4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

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).

Paediatric patients

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)

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 3 months to 18 years with creatinine clearance less than 30 ml/min/1.73 m2 and for 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, or requirement for dialysis. 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).

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 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 3 months to 18 years old with creatinine clearance less than 30ml/min/1.73 m2 and for 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, or requirement for dialysis.

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).

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

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 169 paediatric patients from birth to less than 18 years of age with ABSSSI (or suspected or confirmed sepsis if aged less than 3 months old) treated with dalbavancin (91 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). Out of these 169 paediatric patients, 58 were adolescents (12 years and older), 49 were children from 6 years to less than 12 years, 35 were 2 years to less than 6 years, 17 were aged 3 months to less than 2 years, and 10 were under 3 months of age. Additionally, in a Phase 1, open-label, pharmacokinetic trial, 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 5 term neonates. 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.