CEDIA DIGOXIN II

K970883 · Boehringer Mannheim Corp. · KXT · May 21, 1997 · Clinical Toxicology

Device Facts

• Record ID: K970883
• Device Name: CEDIA DIGOXIN II
• Applicant: Boehringer Mannheim Corp.
• Product Code: KXT · Clinical Toxicology
• Decision Date: May 21, 1997
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3320
• Device Class: Class 2

Intended Use

The CEDIA Digoxin II homogeneous enzyme immunoassay is for the quantitation of digoxin in human serum or plasma using automated clinical chemistry analyzers. Measurements are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure proper therapy. Digoxin is widely prescribed for the treatment of congestive heart failure and various disturbances of cardiac rhythm. Therapeutic use of digoxin improves the strength of myocardial contraction and results in the beneficial effects of increased cardiac output, decreased heart size, decreased venous pressure and decreased blood volume. Digoxin therapy also results in stabilized and slowed ventricular pulse rate. Although the availability of crystalline digoxin has permitted the standardization of drug dosage, therapeutic administration inadvertently, yet frequently, results in toxicity. Importantly, symptoms of digoxin toxicity often mimic the cardiac arrhythmias for which the drug was originally prescribed. Studies suggest that up to 25% of all hospitalized patients treated with digoxin experienced some degree of toxicity, and that the mortality rate among toxic patients was more than twice that of nontoxic patients. Digoxin concentrations of 0.9 to 2.0 ng/mL in serum or plasma are normally considered to be therapeutic. Symptoms of human toxicity generally only appear at concentrations above 2.0 ng/mL; however, concentrations as low as 1.4 ng/mL may be toxic for others. Toxicity of digoxin may reflect several factors: a) The drug has a low therapeutic ratio (i.e., a very small difference exists between therapeutic and toxic tissue levels). b) Individuals vary in their response to digoxin. c) Absorption of various tablet forms of digoxin may vary over a two-fold range. d) Susceptibility to digitalis toxicity apparently increases with age. In combination with other clinical data, monitoring serum or plasma levels may provide the physician with useful information to aid in adjusting patient dosage, and achieving optimal therapeutic effect, while avoiding both subtherapeutic and harmful toxic drug levels. The CEDIA Digoxin II Assay performance has not been established with body fluids other than human serum and plasma (Na or Li heparin; Na EDTA). Digoxin-like immunoreactive substances (DLIS) have been identified in blood from patients in renal failure, liver failure, and pregnant women in the third trimester. Studies have established that the presence of DLIS in a sample can result in a false elevation of digoxin when assayed by commercially available immunoassay.

Device Story

CEDIA Digoxin II Assay is a homogeneous enzyme immunoassay for in vitro quantitative determination of digoxin in human serum/plasma. Input: patient serum/plasma sample. Principle: competitive immunoassay using genetically engineered beta-galactosidase fragments. Digoxin in sample competes with analyte-conjugated inactive enzyme fragment for antibody binding sites. If digoxin is present, antibody binds to sample analyte, allowing inactive enzyme fragments to reassociate into active enzyme; active enzyme cleaves substrate, producing color change measured spectrophotometrically at 570 nm. Output: quantitative digoxin concentration (ng/mL). Used in clinical laboratories on automated chemistry analyzers (e.g., Hitachi 911). Results interpreted by physicians to adjust dosage, ensure therapeutic efficacy, and avoid toxicity. Benefits: aids in managing narrow therapeutic index of digoxin, reducing risk of toxicity-related mortality.

Clinical Evidence

Bench testing only. Precision studies (N=120 per level) showed within-run %CV of 1.56-4.25% and total %CV of 2.34-5.44%. Method comparison against Abbott TDx (N=99) yielded correlation r=0.955 (Least Squares y=0.98x-0.12; Deming y=1.02x-0.17). Linearity established from 0.15-4 ng/mL. Interference testing performed for bilirubin, hemoglobin, triglycerides, lipemia, and total protein. Specificity evaluated via cross-reactivity testing against various digoxin metabolites and related compounds.

Technological Characteristics

Homogeneous enzyme immunoassay using genetically engineered beta-galactosidase fragments. Detection: spectrophotometric at 570 nm. Sample types: human serum and plasma (Na/Li heparin, Na EDTA). Assay range: 0.15-4 ng/mL. Instrument: Hitachi 911 automated clinical chemistry analyzer.

Indications for Use

Indicated for quantitative determination of digoxin in human serum or plasma for patients undergoing digoxin therapy for congestive heart failure or cardiac rhythm disturbances. Used to monitor therapeutic levels, diagnose overdose, and adjust dosage. Contraindicated for use with body fluids other than serum or plasma; caution advised for patients with renal failure, liver failure, or third-trimester pregnancy due to potential for false elevations from Digoxin-like immunoreactive substances (DLIS).

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

• Abbott TDx® Digoxin II Assay (K882233)

Reference Devices

• Baxter Dade Stratus

Submission Summary (Full Text)

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K970883
MAY 21, 1997

# 510(k) Summary

## BOEHRINGER MANNHEIM CORPORATION

### Introduction

According to the requirements of 21 CFR 807.92, the following information provides sufficient detail to understand the basis for a determination of substantial equivalence.

---

### 1. Submitter name, address, contact

Boehringer Mannheim Corporation
2400 Bisso Lane
P.O. Box 4117
Concord, CA 94524-4117
(510) 674 - 0690, extension 8240
Fax: [phone]
Contact Person: Yvette Lloyd

Date Prepared: March 6, 1997

---

### 2. Device name

Proprietary name: CEDIA® Digoxin II Assay

Common name: Homogeneous enzyme immunoassay for the determination of Digoxin.

Classification name: Enzyme immunoassay, Digoxin

---

### 3. Predicate device

The Boehringer Mannheim CEDIA® Digoxin II is substantially equivalent to other products in commercial distribution intended for similar use. Most notably it is substantially equivalent to the currently marketed Abbott TDx® Digoxin II Assay (K882233).

---

Continued on next page

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510(k) Summary, Continued

BOEHRINGER MANNHEIM CORPORATION

4. Device Description

The CEDIA® Digoxin II Assay is based on the bacterial enzyme β-galactosidase, which has been genetically engineered into two inactive fragments. These fragments spontaneously reassociate to form fully active enzyme that, in the assay format, cleaves a substrate, generating a color change that can be measured spectrophotometrically.

In the assay, digoxin in the sample competes with analyte conjugated to one inactive fragment of β-galactosidase for antibody binding site. If analyte is present in the sample, it binds to antibody, leaving the inactive enzyme fragments free to form active enzyme. If analyte is not present in the sample, antibody binds to analyte conjugated on the inactive fragment, inhibiting the reassociation of inactive β-galactosidase fragments, and no active enzyme is formed.

Continued on next page

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510(k) Summary, Continued

## BOEHRINGER MANNHEIM CORPORATION

5. Intended use
Immunoassay for the in vitro quantitative determination of Digoxin in human serum and plasma.

6. Comparison to predicate device
The Boehringer Mannheim CEDIA® Digoxin II Assay is substantially equivalent to other products in commercial distribution intended for similar use. Most notably it is substantially equivalent to the currently marketed Abbott TDx® Digoxin II Assay (K882233).

The following table compares the CEDIA® Digoxin II Assay with the predicate device, Abbott TDx® Digoxin II Assay. Specific data on the performance of the test have been incorporated into the draft labeling in attachment 5. Labeling for the predicate device is provided in attachment 6.

### Similarities:

- Intended Use: Immunoassay for the in vitro quantitative determination of Digoxin
- Sample type: Serum and plasma
- Assay range: 0.15 - 4 ng/mL

Continued on next page

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510(k) Summary, Continued
BOEHRINGER MANNHEIM CORPORATION
6. Comparison to predicate device cont.

## Differences:

| Feature | CEDIA® Digoxin II | TDx Digoxin II |
| --- | --- | --- |
| Reaction test principle | Spectrophotometric 570 nm | Fluorescence Polarization |
| Instrument required | Hitachi 911 | Abbott TDx |

## Performance Characteristics:

| Feature | CEDIA® Digoxin II | | | TDx Digoxin II | | |
| --- | --- | --- | --- | --- | --- | --- |
| Precision | Modified NCCLS (ng/mL): | | | NCCLS (ng/mL): | | |
| Level | Level 1 | Level 2 | Level 3 | Low | Mid | High |
| N | 120 | 120 | 120 | 50 | 50 | 50 |
| Within run | 1.1 | 1.8 | 3.8 | 0.70 | 1.44 | 3.66 |
| %CV | 4.25 | 2.22 | 1.56 | 5.75 | 3.15 | 1.87 |
| Total | 1.1 | 1.8 | 3.8 | 0.70 | 1.44 | 3.66 |
| %CV | 5.44 | 3.58 | 2.34 | 7.67 | 3.98 | 1.91 |

Continued on next page

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510(k) Summary, Continued

BOEHRINGER
MANNHEIM
CORPORATION

6. Comparison to predicate device, (cont.)

Performance Characteristics:

| Feature | CEDIA® Digoxin II | TDx Digoxin II |
| --- | --- | --- |
| Lower Detection Limit | 0.15 ng/mL | 0.2 ng/mL |
| Linearity | 0.15 - 4 ng/mL | 0.0 - 4.0 ng/mL |
| Method Comparison | Vs Abbott TDx Digoxin | Vs Baxter Dade Stratus |
| | Least Squares
y =0.98x - 0.12
r=0.955
N=99 | y =0.94x + 0.08
r=0.962
N=200 |
| | Deming's:
y=1.02x - 0.17
r=0.955
N=99 | |

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510(k) Summary, Continued
BOEHRINGER MANNHEIM CORPORATION
6. Comparison to predicate device, (cont.)

Performance Characteristics:
p.58
p.61

| Feature | CEDIA® Digoxin II | TDx Digoxin II |
| --- | --- | --- |
| Interfering substances | No interference at: (within ±10% of baseline)
1€ | No interference at: |
| Bilirubin | 66 mg/dL | 20 mg/dL |
| Hemoglobin | 1000 mg/dL | 1000 mg/dL |
| Triglyceride | 100 mg/dL | 2500 mg/dL |
| Lipemia | 10 g/dL | N/A |
| Total Protein | 100 IU/mL | N/A |
| Rheumatoid Factor | | |
| Specificity | % Cross-reactivity | % Cross-reactivity |
| Digoxigenin | 60.5 | up to 200 |
| β-Acetyldigoxin | 77.0 | not tested |
| α-Acetyldigoxin | 75.3 | not tested |
| Gitalin | 2.1 | not tested |
| Digoxigenin-Mono-Digitoxiside | 102.5 | up to 200 |
| Digitoxin-Bis-Digitoxiside | 86.3 | up to 200 |
| Digitoxin | 1.5 | 4.8 |
| β-Methyldigoxin | 76.3 | not tested |
| 3-Epe-Digoxigenin | 37.6 | not tested |
| Dehydrodigoxigenin | 82.6 | not tested |
| Epi-Digoxigenin-Glucuronide | 42.9 | not tested |

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DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration
2098 Gaither Road
Rockville MD 20850

MAY 21 1997

Yvette R. Lloyd
Regulatory Affairs Specialist
Boehringer Mannheim Corporation
2400 Bisso Lane
P.O. Box 4117
Concord, California 94524-4117

Re: K970883
CEDIA® Digoxin II Assay
Regulatory Class: II
Product Code: KXT
Dated: April 18, 1997
Received: April 24, 1997

Dear Ms. Lloyd:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Good Manufacturing Practice for Medical Devices: General (GMP) regulation (21 CFR Part 820) and that, through periodic GMP inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Page 2

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at [phone].

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at [phone]. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at [phone]. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number [phone] or [phone] or at its internet address "http://www.fda.gov/cdrh/dsmamain.html".

Sincerely yours,
Steven I. Gutman

Steven I. Gutman, M.D., M.B.A.
Director
Division of Clinical Laboratory Devices
Office of Device Evaluation
Center for Devices and Radiological Health

Enclosure

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510(k) Number (if known): N/A

K910883

Device Name: CEDIA® Digoxin II Assay

Indications For Use:

The CEDIA Digoxin II homogeneous enzyme immunoassay is for the quantitation of digoxin in human serum or plasma using automated clinical chemistry analyzers. Measurements are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure proper therapy.

Digoxin is widely prescribed for the treatment of congestive heart failure and various disturbances of cardiac rhythm. Therapeutic use of digoxin improves the strength of myocardial contraction and results in the beneficial effects of increased cardiac output, decreased heart size, decreased venous pressure and decreased blood volume. Digoxin therapy also results in stabilized and slowed ventricular pulse rate.

Although the availability of crystalline digoxin has permitted the standardization of drug dosage, therapeutic administration inadvertently, yet frequently, results in toxicity. Importantly, symptoms of digoxin toxicity often mimic the cardiac arrhythmias for which the drug was originally prescribed. Studies suggest that up to 25% of all hospitalized patients treated with digoxin experienced some degree of toxicity, and that the mortality rate among toxic patients was more than twice that of nontoxic patients. Digoxin concentrations of 0.9 to 2.0 ng/mL in serum or plasma are normally considered to be therapeutic. Symptoms of human toxicity generally only appear at concentrations above 2.0 ng/mL; however, concentrations as low as 1.4 ng/mL may be toxic for others.

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use ☑ (Per 21 CFR 801.109)

OR

Over-The-Counter Use ☐ (Optional Format 1-2-96)


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INDICATIONS FOR USE, Continued:

Toxicity of digoxin may reflect several factors: a) The drug has a low therapeutic ratio (i.e., a very small difference exists between therapeutic and toxic tissue levels). b) Individuals vary in their response to digoxin. c) Absorption of various tablet forms of digoxin may vary over a two-fold range. d) Susceptibility to digitalis toxicity apparently increases with age.

In combination with other clinical data, monitoring serum or plasma levels may provide the physician with useful information to aid in adjusting patient dosage, and achieving optimal therapeutic effect, while avoiding both subtherapeutic and harmful toxic drug levels.

The CEDIA Digoxin II Assay performance has not been established with body fluids other than human serum and plasma (Na or Li heparin; Na EDTA). Digoxin-like immunoreactive substances (DLIS) have been identified in blood from patients in renal failure, liver failure, and pregnant women in the third trimester. Studies have established that the presence of DLIS in a sample can result in a false elevation of digoxin when assayed by commercially available immunoassay.

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use (Per 21 CFR 801.109)
OR
Over-The-Counter Use

(Optional Format 1-2-96)

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