Dalbavancin

Dalbavancin is an antibacterial agent belonging to the pharmacological class of Glycopeptide Antibiotics.

Dalbavancin has been approved to relieve symptoms and also for the treatment and maintenance of Skin and soft tissue infection

Dalbavancin demonstrates linear pharmacokinetics, with the area under the concentration-time curve (AUC0-24h) and maximum plasma concentration (Cmax) increasing proportionally to the dose when administered intravenously (IV) in single doses ranging from 140 mg to 1500 mg. Multiple IV infusions of dalbavancin once weekly for up to eight weeks in healthy adults with normal renal function did not result in significant drug accumulation. The volume of distribution at steady state is comparable between healthy subjects and patients with infections, indicating widespread distribution of dalbavancin throughout the body. Dalbavancin exhibits reversible binding to plasma proteins, primarily albumin, with approximately 93% of the drug bound. It is not metabolized by cytochrome P450 (CYP450) isoenzymes and does not significantly affect their activity. The main route of elimination is through the kidneys, with approximately 33% of the administered dose excreted unchanged in urine and about 12% excreted as the hydroxy-dalbavancin metabolite. Minor amounts of metabolites have been detected in urine, but they exhibit reduced antibacterial activity compared to dalbavancin.

The common side effects involved in using Dalbavancin are Nausea, Vomiting, Diarrhea, Abdominal pain, Gastrointestinal discomfort, Skin rash, Itching, Hives (urticaria), Injection site pain, Injection site redness, Injection site swelling, Allergic reactions.

Dalbavancin is available in the form of Lyophilized Injections.

Dalbavancin is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Dalbavancin belongs to the pharmacological class of Glycopeptide Antibiotics

Specifically, dalbavancin prevents the integration of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) peptide subunits into the peptidoglycan matrix, which forms a crucial structural component of Gram-positive cell walls. This inhibition is facilitated by dalbavancin's ability to form hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides, normally involving a five-point interaction. By binding to D-Ala-D-Ala, dalbavancin impedes the incorporation of NAM/NAG-peptide subunits into the peptidoglycan matrix. Moreover, dalbavancin also modifies bacterial cell membrane permeability and RNA synthesis.

Dalbavancin has been approved to relieve symptoms and also for the treatment and maintenance of Skin and soft tissue infection

After a single 1000 mg dose, the maximum plasma concentration (Cmax) was observed to be 287 mg/L, with an associated coefficient of variation of 13.9%. The area under the concentration-time curve from 0 to 24 hours (AUC0-24) was determined to be 3185 mg•h/L, with a coefficient of variation of 12.8%. Similarly, a single 1500 mg dose resulted in a higher Cmax of 423 mg/L and a larger AUC0-24 of 4837 mg•h/L, with coefficient variations of 13.2% and 13.7%, respectively. Additional pharmacokinetic parameters, such as AUC0-Day7 and AUC0-inf, were assessed at 11160 mg•h/L and 23443 mg•h/L, respectively, after the 1000 mg dose but were not determined (ND) for the 1500 mg dose. The terminal half-life (t½) of Dalbavancin was calculated to be 346 hours (16.5%) for the 1000 mg dose, while the value was not available (ND) for the 1500 mg dose.

Dalbavancin exhibits a high degree of plasma protein binding and is characterized by an exceptionally long elimination half-life of approximately 11 days.

Dalbavancin is found to be available in the form of Lyophilized Injections.

Dalbavancin can be used in the following treatment:

• Skin and soft tissue infection

Dalbavancin can help to relieve symptoms and also for the treatment and maintenance of Skin and soft tissue infection .

Dalbavancin is approved for use in the following clinical indications:

• Skin and soft tissue infection

Skin and soft tissue infection (alternative agent):

Intravenous (IV) administration: The recommended dosage is 1.5 g as a single dose , or alternatively, 1 g as a single dose initially, followed by 500 mg as a single dose one week later. It is worth mentioning that some experts prefer the single-dose regimen .

Lyophilized form of injections.

• Dosage Adjustments in Kidney Patients:

For patients with a creatinine clearance (CrCl) of 30 mL/minute or greater, no adjustment in dosage is required.

For patients with a CrCl less than 30 mL/minute who are not on regularly scheduled dialysis, the recommended dosage options are as follows:

• Single-dose regimen: Administer 1.125 g as a single dose.
• Two-dose regimen: Administer 750 mg as a single dose initially, followed by 375 mg as a single dose one week later.

For end-stage renal disease patients receiving intermittent hemodialysis on a regularly scheduled basis, no adjustment in dosage is necessary. Dalbavancin should be administered without regard to the timing of hemodialysis.

• Dosage Adjustments in Hepatic Impairment Patients:

For patients with mild impairment of liver function (Child-Pugh class A), no adjustment in dosage is necessary.

For patients with moderate or severe impairment of liver function (Child-Pugh class B or C), the manufacturer's labeling does not provide specific dosage adjustments as it has not been studied extensively. However, caution should be exercised when administering Dalbavancin in these patients.

• Dosage Adjustments in Pediatric Patients:

For skin and soft tissue infections:

• Infants and children under 6 years of age: The recommended intravenous dose is 22.5 mg/kg given as a single dose, with a maximum dose of 1,500 mg.

• Children 6 years and older and adolescents: The recommended intravenous dose is 18 mg/kg given as a single dose, with a maximum dose of 1,500 mg.

There are no specific dietary restrictions associated with the use of Dalbavancin.

Dalbavancin may be contraindicated under the following conditions:

Dalbavancin should not be used in patients who have a known hypersensitivity to dalbavancin. There is no available data regarding cross-reactivity between dalbavancin and other glycopeptides, such as vancomycin.

Hypersensitivity Reactions:

• Serious allergic reactions (anaphylactic) and skin reactions have been reported in patients receiving Dalbavancin. If an allergic reaction occurs, Dalbavancin treatment should be discontinued. Prior to using Dalbavancin, inquire about any previous hypersensitivity reactions to glycopeptides and exercise caution in patients with a history of glycopeptide allergy, as there may be a possibility of cross-sensitivity.

Infusion-Related Reactions:

• Dalbavancin is administered through intravenous infusion with a total infusion time of 30 minutes to minimize the risk of infusion-related reactions. Rapid intravenous infusions of Dalbavancin can lead to reactions similar to "Red-Man Syndrome," characterized by flushing of the upper body, rash, urticaria, pruritus, and/or back pain. Stopping or slowing down the infusion may result in the cessation of these reactions.

Hepatic Effects:

• In Phase 2 and 3 clinical trials, a higher number of subjects treated with Dalbavancin, compared to the comparator, experienced post-baseline elevation of alanine aminotransferase (ALT) levels greater than 3 times the upper limit of normal (ULN) among those with normal baseline transaminase levels. Overall, abnormalities in liver tests (ALT, AST, bilirubin) were reported with similar frequency in both the Dalbavancin and comparator treatment groups.

Clostridium difficile-Associated Diarrhea:

• The use of Dalbavancin, like other systemic antibacterial drugs, has been associated with Clostridium difficile-associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis. Alteration of the normal colon flora due to antibacterial treatment may facilitate the overgrowth of C. difficile. Hypertoxin-producing strains of C. difficile can cause severe complications that may be unresponsive to antibacterial therapy and require surgical intervention. CDAD should be considered in patients presenting with diarrhea after antibacterial use, even if it occurs more than 2 months following administration. If CDAD is suspected or confirmed, antibacterial treatment not directed against C. difficile should be discontinued, if possible, and appropriate management measures implemented.

Development of Drug-Resistant Bacteria:

• Prescribing Dalbavancin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefits to the patient and increases the risk of developing drug-resistant bacteria.

While there is no specific food interaction between Dalbavancin and alcohol, it's generally recommended to avoid alcohol when taking any antibiotic medication. Alcohol can interfere with the effectiveness of the medication and may also exacerbate certain side effects.

The excretion of dalbavancin or its metabolite in human milk is currently unknown. Therefore, it is advised to exercise caution when administering Dalbavancin to a nursing woman.

When considering the use of Dalbavancin in breastfeeding women, it is important to weigh the developmental and health benefits of breastfeeding against the clinical need for Dalbavancin in the mother. Additionally, potential adverse effects on the breastfed child from both Dalbavancin and the underlying maternal condition should be taken into account and carefully evaluated.

Pregnancy Category C

There is a lack of sufficient and well-controlled studies involving Dalbavancin use in pregnant women. The administration of Dalbavancin during pregnancy should only be considered if the potential benefits outweigh the potential risks to the fetus.

In studies conducted on pregnant rats and rabbits, no treatment-related malformations or harm to the embryo-fetal development were observed at clinically relevant exposures of dalbavancin. However, when pregnant rats were treated 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, delayed fetal maturation and increased fetal loss were observed.

The specific background risk of major birth defects and miscarriage in the indicated population is unknown. However, in the general population in the United States, the background risk of major birth defects is estimated to be around 2 to 4%, and the risk of miscarriage is approximately 15 to 20% among clinically recognized pregnancies.

Additional data from animal studies revealed that at a dose of 15 mg/kg/day (1.2 and 0.7 times the human dose on an exposure basis in rats and rabbits, respectively), no evidence of embryo or fetal toxicity was found. However, delayed fetal maturation was observed in rats at a higher dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis). Furthermore, in a rat study focusing on prenatal and postnatal development, increased embryo lethality and higher offspring deaths during the first week after birth were observed at the dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis).

No food warning has been identified

The adverse reactions related to Dalbavancin can be categorized as follows:

Common:

1. Nausea
2. Headache
3. Diarrhea
4. Rash
5. Vomiting
6. Injection site reactions (e.g., pain, redness, swelling)

Less common:

1. Elevated liver enzymes (transaminases)
2. Decreased hemoglobin levels (anemia)
3. Increased prothrombin time (a measure of blood clotting)

Rare:

1. Hypersensitivity reactions, including allergic reactions and anaphylaxis (severe allergic reaction)

Interactions with Laboratory Tests

No interactions between Dalbavancin and laboratory tests have been reported. Dalbavancin, when used at therapeutic levels, does not cause an artificial prolongation of prothrombin time (PT) or activated partial thromboplastin time (aPTT).

Interactions with Other Drugs

No clinical studies had been conducted to evaluate drug-drug interactions with Dalbavancin. The likelihood of drug interactions between Dalbavancin and cytochrome P450 (CYP450) substrates, inhibitors, or inducers is minimal.

The following are the side effects involving Dalbavancin:

• Nausea
• Headache
• Diarrhea
• Rash
• Vomiting
• Elevated liver enzymes (transaminases)
• Decreased hemoglobin levels (anemia)
• Increased prothrombin time (a measure of blood clotting)
• Injection site reactions, such as pain, redness, or swelling
• Hypersensitivity reactions, including allergic reactions and anaphylaxis (rare)

Pregnancy:

Pregnancy Category C

There is a lack of sufficient and well-controlled studies involving Dalbavancin use in pregnant women. The administration of Dalbavancin during pregnancy should only be considered if the potential benefits outweigh the potential risks to the fetus.

In studies conducted on pregnant rats and rabbits, no treatment-related malformations or harm to the embryo-fetal development were observed at clinically relevant exposures of dalbavancin. However, when pregnant rats were treated 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, delayed fetal maturation and increased fetal loss were observed.

The specific background risk of major birth defects and miscarriage in the indicated population is unknown. However, in the general population in the United States, the background risk of major birth defects is estimated to be around 2 to 4%, and the risk of miscarriage is approximately 15 to 20% among clinically recognized pregnancies.

Additional data from animal studies revealed that at a dose of 15 mg/kg/day (1.2 and 0.7 times the human dose on an exposure basis in rats and rabbits, respectively), no evidence of embryo or fetal toxicity was found. However, delayed fetal maturation was observed in rats at a higher dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis). Furthermore, in a rat study focusing on prenatal and postnatal development, increased embryo lethality and higher offspring deaths during the first week after birth were observed at the dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis).

Lactation:

The excretion of dalbavancin or its metabolite in human milk is currently unknown. Therefore, it is advised to exercise caution when administering Dalbavancin to a nursing woman.

When considering the use of Dalbavancin in breastfeeding women, it is important to weigh the developmental and health benefits of breastfeeding against the clinical need for Dalbavancin in the mother. Additionally, potential adverse effects on the breastfed child from both Dalbavancin and the underlying maternal condition should be taken into account and carefully evaluated.

Pediatric:

The safety as well as effectiveness of this medication have not been established in pediatric patients.

Geriatric Use:

Out of the 2473 patients who participated in Phase 2 and 3 clinical trials of Dalbavancin, 403 patients (16.3%) were 65 years of age or older. The effectiveness and tolerability of Dalbavancin were comparable to the comparator treatment regardless of age. The pharmacokinetics of Dalbavancin did not show significant changes associated with age, indicating that no dosage adjustment is necessary based on age alone.

Since Dalbavancin is primarily eliminated through the kidneys, there is a higher risk of adverse reactions in patients with impaired renal function. Considering that elderly patients are more likely to have reduced kidney function, caution should be exercised when selecting the appropriate dosage for this age group.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Dalbavancin.

There is currently no specific information regarding the treatment of overdose with dalbavancin, as dose-limiting toxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers were given single doses of up to 1,500 mg and cumulative doses of up to 4,500 mg over an 8-week period without experiencing any signs of toxicity or abnormal laboratory results. In Phase 3 studies, patients were administered single doses of up to 1,500 mg.

If an overdose of dalbavancin occurs, the recommended approach is to closely monitor the individual and provide general supportive measures. Although there is no specific information available regarding the use of hemodialysis for the treatment of overdose, it is worth noting that in a Phase 1 study involving patients with renal impairment, less than 6% of the recommended dose of dalbavancin was removed after 3 hours of hemodialysis.

Pharmacodynamics

The effectiveness of dalbavancin against Staphylococcus aureus in animal models of infection seems to be most closely related to the ratio of the area under the concentration-time curve to the minimal inhibitory concentration (AUC/MIC). This suggests that the extent of drug exposure relative to the bacterial susceptibility plays a significant role in its antibacterial activity. In a study involving patients with complicated skin and skin structure infections, an analysis of exposure-response relationship supports the dosing regimen of two dalbavancin injections.

As a result, the recommended dosage regimen for dalbavancin in individuals with normal kidney function is 1500 mg. This can be administered as a single dose or as an initial dose of 1000 mg, followed by a 500 mg dose one week later. The intravenous infusion of dalbavancin should be administered over a period of 30 minutes.

In a thorough study evaluating the effects on cardiac repolarization involving 200 healthy subjects, a randomized, positive- and placebo-controlled trial was conducted. Participants received either 1000 mg or 1500 mg of intravenous dalbavancin, oral moxifloxacin 400 mg, or placebo. The results indicated that neither the 1000 mg nor the 1500 mg doses of dalbavancin had any clinically significant adverse effects on cardiac repolarization.

Pharmacokinetics

Absorption:

● In individuals without health conditions, the absorption of dalbavancin was found to be directly proportional to the dose given intravenously (IV), ranging from 140 mg to 1500 mg. Both the area under the curve (AUC0-24h) and maximum concentration (Cmax) increased proportionally with the dose, indicating linear pharmacokinetics. This information suggests that the drug is absorbed predictably and consistently in relation to the administered dose.

● No significant buildup of dalbavancin was observed when multiple IV infusions were administered once weekly for up to eight weeks in healthy adults with normal kidney function. The dosing regimen involved an initial 1000 mg dose on Day 1, followed by up to seven weekly 500 mg doses. This finding indicates that there is no excessive accumulation of the drug over time.

Volume of Distribution:

● The clearance and volume of distribution at steady state are similar between healthy individuals and patients with infections. The volume of distribution at a steady state closely corresponds to the volume of extracellular fluid. This suggests that dalbavancin is distributed throughout the body in a manner consistent with the distribution of fluid outside the cells.

Protein Binding:

● Dalbavancin reversibly binds to human plasma proteins, primarily to albumin. Approximately 93% of the drug is bound to plasma proteins, and this binding is not affected by the concentration of the drug, renal insufficiency, or hepatic insufficiency. The high degree of protein binding indicates that most of the drug remains bound to proteins in the bloodstream.

Metabolism:

● Dalbavancin does not act as a substrate, inhibitor, or inducer of CYP450 isoenzymes, which are involved in drug metabolism. As a result, there have been no significant observations of metabolites in human plasma. However, in urine, metabolites known as hydroxy-dalbavancin and mannosyl aglycone have been detected, accounting for less than 25% of the administered dose. The specific metabolic pathways responsible for the formation of these metabolites have not been identified. Nevertheless, since metabolism plays a minor role in the elimination of dalbavancin, it is not expected to have significant drug interactions through inhibition or induction of dalbavancin metabolism. Additionally, the hydroxy-dalbavancin and mannosyl aglycone metabolites exhibit significantly weaker antibacterial activity compared to dalbavancin itself.

Route of Elimination:

● Following the administration of a single 1000 mg dose of dalbavancin in healthy subjects, approximately 33% of the administered dose was excreted unchanged in the urine, while approximately 12% was excreted as the metabolite hydroxy-dalbavancin within 42 days post-dose. Around 20% of the administered dose was eliminated in feces within 70 days post-dose. This indicates that the drug is eliminated from the body through both urinary and fecal excretion pathways over an extended period.

There are some clinical studies of the drug dalbavancin mentioned below:

• Alvarez-Arango S, Ogunwole SM, Sequist TD, Burk CM, Blumenthal KG. Moving beyond "red man syndrome": A perspective on vancomycin infusion reaction. New England Journal of Medicine. 2021;384(14):1283-1286. doi:10.1056/NEJMp2031891 [PubMed 33830710]
• Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for skin infection. New England Journal of Medicine. 2014;370(23):2169-2179. [PubMed 24897082]
• Dalbavancin (dalbavancin) [prescribing information]. Madison, NJ: Allergan USA; July 2021.
• Dalbavancin (dalbavancin) [prescribing information]. Parsippany, NJ: Durata Therapeutics; October 2018.
• Dunne MW, Puttagunta S, Giordano P, Krievins D, Zelasky M, Baldassarre J. A randomized clinical trial comparing single-dose and weekly dalbavancin for treatment of acute bacterial skin and skin structure infection. Clinical Infectious Diseases. 2016;62(5):545-551. doi:10.1093/cid/civ982 [PubMed 26611777]
• Jauregui LE, Babazadeh S, Seltzer E, et al. A randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clinical Infectious Diseases. 2005;41(10):1407-1415. [PubMed 16231250]
• Leighton A, Gottlieb AB, Dorr MB, et al. Tolerability, pharmacokinetics, and serum bactericidal activity of intravenous dalbavancin in healthy volunteers. Antimicrobial Agents and Chemotherapy. 2004;48(3):940-945. [PubMed 14982787]
• Mitchell KB, Eglash A, Bamberger ET. Treatment of mammary dysbiosis and nipple blebs with intravenous daptomycin and dalbavancin. Journal of Human Lactation. 2020;36(2):365-368. doi:10.1177/0890334419862214 [PubMed 31310726]
• Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clinical Infectious Diseases. 2005;40(3):374-380. [PubMed 15668859]
• Seltzer E, Dorr MB, Goldstein BP, Perry M, Dowell JA, Henkel T; Dalbavancin Skin and Soft-Tissue Infection Study Group. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for the treatment of skin and soft-tissue infections. Clinical Infectious Diseases. 2003;37(10):1298-1303. [PubMed 14583862]
• Spelman D, Baddour LM. Treatment of acute cellulitis and erysipelas in adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 17

1. https://www.mayoclinic.org/drugs-supplements/dalbavancin-intravenous-route/side-effects/drg-20110160?p=1#:~:text=Dalbavancin injection is used to,flu, or other virus infections.
2. https://reference.medscape.com/drug/Dalbavancin-dalbavancin-999921
3. https://go.drugbank.com/drugs/DB06219
4. https://www.drugs.com/mtm/dalbavancin.html
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021883s007lbl.pdf
6. https://www.Dalbavancin.com/
7. https://www.goodrx.com/Dalbavancin/what-is
8. https://www.paladin-labs.com/our_products/PM_Xydalba_EN.pdf
9. https://www.ema.europa.eu/en/documents/product-information/xydalba-epar-product-information_en.pdf
10. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=97107