1.1 Acute Bacterial Skin and Skin Structure Infections

DALVANCE® 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).

1.2 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DALVANCE and other antibacterial agents, DALVANCE 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.

2.1 Recommended Dosage Regimen in Adult Patients with CLcr 30 mL/min and Above

The recommended dosage regimen of DALVANCE in adult patients with CLcr 30 mL/min and above is 1500 mg, administered either as a single dose regimen, or as a two-dose regimen of DALVANCE 1000 mg followed one week later by 500 mg. Administer DALVANCE over 30 minutes by intravenous infusion. For adult patients with CLcr less than 30 mL/min, dosage adjustment is required [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

2.2 Recommended Dosage Regimen in Pediatric Patients with CLcr 30 mL/min/1.73m2 and Above

The recommended dosage regimen of DALVANCE in pediatric patients with CLcr 30 mL/min/1.73m2 and above is a single dose regimen based on the age and weight of the pediatric patient (Table 1). Administer DALVANCE over 30 minutes by intravenous infusion.

There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years with CLcr less than 30 mL/min/1.73m2 [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].

*Estimate CLcr or glomerular filtration rate (GFR) using an age-appropriate equation accepted for pediatric

patients (birth to less than 18 years old) to define renal function impairment.

2.3 Dosage Adjustments in Adult Patients with CLcr less than 30 mL/min

In adult patients with renal impairment whose known CLcr is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended dosage regimen of DALVANCE is 1125 mg, administered either as a single dose regimen, or as a two-dose regimen of DALVANCE 750 mg followed one week later by 375 mg.

No dosage adjustment is recommended for adult patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.4 Preparation and Administration

DALVANCE (dalbavancin) for injection must be reconstituted with either Sterile Water for Injection, USP, or 5% Dextrose Injection, USP, and subsequently diluted only with 5% Dextrose Injection, USP, to a final concentration of 1 mg/mL to 5 mg/mL.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitution: DALVANCE must be reconstituted under aseptic conditions, using 25 mL of either Sterile Water for Injection, USP, or 5% Dextrose Injection, USP, for each 500 mg vial. To avoid foaming, alternate between gentle swirling and inversion of the vial until its contents are completely dissolved. Do not shake. The reconstituted vial contains 20 mg/mL dalbavancin as a clear, colorless to yellow solution.

Reconstituted vials may be stored either refrigerated at 2°C to 8 °C (36°F to 46 °F), or at controlled room temperature 20°C to 25 °C (68°F to 77 °F). Do not freeze.

Dilution:

Adult Patients: Aseptically transfer the required dose of reconstituted DALVANCE solution from the vial(s) to an intravenous bag or bottle containing 5% Dextrose Injection, USP. The diluted solution must have a final dalbavancin concentration of 1 mg/mL to 5 mg/mL. Discard any unused portion of the reconstituted solution.

Pediatric Patients: For pediatric patients, the dose of DALVANCE will vary according to the age and weight of the child up to a maximum of 1500 mg [see Dosage and Administration (2.2)]. Aseptically transfer the required dose of reconstituted DALVANCE solution, based on the child’s weight, from the vial(s) to an intravenous bag or bottle containing 5% Dextrose Injection, USP. The diluted solution must have a final dalbavancin concentration of 1 mg/mL to 5 mg/mL. Discard any unused portion of the reconstituted solution.

Once diluted into an intravenous bag or bottle as described above, DALVANCE may be stored either refrigerated at 2 °C to 8 °C (36 °F to 46 °F) or at a controlled room temperature of 20°C to 25 °C (68 °F to 77 °F). Do not freeze.

The total time from reconstitution to dilution to administration should not exceed 48 hours.

Like all parenteral drug products, diluted DALVANCE should be inspected visually for particulate matter prior to infusion. If particulate matter is identified, do not use.

Administration: After reconstitution and dilution, administer DALVANCE via intravenous infusion, using a total infusion time of 30 minutes.

Do not co-infuse DALVANCE with other medications or electrolytes. Saline-based infusion solutions may cause precipitation and should not be used. The compatibility of reconstituted DALVANCE with intravenous medications, additives, or substances other than 5% Dextrose Injection, USP has not been established.

If a common intravenous line is being used to administer other drugs in addition to DALVANCE, the line should be flushed before and after each DALVANCE infusion with 5% Dextrose Injection, USP.

5.1 Hypersensitivity Reactions

Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with DALVANCE. If an allergic reaction to DALVANCE occurs, discontinue treatment with DALVANCE and institute appropriate therapy for the allergic reaction. Before using DALVANCE, 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 DALVANCE in patients with a history of glycopeptide allergy [see Patient Counseling Information (17)].

5.2 Infusion-Related Reactions

DALVANCE 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 DALVANCE 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.

5.3 Hepatic Effects

In Phase 2 and 3 clinical trials, more DALVANCE 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 DALVANCE and comparator arms [see Adverse Reactions (6.1)].

5.4 Clostridioides difficile-Associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including DALVANCE, 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.

5.5 Development of Drug-Resistant Bacteria

Prescribing DALVANCE 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of DALVANCE 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 2473 patients treated with DALVANCE: 1778 patients were treated with DALVANCE in seven Phase 2/3 trials comparing DALVANCE to comparator antibacterial drugs and 695 patients were treated with DALVANCE in one Phase 3 trial comparing DALVANCE single and two-dose regimens. The median age of patients treated with DALVANCE was 48 years, ranging between 16 and 93 years. Patients treated with DALVANCE were predominantly male (59.5%) and White (81.2%).

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

Serious adverse reactions occurred in 121/2473 (4.9%) of patients treated with any regimen of DALVANCE. In the Phase 2/3 trials comparing DALVANCE to comparator, serious adverse reactions occurred in 109/1778 (6.1%) of patients in the DALVANCE group and 80/1224 (6.5%) of patients in the comparator group. In a Phase 3 trial comparing DALVANCE single and two-dose regimens, serious adverse reactions occurred in 7/349 (2.0%) of patients in the DALVANCE single dose group and 5/346 (1.4%) of patients in the DALVANCE two-dose group. DALVANCE was discontinued due to an adverse reaction in 64/2473 (2.6%) patients treated with any regimen of DALVANCE. In the Phase 2/3 trials comparing DALVANCE to comparator, DALVANCE was discontinued due to an adverse reaction in 53/1778 (3.0%) of patients in the DALVANCE group and 35/1224 (2.9%) of patients in the comparator group. In a Phase 3 trial comparing DALVANCE single and two-dose regimens, DALVANCE was discontinued due to an adverse reaction in 6/349 (1.7%) of patients in the DALVANCE single dose group and 5/346 (1.4%) of patients in the DALVANCE two-dose group.

Most Common Adverse Reactions

The most common adverse reactions in patients treated with DALVANCE 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 DALVANCE. In the Phase 2/3 trials comparing DALVANCE to comparator, the median duration of adverse reactions was 3.0 days for patients in the DALVANCE group and 4.0 days in patients in the comparator group. In a Phase 3 trial comparing DALVANCE single and two-dose regimens, the median duration of adverse reactions was 3.0 days for patients in the DALVANCE single and two-dose group.

Table 2 lists selected adverse reactions occurring in 2% or more of patients treated with DALVANCE in Phase 2/3 clinical trials.

In the Phase 3 trial comparing the single and two-dose regimen of DALVANCE, the adverse reaction that occurred in 2% or more of patients treated with DALVANCE was nausea (3.4% in the DALVANCE single dose group and 2% in the DALVANCE two-dose group).

The following selected adverse reactions were reported in DALVANCE 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 disorders: gastrointestinal hemorrhage, melena, hematochezia, abdominal pain

General disorders 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

Metabolism and nutrition disorders: hypoglycemia

Nervous system disorders: dizziness

Respiratory, thoracic and mediastinal disorders: bronchospasm

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria

Vascular disorders: flushing, phlebitis, wound hemorrhage, spontaneous hematoma

Alanine Aminotransferase (ALT) Elevations

Among patients with normal baseline ALT levels treated with DALVANCE 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-DALVANCE 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 DALVANCE 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 DALVANCE-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 DALVANCE (83 patients treated with a single dose of DALVANCE and 78 patients treated with a two-dose regimen of DALVANCE) and 30 patients treated with comparator agents for a treatment period up to 14 days. The median age of pediatric patients treated with DALVANCE 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 DALVANCE 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 DALVANCE, all in the single-dose arm. There were no adverse reactions leading to DALVANCE 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 DALVANCE-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

6.2 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 [See Warnings and Precautions (5.2)].

7.1 Drug-Laboratory Test Interactions

Drug-laboratory test interactions have not been reported. DALVANCE at therapeutic concentrations does not artificially prolong prothrombin time (PT) or activated partial thromboplastin time (aPTT).

7.2 Drug-Drug Interactions

No clinical drug-drug interaction studies have been conducted with DALVANCE. There is minimal potential for drug-drug interactions between DALVANCE and cytochrome P450 (CYP450) substrates, inhibitors, or inducers [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies with DALVANCE 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 [see Data].

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).

8.2 Lactation

Risk Summary

There are no data on the presence of dalbavancin or its metabolite in human milk, the effects on the breast-fed child, or the effects on milk production. Dalbavancin is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DALVANCE and any potential adverse effects on the breast-fed child from DALVANCE or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of DALVANCE for the treatment of ABSSSI has been established in pediatric patients aged birth to less than 18 years. Use of DALVANCE 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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

There is insufficient information to recommend dosage adjustment for pediatric patients with ABSSSI and CLcr less than 30 mL/min/1.73m2 [see Dosage and Administration (2.2)].

8.5 Geriatric Use

Of the 2473 patients treated with DALVANCE in Phase 2 and 3 clinical trials, 403 patients (16.3%) were 65 years of age or older. The efficacy and tolerability of DALVANCE were similar to comparator regardless of age. The pharmacokinetics of DALVANCE was not significantly altered with age; therefore, no dosage adjustment is necessary based on age alone.

DALVANCE is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this age group.

8.6 Renal Impairment

In patients with renal impairment whose known CLcr is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended regimen for DALVANCE is 1125 mg, administered as a single dose, or 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis. There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years with CLcr less than 30 mL/min/1.73m2 [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage adjustment of DALVANCE is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Caution should be exercised when prescribing DALVANCE to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) as no data are available to determine the appropriate dosing in these patients [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Dalbavancin is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

The antibacterial activity of dalbavancin appears to best correlate with the ratio of area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) for Staphylococcus aureus based on animal models of infection. An exposure-response analysis of a single study in patients with complicated skin and skin structure infections supports the two-dose regimen [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].

Cardiac Electrophysiology

In a randomized, positive- and placebo-controlled, thorough QT/QTc study, 200 healthy subjects received dalbavancin 1000 mg IV, dalbavancin 1500 mg IV, oral moxifloxacin 400 mg, or placebo. Neither dalbavancin 1000 mg nor dalbavancin 1500 mg had any clinically relevant adverse effect on cardiac repolarization.

12.3 Pharmacokinetics

General Pharmacokinetic Properties

Dalbavancin pharmacokinetic parameters have been characterized in healthy subjects, patients, and specific populations. Pharmacokinetic parameters following administration of single intravenous 1000 mg and 1500 mg doses were as shown in Table 4. The pharmacokinetics of dalbavancin can be described using a three-compartment model.

In healthy subjects, dalbavancin AUC0-24h and Cmax both increased proportionally to dose following single IV dalbavancin doses ranging from 140 mg to 1500 mg, indicating linear pharmacokinetics.

The mean plasma concentration-time profile for dalbavancin following the recommended two-dose regimen of 1000 mg followed one week later by 500 mg is shown in Figure 2.

Figure 2. Mean (± standard deviation) dalbavancin plasma concentrations versus time in healthy subjects (n=10) following IV administration over 30 minutes of 1000 mg dalbavancin (Day 1) and 500 mg dalbavancin (Day 8).

No apparent accumulation of dalbavancin was observed following multiple IV infusions administered once weekly for up to eight weeks, with 1000 mg on Day 1 followed by up to seven weekly 500 mg doses, in healthy adults with normal renal function.

Distribution

Dalbavancin is reversibly bound to human plasma proteins, primarily to albumin. The plasma protein binding of dalbavancin is approximately 93% and is not altered as a function of drug concentration, renal impairment, or hepatic impairment. The mean concentrations of dalbavancin achieved in skin blister fluid remain above 30 mg/L up to 7 days (approximately 146 hours) post dose, following 1000 mg IV dalbavancin. The mean ratio of the AUC0-144 hrs in skin blister fluid/AUC0-144 hrs in plasma is 0.60 (range 0.44 to 0.64).

Metabolism

In vitro studies using human microsomal enzymes and hepatocytes indicate that dalbavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. A minor metabolite of dalbavancin (hydroxy-dalbavancin) has been observed in the urine of healthy subjects. Quantifiable concentrations of the hydroxy-dalbavancin metabolite have not been observed in human plasma (lower limit of quantitation = 0.4 µg/mL) [see Drug Interactions (7.2)].

Excretion

Following administration of a single 1000 mg dose in healthy subjects, 20% of the dose was excreted in feces through 70 days post dose. An average of 33% of the administered dalbavancin dose was excreted in urine as unchanged dalbavancin and approximately 12% of the administered dose was excreted in urine as the metabolite hydroxy-dalbavancin through 42 days post dose.

Specific 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.

Following a single dose of 500 mg or 1000 mg dalbavancin, the mean plasma clearance (CLT) was reduced 11%, 35%, and 47% in subjects with CLcr 50 to 79 mL/min, CLcr 30 to 49 mL/min, and CLcr less than 30 mL/min, respectively, compared to subjects with normal renal function. The clinical significance of the decrease in mean plasma CLT, and the associated increase in AUC0-∞ noted in these pharmacokinetic studies of dalbavancin in subjects with CLcr less than 30 mL/min has not been established [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Dalbavancin pharmacokinetic parameters in subjects with end-stage renal disease receiving regularly scheduled hemodialysis (three times/week) are similar to those observed in subjects with mild to moderate renal impairment, and less than 6% of an administered dose is removed after three hours of hemodialysis.

Therefore, no dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and dalbavancin may be administered without regard to the timing of hemodialysis in such patients [see Dosage and Administration (2.1), Overdosage (10)].

Hepatic Impairment

The pharmacokinetics of dalbavancin were evaluated in 17 subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B or C) and compared to those in nine matched healthy subjects with normal hepatic function. The mean AUC0-336 hrs was unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function; however, the mean AUC0-336 hrs decreased 28% and 31% in subjects with moderate and severe hepatic impairment respectively, compared to subjects with normal hepatic function. The clinical significance of the decreased AUC0-336 hrs in subjects with moderate and severe hepatic function is unknown.

No dosage adjustment is recommended for patients with mild hepatic impairment. Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment as no data are available to determine the appropriate dosing.

Gender

Clinically significant gender-related differences in dalbavancin pharmacokinetics have not been observed either in healthy subjects or in patients with infections. No dosage adjustment is recommended based on gender.

Geriatric Patients

Clinically significant age-related differences in dalbavancin pharmacokinetics have not been observed in patients with infections. No dosage adjustment is recommended based solely on age.

Pediatric Patients

The pharmacokinetics of dalbavancin has been evaluated in 211 individual pediatric patients [4 days to 17.9 years of age, including a preterm neonate (gestational age 36 weeks; n=1) and term neonates (gestational age 37 to 40 weeks; n=4)] with CLcr 30 mL/min/1.73 m2 and above. There is insufficient information to assess the exposure of DALVANCE in the pediatric patients with CLcr less than 30 mL/min/1.73 m2. No clinically important differences in drug exposure between pediatric age groups (including preterm neonates) and adults are expected following administration of the age-dependent recommended single dose of DALVANCE. The median plasma AUC from 0 to 120 hours (AUC0-120h) of dalbavancin in pediatric patient age groups from term neonates at birth to less than 18 years is expected to be comparable to that in adult patients (AUC0-120h, 10400 mg*h/L). The expected median plasma AUC0-120h of dalbavancin in preterm neonates at birth (gestational age 26 weeks to <37 weeks) was approximately 62% of that in adult patients. The expected median maximum plasma concentrations (Cmax) of dalbavancin for pediatric patient age groups ranged between approximately 53% to 73% of that in adult patients (Cmax, 412 mg/L). However, in all pediatric age groups, the percentage of patients attaining PK/PD targets related to in vivo drug activity were above 90% or higher for MICs up to 0.25 mg/L.

Drug Interactions

Nonclinical studies demonstrated that dalbavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. In a population pharmacokinetic analysis, dalbavancin pharmacokinetics were not affected by co-administration with known CYP450 substrates, inducers or inhibitors, nor by individual medications including acetaminophen, aztreonam, fentanyl, metronidazole, furosemide, proton pump inhibitors (omeprazole, esomeprazole, pantoprazole, lansoprazole), midazolam, and simvastatin.

12.4 Microbiology

Mechanism of Action

Dalbavancin, a semisynthetic lipoglycopeptide, interferes with cell wall synthesis by binding to the D-alanyl-D-alanine terminus of the stem pentapeptide in nascent cell wall peptidoglycan, thus preventing cross-linking. Dalbavancin is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations similar to those sustained throughout treatment in humans treated according to the recommended dosage regimen.

Resistance

The development of bacterial isolates resistant to dalbavancin has not been observed, either in vitro, in studies using serial passage, or in animal infection experiments.

Interaction with Other Antimicrobials

When tested in vitro, dalbavancin demonstrated synergistic interactions with oxacillin and did not demonstrate antagonistic or synergistic interactions with any of the following antibacterial agents of various classes: gentamicin, vancomycin, levofloxacin, clindamycin, quinupristin/dalfopristin, linezolid, aztreonam, rifampin or daptomycin. The clinical significance of these in vitro findings is unknown.

Antimicrobial Activity

Dalbavancin has been shown to be active against the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Aerobic bacteria

Gram-positive bacteria

Staphylococcus aureus (including methicillin-resistant isolates)

Streptococcus pyogenes

Streptococcus agalactiae

Streptococcus dysgalactiae

Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus)

Enterococcus faecalis (vancomycin-susceptible isolates only)

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for dalbavancin against isolates of similar genus or organism group. However, the efficacy of dalbavancin in treating clinical infections caused by these bacteria has not been established in adequate well-controlled clinical trials.

Aerobic bacteria

Gram-positive bacteria

Enterococcus faecium (vancomycin-susceptible isolates only)

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to determine the carcinogenic potential of dalbavancin have not been conducted.

Mutagenesis

Dalbavancin was not genotoxic in a bacterial reverse mutation (Ames) assay, a mammalian HGPRT gene mutation assay, an in vitro chromosome aberration assay in Chinese Hamster Ovary cells, or an in vivo mouse micronucleus assay.

Impairment of Fertility

Impaired fertility in the rat was not observed at a dose of 15 mg/kg/day (1.2 times the human dose on an exposure basis). Reductions in male and female fertility and increased embryo resorptions occurred at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis), at which signs of parental toxicity were also observed.

13.2 Animal Toxicology and/or Pharmacology

Increases in serum levels of liver enzymes (ALT, AST), associated with microscopic findings in the liver were noted in toxicology studies in rats and dogs where dalbavancin was administered daily for 28 to 90 days. Hepatocellular necrosis was observed in dogs dosed at ≥10 mg/kg/day for longer than 2 months, i.e., at approximately 5 to 7 times the expected human dose on an exposure basis. Histiocytic vacuolation and hepatocyte necrosis were observed in rats dosed daily at 40 and 80 mg/kg/day, respectively, for 4 weeks, (approximately 3 and 6 times the expected human dose on an exposure basis, respectively). In addition, renal toxicity characterized by increases in serum BUN and creatinine and microscopic kidney findings was observed in rats and dogs at doses 5 to 7 times the expected human dose on an exposure basis. The relationship between these findings in the animal toxicology studies after 28 and 90 consecutive days of dosing to the indicated clinical dosing of 2 doses 7 days apart are unclear.