Oritavancin

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

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

Oritavancin exhibits pharmacokinetic properties characterized by a Cmax of 138 μg/mL and an AUC0-∞ of 2800 μg•h/mL, as determined by pharmacokinetic analysis. Another study on healthy volunteers showed an AUC0-t of 1,111 μg•h/mL after an 800 mg dose. Within 24 hours of administration, a Cmax ranging from 4.7 to 7.6 micrograms/mL was generally observed. The estimated volume of distribution for oritavancin is approximately 87.6 L, indicating extensive tissue distribution. It binds to plasma proteins to a level of around 85%. Oritavancin is not extensively metabolized, as demonstrated by in vitro studies on human hepatocytes, and is primarily excreted unchanged. Both urine and feces serve as routes of elimination, with less than 5% recovered in the urine and 1% in the feces.

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

Oritavancin is available in the form of Lyophilized Injections.

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

Oritavancin belongs to the pharmacological class of Glycopeptide Antibiotics

The bacterial cell wall plays a crucial role in the survival and replication of bacteria, making it a primary target for antibiotic treatment. Oritavancin employs three distinct mechanisms to combat susceptible gram-positive organisms. Firstly, it attaches to the stem peptide of peptidoglycan precursors, impeding transglycosylation (polymerization) that normally occurs during cell wall synthesis. Secondly, oritavancin hinders crosslinking during bacterial cell wall biosynthesis by binding to cell wall pentaglycyl peptide bridging segments. Lastly, this medication disrupts the integrity of the bacterial cell membrane, leading to cell death through various mechanisms.

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

Oritavancin exhibits pharmacokinetic properties characterized by a Cmax of 138 μg/mL and an AUC0-∞ of 2800 μg•h/mL, as determined by pharmacokinetic analysis. Another study on healthy volunteers showed an AUC0-t of 1,111 μg•h/mL after an 800 mg dose. Within 24 hours of administration, a Cmax ranging from 4.7 to 7.6 micrograms/mL was generally observed.

Following the administration of a single 1,200 mg dose, Oritavancin has demonstrated the ability to artificially extend aPTT for a duration of up to 120 hours, PT and INR for up to 12 hours, and ACT for up to 24 hours. This effect is achieved by binding to and inhibiting the activity of the phospholipid reagents commonly utilized in laboratory coagulation tests.

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

Oritavancin can be used in the following treatment:

• Skin and soft tissue infection

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

Oritavancin is approved for use in the following clinical indications:

• Skin and soft tissue infection

Skin and soft tissue infection

Skin and soft tissue infection (alternative treatment):

Please note: This option should be reserved for patients with methicillin-resistant S. aureus infection or those who are unable to receive the preferred agents.

Intravenous (IV) administration: A single dose of 1.2 g

Lyophilized Injection: 400 mg/vial, 1200 mg/vial.

Lyophilized form of injections.

•  Dosage Adjustments in Kidney Patients:

If the patient's CrCl (creatinine clearance) is 30 mL/minute or higher, no dosage adjustment is needed for Oritavancin.

If the patient's CrCl is less than 30 mL/minute, the manufacturer's labeling does not provide specific dosage adjustments as it has not been studied.

•   Dosage Adjustments in Hepatic Impairment Patients:

No dosage adjustments are necessary.

• Dosage Adjustments in Pediatric Patients:

For patients 18 years and older, the recommended dosage of Oritavancin is a single intravenous infusion over 3 hours, with a dose of 1200 mg.

There are no specific dietary restrictions related to the use of oritavancin mentioned in the available information. However, it is always advisable to follow a healthy and balanced diet while undergoing any medical treatment.

Oritavancin may be contraindicated under the following conditions:

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

Potential Risk of Bleeding with Concomitant Use of Warfarin

• Co-administration of Oritavancin and warfarin may lead to higher exposure to warfarin, increasing the risk of bleeding.
• Use Oritavancin in patients on chronic warfarin therapy only if the benefits outweigh the risk of bleeding.
• Regularly monitor patients for signs of bleeding.

Coagulation Test Interference

• Oritavancin artificially prolongs PT and INR for up to 24 hours, making the monitoring of warfarin's anticoagulation effect unreliable during this period.
• Consider using non-phospholipid-dependent coagulation tests or alternative anticoagulants not requiring PT/INR monitoring within 48 hours of Oritavancin dosing.
• Oritavancin has no direct effect on the coagulation system.

Hypersensitivity

• Serious hypersensitivity reactions have been reported with the use of Oritavancin.
• If an acute hypersensitivity reaction occurs during Oritavancin infusion, discontinue it immediately and provide appropriate supportive care.
• Inquire about previous hypersensitivity reactions to glycopeptides before using Oritavancin, and carefully monitor patients with a history of glycopeptide allergy.

Infusion Related Reactions

• Infusion-related reactions, including pruritus, urticaria, or flushing, have been reported with Oritavancin.
• Consider slowing or interrupting Oritavancin infusion if such reactions occur.

Clostridium difficile-associated Diarrhea

• CDAD, ranging from mild diarrhea to fatal colitis, has been reported with the use of Oritavancin.
• CDAD should be considered in patients presenting with diarrhea following antibacterial use.
• Discontinuation of antibacterial treatment not directed against C. difficile may be necessary, and appropriate management should be initiated.

Osteomyelitis

• In clinical trials, more cases of osteomyelitis were reported in the Oritavancin-treated group compared to the vancomycin-treated group.
• Monitor patients for signs and symptoms of osteomyelitis and initiate appropriate alternate antibacterial therapy if suspected or diagnosed.

Development of Drug-Resistant Bacteria

• Prescribing Oritavancin without a proven or strongly suspected bacterial infection is unlikely to benefit the patient and increases the risk of developing drug-resistant bacteria.

While there is no specific food interaction between Oritavancin 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 oritavancin in human milk is currently unknown. However, studies in lactating rats have shown that radio-labeled [14C]-oritavancin was excreted in milk and absorbed by nursing pups following a single intravenous infusion. Therefore, caution should be exercised when administering Oritavancin to nursing women.

Pregnancy Category C

Reproduction studies conducted in rats and rabbits have shown no evidence of fetal harm caused by oritavancin at the highest administered concentrations of 30 mg/kg/day and 15 mg/kg/day, respectively. These daily doses would be equivalent to a human dose of 300 mg, which is 25% of the clinical dose of 1200 mg. However, higher doses were not tested in nonclinical studies assessing developmental and reproductive toxicity.

There have been no adequate and well-controlled trials in pregnant women. Oritavancin should only be used during pregnancy if the potential benefits outweigh the potential risks to the fetus.

No food warning has been identified

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

Common:

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

Less common:

1. Rash
2. Itching
3. Dizziness
4. Abdominal pain
5. Fatigue

Rare:

1. Allergic reactions (e.g., hives, difficulty breathing, swelling of the face, lips, tongue, or throat)
2. Severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)
3. Liver problems (e.g., yellowing of the skin or eyes, dark urine, persistent nausea or vomiting, abdominal pain)
4. Kidney problems (e.g., decreased urine output, swelling in the legs or ankles)
5. Blood disorders (e.g., decreased platelets, decreased white blood cells, decreased red blood cells)

Influence of Oritavancin on CYP Substrates

A study was conducted in healthy volunteers (n=16) to assess the concurrent administration of a single 1200 mg dose of Oritavancin with probe substrates for various CYP450 enzymes. Oritavancin was determined to be a nonspecific, mild inhibitor (CYP2C9 and CYP2C19) or inducer (CYP3A4 and CYP2D6) of several CYP isoforms.

Caution is advised when administering Oritavancin together with drugs that have a narrow therapeutic range and are primarily metabolized by one of the affected CYP450 enzymes (e.g., warfarin), as co-administration may increase (e.g., for CYP2C9 substrates) or decrease (e.g., for CYP2D6 substrates) the concentrations of the drug with a narrow therapeutic range. Close monitoring of patients for signs of toxicity or lack of efficacy is recommended if they have received Oritavancin while on a potentially affected medication (e.g., patients should be monitored for bleeding if they are receiving Oritavancin and warfarin concurrently).

Interactions with Drug-Laboratory Tests

Oritavancin has been shown to artificially extend aPTT for 48 hours and PT and INR for up to 24 hours by binding to and inhibiting the action of the phospholipid reagents responsible for activating coagulation in commonly used laboratory coagulation tests. Effects on ACT are also anticipated since the phospholipid reagents are used in this coagulation test as well. Oritavancin does not impact the coagulation system itself.

The following are the side effects involving Oritavancin:

• Nausea
• Vomiting
• Headache
• Diarrhea
• Rash
• Infusion site reactions (such as redness, swelling, or pain)
• Increased liver enzyme levels (as shown in blood tests)
• Changes in certain blood tests, including prothrombin time (PT) and international normalized ratio (INR)

Pregnancy:

Pregnancy Category C

Reproduction studies conducted in rats and rabbits have shown no evidence of fetal harm caused by oritavancin at the highest administered concentrations of 30 mg/kg/day and 15 mg/kg/day, respectively. These daily doses would be equivalent to a human dose of 300 mg, which is 25% of the clinical dose of 1200 mg. However, higher doses were not tested in nonclinical studies assessing developmental and reproductive toxicity.

There have been no adequate and well-controlled trials in pregnant women. Oritavancin should only be used during pregnancy if the potential benefits outweigh the potential risks to the fetus.

Lactation:

The excretion of oritavancin in human milk is currently unknown. However, studies in lactating rats have shown that radio-labeled [14C]-oritavancin was excreted in milk and absorbed by nursing pups following a single intravenous infusion. Therefore, caution should be exercised when administering Oritavancin to nursing women.

Pediatric:

The safety and efficacy of Oritavancin have not been investigated in pediatric patients below 18 years of age.

Geriatric Use:

The combined Phase 3 clinical trials for Oritavancin in ABSSSI did not enroll an adequate number of participants aged 65 and above to establish if they exhibit distinct responses compared to younger subjects. Although no notable differences in responses between elderly and younger patients have been observed in other reported clinical experiences, it is still possible that certain older individuals may display increased sensitivity, although this cannot be definitively ruled out.

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

Throughout the clinical program involving 3,017 individuals treated with oritavancin, no instances of accidental overdose were reported.

Oritavancin is not eliminated from the bloodstream through hemodialysis procedures. In case of an overdose, it is recommended to provide supportive measures.

Pharmacodynamics

Oritavancin disrupts the synthesis and structure of bacterial cell walls, effectively treating skin and subcutaneous tissue infections caused by gram-positive bacteria. Additionally, this medication has been found to artificially elevate INR and aPTT levels, thereby affecting coagulation tests. Infusion reactions have also been documented as potential side effects of Oritavancin.

Pharmacokinetics

Absorption:

● The pharmacokinetic analysis of oritavancin showed a maximum concentration (Cmax) of 138 μg/mL and an area under the curve from time zero to infinity (AUC0-∞) of 2800 μg•h/mL. In a study of healthy volunteers, the AUC0-t after an 800 mg dose was 11111 μg•h/mL. Another pharmacokinetic study reported a Cmax of 4.7-7.6 micrograms/mL, typically achieved within 24 hours after administration.

The volume of distribution:

● Oritavancin has an estimated volume of distribution of 87.6 L, indicating extensive distribution throughout the body's tissues.

Protein binding:

● Approximately 85% of oritavancin is bound to plasma proteins.

Metabolism:

● In vitro studies using human hepatocytes suggest that oritavancin is not metabolized and is excreted unchanged.

Route of elimination:

● Oritavancin is excreted primarily as an unchanged drug in both urine and feces. Less than 5% of the drug is recovered in the urine, and 1% is recovered in the feces.

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

1. Corey GR, Kablier H, Mehra P, et al.; SOLO I Investigators. The study published in the New England Journal of Medicine in 2014 (370(23):2180-2190) investigated the efficacy of single-dose oritavancin in treating acute bacterial skin infections.
2. Corey GR, Good S, Jiang H, et al.; SOLO II investigators. The Clinical Infectious Diseases publication in 2015 (60(2):254-262) focused on comparing single-dose oritavancin with 7-10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections.
3. Dunbar LM, Milata J, McClure T, Wasilewski MM; SIMPLIFI Study Team. The Antimicrobial Agents and Chemotherapy journal featured an analysis of the SIMPLIFI trial, comparing the efficacy and safety of front-loaded dosing regimens of oritavancin to daily dosing.
4. Karaoui LR, El-Lababidi R, Chahine EB. An article in the American Journal of Health-System Pharmacy provided an overview of oritavancin as an investigational lipoglycopeptide antibiotic.
5. The prescribing information for oritavancin is available under the brand names Kimyrsa (July 2021) and Oritavancin (January 2022), both published by Melinta Therapeutics LLC.

1. https://go.drugbank.com/drugs/DB04911
2. https://reference.medscape.com/drug/kimyrsa-Oritavancin-oritavancin-999944
3. https://www.Oritavancin.com/
4. https://medlineplus.gov/druginfo/meds/a614042.html
5. https://www.ema.europa.eu/en/documents/product-information/tenkasi-previously-Oritavancin-epar-product-information_en.pdf
6. https://www.drugs.com/mtm/oritavancin.html
7. https://my.clevelandclinic.org/health/drugs/18501-oritavancin-injection
8. https://pharmacy.services.conduent.com/mohealthnet/2021 September Drug Monographs/9-1 Kimyrsa Vial.pdf
9. https://ec.europa.eu/health/documents/community-register/2016/20161212136678/anx_136678_en.pdf
10. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf