Elecsys Digoxin Immunoassay, Elecsys PreciControl Cardiac II

K153301 · Roche Diagnostics · KXT · Apr 8, 2016 · Clinical Toxicology

Device Facts

• Record ID: K153301
• Device Name: Elecsys Digoxin Immunoassay, Elecsys PreciControl Cardiac II
• Applicant: Roche Diagnostics
• Product Code: KXT · Clinical Toxicology
• Decision Date: Apr 8, 2016
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3320
• Device Class: Class 2

Indications for Use

Immunoassay for the in vitro quantitative determination of digoxin in human serum and plasma. Measurements are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure proper therapy. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers. PreciControl Cardiac II is used for quality control of specified immunoassays on the Elecsys and cobas e immunoassay analyzers.

Device Story

Elecsys Digoxin Immunoassay is an in vitro diagnostic test for quantitative digoxin measurement in human serum/plasma. It utilizes a competitive electrochemiluminescence immunoassay (ECLIA) principle; patient sample competes with biotin-labeled digoxin derivative for binding sites on a ruthenylated monoclonal antibody. The complex binds to streptavidin-coated microparticles. Analyzers measure the resulting signal to determine analyte concentration via a master curve. Used in clinical laboratories by trained personnel to monitor therapeutic digoxin levels and manage overdose. Output is a numerical concentration value (ng/mL) used by physicians to adjust dosage or assess toxicity. Benefits include accurate therapeutic drug monitoring to optimize patient outcomes and prevent adverse effects from sub- or supra-therapeutic levels.

Clinical Evidence

Bench testing only. Performance evaluated on cobas e 411 analyzers. Precision (repeatability/intermediate) assessed per CLSI EP5-A3; LoB/LoD/LoQ per CLSI EP17-A2. Linearity (CLSI EP6-A), dilution, and interference (endogenous/exogenous/anticoagulants) studies performed. Method comparison (N=168) against predicate showed high correlation (Passing/Bablok: y = 1.03x + 0.001; r = 0.998). Stability studies (reagent, calibration, sample) confirmed performance claims.

Technological Characteristics

Competitive ECLIA; ruthenylated monoclonal antibody; biotin-labeled digoxin derivative; streptavidin-coated microparticles. Analyzers: Elecsys and cobas e series. Sample types: serum, Li-Heparin, K2/K3-EDTA plasma. Calibration: 2-point, master curve via reagent barcode. Standardization: USP digoxin reference material. Software: Instrument-specific firmware for signal processing and concentration calculation.

Indications for Use

Indicated for in vitro quantitative determination of digoxin in human serum and plasma for diagnosis/treatment of digoxin overdose and therapeutic drug monitoring.

Regulatory Classification

Identification

A digoxin test system is a device intended to measure digoxin, a cardiovascular drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure appropriate therapy.

Predicate Devices

• Elecsys Digoxin Immunoassay (k973112)

Submission Summary (Full Text)

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510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION
DECISION MEMORANDUM
ASSAY ONLY TEMPLATE

A. 510(k) Number:
K153301

B. Purpose for Submission:
New Device

C. Measurand:
Digoxin

D. Type of Test:
Quantitative enzyme immunoassay

E. Applicant:
Roche Diagnostics

F. Proprietary and Established Names:
Elecsys Digoxin Immunoassay
Elecsys PreciControl Cardiac II

G. Regulatory Information:
1. Regulation section:
21 CFR 862.3320
21 CFR 862.1160
2. Classification:
Class II, Class I
3. Product code:
KXT

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JJY

4. Panel:
Toxicology
Clinical Chemistry

H. Intended Use:

1. Intended use(s):
See indications for use below

2. Indication(s) for use:
Elecsys Digoxin Immunoassay

Immunoassay for the in vitro quantitative determination of digoxin in human serum and plasma. Measurements are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure proper therapy. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Elecsys PreciControl Cardiac II

PreciControl Cardiac II is used for quality control of specified immunoassays on the Elecsys and cobas e immunoassay analyzers.

3. Special conditions for use statement(s):
For prescription use only.

4. Special instrument requirements:
This submission demonstrates performance on the cobas e 411 immunoassay analyzer.

I. Device Description:

The assay consists of three liquid components supplied as working solutions:

- Streptavidin-coated microparticles, 1 bottle, 6.5 mL: Streptavidin-coated microparticles 0.72 mg/mL; preservative.
- Ruthenlyated Anti-digoxin-antibody, 1 bottle, 10 mL: Monoclonal anti-digoxin antibody (mouse) labeled with ruthenium complex 15 µg/L; phosphate buffer 100 mmol/L, pH 7.0; preservative.

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- Biotinylated digoxin-derivative, 1 bottle, 10 mL: Biotinylated digoxigenin 1.06 ng/mL; biotin 15 µg/L; phosphate buffer 100 mmol/L, pH 7.0; preservative.

The Elecsys PreciControl Cardiac II controls are sold separately. These are lyophilized control serum based on human serum, and consist of two concentration ranges. The two available concentration ranges (PC CARDII 1 and PC CARDII 2) are each supplied as 2 bottles; each bottle contains 2 mL of control serum.

The Digoxin CalSet is sold separately. The CalSet calibrator is bovine serum matrix with added digoxin with two concentration ranges. The two available concentration ranges (DIGO Cal1 and DIGO Cal2) are each supplied as two bottles; each bottle contains 1.5 mL of calibrator.

# J. Substantial Equivalence Information:

1. Predicate device name(s): Elecsys Digoxin Immunoassay
2. Predicate 510(k) number(s): K973112
3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | Predicate – Elecsys Digoxin Immunoassay (K973112) | Candidate – Elecsys Digoxin Immunoassay (K153301) |
| Intended Use/Indications for Use | Immunoassay for the in vitro quantitative determination of digoxin in human serum and plasma. | SAME |
| Assay Protocol | Competitive Immunoassay | SAME |
| Detection Protocol | Electrochemiluminescent Assay | SAME |
| Applications | 18 minute application | SAME |
| Calibrator | Elecsys Digoxin CalSet | SAME |
| Calibration Interval | Calibration must be performed once per reagent lot using fresh reagent Renewed calibration is recommended:
-after 1 month (28 days) when using the same reagent lot
-after 7 days (when using the same reagent kit on the | SAME |

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| Similarities | | |
| --- | --- | --- |
| Item | Predicate – Elecsys Digoxin Immunoassay (K973112) | Candidate – Elecsys Digoxin Immunoassay (K153301) |
| | analyzer) -as required: e.g. quality control findings outside the specified limits | |
| Traceability/Standardization | (USP) digoxin reference material into analyte free human serum. | SAME |
| Storage and Stability | Store at 2-8 °C. Do not freeze. Store upright. Stability: -unopened at 2-8 °C: up to the stated expiration date -after opening at 2-8 °C: 12 weeks -on the analyzers: 8 weeks | SAME |
| Hook Effect | not applicable | SAME |
| Differences | | |
| --- | --- | --- |
| Item | Predicate | Device |
| Sample Type | Serum, Li-, Na-, NH+4 - heparin, K3-EDTA, sodium citrate, and sodium fluoride/potassium oxalate plasma. | Serum, Li-Heparin, K2- and K3-EDTA plasma. Li-Heparin plasma tubes containing separating gel |
| Controls | A suitable commercially available control | Elecsys PreciControl Cardiac II or other suitable control material |
| Measuring Range | 0.150 (LDL)-5.00 ng/mL | 0.4 ng/mL (LoQ) – 5.00 ng/mL |
| LoB | Not Reported | 0.15 ng/mL |
| LoD | Not Reported | 0.2 ng/mL |
| LoQ | Not Reported | 0.4 ng/mL |
| Lower Detection Limit | 0.150 ng/mL | Not Reported |

# K. Standard/Guidance Document Referenced (if applicable):

CLSI EP5-A3 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline—Third Edition

CLSI EP17-A2 Evaluation of Detection Capability for Clinical Laboratroy Measurement Procedures; Approved Guideline—Second Edition

CLSI EP6-A Evaluation of the Linearity of Quantitative Measurement Procedures: A

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Statistical Approach; Approved Guideline

L. Test Principle:
The Elecsys Digoxin assay employs a competitive test principle using a monoclonal antibody specifically directed against digoxin. Digoxin in the sample competes with the added digoxin derivative labeled with biotin for the binding sites on the ruthenylated antibody-complex. The total duration of the assay is 18 minutes.

By incubating the sample (10 μL) with a digoxin specific ruthenium-labeled antibody, an immunocomplex is formed, the amount of which is dependent upon the analyte concentration in the sample. After addition of streptavidin-coated microparticles and a digoxin derivative labeled with biotin, the still-vacant sites of the ruthenium labeled antibodies become occupied, with formation of an antibody-hapten complex. The entire complex becomes bound to the solid phase via interaction of biotin and streptavidin. The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier.

M. Performance Characteristics (if/when applicable):
All performance characteristics were established on the cobas e 411 analyzer.

1. Analytical performance:
a. Precision/Reproducibility:
Precision
Repeatability and intermediate precision of the Elecsys Digoxin assay were evaluated on one cobas e 411 analyzer. One reagent lot was evaluated.

A seven sample panel consisting of five pooled human serum samples (HS) spiked with digoxin and two controls (PCC II = PreciControl Cardiac II, Level 1 and 2) were measured. The protocol consisted of testing 2 replicates of each control and human serum sample per run, divided into 2 runs per day for 21 operating days. The samples were run in randomized order.

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| | | Repeatability | | Intermediate Precision | | |
| --- | --- | --- | --- | --- | --- | --- |
| Sample | Mean [ng/mL] | SD [ng/mL] | CV [%] | SD [ng/mL] | CV [%] | n |
| Human Serum 1 | 0.565 | 0.019 | 3.4 | 0.036 | 6.4 | 84 |
| Human Serum 2 | 1.09 | 0.027 | 2.5 | 0.063 | 5.8 | 84 |
| Human Serum 3 | 1.85 | 0.039 | 2.1 | 0.083 | 4.5 | 84 |
| Human Serum 4 | 2.38 | 0.055 | 2.3 | 0.092 | 3.8 | 84 |
| Human Serum 5 | 4.67 | 0.119 | 2.5 | 0.299 | 6.4 | 84 |
| PCC II 1 | 1.20 | 0.035 | 2.9 | 0.051 | 4.3 | 84 |
| PCC II 2 | 2.74 | 0.102 | 3.7 | 0.111 | 4.1 | 84 |

## Reproducibility

Reproducibility of the Elecsys Digoxin assay across multiple reagent lots was evaluated on three cobas e 411 analyzers according to the $3 \times 5 \times 5$ design described in CLSI EP5-A3. The protocol consisted of testing 5 aliquots for each of two control solutions (PreciControl Cardiac II,) and five serum sample pools spiked with digoxin over 5 days on three instruments with three reagent lots, with 1 run per aliquot per day, for a total of 225 measurements per sample.

| Sample material | n | Mean [ng/mL] | SD [ng/mL] | CV [%] |
| --- | --- | --- | --- | --- |
| HS 01 | 225 | 0.442 | 0.074 | 16.65 |
| HS 02 | 225 | 0.810 | 0.051 | 6.28 |
| HS 03 | 225 | 1.07 | 0.063 | 5.85 |
| HS 04 | 225 | 2.30 | 0.144 | 6.27 |
| HS 05 | 225 | 4.46 | 0.274 | 6.13 |
| Control 01 | 225 | 1.21 | 0.060 | 4.97 |
| Control 02 | 225 | 2.71 | 0.139 | 5.13 |

## b. Linearity/assay reportable range:

Linearity of the Elecsys Digoxin assay was assessed on the cobas e 411 analyzer according to CLSI EP6-A.

A high analyte serum sample pool spiked with digoxin was diluted with digoxin free human serum. Fifteen concentrations throughout the measuring range were prepared. Samples were measured in triplicate within a single run.

The linearity data were analyzed with regards to linear, quadratic and cubic polynomials according to CLSI EP6-A. In the first step, a linearity check was performed with a first order (linear) regression and then with higher order models

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(quadratic and cubic). Results of this study support the claimed measuring range of 0.4 to 5.0 ng/mL.

A dilution study was performed to determine the recommended dilution factor for samples. The dilution study for Elecsys Digoxin assay was performed on two cobas e 411 analyzers using four human serum samples with Digoxin concentrations above the measuring range. Samples were diluted 1:2 manually and automatically by the instrument. Results support the recommended dilution factor of 1:2 yielding a diluted sample concentration of 2.5 ng/mL or lower.

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

## Traceability

This method is standardized to United States Pharmacopoeia (USP) digoxin reference material

## Stability

Protocols and acceptance criteria for PreciControl Cardiac II control solution stability were reviewed and found acceptable to support stability of reconstituted control serum for up to 3 months at -20°C, 3 days at 2-8°C, on-board the analyzer at 20-25°C. Controls should not be re-frozen after thawing. Protocols and acceptance criteria for stability of lyophilized control were reviewed and found acceptable to support stability of lyophilized control serum stored between 2-8°C for up to 18 months; real-time stability stability studies are ongoing.

d. Detection limit:

## Limit of Blank (LoB):

The Limit of Blank (LoB) was defined as the highest apparent analyte concentration expected to be found when replicates of a blank sample containing no analyte were tested. The distribution of values for five analyte-free human serum samples was determined with three reagent lots on two cobas e 411 analyzers with two runs per day over a period of three days.

The sample was measured in one-fold determination in each run. In summary, 30 measuring points were collected per instrument for a total of 60 measured values per reagent lot. Results support the LoB of 0.15 ng/mL.

## Limit of Detection (LoD)

The distribution of values for five low level human serum samples was determined using three reagent lots on two cobas e 411 analyzers with two runs per day over a period of three days. Each sample was measured once per run. In summary, 30 measuring points were collected per instrument for a total of 60 measured values per reagent lot. The Limit of Detection (LoD) was defined as LoB + 1.653 x SDtotal where SDtotal refers to the total standard deviation of low analyte samples. Results support the LoD of 0.2 ng/mL.

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# Limit of Quantitation (LoQ)

The Limit of Quantitation (LoQ) was defined as the lowest amount of analyte that can be quantitatively determined with the stated accuracy. The distribution of values for $\geq 4$ low level samples each diluted to concentrations which covered the range between LoB to $2 \times \mathrm{LoQ}$ was determined with three reagent lots on a cobas e 411 analyzer with six runs distributed over three days. Each sample was measured in two replicates per run with a total of twelve replicates per sample per reagent lot.

A set of ten human serum samples (sample pools spiked with Digoxin) with known concentrations in the specified LoQ-area (approx. from LoB to $2 \times \mathrm{LoQ}$) was evaluated for each reagent lot. Target values for the Low Level Sample Set were determined using mass spectrometry during Reference Standardization. Results support the LoQ of $0.4 \, \mathrm{ng/mL}$.

e. Analytical specificity:

# Cross Reactivity

A cross reactivity study was performed to determine the specificity of the Elecsys Digoxin assay with both co-analytes and cross-reactant compounds. A dilution series was prepared and assayed for each co-analyte and cross reactant with Digoxin concentration of 0.5 and $2.0\,\mathrm{ng/mL}$.

| Co-Analyte | Cross-reactivity [%] |
| --- | --- |
| β-Methyldigoxin | 87.9 % |
| α-Acetyldigoxin | 77.9 % |
| β-Acetyldigoxin | 84.4 % |
| Lanatoside C | 65.2 % |
| Deslanoside | 85.6 % |
| Digoxigenin-bis-digitoxoside | 108.1 % |
| Digoxigenin-mono-digitoxoside | 141.1% |

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| Substance | Concentration tested [ng/mL] | Cross Reactivity |
| --- | --- | --- |
| Digoxin Metabolites | | |
| Digoxigenin | 6 | < 50 % |
| Dihydrodigoxin | 1000 | < 20 % |
| Other substances used as drugs & their metabolites | | |
| Digitoxin | 250 | < 2 % |
| Digitoxigenin | 250 | < 5 % |
| Ouabain | 5000 | < 0.1 % |
| k-Strophanthin | 1250 | < 0.2 % |
| Steroids | | |
| Cortisol | 5000 | < 0.01 % |
| Prednisone | 5000 | < 0.01 % |
| Dexamethasone | 5000 | < 0.01 % |
| D-Aldosterone | 5000 | < 0.01 % |
| Progesterone | 5000 | < 0.05 % |
| Estradiol | 5000 | < 0.01 % |
| DHEA | 5000 | < 0.01 % |
| Testosterone | 5000 | < 0.15 % |
| Others | | |
| Oleandrin | 5000 | < 0.01 % |
| Furosemide | 5000 | < 0.01 % |
| Sulthiame | 5000 | < 0.01 % |
| Quinidine (free base) | 5000 | < 0.01 % |

# Human Anti-Mouse Antibodies (HAMA)

The effect of the presence of human anti-mouse antibodies in patient samples on the Elecsys Digoxin assay was assessed on the cobas e 411 analyzer. A high HAMA and HAMA-free serum pool were each divided into two aliquots and spiked with analyte to yield two different digoxin concentrations: 0.843 and $2.37\mathrm{ng / mL}$ . Each high HAMA serum pool was diluted in 11 steps with the corresponding HAMA-free serum pool containing the same digoxin concentration. Each dilution was analyzed in 3-fold determination. The sponsor defined significant interference as recovery of the HAMA serum sample beyond $\pm 10\%$ of the corresponding HAMA-free sample. No significant interference was observed at all tested concentrations.

# Endogenous Interference

The potential interfering effect of endogenous substances on the Elecsys Digoxin assay was determined on the cobas e 411 analyzer using human serum samples spiked with digoxin. For each interfering substance 3 serum samples containing low, mid and high concentrations of digoxin were tested.

One aliquot of each serum sample was spiked with the potentially interfering substance; another aliquot was spiked with the same volume of isotonic NaCl solution

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(dilution pool). The interfering pool was then diluted into the dilution pool in 10% increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample.

The sponsor defined significant interference as recovery of the digoxin sample spiked with potential interferent beyond ±0.08 ng/mL at concentrations less than 0.8 ng/mL, beyond ±10% at concentrations between 0.8 and 4.0 ng/mL, and beyond ±12% at concentrations above 4.0ng/mL when compared to the corresponding un-spiked reference sample. No significant interference was observed for any tested endogenous substance at the levels indicated in the table below:

| Compound | Highest concentration with no significant interference |
| --- | --- |
| Lipemia | 1500 mg/dL |
| Biotin | 100 ng/mL |
| Bilirubin | 66 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Rheumatic Factor | 1630 IU/mL |
| human Serumalbumin | 11.2 g/dL |
| human IgG | 8.0 g/dL |

## Exogenous Interference

To test for interference from exogenous substances, seventeen common pharmaceutical compounds were spiked into two human serum samples and tested with the Elecsys Digoxin assay. The analyte concentrations of the samples were approximately 0.6 and 2.4 ng/mL. In addition, 17 cardiac drug compounds were assessed using the same serum sample pools and tested with the Elecsys Digoxin assay.

For testing, two serum sample pools were divided into aliquots and spiked with the potential interferents. The interferent concentrations were determined based on recommendations in the CLSI guideline EP7-A2. The reference samples without interferent were spiked with solvent.

The digoxin concentration of the spiked samples was determined in triplicate and compared to the digoxin concentration determined for the reference samples (also measured in triplicate). These studies were conducted on a cobas e 411 analyzer.

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Common Pharmaceutical Compounds:

| Drug | Drug concentration [mg/L] | Recovery in ≈0.6 ng/mL Digoxin [%] | Recovery in ≈2.4ng/mL Digoxin [%] |
| --- | --- | --- | --- |
| Acetylcysteine | 1660 | 105.3 | 98.7 |
| Ampicillin-Na | 1000 | 95.6 | 92.4 |
| Ascorbic acid | 300 | 102.1 | 94.5 |
| Cyclosporine | 5 | 98.6 | 91.1 |
| Cefoxitin | 2500 | 111.7 | 106.3 |
| Heparin | 5000 U | 99.8 | 97.5 |
| Levodopa | 20 | 97.7 | 96.2 |
| Methyldopa | 20 | 96.3 | 97.5 |
| Metronidazole | 200 | 104.7 | 96.6 |
| Phenylbutazone | 400 | 105.5 | 92.7 |
| Doxycycline | 50 | 98.4 | 97.5 |
| Acetylsalicylic Acid | 1000 | 102.4 | 97.1 |
| Rifampicin | 60 | 99.1 | 99.2 |
| Acetaminophen | 200 | 105.8 | 95.5 |
| Ibuprofen | 500 | 101.1 | 95.5 |
| Theophylline | 100 | 102.8 | 94.3 |

Cardiac Drugs

| Drug | Drug concentration [mg/L] | Recovery in ≈0.6 ng/mL Digoxin [%] | Recovery in ≈2.4ng/mL Digoxin [%] |
| --- | --- | --- | --- |
| Carvedilol | 37.5 | 100.2 | 100.9 |
| Clopidogrel | 75 | 101.1 | 100.0 |
| Epinephrine | 0.5 | 107.7 | 99.6 |
| Insulin | 1.6 | 102.9 | 100.0 |
| Lidocaine | 80 | 98.3 | 102.2 |
| Lisinopril | 10 | 102.9 | 97.8 |
| Methylprednisolone | 7.5 | 98.0 | 109.0 |
| Metoprolol | 150 | 96.6 | 101.9 |
| Nifedipine | 30 | 103.3 | 106.0 |
| Phenprocoumon | 3 | 107.2 | 104.8 |
| Propafenone | 300 | 103.1 | 107.1 |
| Reteplase | 33.3 | 102.9 | 102.7 |
| Simvastatin | 30 | 98.3 | 105.0 |
| Tolbutamide | 1500 | 101.3 | 107.2 |
| Torasemide | 15 | 102.9 | 101.8 |
| Verapamil | 240 | 102.9 | 98.7 |
| Fluindione | 20 | 102.2 | 100.4 |

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f. Assay cut-off:

Not applicable

2. Comparison studies:

a. Method comparison with predicate device:

A method comparison was performed using the Elecsys Digoxin assay (K973112) as the predicate device.

A total of 168 human serum samples (all single donors, native and spiked) were measured in singlicate. Digoxin values ranged from 0.413 to $4.78\mathrm{ng / mL}$ .

The study was performed on the cobas e 411 analyzer over 3 runs. Regression analysis for all samples comparing performance on the predicate device Elecsys Digoxin assay (X) and the new device Elecsys Digoxin assay (Y) are as follows:

| | N | Sample Concentration Range | Slope (95% CI) | Y intercept (95% CI) | Correlation coefficient |
| --- | --- | --- | --- | --- | --- |
| Passing/Bablok Regression Analysis | 168 | 0.413 – 4.78 ng/mL | 1.03 (1.017 – 1.047) | 0.001 ng/mL (-0.018 to 0.017 ng/mL) | t=0.960 |
| Linear Regression | | | 1.04 (1.03 – 1.05) | -0.009 ng/mL (-0.027 to 0.009 ng/mL) | r = 0.998 |

b. Matrix comparison:

Anticoagulants

The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys Digoxin assay was determined by comparing values obtained from native samples spiked with digoxin (single donors) drawn into Serum, Li-Heparin, K2-EDTA-, and K3-EDTA-plasma primary tubes, and Li-Heparin Plasma Separation Tubes.

Either 65 or 66 serum/plasma pairs per sample material were tested in duplicate with one reagent lot on a cobas e 411 analyzer. Potential effects were assessed by Passing/Bablok regression analysis.

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| Anticoagulant | Slope | Intercept | Correlation coefficient (r) |
| --- | --- | --- | --- |
| K2-EDTA | 0.980 | 0.00595 | 0.999 |
| K3-EDTA | 0.981 | 0.00753 | 0.999 |
| Li-Heparin | 0.993 | 0.005 | 0.999 |
| Li-Heparin Plasma with Gel Separator | 0.992 | -0.008 | 0.999 |

No significant interference was observed.

3. Clinical studies:

a. Clinical Sensitivity:

Not Applicable

b. Clinical specificity:

Not Applicable

c. Other clinical supportive data (when a. and b. are not applicable):

Not Applicable

4. Clinical cut-off:

Not Applicable

5. Expected values/Reference range:

The sponsor included the following information and references in the labeling:

The recommended therapeutic range for digoxin is 0.6-1.2 ng/mL (0.77-1.5 nmol/L) (ESC Guideline 2008¹⁰) or even 0.5-1.0 ng/mL (0.64-1.3 nmol/L).²⁰ Particularly the upper end of the therapeutic range is controversial and concentrations up to 2.0 ng/mL (2.6 nmol/L) may still be applied.⁶,⁷ Concentrations above 2.0 ng/mL are generally considered toxic.²¹ Some overlap of toxic and non-toxic values has been reported.²² Therefore, clinical diagnosis should be based on clinical and laboratory data.

Each laboratory should establish an acceptable reporting format and identify procedures for the reporting of abnormal results. Each laboratory should investigate the transferability of the expected values to its own patient population and if necessary determine its own reference ranges.

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References:

6. Lindenbaum J, Mellow MH, Blackstone MO, et al. Variation in Biologic Availability of Digoxin from Four Preparations. New Engl J Med 1971;285:1344-1347.
7. Lindenbaum J, Butler VP Jr., Murphy JE, et al. Correlation of Digoxin- Tablet Dissolution Rate with Biological Availability. Lancet 1973;1:1215-1217.
10. Keys PW, Stafford RW. In: Taylor WJ, Finn AL, eds. Individualizing Drug Therapy: Practical Applications of Drug Monitoring. New York, Gross, Townsend, Frank, Inc; 1981;vol 3:1-21.
20. Terra SG, Washam JB, Dunham GD, et al. Therapeutic Range of Digoxin's Efficacy in Heart Failure: What Is The Evidence? Pharmacotherapy 1999;19(10):1123-1126.
21. Matzuk MM, Shlomchik M, Shaw LM. Therapeutic Drug Monitoring 1991;13:215-219.
22. Beller GA, Smith TW, Abelmann WH, et al. Digitalis Intoxication: A Prospective Clinical Study with Serum Level Correlations. New Engl J Med 1971;284:989-997.

N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

O. Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

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