ORITAVANCIN Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Effect of ORBACTIV on CYP Substrates A screening drug-drug interaction study indicated that ORBACTIV is a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or inducer (CYP3A4 and CYP2D6) of several CYP isoforms <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . A drug-drug interaction study that assessed the interaction potential of a single 1,200 mg dose of ORBACTIV on the pharmacokinetics of S-warfarin (CYP2C9 probe substrate) showed no effect of ORBACTIV on S-warfarin C max or AUC. Avoid administering ORBACTIV concomitantly with drugs that are predominantly metabolized by one of the affected CYP450 enzymes, as co-administration may increase or decrease concentrations of those drugs. Patients should be closely monitored for signs of toxicity or lack of efficacy if they have been given ORBACTIV while on a potentially affected compound (e.g. patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin).

7.2 Drug-Laboratory Test Interactions Prolongation of Certain Laboratory Coagulation Tests ORBACTIV may artificially prolong certain laboratory coagulation tests (see Table 2 ) by binding to and preventing the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests <span class="opacity-50 text-xs">[see Contraindications (4.1) and Warnings and Precautions (5.1 , 5.5) ]</span> . For patients who require monitoring of anticoagulation effect within the indicated time after ORBACTIV dosing, a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered. ORBACTIV does not interfere with coagulation in vivo. In addition, ORBACTIV does not affect tests that are used for diagnosis of Heparin Induced Thrombocytopenia (HIT).

Table

2: Coagulation Tests Affected and Unaffected by ORBACTIV Elevated by ORBACTIV Unaffected by ORBACTIV Prothrombin time (PT) up to 12 hours Chromogenic Factor Xa Assay International normalized ratio (INR) up to 12 hours Thrombin Time (TT) Activated partial thromboplastin time (aPTT) up to 120 hours Activated clotting time (ACT) up to 24 hours Silica clot time (SCT) up to 18 hours Dilute Russell's viper venom time (DRVVT) up to 72 hours D-dimer up to 72 hours Positive Indirect and Direct Antiglobulin Tests (IAT/DAT) Positive IAT/DAT were noted with administration of oritavancin products, including ORBACTIV, in studies with healthy volunteers and patients with ABSSSI. Positive IAT may interfere with cross-matching before blood transfusion [see Adverse Reactions (6.2) ] .

Use of intravenous unfractionated heparin sodium is contraindicated for 120 hours (5 days) after ORBACTIV administration. ( 4.1 , 5.1 ) Known hypersensitivity to oritavancin products. ( 4.2 , 5.2 )

4.1 Intravenous Unfractionated Heparin Sodium Use of intravenous unfractionated heparin sodium is contraindicated for 120 hours (5 days) after ORBACTIV administration because the activated partial thromboplastin time (aPTT) test results may remain falsely elevated for up to 120 hours (5 days) after ORBACTIV administration <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Drug Interactions (7.2) ]</span>.

4.2 Hypersensitivity ORBACTIV is contraindicated in patients with known hypersensitivity to oritavancin products.

AND PRECAUTIONS Coagulation test interference: ORBACTIV has been shown to artificially prolong aPTT for up to 120 hours, and may prolong PT and INR for up to 12 hours and ACT for up to 24 hours. For patients who require aPTT monitoring within 120 hours of ORBACTIV dosing, consider a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT. ( 5.1 , 7.2 ) Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of oritavancin products, including ORBACTIV. Discontinue infusion if signs of acute hypersensitivity occur. Carefully monitor patients with known hypersensitivity to glycopeptides. ( 5.2 )

Infusion Related

Reactions: Administer ORBACTIV over 3 hours to minimize infusion. Infusion related reactions have been reported with the glycopeptide class of antimicrobial agents, including oritavancin products (e.g. ORBACTIV). Stopping or slowing the infusion may result in cessation of these reactions. ( 5.3 ) Clostridioides difficile -associated diarrhea: Evaluate patients if diarrhea occurs. ( 5.4 ) Concomitant warfarin use: ORBACTIV has been shown to artificially prolong PT/INR for up to 12 hours ( 5.1 ). Patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin. ( 5.5 ) Osteomyelitis: Institute appropriate alternate antibacterial therapy in patients with confirmed or suspected osteomyelitis. ( 5.6 )

5.1 Coagulation Test Interference ORBACTIV has been shown to artificially prolong aPTT for up to 120 hours, PT and INR for up to 12 hours, and activated clotting time (ACT) for up to 24 hours following administration of a single 1,200 mg dose by binding to and preventing action of the phospholipid reagents commonly used in laboratory coagulation tests. ORBACTIV has also been shown to elevate D-dimer concentrations up to 72 hours after ORBACTIV administration. For patients who require aPTT monitoring within 120 hours of ORBACTIV dosing, a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered <span class="opacity-50 text-xs">[see Contraindications (4.1) and Drug Interactions (7.2) ]</span> . ORBACTIV has no effect on the coagulation system in vivo.

5.2 Hypersensitivity Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of oritavancin products, including ORBACTIV. If an acute hypersensitivity reaction occurs during ORBACTIV infusion, discontinue ORBACTIV immediately and institute appropriate supportive care. Before using ORBACTIV, inquire carefully about previous hypersensitivity reactions to glycopeptides. Due to the possibility of cross-sensitivity, carefully monitor for signs of hypersensitivity during ORBACTIV infusion in patients with a history of glycopeptide allergy. In the Phase 3 ABSSSI clinical trials, the median onset of hypersensitivity reactions in ORBACTIV-treated patients was 1.2 days and the median duration of these reactions was 2.4 days <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

5.3 Infusion Related Reactions ORBACTIV is administered as a single dose by intravenous infusion, using a total infusion time of 3 hours to minimize the risk of infusion-related reactions. Infusion related reactions have been reported with the glycopeptide class of antimicrobial agents, including oritavancin products (e.g. ORBACTIV), including flushing of the upper body, urticaria, pruritus and/or rash <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Infusion reactions characterized by chest pain, back pain, chills and tremor have been observed with the use of ORBACTIV, including after the administration of more than one dose of ORBACTIV during a single course of therapy. Stopping or slowing the infusion may result in cessation of these reactions. The safety and effectiveness of more than one dose of ORBACTIV during a single course of therapy have not been established <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>.

5.4 Clostridioides difficile -associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including ORBACTIV, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters 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, antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated .

5.5 Potential Risk of Bleeding with Concomitant Use of Warfarin ORBACTIV has been shown to artificially prolong prothrombin time (PT) and international normalized ratio (INR) for up to 12 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 12 hours after an ORBACTIV dose <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 )]</span> . Patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> .

5.6 Osteomyelitis In Phase 3 ABSSSI clinical trials, more cases of osteomyelitis were reported in the ORBACTIV treated arm than in the vancomycin-treated arm. Monitor patients for signs and symptoms of osteomyelitis. If osteomyelitis is suspected or diagnosed, institute appropriate alternate antibacterial therapy <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

5.7 Development of Drug Resistant Bacteria Prescribing ORBACTIV 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 <span class="opacity-50 text-xs">[see Patient Counseling Information (17) ]</span> .