Orbactiv

ORBACTIV is a lipoglycopeptide antibacterial drug indicated for the treatment of adult patients with acute bacterial skin and skin structure infections caused or suspected to be caused by susceptible isolates of designated Gram-positive microorganisms. (

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ORBACTIV and other antibacterial drugs, ORBACTIV should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (

• There are two oritavancin products (ORBACTIV and KIMYRSA™, another oritavancin product) that have differences in dose strength, duration of infusion and preparation instructions, including reconstitution and dilution instructions and compatible diluents (

  2.1 Dosage and Administration Overview

  There are two oritavancin products (ORBACTIV and KIMYRSA™, another oritavancin product) that:

  • Are supplied in different dose strengths of oritavancin
    [see Dosage Forms and Strengths (3)]
    .
  • Have different recommended durations of infusion
    [see Dosage and Administration (2.2)].
  • Have different preparation instructions, including differences in reconstitution, dilution, and compatible diluents
    [see Dosage and Administration (2.3, 2.4)]
    .

  Carefully follow the recommended dosage and dose preparation instructions for ORBACTIV in this prescribing information (PI)

  [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

  Refer to the KIMYRSA prescribing information for relevant information of the other oritavancin product.

  ,

  2.2 Recommended Dosage

  The recommended dosage of ORBACTIV is 1,200 mg administered as a single dose by intravenous infusion over

  3 hours

  in patients 18 years and older

  [see Warnings and Precautions (5.3)]

  .

  ,

  2.3 Preparation of ORBACTIV for Intravenous Infusion

  There are two oritavancin products (ORBACTIV and KIMYRSA, another oritavancin product) that have differences in dose strengths, duration of infusion, reconstitution and dilution instructions, and compatible diluents. Carefully follow the reconstitution, and dilution instructions with the appropriate compatible diluent for ORBACTIV specified in this prescribing information.

  Refer to the KIMYRSA prescribing information for relevant information of the other oritavancin product.

  ORBACTIV is intended for intravenous infusion, only after reconstitution and dilution.

  Three

  ORBACTIV 400 mg vials need to be reconstituted and diluted to prepare a single 1,200 mg intravenous dose.

  Reconstitution

  : Aseptic technique should be used to reconstitute

  three

  ORBACTIV 400 mg vials.

  • Add 40 mL of sterile water for injection (WFI) to reconstitute each vial to provide a 10 mg/mL solution per vial.
  • For
    each
    vial, gently swirl the contents to avoid foaming and ensure that all ORBACTIV powder is completely dissolved to form a reconstituted solution.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Each reconstituted vial should appear to be a clear, colorless to pale yellow solution, free of visible particles.

  Dilution

  : Use ONLY 5% dextrose injection (D5W) for dilution to prepare the final intravenous solution for infusion.

  Do NOT use Sodium Chloride Injection

  for dilution as it is incompatible with ORBACTIV and may cause precipitation of the drug. Since no preservative or bacteriostatic agent is present in ORBACTIV, aseptic technique must be used in preparing the final intravenous solution as follows:

  • Withdraw and discard
    120
    mL from a
    1000
    mL intravenous bag of
    D5W
    .
  • Withdraw 40 mL from each of the three reconstituted vials of ORBACTIV and add to D5W intravenous bag to bring the bag volume to
    1000
    mL. This yields a concentration of 1.2 mg/mL.

  Discard any unused portion of the reconstituted solution remaining in each vial.

  Storage and Use of Intravenous Solution

  : Diluted intravenous solution in an infusion bag should be used within

  6 hours

  when stored at room temperature, or used within 12 hours when refrigerated at 2 to 8°C (36 to 46°F). The combined storage time (reconstituted solution in the vial and diluted solution in the bag) and 3 hour infusion time should not exceed

  6 hours

  at room temperature or 12 hours if refrigerated.

  ,

  2.4 Compatibility

  ORBACTIV solution for administration by 3-hour infusion is

  ONLY

  compatible with:

  • 5% dextrose injection (D5W)

  )
• Administer 1,200 mg of ORBACTIV as a single dose by intravenous infusion over 3 hours. (
  2.1 Dosage and Administration Overview

  There are two oritavancin products (ORBACTIV and KIMYRSA™, another oritavancin product) that:

  • Are supplied in different dose strengths of oritavancin
    [see Dosage Forms and Strengths (3)]
    .
  • Have different recommended durations of infusion
    [see Dosage and Administration (2.2)].
  • Have different preparation instructions, including differences in reconstitution, dilution, and compatible diluents
    [see Dosage and Administration (2.3, 2.4)]
    .

  Carefully follow the recommended dosage and dose preparation instructions for ORBACTIV in this prescribing information (PI)

  [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

  Refer to the KIMYRSA prescribing information for relevant information of the other oritavancin product.
  ,
  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

  [see Adverse Reactions (6.1)]

  . 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

  [see Dosage and Administration (2.2)].
  )
• Carefully follow the recommended dosage and dose preparation instructions for ORBACTIV in the full prescribing information. (
  2.1 Dosage and Administration Overview

  There are two oritavancin products (ORBACTIV and KIMYRSA™, another oritavancin product) that:

  • Are supplied in different dose strengths of oritavancin
    [see Dosage Forms and Strengths (3)]
    .
  • Have different recommended durations of infusion
    [see Dosage and Administration (2.2)].
  • Have different preparation instructions, including differences in reconstitution, dilution, and compatible diluents
    [see Dosage and Administration (2.3, 2.4)]
    .

  Carefully follow the recommended dosage and dose preparation instructions for ORBACTIV in this prescribing information (PI)

  [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

  Refer to the KIMYRSA prescribing information for relevant information of the other oritavancin product.
  ,
  2.2 Recommended Dosage

  The recommended dosage of ORBACTIV is 1,200 mg administered as a single dose by intravenous infusion over

  3 hours

  in patients 18 years and older

  [see Warnings and Precautions (5.3)]

  .
  ,
  2.3 Preparation of ORBACTIV for Intravenous Infusion

  There are two oritavancin products (ORBACTIV and KIMYRSA, another oritavancin product) that have differences in dose strengths, duration of infusion, reconstitution and dilution instructions, and compatible diluents. Carefully follow the reconstitution, and dilution instructions with the appropriate compatible diluent for ORBACTIV specified in this prescribing information.

  Refer to the KIMYRSA prescribing information for relevant information of the other oritavancin product.

  ORBACTIV is intended for intravenous infusion, only after reconstitution and dilution.

  Three

  ORBACTIV 400 mg vials need to be reconstituted and diluted to prepare a single 1,200 mg intravenous dose.

  Reconstitution

  : Aseptic technique should be used to reconstitute

  three

  ORBACTIV 400 mg vials.

  • Add 40 mL of sterile water for injection (WFI) to reconstitute each vial to provide a 10 mg/mL solution per vial.
  • For
    each
    vial, gently swirl the contents to avoid foaming and ensure that all ORBACTIV powder is completely dissolved to form a reconstituted solution.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Each reconstituted vial should appear to be a clear, colorless to pale yellow solution, free of visible particles.

  Dilution

  : Use ONLY 5% dextrose injection (D5W) for dilution to prepare the final intravenous solution for infusion.

  Do NOT use Sodium Chloride Injection

  for dilution as it is incompatible with ORBACTIV and may cause precipitation of the drug. Since no preservative or bacteriostatic agent is present in ORBACTIV, aseptic technique must be used in preparing the final intravenous solution as follows:

  • Withdraw and discard
    120
    mL from a
    1000
    mL intravenous bag of
    D5W
    .
  • Withdraw 40 mL from each of the three reconstituted vials of ORBACTIV and add to D5W intravenous bag to bring the bag volume to
    1000
    mL. This yields a concentration of 1.2 mg/mL.

  Discard any unused portion of the reconstituted solution remaining in each vial.

  Storage and Use of Intravenous Solution

  : Diluted intravenous solution in an infusion bag should be used within

  6 hours

  when stored at room temperature, or used within 12 hours when refrigerated at 2 to 8°C (36 to 46°F). The combined storage time (reconstituted solution in the vial and diluted solution in the bag) and 3 hour infusion time should not exceed

  6 hours

  at room temperature or 12 hours if refrigerated.
  )

ORBACTIV is supplied as sterile, white to off-white lyophilized powder containing 400 mg of oritavancin (as oritavancin diphosphate) in a single-dose clear glass vial, which must be reconstituted and further diluted prior to intravenous administration.

There are no available data on ORBACTIV use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no effects on embryo-fetal development or survival were observed in pregnant rats or rabbits treated at the highest doses throughout organogenesis with intravenous oritavancin, at doses equivalent to 25% of the single clinical dose of 1,200 mg

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

• 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 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

  [see Contraindications (4.1)and Drug Interactions (7.2)]

  .

  ORBACTIV has no effect on the coagulation system in vivo.
  ,
  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

  [see Contraindications (4.1)and Warnings and Precautions (5.1, 5.5)]

  . 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)]

  .
  )
• 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 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

  [see Adverse Reactions (6.1)]

  .
  )
• 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 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

  [see Adverse Reactions (6.1)]

  . 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

  [see Dosage and Administration (2.2)].
  )
• Clostridioides difficile
  -associated diarrhea: Evaluate patients if diarrhea occurs. (
  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

  .
  )
• Concomitant warfarin use: ORBACTIV has been shown to artificially prolong PT/INR for up to 12 hours (
  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

  [see Contraindications (4.1)and Drug Interactions (7.2)]

  .

  ORBACTIV has no effect on the coagulation system in vivo.
  ). Patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin. (
  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

  [see Warnings and Precautions (5.1)]

  .

  Patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin

  [see Drug Interactions (7.1)]

  .
  )
• Osteomyelitis: Institute appropriate alternate antibacterial therapy in patients with confirmed or suspected osteomyelitis. (
  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

  [see Adverse Reactions (6.1)]

  .
  )