XYDALBA 500 MG POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION - summary of medicine characteristics

Xydalba 500 mg powder for concentrate for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains dalbavancin hydrochloride equivalent to 500 mg dalbavancin.

After reconstitution each ml contains 20 mg dalbavancin.

The diluted solution for infusion must have a final concentration of 1 to 5 mg/ml dalbavancin (see section 6.6).

For the full list of excipients, see section 6.1.

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

White to off-white to pale yellow powder.

4.1 Therapeutic indications

Xydalba is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults (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

Recommended dose and duration of treatment for adults

The recommended dose of dalbavancin in adult patients with ABSSSI 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).

Elderly

No dose adjustment is necessary (see section 5.2).

Renal impairment

Dose adjustments are not required for patients with mild or moderate renal impairment (creatinine clearance > 30 to 79 ml/min). Dose adjustments are not required for patients receiving regularly scheduled haemodialysis (3 times/week), and dalbavancinmay be administered without regard to the timing of haemodialysis.

In 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).

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 from birth to < 18 years 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

Xydalba 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

Xydalba 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 that resemble “Red-

Man Syndrome”, 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 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).

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 microorganisms. 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).

Xydalba 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 Xydalba 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

Xydalba 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

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antibacterials for systemic use, glycopeptide antibacterials, ATC code: J01XA04.

Mechanism of action

Dalbavancin is a bactericidal lipoglycopeptide.

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

Mechanism of resistance

All Gram-negative bacteria are inherently resistant to dalbavancin.

Resistance to dalbavancin in Staphylococcus spp. and Enterococcus spp. is mediated by VanA, a genotype that results in modification of the target peptide in nascent cell wall. Based on in vitro studies the activity of dalbavancin is not affected by other classes of vancomycin resistance genes.

Dalbavancin MICs are higher for vancomycin-intermediate staphylococci (VISA) than for fully vancomycin susceptible strains. If the isolates with higher dalbavancin

MICs represent stable phenotypes and are correlated with resistance to the other glycopeptides, then the likely mechanism would be an increase in the number of glycopeptide targets in nascent peptidoglycan.

Cross-resistance between dalbavancin and other classes of antibiotics was not seen in in vitro studies. Methicillin resistance has no impact on dalbavancin activity.

Interactions with other antibacterial agents

In in vitro studies, no antagonism has been observed between dalbavancin and other commonly used antibiotics (i.e. cefepime, ceftazidime, ceftriaxone, imipenem, meropenem, amikacin, aztreonam, ciprofloxacin, piperacillin/ta­zobactam and trimethoprim/sul­famethoxazole), when tested against 12 species of Gram-negative pathogens (see section 4.5).

Susceptibility testing breakpoints

Minimum inhibitory concentration (MIC) breakpoints determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are:

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 that showed that net reduction in the log10 of colony-forming units (CFU) was greatest when larger doses were given less frequently.

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

The European Medicines Agency has deferred the obligation to submit the results of studies with Xydalba 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

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol (E421)

Lactose monohydrate

Hydrochloric acid (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: 4 years

Chemical and physical in-use stability of Xydalba 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

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

Each pack contains 1 vial.

6.6 Special precautions for disposal

Xydalba must be reconstituted with sterile water for injections and subsequently diluted with 50 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 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.

Xydalba 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 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 solution for infusion.

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.

7 MARKETING AUTHORISATION HOLDER

Allergan Pharmaceuticals International Ltd.,

Clonshaugh Business & Technology Park,

Dublin 17, D17 E400, Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 45496/0014

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

01/01/2021