Xydalba

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.

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) in adults.

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

Posology

Recommended dose and duration of treatment for adults

The recommended dose of dalbavancin in adult patients with ABSSSI is 1500 mg administered as either a single infusion of 1500 mg or as 1000 mg followed one week later by 500 mg.

Elderly

No dose adjustment is necessary.

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 dalbavancin may 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 1000 mg administered as a single infusion or 750 mg followed one week later by 375 mg.

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.

Paediatric population

The safety and efficacy of dalbavancin in children aged from birth to < 18 years has not yet been established.

Method of administration

Intravenous use

Xydalba must be reconstituted and then further diluted prior to administration by intravenous infusion over a 30 - minute period.

Hypersensitivity reactions

Xydalba should be administered with caution in patients known to be hypersensitive to other glycopeptides since cross-hypersensitivity may occur. If an allergic reaction to Xydalba occurs, administration should be discontinued and appropriate therapy for the allergic reaction should be instituted.

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. In such circumstance, the discontinuation of dalbavancin and the use of supportive measures together with the administration of specific treatment for 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.

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 .

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.

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.

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.

Pregnancy

There are no data from the use of dalbavancin in pregnant women. Studies in animals have shown reproductive toxicity.

Xydalba is not recommended during pregnancy unless clearly necessary.

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. The potential risk for humans is unknown.

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.

Summary of the safety profile

In Phase 2 / 3 clinical studies, 2,473 patients received dalbavancin administered as either a single infusion of 1500 mg or as 1000 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

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 agent, such as an aminoglycoside, may be at increased risk.

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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 1500 mg, and cumulative doses up to 4500 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 1500 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.

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.

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 perfringen

- Peptostreptococcus spp.

Paediatric population

2 for information on paediatric use).

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 (1000 mg on Day 1, followed by up to 7 weekly 500 mg doses) in healthy adults.

The mean terminal elimination half-life (t_1/2) 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 (t_1/2β), 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

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 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 1000 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 1000 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 subjects with varying degrees of renal impairment and in 15 matched control subjects with normal renal function.

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.

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. 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 safety and efficacy of Xydalba in children aged from birth to < 18 years have not yet been established.

A total of 10 paediatric patients with ages 12 to 16 years who had resolving infections were given single doses of either dalbavancin 1000 mg (body weight > 60 kg) or dalbavancin 15 mg/kg (body weight < 60 kg).

Mean plasma exposures for dalbavancin, based on AUCinf (17,495 µg-h/ml and 16,248 µg -h/ml) and C_max (212 µg/ml and 191 µg/ml) were similar when administered as 1000 mg to paediatric subjects (12-16 years) weighing > 60 kg (61.9 - 105.2 kg) or as 15 mg/kg to paediatric subjects weighing < 60 kg (47.9-58.9 kg). Apparent terminal t½ was similar for dalbavancin doses of 1000 mg and 15 mg/kg, with mean values of 227 and 202 hours, respectively. The safety profile of dalbavancin in the subjects aged between 12 and 16 years in this study was consistent with the safety profile observed in adults treated with dalbavancin.

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.

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.

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.

This medicinal product does not require any special storage conditions.

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 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.

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.

Allergan Pharmaceuticals International Ltd.,

Clonshaugh Industrial Estate, Coolock,

Dublin 17,

Ireland

EU/1/14/986/001

Date of first authorisation: 19 February 2015

27/01/2017