DALBAVANCIN HYDROCHLORIDE 500 mg/25mL Injection, Powder, For Solution — NDC 65219-120-12 (Billing 65219-0120-12)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Dalbavancin is an antibacterial drug [see Microbiology ( 12.4 )] .

12.2Pharmacodynamics 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 [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 1,000 mg IV, dalbavancin 1,500 mg IV, oral moxifloxacin 400 mg, or placebo.

Neither dalbavancin 1,000 mg nor dalbavancin 1,500 mg had any clinically relevant adverse effect on cardiac repolarization.

12.3Pharmacokinetics General Pharmacokinetic Properties Dalbavancin pharmacokinetic parameters have been characterized in healthy subjects, patients, and specific populations. Pharmacokinetic parameters following administration of single intravenous 1,000 mg and 1,500 mg doses were as shown in Table 4 . The pharmacokinetics of dalbavancin can be described using a three-compartment model.

Table 4. Dalbavancin Pharmacokinetic Parameters in Healthy Subjects All values are presented as mean (% coefficient of variation) 1 Data from 50 healthy subjects. 2 Data from 12 healthy subjects.

3 Based upon population pharmacokinetic analyses of data from patients, the effective half-life is approximately 8.5 days (204 hours). 4 Data from 49 healthy subjects. Abbreviation: ND – not determined Parameter Single 1,000 mg Dose Single 1,500 mg Dose C max (mg/L) 287 (13.9) 1 423 (13.2) 4 AUC 0-24 (mg•h/L) 3,185 (12.8) 1 4,837 (13.7) 4 AUC 0-Day7 (mg•h/L) 11,160 (41.1) 2 ND AUC 0-inf (mg•h/L) 23,443 (40.9) 2 ND Terminal t ½ (h) 346 (16.5) 2,3 ND CL (L/h) 0.0513 (46.8) 2 ND In healthy subjects, dalbavancin AUC 0-24h and C max both increased proportionally to dose following single IV dalbavancin doses ranging from 140 mg to 1,500 mg, indicating linear pharmacokinetics.

No apparent accumulation of dalbavancin was observed following multiple IV infusions administered once weekly for up to eight weeks, with 1,000 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 1,000 mg IV dalbavancin. The mean ratio of the AUC 0-144 hrs in skin blister fluid/AUC 0-144 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 1,000 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 1,000 mg dalbavancin, the mean plasma clearance (CL T ) was reduced 11%, 3… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Dalbavancin is an antibacterial drug [see Microbiology ( 12.4 )] .

12.3Pharmacokinetics General Pharmacokinetic Properties Dalbavancin pharmacokinetic parameters have been characterized in healthy subjects, patients, and specific populations. Pharmacokinetic parameters following administration of single intravenous 1,000 mg and 1,500 mg doses were as shown in Table 4 . The pharmacokinetics of dalbavancin can be described using a three-compartment model.

Table 4. Dalbavancin Pharmacokinetic Parameters in Healthy Subjects All values are presented as mean (% coefficient of variation) 1 Data from 50 healthy subjects. 2 Data from 12 healthy subjects.

3 Based upon population pharmacokinetic analyses of data from patients, the effective half-life is approximately 8.5 days (204 hours). 4 Data from 49 healthy subjects. Abbreviation: ND – not determined Parameter Single 1,000 mg Dose Single 1,500 mg Dose C max (mg/L) 287 (13.9) 1 423 (13.2) 4 AUC 0-24 (mg•h/L) 3,185 (12.8) 1 4,837 (13.7) 4 AUC 0-Day7 (mg•h/L) 11,160 (41.1) 2 ND AUC 0-inf (mg•h/L) 23,443 (40.9) 2 ND Terminal t ½ (h) 346 (16.5) 2,3 ND CL (L/h) 0.0513 (46.8) 2 ND In healthy subjects, dalbavancin AUC 0-24h and C max both increased proportionally to dose following single IV dalbavancin doses ranging from 140 mg to 1,500 mg, indicating linear pharmacokinetics.

No apparent accumulation of dalbavancin was observed following multiple IV infusions administered once weekly for up to eight weeks, with 1,000 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 1,000 mg IV dalbavancin. The mean ratio of the AUC 0-144 hrs in skin blister fluid/AUC 0-144 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 1,000 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 1,000 mg dalbavancin, the mean plasma clearance (CL T ) 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 CL T , and the associated increase in AUC 0-∞ 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… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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 [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 1,000 mg IV, dalbavancin 1,500 mg IV, oral moxifloxacin 400 mg, or placebo.

Neither dalbavancin 1,000 mg nor dalbavancin 1,500 mg had any clinically relevant adverse effect on cardiac repolarization.

14 CLINICAL STUDIES 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 Secondary Efficacy Results in ABSSSI Patients (Trial 3) 1,2 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 Dalbavancin for Injection, n/N (%) Single Dose (1,500 mg) Another Dalbavancin Dosing Regimen Difference (95% CI) 3 Clinical Responders at 48-72 Hours (ITT) 284/349 (81.4) 294/349 (84.2) -2.9 (-8.5, 2.8) Clinical Success at Day 26-30 (ITT) 295/349 (84.5) 297/349 (85.1) -0.6 (-6.0, 4.8) Clinical Success at Day 26-30 (CE) 250/271 (92.3) 247/267 (92.5) -0.3 (-4.9, 4.4) 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 48-72 hours ≥ 20% reduction in lesion size Clinical Success at Day 26 to 30 Single dose (1,500 mg) Another Dalbavancin Dosing Regimen Single dose (1,500 mg) Another Dalbavancin Dosing Regimen Pathogen n/N (%) n/N (%) n/N (%) n/N (%) Staphylococcus aureus 123/139 (88.5) 133/156 (85.3) 124/139 (89.2) 140/156 (89.7) Methicillin-susceptible Methicillin-resistant 92/103 (89.3) 31/36 (86.1) 89/96 (89.6) 48/61 (78.7) 93/103 (90.3) 31/36 (86.1) 86/96 (89.6) 55/61 (90.2) Streptococcus agalactiae 6/6(100.0) 4/6 (66.7) 5/6 (83.3) 5/6 (83.3) Streptococcus anginosus group 31/33 (93.9) 19/19 (100.0) 29/33 (87.9) 17/19 (89.5) Streptococcus pyogenes 14/14 (100.0) 18/22 (81.8) 13/14 (92.9) 19/22 (86.4) Enterococcus faecalis 4/4 (100.0) 8/10 (80.0) 4/4 (100.0) 9/10 (90.0) In Tria… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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.

13.2Animal 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.