Dalbavancin (Monograph)

Brand name: Dalvance
Drug class: Glycopeptides
Chemical name: 5,31-Dichloro-38-de(methoxycarbonyl)-7-demethyl-19-deoxy-56-O-[2-deoxy-2-[(10-methyl-1-oxoundecyl)amino]-β-d-glucopyranuronosyl]-38-[[[3-(dimethylamino)propyl]amino]carbonyl]-42-O-α-d-mannopyranosyl-N15-methyl ristomycin A aglycone
Molecular formula: C₈₈H₁₀₀Cl₂N₁₀O₂₈
CAS number: 171500-79-1

Introduction

Antibacterial; lipoglycopeptide; semisynthetic derivative of a naturally occurring glycopeptide.

Uses for Dalbavancin

Skin and Skin Structure Infections

Treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA] and methicillin-susceptible S. aureus), Streptococcus pyogenes (group A β-hemolytic streptococci, GAS), S. agalactiae (group B streptococci, GBS), or S. anginosus group (includes S. anginosus, S. intermedius, and S. constellatus).

Dalbavancin Dosage and Administration

Administration

Administer by IV infusion.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Must be reconstituted and further diluted prior to IV infusion.

Do not infuse with other drugs or electrolytes. Compatibility with IV solutions, drugs, additives, or substances other than 5% dextrose injection not established.

If the same IV line is used for sequential infusion of other drugs, flush IV line with 5% dextrose injection before and after dalbavancin infusion.

Vials contain no preservatives; for single use only.

Reconstitution

Reconstitute vial containing 500 mg of dalbavancin by adding 25 mL of sterile water for injection to provide a solution containing 20 mg/mL.

To avoid foaming, alternately swirl and invert vial until contents are completely dissolved; do not shake. Reconstituted solution should appear clear and colorless to yellow.

Dilution

To further dilute reconstituted solution, withdraw correct dose and add to IV bag or bottle containing 5% dextrose injection.

Final diluted solution must have a dalbavancin concentration of 1–5 mg/mL.

Discard any unused portion of reconstituted solution.

Rate of Administration

Administer by IV infusion over 30 minutes.

Dosage

Available as dalbavancin hydrochloride; dosage expressed in terms of dalbavancin.

Adults

Skin and Skin Structure Infections

IV

Two-dose regimen of 1 g followed 1 week later by 500 mg.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.

Moderate or severe hepatic impairment (Child-Pugh class B or C): Dosage recommendations not available; use with caution. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild (Cl_cr 50–79 mL/minute) or moderate (Cl_cr 30–49 mL/minute) renal impairment: Dosage adjustments not needed.

Severe renal impairment (Cl_cr <30 mL/minute) not receiving regularly scheduled hemodialysis: Two-dose regimen of 750 mg followed 1 week later by 375 mg.

Renal impairment receiving regularly scheduled hemodialysis: Dosage adjustments not recommended; administer without regard to hemodialysis timing. (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustment not needed based solely on age. Select dosage with caution since geriatric patients more likely to have decreased renal function than younger adults. (See Geriatric Use under Cautions.)

Cautions for Dalbavancin

Contraindications

• Hypersensitivity to dalbavancin.

Warnings/Precautions

Sensitivity Reactions

Serious hypersensitivity (anaphylactic) and skin reactions reported.

Data not available to date regarding cross-reactivity between dalbavancin and other glycopeptides (e.g., oritavancin, telavancin, vancomycin). Because of possibility of cross-sensitivity, question patients about previous hypersensitivity reactions to glycopeptides; use with caution in those with a history of glycopeptide allergy.

If an allergic reaction occurs, discontinue dalbavancin.

Infusion Reactions

Rapid IV infusion of dalbavancin can cause a reaction referred to as “red-man syndrome” (i.e., flushing of upper body, urticaria, pruritus, rash).

To reduce risk of infusion-related reactions, administer by IV infusion over 30 minutes.

If infusion-related reaction occurs, stopping or decreasing infusion rate may result in cessation of symptoms.

Hepatic Effects

In clinical trials in patients with normal baseline aminotransferase concentrations, more dalbavancin-treated patients developed ALT elevations >3 times ULN compared with patients receiving a comparator treatment. Overall, frequency of liver laboratory test abnormalities (e.g., ALT, AST, bilirubin) was similar between those receiving dalbavancin or a comparator treatment.

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Possible emergence and overgrowth of nonsusceptible bacteria or fungi. Monitor carefully; institute appropriate therapy if superinfection occurs.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile. C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including dalbavancin, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible. Initiate appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of dalbavancin and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Specific Populations

Pregnancy

Category C.

Use during pregnancy only if potential benefits justify potential risks to fetus.

No adequate and well-controlled studies in pregnant women; animal studies (rats) revealed delayed fetal maturation, increased embryolethality, and increased offspring deaths at dosage 3.5 times human dosage on exposure basis.

Lactation

Distributed into milk in lactating rats; not known whether distributed into human milk.

Use with caution in nursing women.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Efficacy and tolerability similar to comparator treatments regardless of age.

No substantial differences in pharmacokinetics according to age; dosage adjustments not needed based solely on age.

Substantially eliminated by kidneys; risk of adverse effects may be greater in patients with impaired renal function. Select dosage with caution since geriatric patients are more likely to have decreased renal function.

Hepatic Impairment

Moderate or severe hepatic impairment (Child-Pugh class B or C): Use with caution; no data available to determine an appropriate dosage in such patients.

Mild hepatic impairment (Child-Pugh class A): Pharmacokinetics not altered.

Renal Impairment

Mild or moderate renal impairment: Mean plasma clearance decreased and AUC increased.

Severe renal impairment (Cl_cr <30 mL/minute) not receiving regularly scheduled hemodialysis: Mean plasma clearance decreased and AUC increased. Reduced dosage recommended. (See Renal Impairment under Dosage and Administration.)

End-stage renal disease receiving regularly scheduled hemodialysis: Pharmacokinetics similar to those in patients with mild to moderate renal impairment; dosage adjustments not needed.

Common Adverse Effects

Nausea, vomiting, diarrhea, headache, rash, pruritus.

Drug Interactions

No formal drug interaction studies conducted to date.

Not a substrate, inhibitor, or inducer of CYP isoenzymes. Minimal potential for interaction with substrates, inhibitors, or inducers of CYP isoenzymes.

Specific Drugs

Dalbavancin Pharmacokinetics

Absorption

Plasma Concentrations

Linear, dose-dependent pharmacokinetics following single IV dose; no apparent accumulation following multiple IV doses.

Following a single 1-g IV dose on day 1 followed by a single 500-mg IV dose on day 8 in adults with skin and skin structure infections, mean plasma dalbavancin concentrations were 30 mg/L immediately before the second dose and 21 mg/mL (range 8–40 mg/L) 20 days after the initial dose.

Distribution

Extent

Distributed into skin blister fluid; mean concentrations in skin blister fluid are ≥30 mg/L for up to 7 days following a single 1-g dose.

Distributed into milk in lactating rats; not known whether distributed into milk in humans.

Plasma Protein Binding

Approximately 93% (mainly albumin).

Special Populations

Renal or hepatic impairment does not affect protein binding.

Elimination

Metabolism

Not metabolized by CYP isoenzymes. Minor metabolite (hydroxydalbavancin) observed in urine.

Elimination Route

Excreted in feces (20% by day 70 after a dose) and urine (33% unchanged and 12% as hydroxydalbavancin by day 42 after a dose).

A 3-hour hemodialysis session removes <6% of an IV dose.

Half-life

Approximately 8.5 days (204 hours).

Special Populations

Mild hepatic impairment (Child-Pugh class A): Pharmacokinetics not altered.

Moderate or severe hepatic impairment (Child-Pugh class B or C): Mean AUC decreased by 28 or 31%, respectively.

Mild, moderate, or severe renal impairment not receiving hemodialysis: Lower mean plasma clearance (decreased by 11, 35, or 47%, respectively) and increased AUC.

End-stage renal disease receiving regularly scheduled hemodialysis: Pharmacokinetics similar to those in patients with mild to moderate renal impairment.

Age or gender: effects on pharmacokinetics not observed.

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).

Reconstituted or further diluted solutions may be stored under refrigeration (2–8°C) or at controlled room temperature (20–25°C); do not freeze.

Total storage time from reconstitution to administration should not exceed 48 hours whether stored at 2–8°C or room temperature.

Compatibility

Parenteral

Solution Compatibility1

Do not use saline-based infusion solutions; may cause precipitation.

Actions and Spectrum

• Semisynthetic lipoglycopeptide antibacterial derived from a naturally occurring glycopeptide produced by Nonomuraea, an actinomycete. Teicoplanin-type lipoglycopeptide.

• Mixture of 5 closely related homologs (i.e., A₀, A₁, B₀, B₁, B₂), each sharing same core structure. B₀ is the major component.

• Mechanism of action similar to that of other glycopeptides (e.g., oritavancin, telavancin, vancomycin). Binds to d-alanyl-d-alanine terminus of growing peptidoglycan chains, thereby inhibiting bacterial cell wall synthesis. Also appears to dimerize and anchor in bacterial membranes.

• Bactericidal in vitro against certain gram-positive bacteria, including staphylococci, streptococci, and enterococci.

• Active in vitro and in clinical studies against S. aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA]), S. pyogenes (group A β-hemolytic streptococci, GAS), S. agalactiae (group B streptococci, GBS), and S. anginosus group (includes S. anginosus, S. intermedius, and S. constellatus).

• Active in vitro against some vancomycin-susceptible E. faecium and E. faecalis; safety and efficacy in treating clinical infections caused by these bacteria not established. Active in vitro against some vancomycin-intermediate S. aureus (VISA) and VanB and VanC phenotypes of vancomycin-resistant enterococci (VRE), but VRE with the VanA phenotype have reduced in vitro susceptibility or resistance to dalbavancin.

• Reduced susceptibility or resistance to dalbavancin not produced in vitro by serial passage of S. aureus in the presence of increasing concentrations of the drug.

• Certain intrinsically glycopeptide-resistant bacteria and those expressing the VanA phenotype of acquired resistance to vancomycin may also be resistant to dalbavancin.

• Cross-resistance between dalbavancin and nonglycopeptide anti-infectives unlikely.

Advice to Patients

• Advise patients that antibacterials (including dalbavancin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).

• Importance of completing full course of therapy, even if feeling better after a few days.

• Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with dalbavancin or other antibacterials in the future.

• Advise patients that allergic reactions, including serious allergic reactions, could occur and require immediate treatment. Importance of informing clinician about any previous hypersensitivity reactions to dalbavancin or other glycopeptides (e.g., oritavancin, telavancin, vancomycin).

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued. Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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