Dalvance by Durata Therapeutics

Background

Dalvance (dalbavancin), manufactured by Durata Therapeutics, is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible strains of Gram-positive bacteria. Dalvance is the first drug with the designation of Qualified Infectious Disease Product to receive FDA approval. Under the Generating Antibiotic Incentives Now title of the FDA Safety and Innovation Act, Dalvance was granted as such because it is an “antibacterial or antifungal human drug intended to treat serious or life-threatening infections.”^1,2

Pharmacology/Pharmacokinetics

Dalvance is a semisynthetic lipoglycopeptide antibacterial agent that inhibits peptidoglycan crosslinking in bacterial cell walls by binding to the end of the D-alanyl-D-alanine pentapeptide chain in the nascent peptidoglycan. Dalvance is bactericidal against Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group.

Dalvance time to peak is 0.5 to 1 hour. The volume of distribution is 9.75 to 15.7 L. Dalvance is not a substrate, inhibitor, or inducer of any cytochrome P450 enzyme. Elimination half-life of the drug is approximately 8.5 days, allowing for once-weekly dosing.^1,3

Dosage and Administration

Adults with ABSSSI should be treated with a 2-dose regimen of 1000 mg followed 1 week later by 500 mg. Dalvance should be given over 30 minutes by intravenous (IV) infusion. In patients with renal impairment (creatinine clearance <30 mL/min) who are not receiving regular hemodialysis, the recommended 2-dose regimen is 750 mg followed 1 week later by 375 mg. Prior to use, Dalvance must be reconstituted under aseptic conditions using 25 mL of sterile water for injection for each 500-mg vial. After gently swirling to allow for dissolution, the required dose of reconstituted solution is then aseptically transferred from the vial to an IV bag or bottle containing 5% dextrose injection (D5W). The diluted solution must have a final concentration of 1 to 5 mg/ mL. The total time from reconstitution to dilution to administration should not exceed 48 hours.^1,3

Clinical Efficacy

Dalvance obtained FDA approval based on results from DISCOVER 1 and DISCOVER 2 trials of identical design performed by Boucher and colleagues. A total of 1312 adult patients with ABSSSI were enrolled in these Phase III, randomized, double-blind, doubledummy non-inferiority trials. Patients were treated for 2 weeks with either a 2-dose regimen of Dalvance (1000 mg followed by 500 mg one week later) or with IV vancomycin with the option to switch to oral linezolid after 3 days to complete 10 to 14 days of therapy. Eligible patients had cellulitis, major abscess, or wound infections, each associated with at least 75 cm² of erythema. Patients were required to have at least 1 systemic sign of disease at baseline, defined as temperature at or greater than 38°C, white blood cell (WBC) count greater than 12,000 cells/mm³, or 10% or more band forms on the WBC differential, along with local infection signs and symptoms. The primary end point was defined as both the cessation of spread of infection- related erythema and the absence of fever (temperature consistently at or below 37.6°C for 3 consecutive readings performed 6 hours apart) at 48 to 72 hours after initiation of therapy.

In the pooled analysis of DISCOVER 1 and 2, 525 of 659 patients (79.7%) in the Dalvance group and 521 of 653 (79.8%) in the vancomycin-linezolid group met the primary end point criteria (weighted difference, -0.1%; 95% confidence interval, -4.5 to 4.2). With these differences deemed nonsignificant at a non-inferiority margin of 10% and a 1-sided alpha level of 0.025, investigators concluded that the efficacy of Dalvance, administered once weekly, was not inferior to that of a conventional twice-daily antibiotic regimen for treatment of ABSSSI.⁴

Medication Safety

The most commonly observed adverse events of Dalvance in clinical trials were nausea, diarrhea, pruritus, and headache, lasting a median of 4 days in patients receiving Dalvance and 3 days in those receiving vancomycin-linezolid. Dalvance should not be coinfused with other medications or electrolytes. Saline-based infusion solutions may cause precipitation and, thus, should not be used. If a common IV line is being used to administer other drugs in addition to Dalvance, the line should be flushed with D5W before and after each diluted Dalvance infusion.

Availability and Cost

Dalvance is supplied as 500-mg vials for injection. The wholesale acquisition cost of Dalvance is $1490 for a 500-mg vial. More information is available at www .dalvance.com.^1,5

Ashley L. Pappas, PharmD, BCPS, is a drug information specialist at University of North Carolina (UNC) Hospitals and an adjunct assistant professor at the UNC Eshelman School of Pharmacy.Sandra Hanna, PharmD candidate, is a thirdyear pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.

References:

1. Dalvance [package insert]. Chicago, IL: Durata Therapeutics, Inc; June 2014.

2. FDA approves Dalvance to treat skin infections [press release]. FDA website. May 23, 2014. Accessed July 8, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm398724.htm.

3. Dalvance. Micromedex [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated June 27, 2014.

4. Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014;370(23):2169-2179.

5. Pricing obtained from AmerisourceBergen wholesaler.