XYDALBA Powder for concentrate for solution for infusion Ref.[8445] Active ingredients: Dalbavancin

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 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 (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.

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.

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).

Summary of the safety profile

In Phase ⅔ clinical studies, 2,473 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 ⅔ 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:

Infections and infestations

Uncommon: vulvovaginal mycotic infection, urinary tract infection, fungal infection, Clostridioides (formerly Clostridium) difficile colitis, oral candidiasis

Blood and lymphatic system disorders

Uncommon: anaemia, thrombocytosis, eosinophilia, leucopenia, neutropenia

Immune system disorders

Rare: anaphylactoid reaction

Metabolism and nutrition disorders

Uncommon: decreased appetite

Psychiatric disorders

Uncommon: insomnia

Nervous system disorders

Common: headache

Uncommon: dysgeusia, dizziness

Vascular disorders

Uncommon: flushing, phlebitis

Respiratory, thoracic and mediastinal disorders

Uncommon: cough

Rare: bronchospasm

Gastrointestinal disorders

Common: nausea, diarrhoea

Uncommon: constipation, abdominal pain, dyspepsia, abdominal discomfort, vomiting

Skin and subcutaneous tissue disorders

Uncommon: pruritus, urticaria, rash

Reproductive system and breast disorders

Uncommon: vulvovaginal pruritus

General disorders and administration site conditions

Uncommon: infusion-related reactions

Investigations

Uncommon: 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.

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 national reporting system listed in Appendix V.

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.