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QMSTM Plazomicin Immunoassay

For In Vitro Diagnostic Use Only

Rx Only 10023647 The unopened reagents are stable until the expiration date when stored at 2 to 8 °C. Do not freeze reagents or expose them to temperatures above 32 °C.

This Quantitative Microsphere System (QMS) instructions for use must be read carefully prior Warnings and Precautions to use. Package insert instructions must be followed accordingly. Reliability of assay results Exercise the standard precautions required for handling all laboratory reagents. cannot be guaranteed if there are any deviations from the instructions in this package insert. Precautions for Users Intended Use • For in vitro diagnostic use. The QMSTM Plazomicin Immunoassay is intended for the quantitative determination of • Do not mix materials from different kit lot numbers.

plazomicin in human K2 EDTA plasma on automated clinical chemistry analyzers. • Do not use kits beyond the expiration date. • Carryover: To avoid a falsely elevated result, retest any patient sample that was The assay results obtained should only be used as an aid in the management of patients with tested after a patient sample with a reportable plazomicin concentration greater than complicated (cUTI) receiving plazomicin therapy. 34.0 µg/mL. Plazomicin, as a molecule, is known to adhere to instrument pipette surfaces and can carry over into the next patient sample, potentially producing a falsely elevated The assay should only be used in conjunction with information available from clinical result. evaluations and other diagnostic procedures. • The assay should only be used in conjunction with information available from clinical evaluations and other diagnostic procedures. Summary and Explanation of the Test 1,2 Plazomicin (plazomicin sulfate) is a novel compound in the class of CAUTION: Materials of human origin used in this kit were tested for HIV1 and 2, Hepatitis with activity against Gram-negative and selected Gram-positive bacterial species, including B and Hepatitis C by FDA approved methods, and the findings were negative. However, no those that produce aminoglycoside-modifying enzymes that inactivate such test method can rule out the potential risk of infection with absolute certainty; therefore, the as , , and . Plazomicin is active against Enterobacteriaceae, material must be handled with universal precautions. In the event of exposure, the directives including those that produce extended spectrum ß-lactamases (ESBL) and carbapenemases of the responsible health authorities should be followed. such as K. pneumoniae carbapenemase (KPC). Plazomicin plasma concentrations can be influenced by the volume of extracellular fluid, renal function, and physiological changes during therapy and this can impact efficacy and safety of plazomicin. Similar to other aminoglycosides, CAUTION: The reagents included with the QMS Plazomicin Immunoassay contain less plazomicin concentrations are measured to guide and monitor dosing regimens to ensure that than 0.1% sodium azide. Avoid contact with skin and mucous membranes. Flush affected areas plazomicin concentrations fall within a desired range. with copious amounts of water. Seek immediate medical attention if reagents are ingested or come into contact with eyes. Sodium azide may react with lead or copper plumbing to form Principles of the Procedure potentially explosive metal azides. When disposing of such reagents, always flush with large The QMS Plazomicin Immunoassay is a homogeneous particle-enhanced turbidimetric amounts of water to prevent accumulation of azide. Clean exposed metal surfaces with a 10% immunoassay. The assay is based on competition between drug in the sample and drug coated solution of sodium hydroxide. onto microparticles for antibody binding sites of the anti-plazomicin antibody reagent. The plazomicin-coated microparticle reagent is rapidly agglutinated in the presence of the anti- DANGER: QMS Plazomicin Immunoassay contains ≤3.5% Goat Serum, ≤2% Human Serum plazomicin antibody reagent and in the absence of any competing drug in the sample. The rate Albumin and ≤1% Antibody (Mouse). of absorbance change is measured photometrically. When a sample containing plazomicin is H317 - May cause allergic skin reaction. added, the agglutination reaction is partially inhibited, slowing down the rate of absorbance H334 - May cause allergy or asthma symptoms or breathing difficulties if inhaled. change. A concentration-dependent classic agglutination inhibition curve can be obtained with the maximum rate of agglutination at the lowest plazomicin concentration and the lowest Avoid breathing mist or vapor. Contaminated work clothing should not be allowed out of the agglutination rate at the highest plazomicin concentration. workplace. Wear protective gloves/eye protection/face protection. In case of inadequate ventilation wear respiratory protection. If on skin: Wash with plenty of soap and water. IF Reagents INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. If skin irritation or rash occurs: Get medical advice/attention. QMS Plazomicin Immunoassay, 10023647, is supplied as a liquid, ready-to-use, two- If experiencing respiratory symptoms: Call a POISON CENTER or doctor/physician. Wash reagent kit that contains: contaminated clothing before reuse. Dispose of contents/container to location in accordance R1 Reagent 1 Antibody Reagent 1 x 17 mL with local/regional/national/international regulations. R2 Reagent 2 Microparticle Reagent 1 x 10 mL Specimen Collection and Handling Reactive Ingredients The following specimen collection tubes may be used for the QMS Plazomicin Immunoassay: Ingredient Concentration R1 Reagent 1 Anti-Plazomicin Monoclonal Antibody (Mouse) <1.0% Plasma R2 Reagent 2 Plazomicin-coated Microparticles <0.3% K2 EDTA Plastic

Inactive Ingredients • Remove the plasma from the cells as soon as possible after collection. Both R1 and R2 contain sodium azide (0.09%). R1 contains human-, goat- and mouse-sourced • Inadequate centrifugation of the specimen may cause an erroneous result. materials, buffer salts, and anti-foaming agent. • Ensure specimens are free of fibrin, red blood cells, and other particulate matter. • Specimens removed from the cells may be stored up to 24 hours at room temperature Reagent Handling and Storage (up to 25 °C) or 3 days at 2 to 8 °C. • R1 and R2 - Ready-to-use • Specimens should not undergo more than three (3) freeze-thaw cycles. • Before use, gently invert reagents several times, avoiding the formation of bubbles. • Specimens thawed from frozen may be stored up to 4 hours at room temperature (up to • Remove air bubbles, if present in the reagent bottle. Alternatively, allow the reagent to 25 °C) or 3 days at 2 to 8 °C. sit at the appropriate storage temperature to allow the bubbles to dissipate. To minimize volume depletion, do not use a transfer pipette to remove the bubbles. Procedure • When either the R1 or the R2 bottle becomes empty, replace both bottles and verify Materials Provided calibration with three levels of controls according to the established Quality Control • QMS Plazomicin Immunoassay Kit, 10023647 requirements for your laboratory. If control results fall outside acceptable ranges, recalibration may be necessary. Materials Required but not Provided • In the case of accidental spill, clean and dispose of material according to your • QMS Plazomicin Immunoassay Calibrator Kit, 10023684, Calibrator A: 1 x 2 mL, laboratory’s standard operating procedures and local, state, and country regulations, Calibrator B-F: 1 x 1.0 mL each with consideration that the material contains potentially infectious materials. • In the case of damaged packaging on arrival, contact your technical support • QMS Plazomicin Immunoassay Control Kit, 10023697, Control 1-3, 1 x 1.5 mL each representative (contact details listed at the end of this instructions for use). • Automated clinical chemistry analyzer, Beckman Coulter AU680 Assay Procedure CAUTION: Reagent bubbles may interfere with proper detection of reagent level in the The assay is performed at a wavelength of 700 nm. For a detailed description of how to run bottle, causing insufficient reagent aspiration that could impact results. and calibrate an assay, refer to the instrument-specific operations manual. Refer to the QMS Plazomicin Immunoassay Application - Beckman Coulter AU680 for system-specific information. Sample Preparation Specific Performance Characteristics Allow calibrators and controls to equilibrate to room temperature. Samples must be thawed Representative performance results obtained on a commercially available automated clinical and equilibrated to room temperature and processed immediately. Mix samples, calibrators chemistry analyzer that employs turbidimetric quantitative analysis are shown below. Unless and controls thoroughly by gentle inversion using a rocker for 15-20 minutes. Following the otherwise stated all studies were conducted in accordance with the assay procedure provided Beckman Coulter AU680 User Guide, verify all bubbles are removed from the surface of the herein using the Beckman Coulter AU680 analyzer. Results obtained in individual laboratories sample before placing on the system. may differ from these data. For additional analyzer-specific performance data, refer to the • Specimens removed from the cells may be stored up to 24 hours at room temperature analyzer-specific application sheet. (up to 25 °C) or 3 days at 2 to 8 °C. • Specimens should not undergo more than three (3) freeze-thaw cycles. Reportable Range • Specimens thawed from frozen may be stored up to 4 hours at room temperature (up to The reportable range of the assay is 0.8 µg/mL to 34.0 µg/mL plazomicin. 25 °C) or 3 days at 2 to 8 °C. Lower Limit of Quantitation (LLoQ) Calibration The LLoQ of the assay was determined based on the guidelines from Clinical and Laboratory The QMS Plazomicin Immunoassay must be calibrated using a full calibration (6-point) Standard Institute (CLSI) standard protocol EP17-A023. The LLoQ is defined as the lowest procedure. To perform a full calibration, test the QMS Plazomicin Immunoassay Calibrators A, concentration which results in inter-assay precision ≤20% CV and bias ≤15% that have been B, C, D, E, and F in duplicate. measured over an extended period. The LLoQ was determined to be ≤0.8 µg/mL for K2 EDTA plasma samples. Calibration is required with each new lot number. Validate the calibration curve with three levels of controls according to the established Quality Control requirements for your laboratory. Dilution Linearity If control results fall outside acceptable ranges, corrective action should be taken. Dilution linearity was performed following CLSI standard protocol EP06-A4. Two plazomicin sample panels, with concentrations ranging from 0.3 to 34.0 µg/mL, were respectively Calibration Frequency created by serially diluting a higher concentration spiked K EDTA plasma sample or patient Recalibration is recommended 2 pooled plasma sample with blank K2 EDTA plasma. Each prepared dilution was measured • After calibrator or reagent (kit) lot change in a replicate of five and the mean value was calculated. The assay demonstrated a linear • After performance of monthly instrument maintenance or lamp change range of 0.8 µg/mL to 34.0 µg/mL, determined from the regression analyses between the mean • As required following quality control procedures measured values and expected values of the linearity panels. Representative results of linear regression are shown below. Quality Control As appropriate, refer to your laboratory Standard Operating Procedure(s) and/or Quality Spiked K2 EDTA Plasma Assurance Plan for additional quality control requirements and potential corrective actions. Site Slope Intercept Correlation (r) Recommended control requirements for the QMS Plazomicin Immunoassay: Internal (Manufacturer’s Laboratory) 1.04 0.32 1.00 • Three levels of QMS Plazomicin Immunoassay Controls spanning the reportable range, and including the medical decision point(s) should be run as frequently as needed. External Laboratory 1 0.98 0.36 1.00 • If more frequent control monitoring is required, follow the established Quality Control External Laboratory 2 1.02 0.34 1.00 procedures for your laboratory. • All QC requirements should be performed in conformance with local, state and/or federal Patient Pooled Plasma guidelines. • If quality control results do not fall within an acceptable range defined by your laboratory, Site Slope Intercept Correlation (r) assay results may be suspect and should not be reported. Corrective action should be taken. Internal (Manufacturer’s Laboratory) 0.98 0.23 1.00

Results Accuracy 5 The result units for the QMS Plazomicin Immunoassay are reported as µg/mL. As with all Accuracy by recovery was performed following CLSI standard protocol EP15-A3 . One sample analyte determinations, the plazomicin value should be used in conjunction with information panel was prepared by spiking known amounts of plazomicin into negative human K2 EDTA available from clinical evaluations and other diagnostic procedures. plasma at concentrations across the assay range. Each sample was analyzed over a course of 5 days with 4 replicates each day for a total of 20 measurements. The mean measured Result Error Codes concentration was compared to the gravimetric target concentration for percent recovery. Some results may contain Result Error Codes. Refer to the instrument specific operations Recovery ranged between 98% and 104% for samples with concentrations throughout the manual for a description of the error codes. claimed measuring interval of the device.

Limitations of the Procedure Method Comparison 6 See also the SPECIMEN COLLECTION AND HANDLING and SPECIFIC PERFORMANCE Correlation studies were performed based on guidance from CLSI standard protocol EP09-A3 . CHARACTERISTICS sections of this package insert. A total of 134 K2 EDTA plasma samples were measured by QMS Plazomicin Immunoassay in singlicate over the course of 4 to 5 days, and compared with the results from a validated 7 Only QMS Plazomicin Immunoassay Calibrators and Controls should be used with the QMS LC-MS/MS method. Passing-Bablok regression analysis demonstrated a slope within Plazomicin Immunoassay. Accurate quantitative determination of plazomicin cannot be 0.9 to 1.1, an intercept within ± 0.8 µg/mL and a correlation coefficient greater than 0.975. obtained if the QMS Plazomicin Immunoassay Calibrator Kit (Catalog Number) 10023684, is not Representative results are shown below. used in calibration of the QMS Plazomicin Immunoassay. Summary Results for Method Comparison Study Interfering heterophile antibodies occur at low frequency in the general population. These Deming Passing-Bablok antibodies can cause auto-agglutination of the microparticle reagent leading to erroneous Sample Number of Correlation results that may be unexpectedly low or unexpectedly high. An erroneous result could lead to Matrix Samples Slope Intercept Slope Intercept (R) incorrect patient management; incorrect patient management could potentially cause serious K EDTA Plasma 134 1.0 0.72 1.0 0.41 0.983 injury or death. Test results should not be used in isolation to make patient management 2 decisions. Results should always be assessed in conjunction with the patient’s medical history, clinical examinations, and other clinicopathological findings. An alternative test method should be used to confirm results when results are inconsistent with clinical expectations.

Expected Values See the plazomicin package insert10 for information regarding utilization of assay values and guidance for therapeutic drug management. The recommended plazomicin therapeutic range varies according to the dosage regimen and the time that the blood sample was collected relative to the dose.

Dosing interval increases based on plazomicin trough concentrations are recommended to reduce the risk of nephrotoxicity. Adult patients with complicated urinary tract infection treated with plazomicin had trough levels of <0.8 - 5.7 μg/mL. See the plazomicin package insert for guidance on dosing interval increases based on trough levels. Individual patient results should be interpreted with the aid of the plazomicin package insert and in light of other clinical signs and symptoms.

2 Scatter and Bland-Altman Plots – K2 EDTA Plasma (N=134) Precision Precision studies were conducted as described in CLSI standard protocol EP05-A38 by Scatter Plot measuring tri-level quality control materials, spiked plasma samples, and patient plasma pools at the manufacturer’s laboratory and two external laboratories. Each sample was assayed via two replicates per run, 2 runs per day for 20 days with the exception of patient pools which were tested for 5 days; each intra-day run was separated by a minimum of two hours. The results obtained at each laboratory were analyzed for within-run, between-run and total SD and %CV to demonstrate single-laboratory repeatability and within-laboratory precision. The multi-laboratory total repeatability and reproducibility were calculated from combining precision results across three laboratories. The assay demonstrated single-laboratory within- run precision less than 7% CV and total precision less than 10% CV. The multi-laboratory total repeatability and reproducibility were less than 10% CV. Representative results are shown below.

Single-Laboratory Precision (Manufacturer’s Laboratory)

Within- Within- Between- Total- Total- Sample Mean Between- N Run Run Run Run Run Description (µg/mL) Run SD SD %CV %CV SD %CV QMS Plazomicin Immunoassay (μg/mL) Quality Control 1 80 2.5 0.1 2% 0.1 4% 0.1 5% Quality Control 2 80 8.1 0.2 2% 0.3 4% 0.3 4% Quality Control 3 80 29.6 1.2 4% 0.8 3% 1.7 6% LC-MS/MS (μg/mL) Plasma Patient 20 2.3 0.1 2% 0.1 4% 0.1 5% Pool 1 Plasma Patient 20 8.0 0.2 2% 0.2 2% 0.3 4% Pool 2 Plasma Patient Bland-Altman Plot 20 27.3 0.7 3% 0.9 3% 1.2 4% Pool 3 Plasma Spiked 1 80 2.3 0.1 3% 0.1 4% 0.1 6% Plasma Spiked 2 80 7.8 0.1 2% 0.3 4% 0.5 6% Plasma Spiked 3 80 14.8 0.3 2% 0.8 5% 1.0 7% Plasma Spiked 4 80 28.4 0.9 3% 1.1 4% 1.9 7%

Multi-Laboratory Precision

Total Total Total Total Total Grand Between- Between- Between- Within- Reproducibility

Bias (μg/mL) Sample Repeatability N Mean Description Run Day Site Site (µg/mL) SD %CV SD %CV SD %CV SD %CV SD %CV SD %CV

Control 1 240 2.5 0.1 2% 0.1 4% 0.0 1% 0.0 2% 0.1 4% 0.1 5%

Control 2 240 8.2 0.1 2% 0.2 3% 0.1 1% 0.1 2% 0.3 4% 0.3 4%

Control 3 240 29.6 0.9 3% 0.7 2% 0.6 2% 0.0 0% 1.2 4% 1.2 4% Plasma 60 2.4 0.1 5% 0.0 0% 0.0 0% 0.1 5% 0.1 5% 0.2 7% Average of QMS Plazomicin Immunoassay and LC-MS/MS (μg/mL) Patient Pool 1 Plasma 60 8.4 0.4 4% 0.0 0% 0.2 2% 0.5 6% 0.4 5% 0.6 7% Patient Pool 2 Plasma 60 28.8 1.0 4% 0.5 2% 0.7 2% 1.9 7% 1.3 5% 2.4 8% Patient Pool 3 Plasma Percent Bland-Altman 240 2.4 0.1 3% 0.1 3% 0.1 2% 0.1 4% 0.1 5% 0.2 6% Spiked 1 Plasma 240 8.1 0.2 3% 0.2 3% 0.3 3% 0.3 4% 0.4 5% 0.5 6% Spiked 2 Plasma 240 15.4 0.6 4% 0.5 3% 0.4 3% 0.7 5% 0.9 6% 1.1 7% Spiked 3 Plasma 240 29.7 1.1 4% 0.8 3% 0.6 2% 1.7 6% 1.4 5% 2.2 8% Spiked 4 Percent Bias

Average of QMS Plazomicin Immunoassay and LC-MS/MS (μg/mL)

3 Interfering Substances Table continued Interference studies were conducted using CLSI standard protocol EP07-A29 as a guideline. Concomitant Medication/ Concentration The following endogenous substances, when tested with the QMS Plazomicin Immunoassay Structurally Similar Compounds (µg/mL) at the concentrations indicated, resulted in less than or equal to 10% bias in detecting plazomicin. All concentrations represent the supplemental amount of respective interfering 100 substance added to the plasma samples with the exception of rheumatoid factor. The results are shown below. Enoxaparin 200 Epinephrine hydrochloride 20 Endogenous Substances Concentration Ertapenem 500 Albumin 6 g/dL 100 Unconjugated Bilirubin 30 mg/dL Esmolol 20 Conjugated Bilirubin 30 mg/dL Esomeprazole 20 Cholesterol 500 mg/dL Ethacrynic Acid 100 Creatinine 5 mg/dL Fentanyl 2 Gamma Globulin 10 g/dL Fluconazole 100 Human Anti-Mouse Antibody (HAMA) Type 1&2 20 ng/mL Fondaparinux 20 Hemoglobin 1000 mg/dL Fosfomycin 100 Rheumatoid Factor* 1080 IU/mL Furosemide 100 Triglyceride 1000 mg/dL Gentamicin 50 Uric Acid 30 mg/dL Haloperidol 20 * Naturally existing substance Hydrocortisone 20 Specificity 300 9 / Specificity studies were conducted using CLSI standard protocol EP07-A2 as a guideline. Cilastatin* Cross-reactivity and interference effects were tested for the potential cross-reactants that are 300 either concomitant medications or are structurally similar to plazomicin (e.g., aminoglycoside Insulin human regular 20 class). All compounds, when added into the plasma pool containing 2.5 or 30 µg/mL plazomicin at the concentrations listed below, caused less than or equal to 10% bias in plazomicin Kanamycin B 100 measurement. The results are shown below. Levetiracetam 300 Concomitant Medication/ Concentration Levofloxacin 100 Structurally Similar Compounds (µg/mL) 100 Acetyl-Salicylic Acid 750 Lorazepam 2 Amikacin 200 Meropenem 600 Amiodarone 50 Metamizole (Dipyrone) 100 Amlodipine 5 Metformin 100 Amphotericin 20 Methylprednisolone sodium succinate 100 Ampicillin/ 500 Metoclopramide 2 Sulbactam* 500 Metoprolol 20 50 Metronidazole 300 Aztreonam 750 Micafungin 100 Carvedilol 5 Midazolam 5 Cefazolin 1250 Morphine sulfate 20 500 Nafcillin 100 Ceftaroline fosamil 100 N-desethylamiodarone (metabolite of Amiodarone) 20 Ceftazidime 550 100 Ceftazidime/ 300 Norepinephrine Bitartrate (Noradrenaline) 5 Avibactam* 100 Omeprazole 20 Ceftolozane/ 300 Pantoprazole 20 Tazobactam* 100 Paracetamol (acetaminophen) 500 Ceftriaxone sodium 1000 Phenylephrine hydrochloride 5 Ciprofloxacin 100 Phenytoin (Fosphenytoin IV) 20 Cisatracurium 20 Phenytoin sodium 50 Laudanosine (Cisatracurium metabolite) 3.5 Piperacillin 1300 MQA metabolite (Cisatracurium metabolite) 20 Propofol 100 Clonidine 5 Ramipril 5 Colistimethate Sodium (Colistin) 100 Ranitidine 20 700 20 Dexmedetomidine 5 500 Diltiazem hydrochloride 20 300 Dobutamine hydrochloride 20 Tamsulosin 5 Dopamine hydrochloride 5

4 Table continued References 1. Jana S, Deb JK. Molecular understanding of aminoglycoside action and resistance. Concomitant Medication/ Concentration Appl Microbiol Biotechnol. 2006;70(2):140-50. Structurally Similar Compounds (µg/mL) 2. Livermore DM, Mushtaq S, Warner M, et al. Activity of aminoglycosides, including Tazobactam 200 ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother. 2011;66(1):48-53. 50 3. CLSI. Evaluation of Detection Capability for Clinical Laboratory Measurement 20 Procedures; Approved Guideline – Second Edition. CLSI document EP17-A2. Wayne, PA: Clinical and Laboratory Standards Institute; 2012. Tobramycin 100 4. CLSI. Evaluation of the Linearity of Quantitative Measurement Procedures; A Statistical Tramadol 20 Approach; Approved Guideline. CLSI document EP06-A. Wayne, PA: Clinical and Laboratory Standards Institute, 2003. Vancomycin 200 5. CLSI. User Verification of Precision and Estimation of Bias; Approved Guideline – Third Edition. CLSI document EP15-A3. Wayne, PA: Clinical and Laboratory Standards Vasopressin 5 Institute; 2014. Vecuronium bromide 20 6. CLSI. Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline – Third Edition. CLSI document EP09-A3. Wayne, PA: Clinical and * Tested as combination drugs Laboratory Standards Institute; 2013. 7. Bablok W, Passing H, Bender R, Schneider B. A general regression procedure for

method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry. Part III J Clin Chem Clin Biochem 1988; 26 (11): 783-790. 8. CLSI. Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline – Third Edition. CLSI document EP05-A3. Wayne, PA: Clinical and Laboratory Standards Institute; 2014. 9. CLSI. Interference Testing in Clinical Chemistry; Approved Guideline – Second Edition. CLSI document EP07-A2. Wayne, PA: Clinical and Laboratory Standards Institute; 2014. 10. Plazomicin United States Package Insert 6/2018.

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