Dalbavancin

DALVANCE 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 DALVANCE and other antibacterial drugs, DALVANCE 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 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.

DALVANCE (dalbavancin) for injection is supplied as a white/off-white to pale yellow lyophilized sterile powder for reconstitution in a single-dose clear glass vial containing dalbavancin hydrochloride equivalent to 500 mg of dalbavancin . For injection: 500 mg of lyophilized powder in a vial for reconstitution ( 3 )

DALVANCE is contraindicated in patients with known hypersensitivity to dalbavancin. Known hypersensitivity to dalbavancin ( 4 )

Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with DALVANCE. If an allergic reaction occurs, discontinue treatment with DALVANCE and institute appropriate therapy for the allergic reaction. Carefully monitor patients with known hypersensitivity to glycopeptides. ( 5.1 ) Rapid intravenous infusion 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. ( 5.2 ) Alanine Aminotransferase (ALT) elevations with DALVANCE treatment were reported in clinical trials. ( 5.3 , 6.1 ) Clostridioides difficile -associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including DALVANCE. Evaluate if diarrhea occurs. ( 5.4 )

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.

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 DALVANCE 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 AbbVie Inc. at 1-800-678-1605 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 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 2,473 patients treated with DALVANCE: 1,778 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 121/2,473 (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 109/1,778 (6.1%) of patients in the DALVANCE group and 80/1,224 (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 64/2,473 (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 53/1,778 (3.0%) of patients in the DALVANCE group and 35/1,224 (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. Table 2. Selected Adverse Reactions Occurring in ≥ 2% of Patients Receiving DALVANCE in Phase 2/3 Trials (Number (%) of Patients) Adverse Reactions DALVANCE 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 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 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 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. […]

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 C linical P harmacology ( 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/1.73m 2 [see Dosage and Administration ( 2.2 )]. 8. 5 Geriatric Use Of the 2,473 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 1,125 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/1.73m 2 [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 ) ] .

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