Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA

K190397 · Immunalysis Corporation · QBK · Nov 15, 2019 · Clinical Toxicology

Device Facts

• Record ID: K190397
• Device Name: Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA
• Applicant: Immunalysis Corporation
• Product Code: QBK · Clinical Toxicology
• Decision Date: Nov 15, 2019
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3590
• Device Class: Class 2

Indications for Use

The Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA is a homogenous enzyme immunoassay for the qualitative analysis of carisoprodol metabolite, Meprobamate, at a cutoff of 280 ng/mL in human urine. The assay is intended for use in laboratories with automated clinical chemistry analyzers. This in vitro diagnostic device is for prescription use only. The Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA provides only a preliminary analytical test result. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. Gas Chromatography/ Mass Spectrometry (GC-MS) or Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) is the preferred confirmatory method. Clinical consideration and professional judgment should be applied to any drug of abuse test result, particularly when preliminary positive results are used.

Device Story

Homogeneous enzyme immunoassay for qualitative detection of meprobamate in human urine; utilizes competition between carisoprodol-labeled G6PDH enzyme and free meprobamate in sample for fixed sheep anti-carisoprodol antibody binding sites. In absence of drug, antibody binds conjugate, inhibiting enzyme activity; dose-response relationship established between drug concentration and enzyme activity. G6PDH activity measured spectrophotometrically at 340 nm via conversion of NAD to NADH. Used in clinical laboratories on automated analyzers (e.g., Olympus AU400e) by trained personnel. Provides preliminary analytical result; requires confirmation by GC-MS or LC-MS/MS. Assists clinicians in identifying potential carisoprodol/meprobamate presence in urine samples for toxicology screening.

Clinical Evidence

Bench testing only. Precision/cutoff characterization performed over 10 days (N=80 per concentration) using three lots. Method comparison study analyzed 167 clinical urine samples against LC-MS/MS; demonstrated 100% positive agreement and 92% negative agreement. Specificity/interference testing evaluated structurally related and unrelated compounds; boric acid (1% w/v) identified as causing false negatives. Pharmacokinetic study data supported the clinical validity of the 280 ng/mL cutoff.

Technological Characteristics

Homogeneous enzyme immunoassay; G6PDH enzyme label; sheep anti-carisoprodol polyclonal antibodies. Spectrophotometric detection at 340 nm. Automated clinical chemistry analyzer platform. Stable for 12 months at 2-8 °C. Traceable to certified standard material verified by GC-MS/LC-MS/MS.

Indications for Use

Indicated for the qualitative detection of carisoprodol metabolite (meprobamate) in human urine at a 280 ng/mL cutoff. Intended for use in clinical laboratories using automated chemistry analyzers. Prescription use only.

Regulatory Classification

Identification

A meprobamate test system is a device intended to measure meprobamate in human specimens. Measurements obtained by this device are used to detect the presence of meprobamate to diagnose the use or overdose of meprobamate or structurally-related drug compounds (e.g., prodrugs).

Special Controls

(b) Classification. Class II (special controls). The special controls for this device are: - 1) Design verification and validation must include: - Robust data demonstrating the accuracy of the device when used in the intended (i) specimen matrix. The accuracy data must include a comparison between the meprobamate test system results and meprobamate results that are measured on an FDA-accepted measurement method that is specific and accurate (e.g., gas or liquid chromatography combined with tandem mass spectrometry). - (ii) Robust analytical data demonstrating the performance characteristics of the device, including, but not limited to, specificity, cross-reactivity to relevant endogenous and exogenous substances, and the reproducibility of analyte detection around the cutoff(s). - 2) The intended use of the device must not include an indication for use in monitoring therapeutic drug concentrations or informing dosing adjustment decisions. - 3) Your 21 CFR 809.10 labeling must include the following: - (i) If indicated for use as a screening test to identify preliminary results for further confirmation, the intended use must state "This assay provides only a preliminary analytical result. A more specific alternative chemical confirmatory method (e.g., gas or liquid chromatography and mass spectrometry) must be used to obtain a confirmed analytical result. Clinical consideration and professional judgment must be exercised with any drug of abuse test, particularly when the preliminary test result is positive." - (ii) A limiting statement that reads as follows: "This test should not be used to monitor therapeutic drug concentrations or to inform dosing adjustment decisions."

*Classification.* Class II (special controls). The special controls for this device are:(1) Design verification and validation must include: (i) Robust data demonstrating the accuracy of the device when used in the intended specimen matrix. The accuracy data must include a comparison between the meprobamate test system results and meprobamate results that are measured on an FDA-accepted measurement method that is specific and accurate (e.g., gas or liquid chromatography combined with tandem mass spectrometry). (ii) Robust analytical data demonstrating the performance characteristics of the device, including, but not limited to, specificity, cross-reactivity to relevant endogenous and exogenous substances, and the reproducibility of analyte detection around the cutoff(s). (2) The intended use of the device must not include an indication for use in monitoring therapeutic drug concentrations or informing dosing adjustment decisions. (3) Your 21 CFR 809.10 labeling must include the following: (i) If indicated for use as a screening test to identify preliminary results for further confirmation, the intended use must state “This assay provides only a preliminary analytical result. A more specific alternative chemical confirmatory method (e.g., gas or liquid chromatography and mass spectrometry) must be used to obtain a confirmed analytical result. Clinical consideration and professional judgment must be exercised with any drug of abuse test, particularly when the preliminary test result is positive.” (ii) A limiting statement that reads as follows: “This test should not be used to monitor therapeutic drug concentrations or to inform dosing adjustment decisions.”

Predicate Devices

• Lin-Zhi Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay, Meprobamate Drugs of Abuse Calibrators and Controls [DEN170010]

Submission Summary (Full Text)

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FDA

U.S. FOOD & DRUG

ADMINISTRATION

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY ONLY

## I Background Information:

A 510(k) Number

k190397

B Applicant

Immunalysis Corporation

C Proprietary and Established Names

Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA

D Regulatory Information

| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| QBK | Class II | 21 CFR 862.3590 - Meprobamate Test System | TX - Clinical Toxicology |

## II Submission/Device Overview:

A Purpose for Submission:

New device

B Measurand:

Carisoprodol metabolite (Meprobamate)

C Type of Test:

Qualitative Immunoassay

Food and Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

www.fda.gov

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III Intended Use/Indications for Use:

A Intended Use(s):
See Indications for Use below.

B Indication(s) for Use:
The Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA is a homogenous enzyme immunoassay for the qualitative analysis of carisoprodol metabolite, Meprobamate, at a cutoff of 280 ng/mL in human urine. The assay is intended for use in laboratories with automated clinical chemistry analyzers. This in vitro diagnostic device is for prescription use only.

The Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA provides only a preliminary analytical test result. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. Gas Chromatography/ Mass Spectrometry (GC-MS) or Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) is the preferred confirmatory method. Clinical consideration and professional judgment should be applied to any drug of abuse test result, particularly when preliminary positive results are used.

C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only

D Special Instrument Requirements:
Assay performance was established using the Olympus AU400e analyzer.

IV Device/System Characteristics:

A Device Description:
The Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA is based on the competition of carisoprodol labeled enzyme glucose-6-phosphate dehydrogenase (G6PDH) and the free Meprobamate in the urine sample for the fixed amount of sheep anti-carisoprodol antibody binding sites. In the absence of the free Meprobamate in the sample, the antibody binds the drug enzyme conjugate and enzyme activity is inhibited. This creates a dose response relationship between drug concentration in the urine and enzyme activity. The enzyme G6PDH activity is determined at 340 nm spectrophotometrically by the conversion of nicotinamide adenine dinucleotide (NAD) to NADH.

B Principle of Operation:
The Immunalysis Carisoprodol Metabolite / Meprobamate Urine HEIA is based on the competition of carisoprodol labeled enzyme glucose-6-phosphate dehydrogenase (G6PDH) and the free drug in the urine sample for the fixed amount of sheep anti-carisoprodol antibody binding sites. In the absence of the free drug in the sample, the antibody binds the drug enzyme conjugate and enzyme activity is inhibited. This creates a dose response relationship between drug concentration in the urine and enzyme activity. The enzyme G6PDH activity is determined

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at 340 nm spectrophotometrically by the conversion of nicotinamide adenine dinucleotide (NAD) to NADH.

## V Substantial Equivalence Information:

A Predicate Device Name(s):

LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay

B Predicate 510(k) Number(s):

DEN170010

C Comparison with Predicate(s):

| Device & Predicate Device(s): | k190397 | DEN170010 |
| --- | --- | --- |
| Device Trade Name | Immunalysis
Carisoprodol
Metabolite /
Meprobamate Urine
HEIA | LZI Carisoprodol
Metabolite
(Meprobamate) Enzyme
Immunoassay |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | For the analysis of carisoprodol metabolite (meprobamate) in human urine. | Same |
| Test Principle | Homogeneous Enzyme Immunoassay | Same |
| User Environment | Laboratory Use | Same |
| Sample Matrix | Human Urine | Same |
| Mass spectrometry confirmation | Required to confirm preliminary positive analytical results | Same |
| General Device Characteristic Differences | | |
| Calibrator material | Carisoprodol | Meprobamate |
| Antibody | Polyclonal sheep antibodies to carisoprodol | Monoclonal mouse antibodies to meprobamate |

## VI Standards/Guidance Documents Referenced:

The sponsor satisfied all special controls as outlined in 21 CFR 862.3590.

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VII Performance Characteristics (if/when applicable):

A Analytical Performance:

1. Precision/Reproducibility:

The following laboratory performance studies were performed to determine substantial equivalence of the Immunalysis Carisoprodol Urine HEIA to the predicate device.

Precision/ Cutoff Characterization

A precision/Cutoff Characterization study for meprobamate was performed for ten days using three product lots with two runs per day in replicates of four on drug free urine (N=80) spiked with meprobamate to concentrations of the equivalent of the meprobamate cutoff and ±25%, ±50%, ±75%, and ±100% of the cutoff. The spiked concentrations were confirmed by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). The study verified that the cutoff serves as a boundary between a negative and positive interpretation of a qualitative result.

Precision test results in qualitative mode are presented in the table below:

| Meprobamate Concentration (ng/mL) | % of Cutoff | Sample Size | Result | | |
| --- | --- | --- | --- | --- | --- |
| | | | Lot 1 | Lot 2 | Lot 3 |
| 0 | -100% | 80 | 80 Negative | 80 Negative | 80 Negative |
| 70 | -75% | 80 | 80 Negative | 80 Negative | 80 Negative |
| 140 | -50% | 80 | 80 Negative | 80 Negative | 80 Negative |
| 210 | -25% | 80 | 80 Negative | 80 Negative | 80 Negative |
| 280 | Cutoff | 80 | 40 Neg/40 Pos | 38 Neg/42 Pos | 39 Neg/41 Pos |
| 350 | +25% | 80 | 80 Positive | 80 Positive | 80 Positive |
| 420 | +50% | 80 | 80 Positive | 80 Positive | 80 Positive |
| 490 | +75% | 80 | 80 Positive | 80 Positive | 80 Positive |
| 560 | +100% | 80 | 80 Positive | 80 Positive | 80 Positive |

2. Analytical Specificity/Interference:

Specificity and Cross-Reactivity

Compounds that were determined by the sponsor to be structurally and functionally similar to meprobamate were spiked into drug-free urine at levels that will yield a result that is equivalent to the cutoff and were evaluated as potential cross-reactant in the test device. Each compound was evaluated in replicates of four. Each compound was an independent spike and no drug mixes were used.

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| Compound | Compound Conc. (ng/mL) | Result | Cross-Reactivity (%) |
| --- | --- | --- | --- |
| Meprobamate | 280 | POS | 100 |
| Carisoprodol | 100 | POS | 280 |
| Buprenorphine | 100,000 | NEG | <0.1% |
| Codeine | 100,000 | NEG | <0.1% |
| Darunavir | 200,000 | NEG | N/D |
| Dihydrocodeine | 100,000 | NEG | <0.1% |
| Efavirenz | 200,000 | NEG | N/D |
| Felbamate | 120,000 | POS | 0.2 |
| Hydrocodone | 100,000 | NEG | <0.1% |
| Hydromorphone | 100,000 | NEG | <0.1% |
| Meperidine | 100,000 | NEG | <0.1% |
| Methocarbamol | 200,000 | NEG | N/D |
| Mitomycin C | 200,000 | NEG | N/D |
| Morphine | 100,000 | NEG | <0.1% |
| Morphine-3-glucuronide | 100,000 | NEG | <0.1% |
| Morphine-6-glucuronide | 100,000 | NEG | <0.1% |
| Naloxone | 100,000 | NEG | <0.1% |
| Naltrexone | 100,000 | NEG | <0.1% |
| Neostigmine | 200,000 | NEG | N/D |
| Norbuprenorphine | 100,000 | NEG | <0.1% |
| Norcodeine | 100,000 | NEG | <0.1% |
| Normorphine | 100,000 | NEG | <0.1% |
| Oxycodone | 100,000 | NEG | <0.1% |
| Oxymorphone | 100,000 | NEG | <0.1% |
| Propoxyphene | 100,000 | NEG | <0.1% |
| Retigabine | 200,000 | NEG | N/D |
| Ritonavir | 200,000 | NEG | N/D |
| Rivastigmine | 200,000 | NEG | N/D |
| Tramadol | 100,000 | NEG | <0.1% |
| Trazadone | 100,000 | NEG | <0.1% |
| Venlafaxine | 100,000 | NEG | <0.1% |
| Zafirlukast | 200,000 | NEG | N/D |

## Interference – Structurally Unrelated Compounds

Structurally unrelated compounds were evaluated by spiking the potential interferent at concentrations of at least $50~\mu \mathrm{g / mL}$ into drug free urine containing analyte at $\pm 25\%$ of the cutoff. The levels of structurally unrelated compounds that did not interfere in the assay are presented in the table below.

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| Compounds for which interference with the assay was not detected | | |
| --- | --- | --- |
| 4-Bromo-2,5,Dimethoxyphenethylamine | Dehydronorketamine | Naproxen |
| Acetaminophen | Delta-9-THC | Nitrazepam |
| Acetylsalicylic Acid | Doxepin | 11-nor-9 carboxy THC |
| 6-Acetylcodeine | Doxylamine | Nordiazepam |
| Alphenal | Ecgonine | Norketamine |
| 6-Acetylmorphine | Ecgonine methyl ester | Norpropoxyphene |
| Alprazolam | EDDP | Norpseudoephedrine |
| 7-Aminoclonazepam | EMDP | Nortriptyline |
| 7-Aminoflunitrazepam | 1R,2S(-)-Ephedrine | O-desmethyl tramadol |
| 7-Aminonitrazepam | 1S,2R(+)-Ephedrine | O-desmethyl venlafaxine |
| Amitriptyline | Ethyl glucuronide | Olanzapine |
| Amobarbital | Ethylmorphine | Oxazepam |
| S-(+)-Amphetamine | Fenfluramine | PCP |
| Aprobarbital | Fentanyl | Pentobarbital |
| Barbital | Flunitrazepam | Pentazocine |
| Benzoylecgonine | Fluoxetine | Phenazepam |
| Benzylpiperazine | Flurazepam | Phenobarbital |
| Bromazepam | Haloperidol | Phentermine |
| Bupropion | Heroin | Phenylephedrine |
| Butabarbital | Hexobarbital | Phenytoin |
| Butalbital | 11-hydroxy-delta-9-THC | Phenylpropanolamine |
| Caffeine | Ibuprofen | PMA |
| Cannabidiol | Imipramine | Prazepam |
| Cannabinol | Ketamine | Propranolol |
| Carbamazepine | Labetalol | Protriptyline |
| Chlordiazepoxide | Lamotrigine | R,R(-)-Pseudoephedrine |
| Chlorpromazine | Levorphanol tartrate | S,S(+)-Pseudoephedrine |
| cis-Tramadol | Lidocaine | Ritalinic Acid |
| Clobazam | Lorazepam | Salicylic Acid |
| Clomipramine | Lorazepam Glucuronide | Secobarbital |
| Clonazepam | Lormetazepam | Sertraline |
| Clozapine | LSD | Sufentanil Citrate |
| Cocaine | Maprotiline | Talbutal |
| Cotinine | MDA | Tapentadol |
| Cyclobenzaprine | MDEA | Temazepam |
| Cyclopentobarbital | MDMA | Theophylline |
| Demoxepam | S(+)-Methamphetamine | Thiopental |
| Desakylflurazepam | Methadone | Thioridazine |
| Desipramine | Methaqualone | Triazolam |
| Dextromethorphan | Methoxetamine | Trifluoromethylphenyl-piperazine |
| Diazepam | Methylone | Trimipramine |

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| Compounds for which interference with the assay was not detected | | |
| --- | --- | --- |
| Digoxin | Methylphenidate | Verapamil |
| Diphenhydramine | Midazolam | Zolpidem Tartrate |

## Interference – Endogenous Compounds

Endogenous compounds and urine preservatives were evaluated by spiking the potential interferent into drug free urine containing meprobamate at ±25% of the cutoff. Due to the interference of boric acid observed at ±25% of the cutoff, potential interference was also evaluated at ±50% of the cutoff. Other than boric acid, assay performance was not affected by all the other internally existing physiological conditions tested. Endogenous compounds tested that did not interfere in the assay are presented in the table below.

| Acetone | 1.0 g/dL |
| --- | --- |
| Ascorbic Acid | 1.5 g/dL |
| Bilirubin | 0.002 g/dL |
| Creatinine | 0.5 g/dL |
| Ethanol | 1.0 g/dL |
| Galactose | 0.01 g/dL |
| γ-Globulin | 0.5 g/dL |
| Glucose | 2.0 g/dL |
| Hemoglobulin | 0.300 g/dL |
| Human Serum Albumin | 0.5 g/dL |
| Oxalic Acid | 0.1 g/dL |
| Riboflavin | 0.0075 g/dL |
| Sodium Azide | 1% w/v |
| Sodium Chloride | 6.0 g/dL |
| Sodium Fluoride | 1% w/v |
| Urea | 6.0 g/dL |

Boric acid interference test results are presented in the table below.

| Interferent | -50% Cutoff (50 ng/mL) Result | +50% Cutoff (150 ng/mL) Result |
| --- | --- | --- |
| Boric Acid (1%w/v) | Negative | Negative |

Boric Acid at 1% w/v may cause false negative results. The assay should not be used to test samples which contain boric acid.

## 3. Assay Reportable Range:

Not applicable. This device is intended for qualitative use only.

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4. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):

The device is traceable to a commercially available, certified, standard material for which the concentration is verified by GC-MS or LC-MS/MS.

Accelerated stability and real time studies have been conducted for the device. Protocols and acceptance criteria were described and found to be acceptable. The manufacturer claims that when stored un-opened at 2-8 °C, the device is stable for 12 months.

5. Detection Limit:

See Precision/Reproducibility section in XII.A.1, above.

6. Assay Cut-Off:

Characterization of how the device performs analytically around the claimed cut-off concentration appears in the precision section, VII.A.1, above.

B Comparison Studies:

1. Method Comparison with Predicate Device:

One hundred and sixty-seven (167) de-identified, unaltered leftover clinical urine samples obtained from clinical testing laboratories were analyzed for total carisoprodol at an assay cutoff of 280 ng/mL with the Immunalysis Carisoprodol Urine HEIA on the Olympus AU400e compared to results by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Method comparison results are presented in the tables below.

| Immunalysis Meprobamate Urine HEIA Result | LC-MS/MS Total Meprobamate Concentration | | | | Agreement (%) |
| --- | --- | --- | --- | --- | --- |
| | < 140 ng/mL (less than -50% cutoff) | 140-279 ng/mL (between - 50% cutoff and cutoff) | 280-420 ng/mL (between cutoff and +50% cutoff) | > 420 ng/mL (greater than +50% cutoff) | |
| Positive | 3 | 2 | 3 | 104 | 100% (107/107) |
| Negative | 51 | 4 | 0 | 0 | 92% (55/60) |

Results from this testing included three false positive samples with meprobamate concentrations less than 50% of the cutoff. It was determined in LC-MS/MS testing that each of these samples included carisoprodol, as described in the table below, which caused the positive device results.

| Sample ID | Qualitative Result | Carisoprodol (ng/mL) |
| --- | --- | --- |
| 17990 | POS | 147 |
| 17977 | POS | 148 |

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18077 | POS | 750

2. **Matrix Comparison:**
Not applicable. Urine is the only claimed matrix for the candidate device.

**C Clinical Studies:**

1. **Clinical Sensitivity:**
Not applicable.

2. **Clinical Specificity:**
Not applicable.

3. **Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):**
To support their proposed cutoff of 280 ng/mL for detection of the carisoprodol metabolite meprobamate, the sponsor provided protocols for and results from a pharmacokinetic study. Urine samples in this study were evaluated both by the sponsor’s device as well as confirmatory LC-MS/MS testing. After review, it was determined that the sponsor’s proposed cutoff was clinically valid for the intended use of the device.

**D Clinical Cut-Off:**
Not applicable.

**E Expected Values/Reference Range:**
Not applicable.

**VIII Proposed Labeling:**
The labeling supports the finding of substantial equivalence for this device.

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