Dalvance

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.

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. (

• Administer by intravenous infusion over 30 minutes (
  2.1

  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

  [see Dosage and Administration (

  2.3

  )

  and Clinical Pharmacology (

  12.3

  )

  ]

  .
  ,
  2.4

  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

  [see Dosage and Administration (

  2.2

  )]

  . 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. 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°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 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.
  )
  
  
• See Full Prescribing Information for instructions on reconstitution of lyophilized powder and preparation of injection (
  2.4

  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

  [see Dosage and Administration (

  2.2

  )]

  . 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. 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°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 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.
  ).

• Dosage adjustment in pediatric patients with CLcr less than 30 mL/min has not been studied.

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

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 2% to 4% and 15% to 20%, respectively.

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).

• 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

  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

  )]

  .
  )
  
  
• 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

  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.
  )
  
  
• Alanine Aminotransferase (ALT) elevations with DALVANCE treatment were reported in clinical trials. (
  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

  )].
  ,
   
  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
  )
  
  
• Clostridioides
  difficile
  -associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including DALVANCE. Evaluate if diarrhea occurs. (
  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.
  )