swelling and/or redness (not associated with theinjection site), mucosal pallor, salivation, vomiting, sedation, and modest declines in blood pressureand increases in heart rate were observed in a dose-dependent manner. These infusion reactions weretransient (resolved within 1 hour post-dosing) and were attributed to histamine release. Dalbavancintoxicity profile in juvenile rats was consistent with that previously observed in adult rats at the samedose (mg/kg /day) levels.

Reproductive toxicity studies in rats and rabbits showed no evidence of a teratogenic effect. In rats, atexposures approximately 3 times above clinical exposure, there was reduced fertility and an increasedincidence of embryo-lethality, reductions in foetal weight and skeletal ossification and increasedneonatal mortality. In rabbits, abortion occurred in conjunction with maternal toxicity at exposuresbelow the human therapeutic range.

Long-term carcinogenicity studies have not been conducted. Dalbavancin was not mutagenic orclastogenic in a battery of in vitro and in vivo genotoxicity tests.

Mannitol (E421)

Lactose monohydrate

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

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 solutionsother than those mentioned in section 6.6.

Dry powder: 4 years

Chemical and physical in-use stability of Xydalba has been demonstrated for both the reconstitutedconcentrate and for the diluted solution for 48 hours at or below 25 °C. The total in-use stability fromreconstitution to administration should not exceed 48 hours.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8 °C, unless reconstitution/dilution has taken placein controlled and validated aseptic conditions. Do not freeze.

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.

Single-use 48 ml type I glass vial with an elastomeric stopper and a green flip off seal.

Each pack contains 1 vial.

Xydalba must be reconstituted with sterile water for injections and subsequently diluted with50 mg/ml (5 %) glucose solution for infusion.

Xydalba vials are for single-use only.

Instructions for reconstitution and dilution

Aseptic technique must be used for reconstitution and dilution of Xydalba.

1. The content of each vial must be reconstituted by slowly adding 25 ml of water forinjections.2. Do not shake. To avoid foaming, alternate between gentle swirling and inversion of thevial, until its contents are completely dissolved. The reconstitution time may be up to5 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 novisible particles.

5. The reconstituted concentrate must be further diluted with 50 mg/ml (5 %) glucosesolution for infusion.

6. To dilute the reconstituted concentrate, the appropriate volume of the 20 mg/mlconcentrate must be transferred from the vial to an intravenous bag or bottle containing50 mg/ml (5 %) glucose solution for infusion. For example: 25 ml of the concentratecontains 500 mg dalbavancin.

7. After dilution the solution for infusion must have a final concentration of 1 to 5 mg/mldalbavancin8. The solution for infusion must be clear, colourless to yellow solution with no visibleparticles.

9. If particulate matter or discoloration is identified, the solution must be discarded.

Xydalba must not be mixed with other medicinal products or intravenous solutions. Sodium chloridecontaining solutions can cause precipitation and should NOT be used for reconstitution or dilution.

The compatibility of reconstituted Xydalba 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

Xydalba, the line should be flushed before and after each Xydalba infusion with 5 % glucose solutionfor infusion.

Use in the paediatric population

For paediatric patients, the dose of Xydalba will vary according to the age and weight of the child upto 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 orbottle containing 50 mg/ml (5 %) glucose solution for infusion. The diluted solution must have a finaldalbavancin concentration of 1 to 5 mg/ml.

Table 4 below provides information to prepare an infusion solution with a final concentration of2 mg/ml or 5 mg/ml (sufficient for most scenarios), to be administered by syringe pump, to achieve adose of 22.5 mg/kg in paediatric patients from birth to 12 months of age weighing from 1 to 12 kg.

Alternative concentrations may be prepared, but must have a final concentration range of 1 to 5 mg/mlof dalbavancin. Refer to Table 4 to confirm the calculations. Values shown are approximate. Note thatthe table is NOT inclusive of all possible calculated doses for every age group but may be utilised toestimate the approximate volume to verify the calculation.

Table 4. Preparation of Xydalba (final infusion concentration 2 mg/ml or 5 mg/ml to beadministered by syringe pump) in paediatric patients from birth to 12 months (22.5 mg/kg dose)

Patient Dose (mg) Volume of Volume of Final Total Volume

Weight (kg) to achieve reconstituted diluent dalbavancin Dosed by syringe22.5 mg/kg dalbavancin 50 mg/ml infusion pump (ml)solution (5 %) glucose solution(20 mg/ml) to be solution to add concentrationwithdrawn from for mixing (ml)vial (ml)1 22.5 11.32 45.0 22.53 67.5 33.84 90.0 45.010 ml 90 ml 2 mg/ml5 112.5 56.36 135.0 67.57 157.5 78.88 180.0 90.09 202.5 40.510 225.0 45.020 ml 60 ml 5 mg/ml11 247.5 49.512 270.0 54.0

Discard any portion of the reconstituted solution that remains unused.

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

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/14/986/001

Date of first authorisation: 19 February 2015

Date of latest renewal: 05 December 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.