Drug Class:
hormonal contraceptives for systemic use

last updated 08/10/2011

Dutch Pharmacogenetics Working Group Guideline for hormonal contraceptives for systemic use and F5

Summary

In individuals who carry the Factor V Leiden allele and have a family history of thrombotic events, estrogen-containing oral contraceptives should be avoided and alternative forms of contraception used.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for hormonal contraceptives for systemic use based on Factor V Leiden (FVL, or F5) genotype [Article:21412232]. They suggest that in individuals who carry the Factor V Leiden allele and have a family history of thrombotic events, estrogen-containing oral contraceptives should be avoided and alternative forms of contraception used.

Phenotype (Genotype) Therapeutic Dose Recommendation Level of Evidence Clinical Relevance
F5 homozygous rs6025 TT Positive (family) history of thrombotic events: avoid estrogen-containing oral contraceptives and select alternative (e.g., copper intrauterine device, progestin-only contraceptive). Negative (family) history of thrombotic events: avoid additional risk factors (e.g., obesity, smoking). Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10 9/l; leucopenia 1.0-2.0x10 9/l; thrombocytopenia 25-50x10 9/l; severe diarrhea
F5 heterozygous rs6025 CT Positive (family) history of thrombotic events: avoid estrogen-containing oral contraceptives and select alternative (e.g., copper intrauterine device, progestin-only contraceptive). Negative (family) history of thrombotic events: avoid additional risk factors (e.g., obesity, smoking). Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10 9/l; leucopenia 1.0-2.0x10 9/l; thrombocytopenia 25-50x10 9/l; severe diarrhea
  • *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
  • S: statistically significant difference.

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PGx Test Variants Assayed Gene?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No Clinical Annotations available VA
rs1799963 *97G>A, 25313G>A, 46701055G>A, 46761055G>A
G > A
3' UTR
No VIP available No Clinical Annotations available VA
rs1801133 11210333G>A, 11796321G>A, 14783C>T, 419C>T, 665C>T, 677C>T, 788C>T, A222V, Ala140Val, Ala222Val, Ala263Val, C677T, MTHFR: c.677C>T, MTHFR:667C>T, p.A222V
G > A
Not Available
Ala140Val
rs6025 1601G>A, 1601G>G, 169519049T>C, 169519049T>T, 21007691T>C, 21007691T>T, 41721G>A, 41721G>G, Arg534=, Arg534Gln, F5:Factor V Leiden
T > C
Missense
Arg534Gln
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138

Overview

Generic Names
Trade Names
Brand Mixture Names

PharmGKB Accession Id:
PA452637

Other Vocabularies

Drugs And Small Molecules

The following have been classified under this therapeutic category:

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
F2
F5
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
MTHFR
No related drugs are available.

Curated Information ?

Publications related to hormonal contraceptives for systemic use: 18

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetics: From Bench to Byte- An Update of Guidelines. Clinical pharmacology and therapeutics. 2011. Swen J J, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Oral contraceptive use, thrombophilia and their interaction in young women with ischemic stroke. Haematologica. 2006. Martinelli Ida, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation. 2005. Straczek Céline, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombosis and haemostasis. 2005. Wu Olivia, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Prothrombotic conditions, oral contraceptives, and the risk of ischemic stroke. Journal of thrombosis and haemostasis : JTH. 2005. Slooter A J C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Estrogen plus progestin and risk of venous thrombosis. JAMA : the journal of the American Medical Association. 2004. Cushman Mary, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives. Contraception. 2004. Sidney Stephen, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial. Blood. 2004. Kemmeren Jeanet M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arteriosclerosis, thrombosis, and vascular biology. 2003. Oger Emmanuel, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Effect of second- and third-generation oral contraceptives on fibrinolysis in the absence or presence of the factor V Leiden mutation. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 2002. Kemmeren J M, et al. PubMed
Venous thromboembolism in young women; role of thrombophilic mutations and oral contraceptive use. European heart journal. 2002. Legnani C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Effects of second and third generation oral contraceptives and their respective progestagens on the coagulation system in the absence or presence of the factor V Leiden mutation. Thrombosis and haemostasis. 2002. Kemmeren J M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Risk of thrombosis associated with oral contraceptives of women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene. Haematologica. 2001. Santamaría A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism?. The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception. 2000. Spannagl M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arteriosclerosis, thrombosis, and vascular biology. 1999. Martinelli I, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Third generation oral contraceptives and heritable thrombophilia as risk factors of non-fatal venous thromboembolism. Thrombosis and haemostasis. 1998. Andersen B S, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden. British journal of haematology. 1996. Rintelen C, et al. PubMed
Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994. Vandenbroucke J P, et al. PubMed

Clinical Trials

These are trials that mention hormonal contraceptives for systemic use and are related to either pharmacogenetics or pharmacogenomics.

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