Billing and Coding: Pharmacogenomics Testing

This Billing and Coding Article provides billing and coding guidance for Local
Coverage Determination (LCD) L39063 Pharmacogenomics Testing. Please refer to
the LCD for reasonable and necessary requirements.  
  
Laboratory tests that investigate the same germline genetic content, for the
same genetic information, that has already been tested in the same Medicare
beneficiary is duplicative and should not be reported.  
  
Examples of germline tests include (but are not limited to) single gene and
specific gene panel tests for: hereditary cancer syndromes or cancer
predisposition, inherited disorders, and pharmacogenomics/cytochrome P450
testing.  
  
Providers should take reasonable measures to be aware of what, if any,
germline testing a beneficiary has had prior to billing for germline testing
so as to avoid billing Medicare for services that are not medically reasonable
and necessary. Clinicians who order germline testing may wish to be aware of
whether the test that they are ordering is covered under Medicare and may wish
to verify that they are not ordering repeat germline testing.

Germline testing, including panels containing some genetic content already
tested in the same Medicare beneficiary, may be considered medically
reasonable and necessary if there is established clinical utility in the
remaining, non-duplicative genetic components of the test.  
  
 **Coding Guidance  
  
Notice:** It is not appropriate to bill Medicare for services that are not
covered (as described by the entire LCD) as if they are covered. When billing
for non-covered services, use the appropriate modifier.  
  

CPT codes 81355 (VKORC1) and 81227 (CYP2C9) are not considered medically
reasonable and necessary for warfarin testing. Please refer to the CMS IOM
Publication 100-03, _Medicare National Coverage Determinations (NCD) Manual_ ,
Chapter 1, Part 2, Section 90.1 Pharmacogenomic Testing to Predict Warfarin
Responsiveness.  
  
If a treating clinician orders a single gene test or a test for a particular
allele(s), but as a matter of operational practicality, the laboratory tests
that single gene or allele on a platform that looks for variants in other
genes/alleles as well, that particular test done in that particular instance
is considered a single gene/allele test for coverage purposes. In this
scenario the provider may bill for the component of the test that was
medically reasonable and necessary (in this example, the single gene test).  
  
Genes can be assayed serially or in parallel. Genes assayed on the same date
of service are considered to be assayed in parallel if the result of one assay
does not affect the decision to complete the assay on another gene, and the
two genes are being tested for the same indication. Genes assayed on the same
date of service are considered to be assayed serially when there is a
reflexive decision component where the results of the analysis of one or more
genes determines whether the results of additional analyses are medically
reasonable and necessary. If two or more genes are tested, please refer to the
Molecular Pathology and Genetic Testing Article A58917 for multi-gene testing.  
  
When billing Part B claims, the drug or drugs in consideration for use that
require the use of the PHARMACOGENOMICS (PGx) test must be submitted in the
applicable detail line 2400 loop.  
  
When billing **CPT code 81418** , the following information should be
provided:

  * List the names of the specific genes that are tested in addition to genes CYP2C19 and CYP2D6 in the comment/narrative field for the following claim field/types: 
    * Part A Claims: 
      * Loop SV202-7 for the 837I electronic claim
      * Block 80 for the UB04 claim form
    * Part B Claims: 
      * Loop 2400 or SV101-7 for the 5010A1 837P
      * Box 19 for the paper claim

NOTE: **** Testing **MUST** **be for at least 6 genes** per the CPT code
descriptor for 81418: Drug metabolism (e.g., pharmacogenomics) genomic
sequence analysis panel, must include testing of at least 6 genes, including
CYP2C19, CYP2D6, and CYP2D6 duplication/deletion analysis  
  
The following 2 tables represent relevant gene/drug associations. Table 1 is
from CPIC and Table 2 is from FDA sources.  
  
 **Table 1.** Current CPIC guidelines as of October 26, 2022:  
  

**Gene/Test**

|

**CPT Code**

|

**Intended use for Drug**

|

**Brand Name**  
  
---|---|---|---  
  
CFTR

|

81220

|

ivacaftor

|

Kalydeco  
  
CYP2B6

|

81479, 0392U

|

efavirenz, sertraline

|

Sustiva, Zoloft  
  
CYP2C19

|

81225, 81418

|

clopidogrel, voriconazole

|

Plavix, Vfend  
  
CYP2C19

|

81225, 81418

|

PPIs (class): omeprazole, lansoprazole, pantoprazole, dexlansoprazole

|

Prilosec, Prevacid, Protonix, Dexilant  
  
CYP2C19

|

81225, 81418

|

SSRIs (class): citalopram, escitalopram, fluvoxamine, paroxetine, sertraline

|

Celexa, Lexapro, Luvox, Paxil, Zoloft  
  
CYP2C19

|

81225, 81418

|

Tricyclic antidepressants (class): amitriptyline, clomipramine, desipramine,
doxepin, imipramine, nortriptyline, trimipramine

|

Anafranil, Norpramin, Silenor,  
Pamelor, Surmontil  
  
CYP2C9

|

81227

|

phenytoin, fosphenytoin

|

Dilantin, Cerebyx  
  
CYP2C9

|

81227

|

warfarin

|

Jantoven, Coumadin  
  
CYP2C9

|

81227

|

NSAIDs (class): celecoxib, flurbiprofen, ibuprofen, lornoxicam, meloxicam,
piroxicam, tenoxicam

|

Celebrex, Ocufen, Chlortenoxicam, Mobic, Feldene, Mobiflex  
  
CYP2C9

|

81227

|

fluvastatin

|

Lescol  
  
HLA-B

|

81381, 81374

|

abacavir, allopurinol, oxcarbazepine, phenytoin, carbamazepine, fosphenytoin

|

Ziagen, Zyloprim, Aloprim, Trileptal, Oxtellar, Dilantin, Tegretol, Cerebyx  
  
CYP4F2

|

81479

|

warfarin

|

Jantoven, Coumadin  
  
VKORC1

|

81355

|

warfarin

|

Jantoven, Coumadin  
  
CYP2D6

|

81226, 81418, 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, 0076U

|

atomoxetine, codeine, ondansetron, tropisetron, tamoxifen, tramadol,
hydrocodone

|

Strattera, Zofran, Soltamox, Ultram  
  
CYP2D6

|

81226, 81418, 0392U

|

venlafaxine

|

Effexor  
  
CYP2D6

|

81226, 81418, 0392U

|

vortioxetine

|

Trintellix  
  
CYP2D6

|

81226, 81418, 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, 0076U

|

SSRIs (class): citalopram, escitalopram, fluvoxamine, paroxetine, sertraline

|

Celexa, Lexapro, Luvox, Paxil, Zoloft  
  
CYP2D6

|

81226, 81418, 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, 0076U

|

Tricyclic antidepressants (class): amitriptyline, clomipramine, desipramine,
doxepin, imipramine, nortriptyline, trimipramine

|

Anafranil, Norpramin, Silenor,  
Pamelor, Surmontil  
  
CYP3A5

|

81231

|

tacrolimus

|

Prograf, Protopic  
  
DPYD

|

81232

|

Fluoropyrimidines (class): fluorouracil, capecitabine

|

Adrucil, Xeloda  
  
G6PD

|

81247

|

rasburicase

|

Elitek  
  
G6PD

|

81247

|

dapsone, methylene blue, nitrofurantoin, pegloticase, primaquine, tafenoquine

|

Aczone, Provayblue, Furadantin, Macrobid, Macrodantin, Krystexxa, Primaquine,
Arakoda, Krintafel  
  
HLA-A

|

81381, 81374

|

carbamazepine

|

Tegretol  
  
IFNL3

|

81283

|

peginterferon alfa-2a, peginterferon alfa-2b

|

Pegasys, Pegintron, Sylatron  
  
IFNL4

|

81479

|

peginterferon alfa-2a, peginterferon alfa-2b

|

Pegasys, Pegintron, Sylatron  
  
RYR1

|

81406

|

Volatile anesthetics (class): desflurane, enflurane, halothane, isoflurane,
methoxyflurane, sevoflurane, succinylcholine

|

Suprane, Ethrane, Fluothane, Forane, Penthrox, Ultane, Anectine, Quelicin  
  
CACNA1S

|

81479

|

Volatile anesthetics (class): desflurane, enflurane, halothane, isoflurane,
methoxyflurane, sevoflurane, succinylcholine

|

Suprane, Ethrane, Fluothane, Forane, Penthrox, Ultane, Anectine, Quelicin  
  
SLCO1B1

|

81328

|

Statins (class): simvastatin, pravastatin, atorvastatin, lovastatin,
rosuvastatin, fluvastatin, pitavastatin

|

Zocor, FloLipid, Pravachol, Lipitor, Altoprev, Crestor, Lescol, Livalo  
  
NUDT15

|

81306, 0286U

|

Thiopurines (class): mercaptopurine, azathioprine, thioguanine

|

Purixan, Azasan, Tabloid  
  
TPMT

|

81335

|

Thiopurines (class): mercaptopurine, azathioprine, thioguanine

|

Purixan, Azasan, Tabloid  
  
UGT1A1

|

81350

|

atazanavir

|

Reyataz  
  
MT-RNR1

|

81401

|

Aminoglycosides (class): gentamicin, amikacin, paromomycin, streptomycin,
plazomicin, tobramycin

|

Arikayce, Zemdri  
  
ABCG2

|

0193U

|

rosuvastatin

|

Crestor  
  
**  
  
Table 2.**[ Table of **PHARMACOGENOMIC** associations
](https://www.fda.gov/medical-devices/precision-medicine/table-
pharmacogenetic-associations) from the FDA for which the data support
therapeutic recommendations or a potential impact on safety or response (last
updated October 26, 2022):

**Gene**

|

**CPT Code**

|

**Drug**

|

**Brand Name**

|

**Affected Subgroups+**  
  
---|---|---|---|---  
  
BCHE

|

81479

|

mivacurium

|

Mivacurium chloride

|

intermediate or poor metabolizers  
  
BCHE

|

81479

|

succinylcholine

|

Anectine

|

intermediate or poor metabolizers  
  
CYP2B6

|

81479

|

efavirenz

|

Sustiva

|

poor metabolizers  
  
CYP2C19

|

81225, 81418

|

brivaracetam

|

Briviact

|

intermediate or poor metabolizers  
  
CYP2C19

|

81225, 81418

|

citalopram

|

Celexa

|

poor metabolizers  
  
CYP2C19

|

81225, 81418

|

clobazam

|

Onfi

|

intermediate or poor metabolizers  
  
CYP2C19

|

81225, 81418

|

clopidogrel

|

Plavix

|

intermediate or poor metabolizers  
  
CYP2C19

|

81225, 81418

|

flibanserin

|

Addyi

|

poor metabolizers  
  
CYP2C19

|

81225, 81418

|

pantoprazole

|

Protonix

|

Intermediate or poor metabolizers  
  
CYP2C19

|

81225, 81418

|

voriconazole

|

Vfend

|

intermediate or poor metabolizers  
  
CYP2C19

|

81225, 81418

|

abrocitinib

|

Cibinqo

|

poor metabolizers  
  
CYP2C19

|

81225, 81418

|

mavacamten

|

Camzyos

|

intermediate or poor metabolizers  
  
CYP2C19 and/or UGT2B17

|

81225, 81418

|

belzutifan

|

Cibinqo

|

poor metabolizers  
  
CYP2C9

|

81227

|

celecoxib

|

Celebrex

|

poor metabolizers or *3 carriers  
  
CYP2C9

|

81227

|

dronabinol

|

Marinol

|

intermediate or poor metabolizers  
  
CYP2C9

|

81227

|

erdafitinib

|

Balversa

|

*3/*3 (poor metabolizers)  
  
CYP2C9

|

81227

|

flurbiprofen

|

Ansaid

|

poor metabolizers or *3 carriers  
  
CYP2C9

|

81227

|

fosphenytoin

|

Cerebyx

|

intermediate or poor metabolizers  
  
CYP2C9

|

81227

|

meloxicam

|

Mobic

|

poor metabolizers or *3 carriers  
  
CYP2C9

|

81227

|

nateglinide

|



|

poor metabolizers  
  
CYP2C9

|

81227

|

phenytoin

|

Dilantin

|

intermediate or poor metabolizers  
  
CYP2C9

|

81227

|

piroxicam

|

Feldene

|

intermediate or poor metabolizers  
  
CYP2C9

|

81227

|

siponimod

|

Mayzent

|

intermediate or poor metabolizers  
  
CYP2C9

|

81227

|

warfarin

|

Coumadin

|

intermediate or poor metabolizers  
  
CYP2D6

|

81226, 81418

|

amphetamine

|

Adderall

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

aripiprazole

|

Abilify

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

aripiprazole lauroxil

|

Aristada

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

atomoxetine

|

Strattera

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

brexpiprazole

|

Rexulti

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

clozapine

|

Clozaril, FazaClo, Versacloz

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

codeine

|   |

ultrarapid metabolizers, poor metabolizers  
  
CYP2D6

|

81226, 81418

|

deutetrabenazine

|

Austedo

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

eliglustat

|

Cerdelga

|

ultrarapid, normal, intermediate, or poor metabolizers  
  
CYP2D6

|

81226, 81418

|

gefitinib

|

Iressa

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

Iloperidone

|

Fanapt

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

lofexidine

|

Lucemyra

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

meclizine

|

Antivert

|

ultrarapid, intermediate, or poor metabolizers  
  
CYP2D6

|

81226, 81418

|

metoclopramide

|

Reglan

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

pimozide

|

Orap

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

propafenone

|

Rythmol

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

tetrabenazine

|

Xenazine

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

thioridazine

|

Mellaril

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

tramadol

|

Ultram

|

ultrarapid metabolizers, or poor metabolizers  
  
CYP2D6

|

81226, 81418

|

valbenazine

|

Ingrezza

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

venlafaxine

|

Effexor

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

vortioxetine

|

Trintellix

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

carvedilol

|

Coreg

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

cevimeline

|

Evoxac

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

perphenazine

|

Trilafon

|

poor metabolizers  
  
CYP2D6

|

81226, 81418

|

tolterodine

|

Detrol

|

poor metabolizers  
  
CYP2D6

|

81226, 81418, 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, 0076U

|

oliceridine

|

Olinvyk

|

poor metabolizers  
  
CYP2D6

|

81226, 81418, 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, 0076U

|

pitolisant

|

Wakix

|

poor metabolizers  
  
CYP3A5

|

81231

|

tacrolimus

|

Prograf

|

intermediate or normal metabolizers  
  
CYP4F2

|

81479

|

warfarin

|

Coumadin

|

V433M variant carriers  
  
DPYD

|

81232

|

capecitabine

|

Xeloda

|

intermediate or poor metabolizers  
  
DPYD

|

81232

|

fluorouracil

|

Fluoroplex, Tolak, Efudex

|

intermediate or poor metabolizer  
  
HLA-A

|

81381, 81374

|

carbamazepine

|

Tegretol

|

*31:01 allele positive  
  
HLA-B

|

81381, 81374

|

abacavir

|

Ziagen

|

*57:01 allele positive  
  
HLA-B

|

81381, 81374

|

carbamazepine

|

Tegretol

|

*15:02 allele positive  
  
HLA-B

|

81381, 81374

|

fosphenytoin

|

Cerebyx

|

*15:02 allele positive  
  
HLA-B

|

81381, 81374

|

allopurinol

|

Zyloprim, Aloprim

|

*58:01 allele positive  
  
HLA-B

|

81381, 81374

|

oxcarbazepine

|

Trileptal, Oxtellar

|

*15:02 allele positive  
  
HLA-B

|

81381, 81374

|

pazopanib

|

Votrient

|

*57:01 allele positive  
  
HLA-B

|

81381, 81374

|

phenytoin

|

Dilantin

|

*15:02 allele positive  
  
HLA-DQA1

|

81383, 81377

|

lapatinib

|

Tykerb

|

*02:01 allele positive  
  
HLA-DRB1

|

81383, 81377

|

lapatinib

|

Tykerb

|

*07:01 allele positive  
  
NAT2

|

81479

|

amifampridine

|

Firdapse, Ruzurgi

|

poor metabolizers  
  
NAT2

|

81479

|

amifampridine phosphate

|   |

poor metabolizers  
  
Nonspecific (NAT)

|

81479

|

isoniazid

|   |

poor metabolizers  
  
Nonspecific (NAT)

|

81479

|

procainamide

|

Pronestyl, Procan

|

poor metabolizers  
  
Nonspecific (NAT)

|

81479

|

sulfamethoxazole and trimethoprim

|

Sulfatrim, Bactrim

|

poor metabolizers  
  
Nonspecific (NAT)

|

81479

|

sulfasalazine

|

Azulfidine

|

poor metabolizers  
  
SLCO1B1

|

81328

|

simvastatin

|

FloLipid, Zocor

|

521 TC or 521 CC (intermediate or poor function transporters)  
  
NUDT15 and/or

TPMT

|

81306, 81335, 0286U

|

azathioprine

|

Imuran, Azasan

|

intermediate or poor metabolizers  
  
NUDT15 and/or

TPMT

|

81306, 81335, 0286U

|

mercaptopurine

|

Purixan, Purinethol

|

intermediate or poor metabolizers  
  
NUDT15 and/or

TPMT

|

81306, 81335, 0286U

|

thioguanine

|

Tabloid

|

intermediate or poor metabolizers  
  
UGT1A1

|

81350

|

belinostat

|

Beleodaq

|

*28/*28 (poor metabolizers)  
  
UGT1A1

|

81350

|

irinotecan

|

Camptosar

|

*1/*6, *1/*28 (intermediate metabolizers) or *6/*6, *6/*28, *28/*28 (poor metabolizers)   
  
UGT1A1

|

81350

|

nilotinib

|

Tasigna

|

*28/*28 (poor metabolizers)  
  
UGT1A1

|

81350

|

pazopanib

|

Votrient

|

*28/*28 (poor metabolizers)  
  
UGT1A1

|

81350

|

sacituzumab  
govitecan-hziy

|

Trodelvy

|

*28/*28 (poor metabolizers)  
  
VKORC1

|

81355

|

warfarin

|

Coumadin

|

-1639G>A variant carriers  
  
  
The CPT codes relevant to the related LCD are listed in the coding section
below. If no CPT code is available for the gene(s) being tested, the unlisted
molecular pathology procedure code 81479 should be used as indicated below.  
  
 **Utilization Parameters  
  
** Germline testing may be performed once in a lifetime per beneficiary.  
  
 **Documentation Requirements**

    1. All documentation must be maintained in the patient's medical record and made available to the contractor upon request.
    2. Every page of the record must be legible and include appropriate patient identification information (e.g., complete name, dates of service[s]). The documentation must include the legible signature of the physician or non-physician practitioner responsible for and providing the care to the patient.
    3. The submitted medical record must support the use of the selected ICD-10-CM code(s). The submitted CPT/HCPCS code must describe the service performed.
    4. The provider performing the service must have a record of what drug(s) is/are being considered and for what indication to ensure the test performed is medically reasonable and necessary.
    5. The clinical record must clearly show the use of or intent to prescribe a drug that has known drug-gene interactions that require a PGx test to be ordered to define the safe use of that drug in that patient.

**  
Coding Information  
  
** When more than two codes from this list are submitted for the same
beneficiary on the same date of service, the claims processing system will
deny every code submitted after the first two services. However, if a lab runs
more than two distinct procedural services from this list on a single date of
service, then the lab must use the 59 modifier with each additional service
billed as an attestation that it is a distinct procedural service. Billing the
59 modifier may result in a request for medical records.  
  
The molecular pathology codes include all analytical services performed during
the test (e.g., cell lysis, nucleic acid stabilization, extraction, digestion,
amplification, and detection).