Dalvance Drug Information

Recommended

Dos ag e 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 1,500 mg, administered either as a single dose regimen, or as a two-dose regimen of DALVANCE 1,000 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.

Recommended Dosage Regimen in Pediatric Patients with CLcr 30 mL/min/ 1.73m 2 and Abov e The recommended dosage regimen of DALVANCE 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 ). 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. Table 1.

Dosage of DALVANCE in Pediatric Patients with CLcr* 30 mL/min/1.73m2 and above *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.

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 1,125 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.

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 1,500 mg.

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. 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.

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. DALVANCE was discontinued due to an adverse reaction in 64/2,473 (2.6%) patients treated with any regimen of DALVANCE.

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 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. 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

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.

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).

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.

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.

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 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).

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. There is insufficient information to recommend dosage adjustment for pediatric patients with ABSSSI and CLcr less than 30 mL/min/1.73m 2.

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

Specific information is not available on the treatment of overdose with DALVANCE, as dose-limiting toxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers have been administered cumulative doses of up to 4,500 mg over a period of up to 8 weeks (not an approved dosing regimen), with no signs of toxicity or laboratory results of clinical concern. Treatment of overdose with DALVANCE should consist of observation and general supportive measures.

Although no information is available specifically regarding the use of hemodialysis to treat overdose, in a Phase 1 study in patients with renal impairment less than 6% of the recommended dalbavancin dose was removed.