Dalvance – Product information
|Manufacture:||Durata Therapeutics Inc. (Allergan)|
|Condition:||Skin and Structure Infection|
|Form:||Intravenous (IV), Powder|
|Ingredients:||dalbavancin, lactose monohydrate (129 mg), mannitol (129 mg)|
Indication and usage
Acute Bacterial Skin and Skin Structure Infections
DALVANCE™ (dalbavancin) for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin- susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus).
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 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.
Dosage and administration
Recommended Dosage Regimen
For treatment of adults with ABSSSI, the recommended two-dose regimen of DALVANCE is 1000 mg followed one week later by 500 mg. DALVANCE should be administered over 30 minutes by intravenous infusion [see Dosage and Administration (2.3)].
Patients with Renal Impairment
In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen of DALVANCE is 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 [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
Preparation and Administration
DALVANCE (dalbavancin) for injection must be reconstituted with Sterile Water for Injection, USP, and subsequently diluted only with 5% Dextrose Injection, USP, to a final concentration of 1 mg/mL to 5 mg/mL.
Reconstitution: DALVANCE must be reconstituted under aseptic conditions, using 25 mL of Sterile Water for 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 to 8 °C (36 to 46 °F), or at controlled room temperature 20 to 25 °C (68 to 77 °F). Do not freeze.
Dilution: Aseptically transfer the required dose of reconstituted dalbavancin 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.
Once diluted into an intravenous bag or bottle as described above, DALVANCE may be stored either refrigerated at 2 to 8 °C (36 to 46 °F) or at a controlled room temperature of 20 to 25 °C (68 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 DALVANCE should be inspected visually for particulate matter prior to infusion. If particulate matter is identified, do not use.
After reconstitution and dilution, DALVANCE is to be administered 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.
Dosage forms and strengths
DALVANCE is supplied in single-use, clear glass vials containing sterile powder (white/off-white to pale yellow) equivalent to 500 mg of anhydrous dalbavancin.
DALVANCE is contraindicated in patients with known hypersensitivity to dalbavancin. No data are available on cross-reactivity between dalbavancin and other glycopeptides, including vancomycin.
Warnings and precautions
Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with DALVANCE. If an allergic reaction occurs, treatment with DALVANCE should be discontinued. Before using DALVANCE, inquire carefully about previous hypersensitivity reactions to glycopeptides, and due to the possibility of cross-sensitivity, exercise caution in patients with a history of glycopeptide allergy [see Patient Counseling Information (17)].
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 reactions that resemble “Red-Man Syndrome,” including flushing of the upper body, urticaria, pruritus, and/or rash. Stopping or slowing the infusion may result in cessation of these reactions.
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)].
Clostridium difficile-Associated Diarrhea
Clostridium 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.
Development of Drug-Resistant Bacteria
Prescribing DALVANCE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug- resistant bacteria.
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.
Adverse Reactions in Clinical Trials
Adverse reactions were evaluated for 1778 patients treated with DALVANCE and 1224 patients treated with comparator antibacterial drugs in seven Phase 2 and Phase 3 clinical trials. A causal relationship between study drug and adverse reactions was not always established. The median age of patients treated with DALVANCE was 47 years, ranging between 16 and 93 years old.
Patients treated with DALVANCE were predominantly male (60%) and Caucasian (78%).
Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation
Serious adverse reactions occurred in 109/1778 (6.1%) of patients treated with DALVANCE and in 80/1224 (6.5%) of patients treated with comparator. DALVANCE was discontinued due to an adverse reaction in 53/1778 (3%) patients and the comparator was discontinued due to an adverse reaction in 35/1224 (2.8%) patients.
Most Common Adverse Reactions
The most common adverse reactions in patients treated with DALVANCE were nausea (5.5%), headache (4.7%), and diarrhea (4.4%). The median duration of adverse reactions was 4.0 days in both treatment groups.
Table 1 lists selected adverse reactions occurring in more than 2% of patients treated with DALVANCE in clinical trials.
Table 1. Selected Adverse Reactions in Phase 2/3 Trials (Number (%) of Patients)
|Dalbavancin (N = 1778)||Comparator* (N = 1224)|
|Nausea||98 (5.5)||78 (6.4)|
|Vomiting||50 (2.8)||37 (3)|
|Diarrhea||79 (4.4)||72 (5.9)|
|Headache||83 (4.7)||59 (4.8)|
|Rash||48 (2.7)||30 (2.4)|
|Pruritus||38 (2.1)||41 (3.3)|
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 Disorders: gastrointestinal hemorrhage, melena, hematochezia, abdominal pain
General Disorders and administration site conditions: infusion-related reactions
Hepatobiliary disorders: hepatotoxicity
Immune system disorders: anaphylactoid reaction
Infections and infestations: Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection
Investigations: hepatic transaminases increased, blood alkaline phosphatase increased, international normalized ratio increased
Metabolism and nutrition disorders: hypoglycemia
Nervous System disorders: dizziness
Respiratory, thoracic and mediastinal disorders: bronchospasm
Skin and Subcutaneous Tissue Disorders: urticarial
Vascular disorders: flushing, phlebitis, wound hemorrhage, spontaneous hematoma
Alanine Aminotransferase (ALT) Elevations
Among patients with normal baseline ALT levels, more DALVANCE than comparator treated patients had post-baseline ALT elevations greater than 3 times the upper limit of normal (ULN), 12 (0.8%) vs. 2 (0.2%), respectively including three subjects with post-baseline ALT values greater than 10 times ULN. Eight of 12 patients treated with DALVANCE and one comparator patient had underlying conditions which could affect liver enzymes, including chronic viral hepatitis and a history of alcohol abuse. 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. No comparator-treated subject with normal baseline transaminases had post-baseline ALT elevation greater than 10 times ULN.
Drug-Laboratory Test Interactions
Drug-laboratory test interactions have not been reported.
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 Clinical Pharmacology (12.3)].USE IN SPECIFIC POPULATIONS
Pregnancy: Category C
There have been no adequate and well-controlled studies with dalbavancin in pregnant women. DALVANCE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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).
Dalbavancin is excreted in the milk of lactating rats. It is not known whether dalbavancin or its metabolite is excreted in human milk; therefore, caution should be exercised when DALVANCE is administered to a nursing woman.
Safety and efficacy in pediatric patients have not been established.
Of the 1778 patients treated with DALVANCE in Phase 2 and 3 clinical trials, 313 patients (17.7%) were 65 years of age or older. The efficacy and tolerability of DALVANCE were similar to comparator regardless of age. The pharmacokinetics of dalbavancin were 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.
In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen for DALVANCE is 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 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
No dosage adjustment of DALVANCE is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Caution should be exercised when prescribing dalbavancin 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)].
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 single doses of up to 1500 mg, and cumulative doses of up to 4500 mg over a period of up to 8 weeks, with no signs of toxicity nor 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 [see Clinical Pharmacology (12.3)].
How supplied/storage and handling
DALVANCE (dalbavancin) for injection is supplied in the following packaging configuration: 500 mg/vial: package of 1 (NDC 57970-100-01)
Unreconstituted DALVANCE (dalbavancin) for injection should be stored at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].
Patient counseling information
Patients should be advised that allergic reactions, including serious allergic reactions, could occur, and that serious allergic reactions require immediate treatment. Patients should inform their healthcare provider about any previous hypersensitivity reactions to DALVANCE, or other glycopeptides.
Patients should be counseled that antibacterial drugs including DALVANCE should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When DALVANCE is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by DALVANCE and other antibacterial drugs in the future.
Patients should be advised that diarrhea is a common problem caused by antibacterial drugs and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider.