DALBAVANCIN: 1,107 Adverse Event Reports & Safety Profile

Dalbavancin for injection is a lipoglycopeptide antibacterial synthesized from a fermentation product of Nonomuraea species. Dalbavancin is a mixture of five closely related active homologs (A 0 , A 1 , B 0 , B 1 , and B 2 ); the component B 0 is the major component of dalbavancin. The homologs share the same core structure and differ in the fatty acid side chain of the N-acylaminoglucuronic acid moiety (R 1 ) structure and/or the presence of an additional methyl group (R 2 ) on the terminal amino group (shown in the Figure 1 and Table 3 below).

Figure

1.

Dalbavancin Structural Formula Table

3.

Substitution

Patterns for Dalbavancin API Homologs Dalbavancin R 1 R 2 Molecular Formula Molecular Weight * A 0 CH(CH 3 ) 2 H C 87 H 98 N 10 O 28 Cl 2 ·

1.6 HCl 1,802.7 A 1 CH 2 CH 2 CH 3 H C 87 H 98 N 10 O 28 Cl 2 ·

1.6 HCl 1,802.7 B 0 CH 2 CH(CH 3 ) 2 H C 88 H 100 N 10 O 28 Cl 2 ·

1.6 HCl 1,816.7 B 1 CH 2 CH 2 CH 2 CH 3 H C 88 H 100 N 10 O 28 Cl 2 ·

1.6 HCl 1,816.7 B 2 CH 2 CH(CH 3 ) 2 CH 3 C 89 H 102 N 10 O 28 Cl 2 ·

1.6 HCl 1,830.7 *Anhydrous free base The B 0 INN chemical name is: 5,31-dichloro-38-de(methoxycarbonyl)-7-demethyl-19-deoxy-56-O-[2-deoxy-2-[(10-methylundecanoyl)amino]-β-D-glucopyranuronosyl]-38-[[3-(dimethylamino)propyl] carbamoyl]-42-O-α-D-mannopyranosyl-15-N-methyl(ristomycin A aglycone) hydrochloride. Dalbavancin for injection is supplied in clear glass vials as a sterile, lyophilized, preservative-free, white to off-white to pale yellow solid. Each vial contains dalbavancin hydrochloride equivalent to 500 mg of dalbavancin as the free base, plus lactose monohydrate (129 mg) and mannitol (129 mg) as excipients. Sodium hydroxide or hydrochloric acid may be added to adjust the pH at the time of manufacture. The powder is to be reconstituted and further diluted for intravenous infusion [ see Dosage and Administration ( 2.4 ) , How Supplied/Storage and Handling ( 16 ) ] .

Figure

1.

Dalbavancin Structural

Formula

AND USAGE Dalbavancin for Injection 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. ( 1.1 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Dalbavancin for Injection and other antibacterial drugs, Dalbavancin for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.2 )

1.1 Acute Bacterial Skin and Skin Structure Infections Dalbavancin for Injection 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 methicillin-resistant isolates), Streptococcus pyogenes , Streptococcus agalactiae , Streptococcus dysgalactiae , Streptococcus anginosus group (including S. anginosus , S. intermedius , S . constellatus ) and Enterococcus faecalis (vancomycin susceptible isolates).

1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Dalbavancin for Injection and other antibacterial agents, Dalbavancin for Injection 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.

AND ADMINISTRATION Dosage in Adult Patients ( 2.1 , 2.3 ): Estimated Creatinine Clearance ( C L cr) Single- Dose Regimen 30 mL/min and above or on regular hemodialysis 1,500 mg Less than 30 mL/min and not on regular hemodialysis 1,125 mg Administer by intravenous infusion over 30 minutes ( 2.1 , 2.4 )

See Full Prescribing

Information for instructions on reconstitution of lyophilized powder and preparation of injection ( 2.4 ) Dosage in Pediatric Patients with CLcr 30 mL/min/1.73m 2 and above ( 2.2 )

Age Range

Dosage (Single-Dose Regimen) Birth to less than 6 years 22.5 mg/kg (maximum of 1,500 mg) 6 to less than 18 years 18 mg/kg (maximum of 1,500 mg) Dosage adjustment in pediatric patients with CLcr less than 30 mL/min has not been studied.

2.1 Recommended Dos ag e Regimen in Adult Patients with CLcr 30 mL/min and Above The recommended dosage regimen of dalbavancin for injection in adult patients with CLcr 30 mL/min and above is 1,500 mg, administered as a single-dose regimen. Administer dalbavancin for injection over 30 minutes by intravenous infusion. For adult patients with CLcr less than 30 mL/min, dosage adjustment is required <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 ) ]</span> .

2.2 Recommended Dosage Regimen in Pediatric Patients with CLcr 30 mL/min/ 1.73m 2 and Abov e The recommended dosage regimen of dalbavancin for injection 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 ). Administer dalbavancin for injection over 30 minutes by intravenous infusion. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.3 )]</span> .

Table

1. Dosage of Dalbavancin for Injection in Pediatric Patients with CLcr* 30 mL/min/1.73m 2 and above Age Range Dosage (Single-Dose Regimen) Birth to less than 6 years 22.5 mg/kg (maximum 1,500 mg) 6 to less than 18 years 18 mg/kg (maximum 1,500 mg) *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.

2.3 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 dalbavancin for injection is 1,125 mg, administered as a single-dose regimen. No dosage adjustment is recommended for adult patients receiving regularly scheduled hemodialysis, and dalbavancin for injection can be administered without regard to the timing of hemodialysis <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span> .

2.4 Preparation and Administration 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 per mL to 5 mg per mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitution

Dalbavancin for injection 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 per 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 Adult Patients

Aseptically transfer the required dose of reconstituted dalbavancin for injection 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 per mL to 5 mg per mL. Discard any unused portion of the reconstituted solution.

Pediatric Patients

For pediatric patients, the dose of dalbavancin for injection 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 dalbavancin for injection 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 per mL to 5 mg per mL. Discard any unused portion of the reconstituted solution. Once diluted into an intravenous bag or bottle as described above, dalbavancin for injection 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 dalbavancin for injection should be inspected visually for particulate matter prior to infusion. If particulate matter is identified, do not use.

Administration

After reconstitution and dilution, administer dalbavancin for injection via intravenous infusion, using a total infusion time of 30 minutes. Do not co-infuse dalbavancin for injection with other medications or electrolytes. Saline-based infusion solutions may cause precipitation and should not be used. The compatibility of reconstituted dalbavancin for injection 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 dalbavancin for injection, the line should be flushed before and after each dalbavancin for injection infusion with 5% Dextrose Injection, USP.

Dalbavancin for injection is contraindicated in patients with known hypersensitivity to dalbavancin. Known hypersensitivity to dalbavancin ( 4 )

REACTIONS The following clinically significant adverse reactions are also discussed elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )]

Infusion Related

Reactions [see Warnings and Precautions ( 5.2 )]

Hepatic

Effects [see Warnings and Precautions ( 5.3 )] Clostridioides difficile -associated Diarrhea [see Warnings and Precautions ( 5.4 )] The most common adverse reactions occurring in >4% of adult patients treated with dalbavancin for injection were nausea, headache, and diarrhea. The most common adverse reaction that occurred in >1% of pediatric patients was pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of dalbavancin for injection 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 dalbavancin for injection: 1,778 patients were treated with dalbavancin for injection in seven Phase 2/3 trials comparing dalbavancin for injection to comparator antibacterial drugs and 695 patients were treated with dalbavancin for injection in one Phase 3 trial comparing dalbavancin for injection single-dose and another dalbavancin dosing regimen. The median age of patients treated with dalbavancin for injection was 48 years, ranging between 16 and 93 years. Patients treated with dalbavancin for injection 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 dalbavancin for injection. In the Phase 2/3 trials comparing dalbavancin for injection to comparator, serious adverse reactions occurred in 109/1,778 (6.1%) of patients in the dalbavancin for injection group and 80/1,224 (6.5%) of patients in the comparator group. In a Phase 3 trial comparing dalbavancin for injection single-dose and another dalbavancin dosing regimen, serious adverse reactions occurred in 7/349 (2.0%) of patients in the dalbavancin for injection single-dose group and 5/346 (1.4%) of patients in another dalbavancin dosing group. Dalbavancin for injection was discontinued due to an adverse reaction in 64/2,473 (2.6%) patients treated with any regimen of dalbavancin for injection. In the Phase 2/3 trials comparing dalbavancin for injection to comparator, dalbavancin for injection was discontinued due to an adverse reaction in 53/1,778 (3.0%) of patients in the dalbavancin for injection group and 35/1,224 (2.9%) of patients in the comparator group. In a Phase 3 trial comparing dalbavancin for injection single-dose and another dalbavancin dosing regimen, dalbavancin for injection was discontinued due to an adverse reaction in 6/349 (1.7%) of patients in the dalbavancin for injection single-dose group and 5/346 (1.4%) of patients in another dalbavancin dosing group.

Most Common Adverse Reactions

The most common adverse reactions in patients treated with dalbavancin for injection 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 dalbavancin for injection. In the Phase 2/3 trials comparing dalbavancin for injection to comparator, the median duration of adverse reactions was 3.0 days for patients in the dalbavancin for injection group and 4.0 days in patients in the comparator group. In a Phase 3 trial comparing dalbavancin for injection single-dose and another dalbavancin dosing regimen, the median duration of adverse reactions was 3.0 days for patients in the dalbavancin for injection single-dose group and another dalbavancin dosing group.

Table

2 lists selected adverse reactions occurring in 2% or more of patients treated with dalbavancin for injection in Phase 2/3 clinical trials.

Table

2.

Selected Adverse Reactions

Occurring in ≥ 2% of Patients Receiving Dalbavancin for Injection in Phase 2/3 Trials (Number (%) of Patients)

Adverse Reactions

Dalbavancin for Injection 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-dose and another dosing regimen of dalbavancin for injection, the adverse reaction that occurred in 2% or more of patients treated with dalbavancin for injection was nausea (3.4% in the dalbavancin for injection single-dose group and 2% in another dalbavancin dosing group). The following selected adverse reactions were reported in dalbavancin for injection 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 dalbavancin for injection 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-dalbavancin for injection 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 dalbavancin for injection 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 dalbavancin for injection-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 dalbavancin for injection (83 patients treated with a single-dose of dalbavancin for injection and 78 patients treated with another dosing regimen of dalbavancin) and 30 patients treated with comparator agents for a treatment period up to 14 days. The median age of pediatric patients treated with dalbavancin for injection 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 dalbavancin for injection 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 dalbavancin for injection, all in the single-dose arm. There were no adverse reactions leading to dalbavancin for injection 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 dalbavancin for injection-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

6.2 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 ( 5.2 )] .

AND PRECAUTIONS Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with dalbavancin for injection. If an allergic reaction occurs, discontinue treatment with dalbavancin for injection and institute appropriate therapy for the allergic reaction. Carefully monitor patients with known hypersensitivity to glycopeptides. ( 5.1 ) Rapid intravenous infusion of dalbavancin for injection 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 )

Alanine

Aminotransferase (ALT) elevations with dalbavancin for injection treatment were reported in clinical trials. ( 5.3 , 6.1 ) Clostridioides difficile -associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including dalbavancin for injection. Evaluate if diarrhea occurs. ( 5.4 )

5.1 Hypersensitivity Reactions Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with dalbavancin for injection. If an allergic reaction to dalbavancin for injection occurs, discontinue treatment with dalbavancin for injection and institute appropriate therapy for the allergic reaction. Before using dalbavancin for injection, 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 dalbavancin for injection in patients with a history of glycopeptide allergy <span class="opacity-50 text-xs">[see Patient Counseling Information ( 17 )]</span> .

5.2 Infusion - Related Reactions Dalbavancin for injection 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 dalbavancin for injection 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.

5.3 Hepatic Effects In Phase 2 and 3 clinical trials, more dalbavancin for injection 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 dalbavancin for injection and comparator arms <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>.

5.4 Clostridioides difficile - Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including dalbavancin for injection, 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.

5.5 Development of Drug-Resistant Bacteria Prescribing dalbavancin for injection 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.

INTERACTIONS

7.1 Drug-Laboratory Test Interactions Drug-laboratory test interactions have not been reported. Dalbavancin for injection at therapeutic concentrations does not artificially prolong prothrombin time (PT) or activated partial thromboplastin time (aPTT).

7.2 Drug-Drug Interactions No clinical drug-drug interaction studies have been conducted with dalbavancin for injection. There is minimal potential for drug-drug interactions between dalbavancin for injection and cytochrome P450 (CYP450) substrates, inhibitors, or inducers <span class="opacity-50 text-xs">[see C linical P harmacology ( 12.3 )]</span> .