APMA News - May/June 2024 - 66

DALVANCE® (dalbavancin) for injection, for intravenous use PROFESSIONAL BRIEF SUMMARY
INDICATION AND USAGE
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 methicillinresistant
isolates), Streptococcus pyogenes, Streptococcus agalactiae,
Streptococcus dysgalactiae, Streptococcus anginosus group (including
S. anginosus, S. intermedius, S. constellatus) and Enterococcus faecalis
(vancomycin susceptible isolates).
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.
CONTRAINDICATIONS
DALVANCE is contraindicated in patients with known hypersensitivity to
dalbavancin.
WARNINGS AND PRECAUTIONS
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].
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.
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].
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.
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.
ADVERSE REACTIONS
The following clinically significant adverse reactions are also discussed
elsewhere in the labeling:
* Hypersensitivity Reactions [see Warnings and Precautions]
* Infusion Related Reactions [see Warnings and Precautions]
* Hepatic Effects [see Warnings and Precautions]
* Clostridioides difficile-associated Diarrhea [see Warnings and
Precautions]
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 2473 patients treated with DALVANCE:
1778 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 121/2473 (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 109/1778 (6.1%) of patients
in the DALVANCE group and 80/1224 (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 64/2473 (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 53/1778 (3.0%) of patients in the DALVANCE group and 35/1224
(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 1 lists selected adverse reactions occurring in 2% or more of patients
treated with DALVANCE in Phase 2/3 clinical trials.
Table 1. Selected Adverse Reactions Occurring in ≥ 2% of
Patients Receiving DALVANCE in Phase 2/3 Trials
(Number (%) of Patients)
Adverse Reactions
Nausea
Diarrhea
Headache
Vomiting
Rash
Pruritus
DALVANCE
(N = 1778)
98 (5.5)
79 (4.4)
83 (4.7)
50 (2.8)
48 (2.7)
38 (2.1)
Comparator*
(N = 1224)
78 (6.4)
72 (5.9)
59 (4.8)
37 (3)
30 (2.4)
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 disorders: gastrointestinal hemorrhage, melena,
hematochezia, abdominal pain
General disorders 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
Metabolism and nutrition disorders: hypoglycemia
Nervous system disorders: dizziness
Respiratory, thoracic and mediastinal disorders: bronchospasm
Skin and subcutaneous tissue disorders: 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 comparatortreated
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 occuring 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 [See Warnings and Precautions].
DRUG INTERACTIONS
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).
CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
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.
USE IN SPECIFIC POPULATIONS
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).
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.
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 wellcontrolled
studies in adults with additional pharmacokinetic and safety data in
pediatric patients aged birth to less than 18 years [see Adverse Reactions].
There is insufficient information to recommend dosage adjustment for pediatric
patients with ABSSSI and CLcr less than 30 mL/min/1.73m2.
Geriatric Use
Of the 2473 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.
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 1125 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/1.73m2.
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.
OVERDOSAGE
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
4500 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.
Distributed by:
Allergan USA, Inc.
Madison, NJ 07940
Patented. See www.allergan.com/patents.
DALVANCE® is a registered trademark of
Allergan Pharmaceuticals International Limited.
© 2021 Allergan. All rights reserved.
Ref: v2.0USPI0100
Revised: 7-2021
US-DAV-210213 MASTER
US-DAV-240021
http://www.allergan.com/patents
APMA News - May/June 2024

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