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Warfarin response

MedGen UID:
148193
Concept ID:
C0750384
Disease or Syndrome
Synonyms: Coumadin response; Coumarin resistance; COUMARIN SENSITIVITY; COUMARIN, POOR METABOLISM OF; Cyp2a6, v1; WARFARIN RESISTANCE; Warfarin sensitivity
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
Drug:
Warfarin
MedGen UID:
22695
Concept ID:
C0043031
Pharmacologic Substance
A synthetic anticoagulant. Warfarin inhibits the regeneration of vitamin K1 epoxide and so the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. This inhibition results in a sequential depression of Factors VII, IX, X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of gamma-carboxyglutamic acid residues in these proteins which are essential for biological activity.
 
Genes (locations): CYP2A6 (19q13.2); CYP2C9 (10q23.33); F9 (Xq27.1); VKORC1 (16p11.2)
OMIM®: 122700

Definition

Warfarin is an oral anti-coagulant used world-wide to treat and prevent thrombotic disorders. While it is highly effective, it has a very narrow therapeutic index making it difficult to dose correctly. Genetic variants in both cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, along with non-genetic factors, are known to affect warfarin dose variability. Patients with specific variants in the gene CYP2C9 (the primary warfarin-metabolizing enzyme), such as CYP2C9*2 and CYP2C9*3, may require a lower dose of warfarin as compared to patients without these variants. Patients with a specific variant in VKORC1 (the target enzyme of warfarin), known as -1639G>A or rs9923231, may require a lower warfarin dose as compared to patients who do not have this variant. The combination of CYP2C9 and VKORC1 genetic variants, along with clinical factors, can put some patients at risk for adverse events such as bleeding. Guidelines regarding the use of pharmacogenomic tests in dosing for warfarin have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

Additional descriptions

From Medical Genetics Summaries
Warfarin (brand name Coumadin) is an anticoagulant (blood thinner). Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors and is used in the prevention and treatment of various thrombotic disorders. Warfarin is a drug with narrow therapeutic index; thus, a small change in its plasma levels may result in concentration dependent adverse drug reactions or therapeutic failure. Therefore, the dose of warfarin must be tailored for each patient according to the patient’s response, measured as INR (International Normalized Ratio), and the condition being treated. There is a wide inter-individual variability in the dose of warfarin required to achieve target anticoagulation, and the time it takes to reach target INR. Approximately half of this variability is known to be caused by clinical or lifestyle factors (e.g., a patient’s age, weight, BMI, gender, smoking status, existing conditions, and concomitant medications) and by genetic factors (known genetic factors include variants in the VKORC1, CYP2C9, CYP4F2 genes, and the rs12777823 variant in the CYP2C gene cluster on chromosome 10). The VKORC1 and CYP2C9 genotypes are the most important known genetic determinants of warfarin dosing. Warfarin targets VKORC1, an enzyme involved in vitamin K recycling. A common variant, VKORC1, c.-1639G>A, is associated with an increased sensitivity to warfarin and lower dose requirements. The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*2 and *3, are also associated with lower dose requirements. The FDA-approved drug label for warfarin states that CYP2C9 and VKORC1 genotype information, when available, can assist in the selection of the initial dose of warfarin. The label provides 2 sets of warfarin dosing recommendations, for when the CYP2C9 and VKORC1 genotypes are either known or not known (taking into account clinical factors, the initial dose of warfarin is usually 2–5 mg once daily). In addition, the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) has published recommendations for the initial standard dose of warfarin. A dose reduction is recommended for individuals who are CYP2C9 poor and intermediate metabolizers (with the exception of intermediate metabolizers with the CYP2C9*1/*2 genotype, no dose change is required), and a dose reduction is recommended for individuals who carry 2 copies of the variant VKORC1 A allele (VKORC1, c.-1639G>A/A). Recently, genetic variation in the CYP4F2 gene, and a variant near the CYP2C gene cluster, rs12777823, have been associated with influencing warfarin therapy. The CYP4F2*3 variant is associated with a modest increase in warfarin dose requirements in individuals with European or Asian ancestry, while in individuals with African ancestry, the rs12777823 A/G or A/A genotype is associated with decreased warfarin dose requirements. The 2017 Update of the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing, provides warfarin dosing recommendations for adults with and without African ancestry, and also for pediatric patients. CPIC recommends that these dosing guidelines are applied after a warfarin dose has been calculated using a validated pharmacogenetic algorithm, which includes genotype information for VKORC1, c.-1639G>A and CYP2C9*2 and *3.  https://www.ncbi.nlm.nih.gov/books/NBK84174
From OMIM
Warfarin is a widely prescribed anticoagulant for the prevention of thromboembolic diseases for subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement (Yuan et al., 2005). The dose requirement is highly variable, both interindividually and interethnically. Variation in the VKORC1 gene is believed to be the most important individual predictor of warfarin dose, accounting for about 30% of the variance observed in dosing (Ross et al., 2010).  http://www.omim.org/entry/122700

Clinical features

Abnormality of blood and blood-forming tissues
MedGen UID:
163092
Concept ID:
C0850715
Finding
An abnormality of the hematopoietic system.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding

Professional guidelines

PubMed

Shaw K, Amstutz U, Kim RB, Lesko LJ, Turgeon J, Michaud V, Hwang S, Ito S, Ross C, Carleton BC; CPNDS Clinical Recommendation Group.
Ther Drug Monit 2015 Aug;37(4):428-36. doi: 10.1097/FTD.0000000000000192. PMID: 26186657
Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB; Clinical Pharmacogenetics Implementation Consortium.
Clin Pharmacol Ther 2011 Oct;90(4):625-9. Epub 2011 Sep 7 doi: 10.1038/clpt.2011.185. PMID: 21900891Free PMC Article
Flockhart DA, O'Kane D, Williams MS, Watson MS, Flockhart DA, Gage B, Gandolfi R, King R, Lyon E, Nussbaum R, O'Kane D, Schulman K, Veenstra D, Williams MS, Watson MS; ACMG Working Group on Pharmacogenetic Testing of CYP2C9, VKORC1 Alleles for Warfarin Use.
Genet Med 2008 Feb;10(2):139-50. doi: 10.1097/GIM.0b013e318163c35f. PMID: 18281922

External

National Academy of Clinical Biochemistry, Clinical practice considerations. In: Laboratory medicine practice guidelines: guidelines and recommendations for laboratory analysis and application of pharmacogenetics to clinical practice, 2010

DailyMed Drug Label, COUMADIN, 2010

Suggested Reading

PubMed

Furie B
N Engl J Med 2013 Dec 12;369(24):2345-6. Epub 2013 Nov 19 doi: 10.1056/NEJMe1313682. PMID: 24251364

External

WarfarinDosing.org

Recent clinical studies

Etiology

He S, Zhang H, Cao Y, Nian F, Chen H, Chen W, Auchoybur ML, Yin L, Tao Z, Tang S, Chen X
Biomed Pharmacother 2018 May;101:251-256. Epub 2018 Feb 27 doi: 10.1016/j.biopha.2018.02.095. PMID: 29494962
Iwuchukwu OF, Ramirez AH, Shi Y, Bowton EA, Kawai VK, Schildcrout JS, Roden DM, Denny JC, Stein CM
Pharmacogenet Genomics 2016 Nov;26(11):510-516. doi: 10.1097/FPC.0000000000000244. PMID: 27632229Free PMC Article
Nahar R, Deb R, Saxena R, Puri RD, Verma IC
Pharmacol Rep 2013;65(1):187-94. PMID: 23563037
Shalia KK, Doshi SM, Parikh S, Pawar PP, Divekar SS, Varma SP, Mehta R, Doctor T, Shah VK, Saranath D
J Assoc Physicians India 2012 Dec;60:34-8. PMID: 23781667
Shrif NE, Won HH, Lee ST, Park JH, Kim KK, Kim MJ, Kim S, Lee SY, Ki CS, Osman IM, Rhman EA, Ali IA, Idris MN, Kim JW
Eur J Clin Pharmacol 2011 Nov;67(11):1119-30. Epub 2011 May 18 doi: 10.1007/s00228-011-1060-1. PMID: 21590310

Diagnosis

Bejarano-Achache I, Levy L, Mlynarsky L, Bialer M, Muszkat M, Caraco Y
Clin Ther 2012 Apr;34(4):811-23. Epub 2012 Mar 13 doi: 10.1016/j.clinthera.2012.02.009. PMID: 22417713
Gong IY, Schwarz UI, Crown N, Dresser GK, Lazo-Langner A, Zou G, Roden DM, Stein CM, Rodger M, Wells PS, Kim RB, Tirona RG
PLoS One 2011;6(11):e27808. Epub 2011 Nov 16 doi: 10.1371/journal.pone.0027808. PMID: 22114699Free PMC Article
Yoshizawa M, Hayashi H, Tashiro Y, Sakawa S, Moriwaki H, Akimoto T, Doi O, Kimura M, Kawarasaki Y, Inoue K, Itoh K
Thromb Res 2009 Jun;124(2):161-6. Epub 2009 Jan 9 doi: 10.1016/j.thromres.2008.11.011. PMID: 19135231
González Della Valle A, Khakharia S, Glueck CJ, Taveras N, Wang P, Fontaine RN, Salvati EA
Clin Orthop Relat Res 2009 Jul;467(7):1773-80. Epub 2008 Nov 26 doi: 10.1007/s11999-008-0641-5. PMID: 19034590Free PMC Article
Le AT, Hasson NK, Lum BL
Ann Pharmacother 1997 Sep;31(9):1006-8. PMID: 9296241

Therapy

He S, Zhang H, Cao Y, Nian F, Chen H, Chen W, Auchoybur ML, Yin L, Tao Z, Tang S, Chen X
Biomed Pharmacother 2018 May;101:251-256. Epub 2018 Feb 27 doi: 10.1016/j.biopha.2018.02.095. PMID: 29494962
Bawadikji AA, Teh CH, Kader MABSA, Sulaiman SAS, Ibrahim B
Curr Pharm Biotechnol 2017;18(9):740-747. doi: 10.2174/1389201018666171103141828. PMID: 29110602
Iwuchukwu OF, Ramirez AH, Shi Y, Bowton EA, Kawai VK, Schildcrout JS, Roden DM, Denny JC, Stein CM
Pharmacogenet Genomics 2016 Nov;26(11):510-516. doi: 10.1097/FPC.0000000000000244. PMID: 27632229Free PMC Article
Nahar R, Deb R, Saxena R, Puri RD, Verma IC
Pharmacol Rep 2013;65(1):187-94. PMID: 23563037
Wallace JL, Reaves AB, Tolley EA, Oliphant CS, Hutchison L, Alabdan NA, Sands CW, Self TH
J Thromb Thrombolysis 2013 Jul;36(1):96-101. doi: 10.1007/s11239-012-0811-x. PMID: 23015280

Prognosis

He S, Zhang H, Cao Y, Nian F, Chen H, Chen W, Auchoybur ML, Yin L, Tao Z, Tang S, Chen X
Biomed Pharmacother 2018 May;101:251-256. Epub 2018 Feb 27 doi: 10.1016/j.biopha.2018.02.095. PMID: 29494962
Bawadikji AA, Teh CH, Kader MABSA, Sulaiman SAS, Ibrahim B
Curr Pharm Biotechnol 2017;18(9):740-747. doi: 10.2174/1389201018666171103141828. PMID: 29110602
Nahar R, Deb R, Saxena R, Puri RD, Verma IC
Pharmacol Rep 2013;65(1):187-94. PMID: 23563037
Shrif NE, Won HH, Lee ST, Park JH, Kim KK, Kim MJ, Kim S, Lee SY, Ki CS, Osman IM, Rhman EA, Ali IA, Idris MN, Kim JW
Eur J Clin Pharmacol 2011 Nov;67(11):1119-30. Epub 2011 May 18 doi: 10.1007/s00228-011-1060-1. PMID: 21590310
Pautas E, Moreau C, Gouin-Thibault I, Golmard JL, Mahé I, Legendre C, Taillandier-Hériche E, Durand-Gasselin B, Houllier AM, Verrier P, Beaune P, Loriot MA, Siguret V
Clin Pharmacol Ther 2010 Jan;87(1):57-64. Epub 2009 Sep 30 doi: 10.1038/clpt.2009.178. PMID: 19794411

Clinical prediction guides

He S, Zhang H, Cao Y, Nian F, Chen H, Chen W, Auchoybur ML, Yin L, Tao Z, Tang S, Chen X
Biomed Pharmacother 2018 May;101:251-256. Epub 2018 Feb 27 doi: 10.1016/j.biopha.2018.02.095. PMID: 29494962
Bawadikji AA, Teh CH, Kader MABSA, Sulaiman SAS, Ibrahim B
Curr Pharm Biotechnol 2017;18(9):740-747. doi: 10.2174/1389201018666171103141828. PMID: 29110602
Nahar R, Deb R, Saxena R, Puri RD, Verma IC
Pharmacol Rep 2013;65(1):187-94. PMID: 23563037
Wallace JL, Reaves AB, Tolley EA, Oliphant CS, Hutchison L, Alabdan NA, Sands CW, Self TH
J Thromb Thrombolysis 2013 Jul;36(1):96-101. doi: 10.1007/s11239-012-0811-x. PMID: 23015280
Shalia KK, Doshi SM, Parikh S, Pawar PP, Divekar SS, Varma SP, Mehta R, Doctor T, Shah VK, Saranath D
J Assoc Physicians India 2012 Dec;60:34-8. PMID: 23781667

Recent systematic reviews

Jorgensen AL, FitzGerald RJ, Oyee J, Pirmohamed M, Williamson PR
PLoS One 2012;7(8):e44064. Epub 2012 Aug 29 doi: 10.1371/journal.pone.0044064. PMID: 22952875Free PMC Article

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted 1 information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2017 Statement from the US Food and Drug Administration (FDA)

Initial and Maintenance Dosing

The appropriate initial dosing of warfarin sodium tablets varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  • Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities
  • Genetic factors (CYP2C9 and VKORC1 genotypes)

Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.

Dosing Recommendations without Consideration of Genotype

If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of warfarin sodium tablets is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

Dosing Recommendations with Consideration of Genotype

Table 1 displays three ranges of expected maintenance warfarin sodium tablets doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.Please review the complete therapeutic recommendations that are located here: (1)

2017 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)

VKORC1 CT: warfarin

NO action is required for this gene-drug interaction.

The genetic variation results in a reduction in the required dose and an increase in the risk of excessively severe inhibition of blood clotting during the first month of the treatment. However, the effect is small and CT is also the most common genotype, meaning that the standard treatment will primarily be based on patients with this genotype.

VKORC1 TT: warfarin

The genetic variation results in increased sensitivity to warfarin. This results in an increase in the risk of excessively severe inhibition of blood clotting (INR >4) during the first month of the treatment.

Recommendation:

  1. use 60% of the standard initial dose

The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT: see https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica.

From day 6 on the standard algorithm without genotype information can be used to calculate the dose.

CYP2C9 IM: warfarin

This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.

Recommendation:

  1. use 65% of the standard initial dose

The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the \*2 and \*3 allele. If the activity of the reduced-activity alleles is comparable to the activity of \*2 or \*3, then the algorithm can be completed as if \*1/\*2 or \*1/\*3 is present. See https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica for Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.

Modified dose algorithms have been developed for patients of African or (East) Asian heritage.

CYP2C9 PM: warfarin

This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.

Recommendation:

  1. use 20% of the standard initial dose

The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the \*2 and \*3 allele. If the activity of the reduced-activity alleles is comparable to the activity of \*2 or \*3, then the algorithm can be completed as if \*2 or \*3 is present. See https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica for Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.

Modified dose algorithms have been developed for patients of African or (East) Asian heritage.

CYP2C9*1/*2: warfarin

NO action is required for this gene-drug interaction.

Genetic variation may lead to a decrease in the required maintenance dose. However, there is insufficient evidence that this causes problems when therapy is initiated as usual.

Please review the complete therapeutic recommendations located here: ( 2, 3 )

2017 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)

Non-African ancestry recommendation

In patients who self-identify as non-African ancestry, the recommendation is to:

  1. Calculate warfarin dosing using a published pharmacogenetic algorithm, including genotype information for VKORC1-1639G>A and CYP2C9*2 and *3. In individuals with genotypes associated with CYP2C9 poor metabolism (e.g., CYP2C9 *2/*3, *3/*3) or both increased sensitivity (VKORC1-1639 A/A) and CYP2C9 poor metabolism, an alternative oral anticoagulant might be considered. The bulk of the literature informing these recommendations is in European and Asian ancestry populations, but consistent data exist for other non-African populations. These recommendations are graded as STRONG.
  2. If a loading dose is to be utilized, the EU-PACT loading dose algorithm that incorporates genetic information could be used. This recommendation is OPTIONAL.
  3. While CYP2C9*5, *6, *8, or *11 variant alleles are commonly referred to as African-specific alleles, they can occur among individuals who do not identify as, or know of their, African ancestry. If these variant alleles are detected, decrease calculated dose by 15–30% per variant allele or consider an alternative agent. Larger dose reductions might be needed in patients homozygous for variant alleles (i.e., 20–40%, e.g., CYP2C9*2/*5). This recommendation is graded as OPTIONAL.
  4. If the CYP4F2*3 (i.e., c.1297A, p.433Met) allele is also detected, increase the dose by 5–10%. This recommendation is also considered OPTIONAL.
  5. The data do not suggest an association between rs12777823 genotype and warfarin dose in non-African Americans, thus rs12777823 should not be considered in these individuals (even if available).

African ancestry recommendation

In patients of African ancestry, CYP2C9*5, *6, *8, *11 are important for warfarin dosing. If these genotypes are not available, warfarin should be dosed clinically without consideration for genotype. If CYP2C9*5, *6, *8, and *11 are known, then the recommendation is to:

  1. Calculate warfarin dose using a validated pharmacogenetic algorithm, including genotype information for VKORC1 c.-1639G>A and CYP2C9*2 and *3;
  2. If the individual carries a CYP2C9*5, *6, *8, or *11 variant allele(s), decrease calculated dose by 15–30%. Larger dose reductions might be needed in patients who carry two variant alleles (e.g., CYP2C9*5/*6) (i.e., 20–40% dose reduction).
  3. In addition, rs12777823 is associated with warfarin dosing in African Americans (mainly originating from West Africa). Thus, in African Americans a dose reduction of 10–25% in those with rs12777823 A/G or A/A genotype is recommended. These recommendations are considered MODERATE.

In individuals with genotypes that predict CYP2C9 poor metabolism or who have increased warfarin sensitivity (VKORC1 c.-1639 A/A) and CYP2C9 poor metabolism, an alternative oral anticoagulant should be considered (see Supplemental Material for definitions of strength of recommendations). As noted above, for non-African ancestry, if a loading dose is to be used, the EU-PACT algorithm that incorporates genetic information could be used to calculate loading dose. This recommendation is OPTIONAL. The data do not support an impact on clinical phenotype for CYP4F2 on warfarin dosing in those of African ancestry and so no recommendation is made for use of CYP4F2 genotype data in blacks.

Please review the complete therapeutic recommendations, including recommendations for pediatric patients, located here: (4).

Table 1. The FDA (2017) Drug Label for Warfarin. Three Ranges of Expected Maintenance Warfarin Doses based on CYP2C9 and VKORC1 Genotype.
Ranges are derived from multiple published clinical studies. The VKORC1, c.–1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. Patients with CYP2C9*1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2–4 weeks) to achieve a maximum international normalized ratio (INR) effect for a given dosage regimen than patients without these CYP variants. Please see Therapeutic Recommendations based on Genotype for more information. This table is adapted from the FDA-approved drug label for warfarin (1).
VKORC1CYP2C9
*1/*1*1/*2*1/*3*2/*2*2/*3*3/*3
GG5–7 mg5–7 mg3–4 mg3–4 mg3–4 mg0.5–2 mg
AG5–7mg3–4 mg3–4 mg3–4 mg0.5–2 mg0.5–2 mg
AA3–4 mg3–4 mg0.5–2 mg0.5–2 mg0.5–2 mg0.5–2 mg

1 The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.

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