Dalbavancin

1 INDICATION AND USAGE Dalbavancin for injection is a lipoglycopeptide antibacterial indicated for the treatment of adult and pediatric patients with acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible strains of Gram-positive microorganisms. ( 1.1 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of dalbavancin for injection and other antibacterial drugs, dalbavancin for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.2 ) 1.1 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). 1.2 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.

2 DOSAGE AND ADMINISTRATION Dosage in Adult Patients ( 2.1 , 2.3 ): Estimated Creatinine Clearance ( C L cr) Single Dose Regimen 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 Administer by intravenous infusion over 30 minutes ( 2.1 , 2.4 ) See Full Prescribing Information for instructions on reconstitution of lyophilized powder and preparation of injection ( 2.4 ) Dosage in Pediatric Patients with CLcr 30 mL/min/1.73m 2 and above ( 2.2 ) Age Range Dosage (Single Dose Regimen) Birth to less than 6 years 22.5 mg/kg (maximum of 1,500 mg) 6 to less than 18 years 18 mg/kg (maximum of 1,500 mg) Dosage adjustment in pediatric patients with CLcr less than 30 mL/min has not been studied. 2.1 Recommended Dos ag e Regimen in Adult Patients with CLcr 30 mL/min and Above The recommended dosage regimen of dalbavancin for injection in adult patients with CLcr 30 mL/min and above is 1,500 mg, administered as a single dose regimen. Administer dalbavancin for injection 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/ 1.73m 2 and Abov e The recommended dosage regimen of dalbavancin for injection in pediatric patients with CLcr 30 mL/min/1.73m 2 and above is a single dose regimen based on the age and weight of the pediatric patient (Table 1). Administer dalbavancin for injection 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/1.73m 2 [see Use in Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.3 )] . Table 1. Dosage of Dalbavancin for Injection in Pediatric Patients with CLcr* 30 mL/min/1.73m 2 and above Age Range Dosage (Single Dose Regimen) Birth to less than 6 years 22.5 mg/kg (maximum 1,500 mg) 6 to less than 18 years 18 mg/kg (maximum 1,500 mg) *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 dalbavancin for injection is 1,125 mg, administered as a single dose regimen. No dosage adjustment is recommended for adult patients receiving regularly scheduled hemodialysis, and dalbavancin for injection 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 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: Dalbavancin for injection 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 dalbavancin for injection 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 dalbavancin for injection will vary according to the age and weight of the child up to a maximum of 1,500 mg [see Dosage and Administration ( 2.2 )] . Aseptically transfer the required dose of reconstituted dalbavancin for injection 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, dalbavancin for injection 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 dalbavancin for injection should be inspected visually for particulate matter prior to infusion. If particulate matter is identified, do not use. Administration : After reconstitution and dilution, administer dalbavancin for injection via intravenous infusion, using a total infusion time of 30 minutes. Do not co-infuse dalbavancin for injection with other medications or electrolytes. Saline-based infusion solutions may cause precipitation and should not be used. The compatibility of reconstituted dalbavancin for injection 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 dalbavancin for injection, the line should be flushed before and after each dalbavancin for injection infusion with 5% Dextrose Injection, USP.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Infusion Related Reactions [see Warnings and Precautions ( 5.2 )] Hepatic Effects [see Warnings and Precautions ( 5.3 )] Clostridioides difficile -associated Diarrhea [see Warnings and Precautions ( 5.4 )] The most common adverse reactions occurring in >4% of adult patients treated with dalbavancin for injection were nausea, headache, and diarrhea. The most common adverse reaction that occurred in >1% of pediatric patients was pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1­888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 (5.5) 78 (6.4) Diarrhea 79 (4.4) 72 (5.9) Headache 83 (4.7) 59 (4.8) Vomiting 50 (2.8) 37 (3) Rash 48 (2.7) 30 (2.4) Pruritus 38 (2.1) 41 (3.3) * 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 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 )].

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 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 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 1/2 (h) 346 (16.5) 2,3 ND CL (L/h) 0.0513 (46.8) 2 ND 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 In healthy subjects, dalbavancin AUC 0-24h and C max both increased proportionally to dose following single intravenous dalbavancin doses ranging from 140 mg to 1,500 mg, indicating linear pharmacokinetics. No apparent accumulation of dalbavancin was observed following multiple intravenous 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 intravenous 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 mcg/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, 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 AUC 0-336 hrs was unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function; however, the mean AUC 0-336 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 AUC 0-336 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 m 2 and above. There is insufficient information to assess the exposure of dalbavancin for injection in the pediatric patients with CLcr less than 30 mL/min/1.73 m 2 . 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 dalbavancin for injection. The median plasma AUC from 0 to 120 hours (AUC 0-120h ) 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 (AUC 0-120h , 10,400 mg*h/L). The expected median plasma AUC 0-120h 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 (C max ) of dalbavancin for pediatric patient age groups ranged between approximately 53% to 73% of that in adult patients (C max , 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.