Dalbavancin Drug Information
Generic name: DALBAVANCIN
Uses of Dalbavancin
Acute Bacterial Skin and Skin Structure Infections Dalbavancin for injection is indicated
for the treatment of adult and pediatric patients with acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible strains of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus ) and Enterococcus faecalis (vancomycin susceptible isolates).
Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness
of dalbavancin for injection and other antibacterial agents, dalbavancin for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Dosage & Administration of Dalbavancin
| 30 mL/min and above or on regular hemodialysis | 1,500 mg |
|---|---|
| Less than 30 mL/min and not on regular hemodialysis | 1,125 mg |
Side Effects of Dalbavancin
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of dalbavancin for injection cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. Clinical Trials Experience in Adult Patients Adverse reactions were evaluated for 2,473 patients treated with dalbavancin for injection: 1,778 patients were treated with dalbavancin for injection in seven Phase 2/3 trials comparing dalbavancin for injection to comparator antibacterial drugs and 695 patients were treated with dalbavancin for injection in one Phase 3 trial comparing dalbavancin for injection single-dose and another dalbavancin dosing regimen. The median age of patients treated with dalbavancin for injection was 48 years, ranging between 16 and 93 years.
Patients treated with dalbavancin for injection were predominantly male (59.5%) and White (81.2%). Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Serious adverse reactions occurred in 121/2,473 (4.9%) of patients treated with any regimen of dalbavancin for injection. In the Phase 2/3 trials comparing dalbavancin for injection to comparator, serious adverse reactions occurred in 109/1,778 (6.1%) of patients in the dalbavancin for injection group and 80/1,224 (6.5%) of patients in the comparator group. In a Phase 3 trial comparing dalbavancin for injection single-dose and another dalbavancin dosing regimen, serious adverse reactions occurred in 7/349 (2.0%) of patients in the dalbavancin for injection single dose group and 5/346 (1.4%) of patients in another dalbavancin dosing regimen group.
Dalbavancin for injection was discontinued due to an adverse reaction in 64/2,473 (2.6%) patients treated with any regimen of dalbavancin for injection. In the Phase 2/3 trials comparing dalbavancin for injection to comparator, dalbavancin for injection was discontinued due to an adverse reaction in 53/1,778 (3.0%) of patients in the dalbavancin for injection group and 35/1,224 (2.9%) of patients in the comparator group. In a Phase 3 trial comparing dalbavancin for injection single-dose and another dalbavancin dosing regimen, dalbavancin for injection was discontinued due to an adverse reaction in 6/349 (1.7%) of patients in the dalbavancin for injection single dose group and 5/346 (1.4%) of patients in another dalbavancin dosing regimen group.
Most Common Adverse Reactions The most common adverse reactions in patients treated with dalbavancin for injection in Phase 2/3 trials were nausea (5.5%), headache (4.7%), and diarrhea (4.4%). The median duration of adverse reactions was 3.0 days in patients treated with dalbavancin for injection. In the Phase 2/3 trials comparing dalbavancin for injection to comparator, the median duration of adverse reactions was 3.0 days for patients in the dalbavancin for injection group and 4.0 days in patients in the comparator group. In a Phase 3 trial comparing dalbavancin for injection single-dose and another dalbavancin dosing regimen, the median duration of adverse reactions was 3.0 days for patients in the dalbavancin for injection single-dose and another dalbavancin dosing regimen group.
Table 2 lists selected adverse reactions occurring in 2% or more of patients treated with dalbavancin for injection in Phase 2/3 clinical trials. Table 2. Selected Adverse Reactions Occurring in ≥ 2% of Patients Receiving Dalbavancin for Injection in Phase 2/3 Trials (Number (%) of Patients) Adverse Reactions Dalbavancin for Injection Comparator* (N = 1,778) (N = 1,224) Nausea 98 78 Diarrhea 79 72 Headache 83 59 Vomiting 50 37 Rash 48 30 Pruritus 38 41 * Comparators included linezolid, cefazolin, cephalexin, and vancomycin. In the Phase 3 trial comparing the single dose and another dalbavancin for injection dosing regimen the adverse reaction that occurred in 2% or more of patients treated with dalbavancin for injection was nausea (3.4% in the dalbavancin for injection single dose group and 2% in another dalbavancin dosing regimen group). The following selected adverse reactions were reported in dalbavancin for injection treated patients at a rate of less than 2% in these clinical trials: Blood and lymphatic system disorders : anemia, hemorrhagic anemia, leucopenia, neutropenia, thrombocytopenia, petechiae, eosinophilia, thrombocytosis Gastrointestinal d isorders : gastrointestinal hemorrhage, melena, hematochezia, abdominal pain General d isorders and administration site conditions : infusion-related reactions Hepatobiliary disorders : hepatotoxicity Immune system disorders : anaphylactic reaction Infections and infestations : Clostridioides difficile colitis, oral candidiasis, vulvovaginal mycotic infection Investigations : hepatic transaminases increased, blood alkaline phosphatase increased, international normalized ratio increased, blood lactate dehydrogenase increased, gamma-glutamyl transferase increased Metaboli sm and nutrition disorders : hypoglycemia Nervous s ystem disorders : dizziness Respiratory, thoracic and media s tinal disorders : bronchospasm Skin and s ubcutaneous t issue d isorders : rash, pruritus, urticaria Vascular disorders : flushing, phlebitis, wound hemorrhage, spontaneous hematoma Alanine Aminotransferase (ALT) Elevations Among patients with normal baseline ALT levels treated with dalbavancin for injection 17 (0.8%) had post-baseline ALT elevations greater than 3 times the upper limit of normal (ULN) including five subjects with post-baseline ALT values greater than 10 times ULN. Among patients with normal baseline ALT levels treated with non-dalbavancin for injection comparators 2 (0.2%) had post-baseline ALT elevations greater than 3 times the upper limit of normal.
Fifteen of the 17 patients treated with dalbavancin for injection and one comparator patient had underlying conditions which could affect liver enzymes, including chronic viral hepatitis, history of alcohol abuse and metabolic syndrome. In addition, one dalbavancin for injection-treated subject in a Phase 1 trial had post-baseline ALT elevations greater than 20 times ULN. ALT elevations were reversible in all subjects with follow-up assessments. No comparator-treated subject with normal baseline transaminases had post-baseline ALT elevation greater than 10 times ULN. Clinical Trials Experience in Pediatric Patients Adverse reactions were evaluated in one Phase 3 pediatric clinical trial which included 161 pediatric patients from birth to less than 18 years of age with ABSSSI treated with dalbavancin for injection (83 patients treated with a single dose of dalbavancin for injection and 78 patients treated with another dalbavancin dosing regimen) and 30 patients treated with comparator agents for a treatment period up to 14 days.
The median age of pediatric patients treated with dalbavancin for injection was 9 years, ranging from birth to <18 years. The majority of patients were male (62.3%) and White (89.0%). The safety findings of dalbavancin for injection in pediatric patients were similar to those observed in adults. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Serious adverse reactions (SARs) occurred in 3/161 (1.9%) of patients treated with dalbavancin for injection, all in the single-dose arm.
There were no adverse reactions leading to dalbavancin for injection discontinuation. Most Common Adverse Reactions Most common adverse reaction occurring in more than 1% of pediatric patients 2/161 (1.2%) was pyrexia. Other Adverse Reactions The following selected adverse reactions were reported in dalbavancin for injection-treated patients at a rate of less than 1% in this pediatric clinical trial: Gastrointestinal disorders : diarrhea Nervous system disorders : dizziness Skin and subcutaneous tissue disorders : pruritus
Post Marketing Experience
The following adverse reaction has been identified during post-approval use of dalbavancin. Because the reaction is reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the frequency or establish a causal relationship to drug exposure. General disorders and administration site conditions: Back pain as an infusion-related reaction.
Warnings & Cautions for Dalbavancin
Hypersensitivity Reactions Serious hypersensitivity (anaphylactic) and skin reactions have been reported in
patients treated with dalbavancin for injection. If an allergic reaction to dalbavancin for injection occurs, discontinue treatment with dalbavancin for injection and institute appropriate therapy for the allergic reaction. Before using dalbavancin for injection, inquire carefully about previous hypersensitivity reactions to other glycopeptides.
Due to the possibility of cross-sensitivity, carefully monitor for signs of hypersensitivity during treatment with dalbavancin for injection in patients with a history of glycopeptide allergy .
Infusion - Related Reactions Dalbavancin for injection is administered via intravenous infusion
using a total infusion time of 30 minutes to minimize the risk of infusion-related reactions. Rapid intravenous infusions of dalbavancin for injection can cause flushing of the upper body, urticaria, pruritus, rash, and/or back pain. Stopping or slowing the infusion may result in cessation of these reactions.
Hepatic Effects
In Phase 2 and 3 clinical trials, more dalbavancin for injection than comparator-treated subjects with normal baseline transaminase levels had post-baseline alanine aminotransferase (ALT) elevation greater than 3 times the upper limit of normal (ULN). Overall, abnormalities in liver tests (ALT, AST, bilirubin) were reported with similar frequency in the dalbavancin for injection and comparator arms.
Clostridioides difficile - Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been
reported in users of nearly all systemic antibacterial drugs, including dalbavancin for injection, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy.
CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible.
Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Development of Drug-Resistant Bacteria Prescribing dalbavancin for injection in the absence of
a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Drug Interactions with Dalbavancin
Drug-Laboratory Test Interactions Drug-laboratory test interactions have not been reported. Dalbavancin for
injection at therapeutic concentrations does not artificially prolong prothrombin time (PT) or activated partial thromboplastin time (aPTT).
Drug-Drug Interactions No clinical drug-drug interaction studies have been conducted with dalbavancin
for injection. There is minimal potential for drug-drug interactions between dalbavancin for injection and cytochrome P450 (CYP450) substrates, inhibitors, or inducers .
Pregnancy Safety for Dalbavancin
Pregnancy Risk Summary There are no adequate and well-controlled studies with dalbavancin for injection use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse developmental outcomes. No treatment-related malformations or embryo-fetal toxicity were observed in pregnant rats or rabbits at clinically relevant exposures of dalbavancin. Treatment of pregnant rats with dalbavancin at 3.5 times the human dose on an exposure basis during early embryonic development and from implantation to the end of lactation resulted in delayed fetal maturation and increased fetal loss, respectively . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data No evidence of embryo or fetal toxicity was found in the rat or rabbit at a dose of 15 mg/kg/day (1.2 and 0.7 times the human dose on an exposure basis, respectively). Delayed fetal maturation was observed in the rat at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis). In a rat prenatal and postnatal development study, increased embryo lethality and increased offspring deaths during the first week post-partum were observed at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis).
Pediatric Use of Dalbavancin
Pediatric Use The safety and effectiveness of dalbavancin for injection for the treatment of ABSSSI has been established in pediatric patients aged birth to less than 18 years. Use of dalbavancin for injection for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged birth to less than 18 years . There is insufficient information to recommend dosage adjustment for pediatric patients with ABSSSI and CLcr less than 30 mL/min/1.73m 2.
Contraindications for Dalbavancin
Dalbavancin for injection is contraindicated in patients with known hypersensitivity to dalbavancin. Known hypersensitivity to dalbavancin
Overdosage Information for Dalbavancin
Specific information is not available on the treatment of overdose with dalbavancin for injection, as dose-limiting toxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers have been administered cumulative doses of up to 4,500 mg over a period of up to 8 weeks (not an approved dosing regimen), with no signs of toxicity or laboratory results of clinical concern. Treatment of overdose with dalbavancin for injection should consist of observation and general supportive measures.
Although no information is available specifically regarding the use of hemodialysis to treat overdose, in a Phase 1 study in patients with renal impairment less than 6% of the recommended dalbavancin dose was removed.
Clinical Studies of Dalbavancin
Clinical Studies of Dalbavancin for Injection in Adult Patients with Acute Bacterial Skin and Skin Structure Infections Dalbavancin for Injection 1,500 mg Single Dose Regimen Adult patients with ABSSSI were enrolled in a Phase 3, double-blind, clinical trial. The ITT population included 698 patients who were randomized to dalbavancin for injection treatment with either a single 1,500 mg dose or another dalbavancin dosing regimen (Trial 3). Patients with creatinine clearance less than 30 mL/min had their dose adjusted (Section 2.2). Approximately 5% of patients also received a protocol-specified empiric course of treatment with intravenous aztreonam for coverage of Gram-negative pathogens. The specific infections and other patient characteristics in this trial were similar to those described above for previous ABSSSI trials.
The primary endpoint in this ABSSSI trial was the clinical response rate where responders were defined as patients who had at least a 20% decrease from baseline in lesion area 48 to 72 hours after randomization without receiving any rescue antibacterial therapy. The secondary endpoint was the clinical success rate at a follow-up visit occurring between Days 26 and 30, with clinical success defined as having at least a 90% decrease from baseline in lesion size, a temperature of 37.6°C or lower, and meeting pre-specified criteria for local signs: purulent discharge and drainage absent or mild and improved from baseline (for patients with wound infections), heat/warmth and fluctuance absent, swelling/induration and tenderness to palpation absent or mild. Table 9 summarizes results for these two endpoints in the ITT population.
Note that there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at the follow-up visit. Therefore, comparisons between treatment groups based on clinical success rates at this visit cannot be utilized to establish non-inferiority. Table 9. Primary and Another Dalbavancin Dosing Regimen Efficacy Results in ABSSSI Patients (Trial 3) 1,2 Dalbavancin for Injection, n/N (%) Single Dose (1,500 mg) Another Dalbavancin Dosing Regimen Difference (95% CI) 3 Clinical Responders at 48 to 72 Hours (ITT) 284/349 294/349 -2.9 (-8.5, 2.8) Clinical Success at Day 26 to 30 (ITT) 295/349 297/349 -0.6 (-6.0, 4.8) Clinical Success at Day 26 to 30 (CE) 250/271 247/267 -0.3 (-4.9, 4.4) 1 There were 3 patients in another dalbavancin dosing regimen group who did not receive treatment and were counted as non-responders. 2 Patients who died or used non-study antibacterial therapy or had missing measurements were classified as non-responders. 3 The 95% Confidence Interval (CI) is computed using the Miettinen and Nurminen approach.
Abbreviations: ITT-intent to treat; CE-clinically evaluable Table 10 shows outcomes in patients with an identified baseline pathogen from Trial 3 in the microbiological ITT (microITT) population. The outcomes shown in the table are clinical response rates at 48 to 72 hours and clinical success rates at follow-up (Day 26 to 30), as defined above. Table 10. Outcomes by Baseline Pathogen (Trial 3; MicroITT) Early Clinical Response at 48 to 72 hours ≥ 20% reduction in lesion size Clinical Success at Day 26 to 30 Pathogen Single dose (1,500 mg) n/N (%) Another Dalbavancin Dosing Regimen Single dose (1,500 mg) n/N (%) Another Dalbavancin Dosing Regimen Staphylococcus aureus 123/139 133/156 124/139 140/156 Methicillin-susceptible Methicillin-resistant 92/103 31/36 89/96 48/61 93/103 31/36 86/96 55/61 Streptococcus agalactiae 6/6 4/6 5/6 5/6 Streptococcus anginosus group 31/33 19/19 29/33 17/19 Streptococcus pyogenes 14/14 18/22 13/14 19/22 Enterococcus faecalis 4/4 8/10 4/4 9/10 In Trials 1, 2, and 3, all patients had blood cultures obtained at baseline.
A total of 40 ABSSSI patients who received dalbavancin for injection had bacteremia at baseline caused by one or more of the following bacteria: 26 S. aureus (21 MSSA and 5 MRSA), 6 S. agalactiae, 7 S. pyogenes, 2 S. anginosus group, and 1 E. faecalis. In patients who received dalbavancin for injection, a total of 34/40 (85%) were clinical responders at 48 to 72 hours and 32/40 (80%) were clinical successes at Day 26 to 30. Clinical Study of Dalbavancin for Injection in Pediatric Patients with Acute Bacterial Skin and Skin Structure Infections The pediatric trial was a multicenter, open-label, randomized, actively controlled trial (NCT02814916, Trial 4) conducted in pediatric patients 3 months of age to less than 18 years with ABSSSI, not known or expected to be caused exclusively by Gram-negative organisms. Patients were randomized in a 3:3:1 ratio to receive either dalbavancin for injection single-dose regimen, another dalbavancin dosing regimen, or comparator.
The comparator regimens included intravenous vancomycin for methicillin-resistant Gram-positive infections, or intravenous oxacillin or flucloxacillin for methicillin-susceptible Gram-positive infections. Patients in the comparator arm received intravenous treatment for a minimum of 72 hours before an optional switch to oral therapy to complete a total of 10 to 14 days of antibacterial drug therapy. Additional 5 patients from birth to < 3 months of age were enrolled and assigned to the dalbavancin for injection single-dose regimen.
A study population of 191 pediatric patients received study medication (dalbavancin for injection single dose regimen n=83, another dalbavancin dosing regimen n=78, comparator n=30); 62% of the patients were male and 89% were white, and 83% were from Eastern Europe. The pediatric age groups who received dalbavancin for injection were as follows: 12 to < 18 years (n=58), 6 to < 12 years (n=49), 2 to < 6 years (n=35), 3 months to < 2 years (n=14), and birth < 3 months (n=5). Patients had diagnoses of major cutaneous abscess (53%), cellulitis (29%), or surgical site/traumatic wound infection (18%). The predominant pathogen at baseline was Staphylococcus aureus (84%). The primary objective was to evaluate the safety and tolerability of dalbavancin for injection. The trial was not powered for a comparative inferential efficacy analysis.
Efficacy was assessed in the modified intent-totreat population (n=183) which included all randomized patients who received any dose of study drug and had a diagnosis of ABSSSI caused by Gram-positive organism(s). Patients with ABSSSI only caused by Gram-negative organisms were excluded. The five patients in the age group birth to < 3 months of age were not included in efficacy analyses since they were enrolled with expanded inclusion criteria and only received the single dose dalbavancin for injection regimen. An early clinical response at 48 to 72 hours was defined as ≥ 20% reduction in lesion size compared to baseline and no receipt of rescue antibacterial therapy.
The proportion of patients with early clinical response, was 97.3% (73/75) in the dalbavancin for injection single-dose arm, 93.6% (73/78) in another dalbavancin dosing regimen arm, and 86.7% (26/30) in the comparator arm. The difference in responder rates between the dalbavancin single-dose and comparator arms was 10.7%, with an exact 97.5% confidence interval (CI) of (-1.7%, 31.6%). The difference in responder rates between another dalbavancin dosing regimen and comparator arms was 6.9%, with an exact 97.5% CI of (-6.4%, 27.7%). Clinical cure was defined as resolution of the clinical signs and symptoms of infection, when compared to baseline, and no additional antibacterial treatment for the disease under study. In patients, 3 months of age or older in the mITT population, the clinical cure rate at the test of cure (TOC) visit (28 ± 2 days) was 94.7% (71/75) in the dalbavancin for injection single-dose arm, 92.3% (72/78) in another dalbavancin dosing regimen arm and 100% (30/30) in the comparator arm.
The difference in cure rates between the dalbavancin single-dose and comparator arms was -5.3%, with an exact 97.5% CI of (-15.1%, 10.5%). The difference in cure rates between another dalbavancin dosing regimen and comparator arms was -7.7%, with an exact 97.5% CI of (-17.9%, 8.3%).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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