Oritavancin is a lipoglycopeptide bactericidal antibiotic for intravenous administration with activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus. It exerts activity by disrupting bacterial cell membrane integrity through inhibition of transglycosylation and transpeptidation steps of cell wall biosynthesis.
TRADE NAME (U.S.):Orbactiv
U.S FDA APPROVAL DATE:August 6, 2014
SIMILAR APPROVED DRUGS
Dalbavancin and telavancin, like oritavancin, are semisynthetic lipoglycopeptides. All three are related to the glycopeptide antibiotic, vancomycin.
U.S FDA-APPROVED INDICATION
Treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), Enterococcus faecalis (vancomycin-susceptible isolates only).
Pharmacokinetc parameters following a single 1200 mg intravenous dose of oritavancin:
Oritavancin exhibits linear pharmacokinetics at a dose up to 1200 mg.
Approximately 85% of oritavancin is bound to human plasma proteins. Oritavancin is extensively distributed into the tissues (total volume of distribution, 87.6 L). After a single 800 mg dose, exposures of oritavancin in skin blister fluid were approximately 20% of those in plasma concentration.
Oritavancin is not metabolized by the liver.
Oritavancin is slowly excreted unchanged in feces and urine with less than 1% and 5% of the dose recovered in feces and urine, respectively, after 2 weeks. Oritavancin has a long terminal elimination phase with a half-life of 245 hours.
No dosage adjustment of oritavancin is needed in patients with mild (CrCL 50-79 mL/min) to moderate (CrCL 30-49 mL/min) renal impairment. Oritavancin has not been evaluated in severe renal impairment. Oritavancin is not removed from blood by hemodialysis.
No dosage adjustment of oritavancin is needed in patients with mild or moderate (Child-Pugh Class B) hepatic impairment. Oritavancin has not been evaluated in severe hepatic impairment.
CLINICAL TRIALS/EVIDENCE SUMMARY
Both the SOLO I and SOLO II trials were identically designed Phase 3 randomized, double-blind, multicenter non-inferiority clinical trials. Patients with ABSSSI thought or proven to be caused by a gram-positive pathogen were randomized 1:1 to receive a single dose of oritavancin 1200 mg on day 1 followed by twice daily infusions of placebo or vancomycin IV 1 gram or 15 mg/kg every 12 hours for 7-10 days. After day 1, the vancomycin dose could be adjusted based on renal function, clinical status, or vancomycin tough plasma concentrations. The primary endpoint in each trial was early clinical response at 48-72 hours: a composite endpoint of cessation of spread or reduction in size of baseline lesion, absence of fever, and no rescue antibiotic medication. In the SOLO I, this endpoint was achieved in 82.3% of oritavancin and 78.9% of vancomycin recipients. In the SOLO II, this endpoint was achieved in 80.1% of oritavancin and 82.9% of vancomycin recipients. Secondary endpoints for lesion size reduction ≥ 20% at early clinical response and investigator-assessed sustained clinical response at post-therapy were evaluated at day 14-24 (7-14 days after the end of therapy). Sustained clinical response was defined as complete or nearly complete resolution of baseline signs or symptoms related to the primary ABSSSI site (erythema, induration/edema, purulent drainage, fluctuance, pain, tenderness, local increase in heat/warmth) such that no further treatment with antibiotics was needed.
Serious adverse reactions were reported in 57/976 (5.8%) patients treated with oritavancin and 58/983 (5.9%) treated with vancomycin (comparator). The most commonly reported serious adverse reaction was cellulitis in both treatment groups: 11/976 (1.1%) in oritavancin and 12/983 (1.2%) in the vancomycin arms, respectively.
Oritavancin was discontinued due to adverse reactions in 36/976 (3.7%) of patients; the most common reported reactions leading to discontinuation were cellulitis (4/976, 0.4%) and osteomyelitis (3/976, 0.3%).
The most commonly reported adverse reactions (≥ 5%): headache, nausea. Adverse reactions reported in 1.5-5% included: diarrhea, vomiting, dizziness, infusion site phlebitis, abscess (limb and subcutaneous), ALT and AST elevation, tachycardia, infusion site reaction.
The following adverse reactions were reported in oritavancin-treated patients at a rate of less than 1.5%:
Blood and lymphatic system disorders: anemia, eosinophilia
Administration: infusion site erythema, extravasation, induration, pruritis, rash, edema peripheral
Immune system disorders: hypersensitivity
Infections and infestations: osteomyelitis
Investigations: total bilirubin increased, hyperuricemia
Metabolism and nutrition disorders: hypoglycemia
Musculoskeletal and connective tissue disorders: tenosynovitis, myalgia
Respiratory, thoracic, and mediastinal disorders: bronchospasm, wheezing
Skin and subcutaneous tissue disorders: urticaria, angioedema, erythema multiforme, pruritis, leucocytoclastic vasculitis, rash
Oritavancin can interfere with coagulation tests by binding and preventing action of the phospholipid reagents, which activate coagulation in commonly used laboratory coagulation tests. This causes activated partial thromboplastin time (aPTT) test results to remain falsely elevated for approximately 48 hours and the PT and INR for 24 hours. Unfractionated heparin is contraindicated for 48 hours after oritavancin administration.
The drug is contraindicated in patients with known hypersensitivity to oritavancin. In the Phase 3 clinical trials, the median onset of hypersensitivity reactions was 1.2 days, and the median duration of these reactions was 2.4 days. No data are available on cross-reactivity between oritavancin and other glycopeptides, including vancomycin.
Co-administration with warfarin may result in higher exposure of warfarin, which may increase the risk of bleeding.
Infusion-related reactions include pruritus, urticarial, or flushing.
USE IN SPECIAL POPULATIONS
Pregnancy Category C
There is no well-controlled study with oritavancin in pregnant women.
Oritavancin is excreted into the breast milk of rats. It is unknown whether oritavancin is excreted in human milk.
Clinical studies of oritavancin did not include sufficient number of subjects aged 65 and older to determine whether they respond differently than younger subjects.
A drug-drug interaction study showed that oritavancin is a weak inducer of CYP3A4 (a decrease of 18% in the mean AUC of midazolam) and CYP2D6 (decrease of 31% in the ratio of dextromethorphan to dextrorphan concentrations in the urine after administration of dextromethorphan). Oritavancin was also a weak inhibitor of CYP2C19 and a weak inhibitor of CYP2C9 (with an increase of 31% in the mean AUC of warfarin).
DOSE AND ADMINISTRATION
The recommended dosing for oritavancin is a single intravenous dose of 1200 mg infused over 3 hours in patients 18 years and older.
Oritavancin is FDA approved for adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible gram-positive microorganisms. The SOLO I and SOLO II trails demonstrated non-inferiority of a single dose administration of oritavancin compared to 7-10 days of vancomycin for the treatment of ABSSSI. The acquisition cost of oritavancin is higher than other broad-spectrum Gram-positive agents; however, its prolonged half-life may offer advantages in the emergency department or outpatient setting.
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