Oritavancin (Monograph)

Brand name: Orbactiv
Drug class: Glycopeptides
Chemical name: (4″R)-22-O-(3-Amino-2,3,6-trideoxy-3-C-methyl-α-l-arabino-hexopyranosyl)-N3″-[p-(p-chlorophenyl)benzyl]vancomycin
Molecular formula: C₈₆H₉₇Cl₃N₁₀O₂₆C₈₆H₉₇Cl₃N₁₀O₂₆•2H₃PO₄
CAS number: 171099-57-3

Introduction

Antibacterial; lipoglycopeptide; semisynthetic derivative of a naturally occurring glycopeptide.

Uses for Oritavancin

Skin and Skin Structure Infections

Treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA] and methicillin-susceptible S. aureus), Streptococcus pyogenes (group A β-hemolytic streptococci, GAS), S. agalactiae (group B streptococci, GBS), S. dysgalactiae, S. anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), or vancomycin-susceptible Enterococcus faecalis.

Oritavancin Dosage and Administration

Administration

Administer by IV infusion.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Must reconstitute and further dilute prior to IV infusion.

Do not administer simultaneously with commonly used IV drugs through a common port.

If the same IV line or port is used for sequential infusion of other drugs, flush IV line with 5% dextrose injection before and after oritavancin infusion.

Vials contain no preservatives; for single use only.

Reconstitution

Reconstitute vials containing 400 mg of oritavancin by adding 40 mL of sterile water for injection to provide a solution containing 10 mg/mL. Total of 3 vials required to prepare a single 1.2-g dose.

To avoid foaming, gently swirl vials until contents completely dissolve. Reconstituted solution should appear clear and colorless to pale yellow.

Dilution

Further dilute reconstituted solution in 5% dextrose injection. Before adding oritavancin to a 1-L IV bag of 5% dextrose injection, withdraw and discard 120 mL of the 5% dextrose injection. Then, withdraw 40 mL of oritavancin solution from each of the 3 reconstituted vials and add to the IV bag to bring the volume to 1 L. Final diluted solution has a concentration of 1.2 mg/mL.

Rate of Administration

Administer by IV infusion over 3 hours.

Dosage

Available as oritavancin diphosphate; dosage expressed in terms of oritavancin.

Adults

Skin and Skin Structure Infections

IV

Single 1.2-g dose.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustments not needed.

Severe hepatic impairment: Pharmacokinetics not evaluated.

Renal Impairment

Mild or moderate renal impairment: Dosage adjustments not needed.

Severe renal impairment: Pharmacokinetics not evaluated.

Cautions for Oritavancin

Contraindications

• Hypersensitivity to oritavancin.

• Unfractionated heparin sodium contraindicated for 48 hours after oritavancin; aPTT expected to be falsely elevated. (See Tests Used to Monitor Coagulation under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Serious hypersensitivity reactions reported. Median onset of hypersensitivity reactions was 1.2 days and median duration was 2.4 days in clinical studies.

Because of possibility of cross-sensitivity, question patients about previous hypersensitivity reactions to glycopeptides (e.g., dalbavancin, telavancin, vancomycin). Carefully monitor those with a history of glycopeptide allergy for signs of hypersensitivity during oritavancin infusion.

If acute hypersensitivity reaction occurs during the infusion, immediately discontinue and initiate appropriate supportive care.

Infusion Reactions

Infusion-related reactions (e.g., pruritus, urticaria, flushing) reported.

If an infusion-related reaction occurs, consider slowing or interrupting infusion.

Tests Used to Monitor Coagulation

Artificially prolongs certain tests used to monitor coagulation, including PT, INR, and aPTT; also expected to prolong activated clotting time (ACT). Oritavancin binds to phospholipid reagents and prevents activation of coagulation in such tests. This may complicate laboratory monitoring in patients receiving certain anticoagulants (e.g., heparin, warfarin).

PT and INR shown to be artificially prolonged for 24 hours after oritavancin; aPTT shown to be artificially prolonged for 48 hours after oritavancin.

For patients requiring aPTT monitoring within 48 hours of oritavancin administration, use a non-phospholipid-dependent coagulation test (e.g., factor Xa [chromogenic] assay) or consider using alternative anticoagulant not requiring aPTT monitoring.

Does not affect the coagulation system.

Concomitant Use with Warfarin

Because of increased warfarin exposure (see Interactions), use oritavancin and chronic warfarin therapy concomitantly only when benefits expected to outweigh risk of bleeding.

If used concomitantly, frequently monitor for signs of bleeding. Consider that laboratory monitoring of anticoagulant effects of warfarin is unreliable for 24 hours after oritavancin. (See Tests Used to Monitor Coagulation under Cautions.)

Osteomyelitis

In clinical studies, osteomyelitis reported more frequently in patients receiving oritavancin than in those receiving vancomycin.

Monitor patients for signs and symptoms of osteomyelitis. If osteomyelitis is suspected or diagnosed, initiate appropriate alternative antibacterial therapy.

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Possible emergence and overgrowth of nonsusceptible bacteria or fungi. Monitor carefully; institute appropriate therapy if superinfection occurs.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile. C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including oritavancin, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible. Initiate appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of oritavancin and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Specific Populations

Pregnancy

Category C.

Use during pregnancy only if potential benefits justify potential risks to fetus.

No adequate and well-controlled studies in pregnant women; animal studies (rats and rabbits) did not reveal evidence of fetal harm at dosages equivalent to 25% of human dosage, but higher doses not evaluated.

Lactation

Distributed into milk in lactating rats; not known whether distributed into human milk.

Use with caution in nursing women.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently then younger adults. Greater sensitivity in some older individuals cannot be ruled out.

Hepatic Impairment

Moderate hepatic impairment (Child-Pugh class B): Pharmacokinetics not altered.

Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics not evaluated.

Renal Impairment

Mild or moderate renal impairment: Pharmacokinetics not altered.

Severe renal impairment or undergoing dialysis: Pharmacokinetics not evaluated.

Common Adverse Effects

GI effects (i.e., diarrhea, nausea, vomiting, constipation), dizziness, headache, infusion site reactions (including phlebitis and extravasation), pruritus, urticaria, pyrexia, chills, abscess (limb or subcutaneous), cellulitis, increased AST and ALT, tachycardia, insomnia, fatigue.

Drug Interactions

Weak inhibitor of CYP2C9 and 2C19; weak inducer of 3A4 and 2D6.

Not a substrate or inhibitor of the P-glycoprotein (P-gp) efflux transporter.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

If used concomitantly with drugs that are metabolized by CYP2C9, 2C19, 3A4, or 2D6 and have a narrow therapeutic index, use caution and closely monitor for signs of toxicity or lack of efficacy.

Specific Drugs and Laboratory Tests

Oritavancin Pharmacokinetics

Absorption

Plasma Concentrations

Linear, dose-dependent pharmacokinetics following IV administration.

Distribution

Extent

Extensively distributed into tissues, including skin blister fluid, extracellular lung fluid, and alveolar macrophages. Mean oritavancin concentrations in skin blister fluid approximately 20% of those in plasma after a single 800-mg dose in healthy individuals.

Plasma Protein Binding

Approximately 85%.

Elimination

Metabolism

Not metabolized.

Elimination Route

Slowly eliminated unchanged in feces and urine; <1 and 5% of a single IV dose recovered in feces and urine, respectively, by 2 weeks after dose.

Not removed by hemodialysis or continuous renal replacement therapy (CRRT).

Half-life

Approximately 10 days (245 hours).

Special Populations

Moderate hepatic impairment (Child-Pugh class B): No clinically important effect on pharmacokinetics.

Mild or moderate renal impairment: No clinically important effect on pharmacokinetics.

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to 15–30°C).

Following reconstitution and further dilution, store at room temperature or refrigerate at 2–8°C.

Combined total storage time and 3-hour infusion time should not exceed 6 hours at room temperature or 12 hours at 2–8°C.

Compatibility

Parenteral

May be incompatible with drugs formulated at an alkaline or neutral pH.

Solution Compatibility1

Drug Compatibility

Actions and Spectrum

• Semisynthetic lipoglycopeptide antibacterial derived from chloroeremomycin, a naturally occurring glycopeptide. Structurally similar to vancomycin, but has side chains that enhance antibacterial activity.

• Mechanism of action similar to that of other glycopeptides (e.g., dalbavancin, telavancin, vancomycin). Binds to d-alanyl-d-alanine terminus of growing peptidoglycan chains, thereby inhibiting bacterial cell wall synthesis; binds to peptide bridging segments of the cell wall, thereby inhibiting transpeptidation (crosslinking) step of cell wall biosynthesis; dimerizes and anchors into bacterial cell membrane, which improves binding to target.

• Bactericidal in vitro against certain gram-positive bacteria, including staphylococci, streptococci, and enterococci.

• Active in vitro and in clinical studies against S. aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA]), S. pyogenes (group A β-hemolytic streptococci, GAS), S. agalactiae (group B streptococci, GBS), S. dysgalactiae, S. anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), and vancomycin-susceptible E. faecalis.

• Active in vitro against vancomycin-susceptible E. faecium, Clostridium perfringens, C. difficile, Peptostreptococcus, Propionibacterium acnes, S. pneumoniae, vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), and daptomycin-nonsusceptible S. aureus (DNSSA). However, safety and efficacy in treating clinical infections due to these bacteria not established.

• Reduced susceptibility or resistance to oritavancin produced in vitro by serial passage of S. aureus and E. faecalis in the presence of increasing concentrations of the drug.

Advice to Patients

• Advise patients that antibacterials (including oritavancin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).

• Importance of completing full course of therapy, even if feeling better after a few days.

• Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with oritavancin or other antibacterials in the future.

• Advise patients that allergic reactions, including serious allergic reactions, could occur and require immediate treatment. Importance of informing clinician about any previous hypersensitivity reactions to oritavancin or other glycopeptides (e.g., dalbavancin, telavancin, vancomycin).

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued. Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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