Kimyrsa Drug Information

Dosage and Administration Overview There are two oritavancin products (KIMYRSA and ORBACTIV ®, another oritavancin product) that: Are supplied in different dose strengths of oritavancin. Have different recommended durations of infusion. Have different preparation instructions, including differences in reconstitution, dilution, and compatible diluents.

Carefully follow the recommended dosage and dose preparation instructions for KIMYRSA in this prescribing information (PI). Refer to the ORBACTIV prescribing information for relevant information of the other oritavancin product.

Recommended Dosage

The recommended dosage of KIMYRSA is 1,200 mg administered as a single dose by intravenous infusion over 1 hour in patients 18 years and older.

Preparation of KIMYRSA for Intravenous Infusion There are two oritavancin products (KIMYRSA and ORBACTIV, 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 KIMYRSA specified in this prescribing information. KIMYRSA is intended for intravenous infusion, only after reconstitution and dilution.

One KIMYRSA 1,200 mg single-dose vial needs to be reconstituted and diluted to prepare a single 1,200 mg intravenous dose. Reconstitution: Aseptic technique should be used to reconstitute one KIMYRSA 1,200 mg vial. Add 40 mL of sterile water for injection (SWFI) to reconstitute the vial to provide a 30 mg/mL solution.

Gently swirl the contents to avoid foaming and ensure that all KIMYRSA 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. The reconstituted vial should appear to be a clear, colorless to pink solution, free of visible particles.

Dilution: Use 0.9% sodium chloride injection or 5% dextrose in sterile water (D5W) for dilution to prepare the final intravenous solution for infusion. Since no preservative or bacteriostatic agent is present in KIMYRSA, aseptic technique must be used in preparing the final intravenous solution as follows: Withdraw and discard 40 mL from a 250 mL intravenous bag of 0.9% sodium chloride injection or D5W. Withdraw 40 mL of the reconstituted vial of KIMYRSA and add to the intravenous bag of 0.9% sodium chloride injection or D5W to bring the bag volume to 250 mL.

This yields a concentration of 4.8 mg/mL. Discard any unused portion of the reconstituted solution remaining in the vial. Storage and Use of Intravenous Solution: Diluted intravenous solution in an infusion bag should be used within 4 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 1 hour infusion time should not exceed 4 hours at room temperature or 12 hours if refrigerated.

Incompatibilities

Drugs formulated at a basic or neutral pH may be incompatible with KIMYRSA. KIMYRSA should not be administered simultaneously with commonly used intravenous drugs through a common intravenous port. If the same intravenous line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of KIMYRSA with 0.9% sodium chloride injection or D5W.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of oritavancin products cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of KIMYRSA has been established from adequate and well-controlled trials of another oritavancin product, ORBACTIV (hereinafter referred to as oritavancin), in patients with ABSSSI, and a study of KIMYRSA in patients with ABSSSI. Safety was evaluated for up to 60 days after dosing.

The most commonly reported adverse reactions (≥3%) in patients receiving a single 1,200 mg dose of oritavancin in the pooled ABSSSI clinical trials were: headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea. Table 1 provides selected adverse reactions occurring in ≥1.5% of patients receiving oritavancin in the pooled ABSSSI clinical trials. KIMYRSA has been evaluated in a randomized, open-label, multi-center ABSSSI study which included 50 adult patients treated with a single 1,200 mg intravenous dose of KIMYRSA administered by intravenous infusion over 1 hour, and 52 patients treated with a single 1,200 mg intravenous dose of oritavancin administered by intravenous infusion over 3 hours.

Selected adverse reactions occurring in ≥2 patients receiving either KIMYRSA or oritavancin in the open-label, multi-center ABSSSI study were diarrhea, nausea, vomiting, hypersensitivity, pruritus, chills, headache and pyrexia.

Effect of KIMYRSA on CYP Substrates

A screening drug-drug interaction study indicated that oritavancin is a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or inducer (CYP3A4 and CYP2D6) of several CYP isoforms. A drug-drug interaction study that assessed the interaction potential of a single 1,200 mg dose of oritavancin on the pharmacokinetics of S-warfarin (CYP2C9 probe substrate) showed no effect of oritavancin on S-warfarin C max or AUC. Avoid administering KIMYRSA 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 KIMYRSA while on a potentially affected compound (e.g., patients should be monitored for bleeding if concomitantly receiving KIMYRSA and warfarin).

Drug-Laboratory Test Interactions Prolongation of Certain Laboratory Coagulation Tests KIMYRSA 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. For patients who require monitoring of anticoagulation effect within the indicated time after KIMYRSA 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. Oritavancin does not interfere with coagulation in vivo.

In addition, oritavancin does not affect tests that are used for diagnosis of Heparin Induced Thrombocytopenia (HIT). Table 2: Coagulation Tests Affected and Positive Indirect and Direct Antiglobulin Tests (IAT/DAT) Positive IAT/DAT were noted with administration of oritavancin products, including KIMYRSA, in studies with healthy volunteers and patients with ABSSSI. Positive IAT may interfere with cross-matching before blood transfusion.

Pregnancy Risk Summary There are no available data on KIMYRSA 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 (see Data ). 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 respectively. Data Animal Data Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to oritavancin at the highest doses administered throughout organogenesis, 30 mg/kg/day (gestation days 6-17) and 15 mg/kg/day (gestation days 7-19), respectively.

Those doses would be equivalent to a human dose of 300 mg, or 25% of the single clinical dose of 1,200 mg. Higher doses were not evaluated in nonclinical developmental and reproductive toxicology studies.

Pediatric Use Safety and effectiveness of KIMYRSA in pediatric patients (younger than 18 years of age) have not been established.

Intravenous Unfractionated Heparin Sodium Use of intravenous unfractionated heparin sodium is contraindicated for 120 hours (5 days) after KIMYRSA administration because the activated partial thromboplastin time (aPTT) test results may remain falsely elevated for up to 120 hours (5 days) after KIMYRSA administration.

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

Based on an in vitro hemodialysis study, KIMYRSA is unlikely to be removed from blood by hemodialysis. In the event of overdose, supportive measures should be taken.