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Oral Contraceptives and GeneMedRx Christopher E. Stephens UW Doctor of Pharmacy Candidate 2007 July 26 th 2006.

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Presentation on theme: "Oral Contraceptives and GeneMedRx Christopher E. Stephens UW Doctor of Pharmacy Candidate 2007 July 26 th 2006."— Presentation transcript:

1 Oral Contraceptives and GeneMedRx Christopher E. Stephens UW Doctor of Pharmacy Candidate 2007 July 26 th 2006

2 Why I chose oral contraceptives Oral contraceptives are a fact of life for a large portion of the population that a pharmacist will encounter. Men, even male medical practitioners, often feel uncomfortable talking to women about contraception, and women often have less confidence that a man can answer their questions on the topic.

3 Why I chose oral contraceptives I want to be able to serve all of my patients, not shy away from a topic because I am unfamiliar with it, or come off as uneducated to my female patients. Nothing in life is to be feared. It is only to be understood. It is only to be understood. Marie Curie

4 Whats in an oral contraceptive? Oral contraceptives contain either a combination of estrogen and progestin or a progestin alone. Estrogen, usually as ethinyl estradiol, prevents the development of follicles by suppressing FSH; increases the effect of progestins; and stabilizes the endometrial lining. Progestins block ovulation by suppressing the LH surge and contributes to contraception by thickening cervical mucus

5 What is GeneMedRx? GeneMedRx is a software tool designed to help physicians predict whether or not drugs are safe and effective for patients. 1 1

6 How does it work? GeneMedRx is designed to predict drug interactions based upon how drugs are metabolized and what enzymes or transporters are usually involved in that metabolism. The program can take into account a persons genetics, the genes that affect each persons ability to make specific enzymes or express transporters, in predicting these drug interactions. If you do not know your genetic information, Genelex, the company that created GeneMedRx, offers genetic testing

7 Contraceptive Drug Interaction A search of PubMed was conducted using the keywords Contraceptive Drug Interaction 692 results were found that were accessible through the University of Washington. 100 of those summaries were reviewed 41 Abstracts were evaluated 31 Full text articles were selected

8 Sixty Five Drug Interactions were Identified and processed through GeneMedRx

9 72% of all information found was already being predicted by the GeneMedRx program!

10 Keeping GeneMedRx Current The most recent article suggesting a drug interaction was only published Mar 2006 Sixty five potential interactions were found on PubMed and this translated into over 30 new notes added to GeneMedRx to ensure that all drug/drug, drug/class and drug/enzyme interactions were updated.

11 Oral contraceptives and GeneMedRx Estrogen metabolized by: Estrogen Inhibits: Estrogen Induces: Progestin metabolized by: some Progestins Inhibit: UGT1A1CYP3A…CYP1A2CYP1A2CYP2C9CYP2C19CYP2B6CYP3A…UGT1A4CYP2C9CYP2C19CYP3A…CYP2C9CYP2C19CYP3A…

12 Beneficial Metabolism Estrogen increases the effect of progestins; as you can see from the previous table, progestins are metabolized by the CYPs 2C9, 2C19, and the 3A series, but estrogen inhibits those same enzymes, this means that progestins are not metabolized as quickly in the presence of estrogen and therefore have more time to act in the body.

13 When interactions go bad Estrogens ability to boost progestins is beneficial, but that same trait turns out to be harmful when the drug that is inhibited has side effects or toxicities. If ethinyl estradiol is given with the drug clozapine, which is metabolized in part by 3A4, the concentrations of clozapine increase in the body and can lead to increased side effects, including drowsiness, tremor or nausea.

14 Drugs that may have increased plasma levels because of oral contraceptives CaffeineCarisoprodolChlorpromazineClozapineNaratriptanOmeprazoleTizanidine Dose reduction may be required for these medications while on contraceptives

15 Drugs that may have decreased plasma levels from oral contraceptives DextromethorphanLamotrigine Valproic acid Warfarin Dose adjustments may be required for these medications while on oral contraceptives

16 Drugs that can decrease the effectiveness of oral contraceptives Antibiotics Carbamazepine FelbamateGriseofulvin Kaletra®Lamotrigine NelfinavirNevirapine OxcarbazepinePhenobarbitol Phenytoin Rifampin RitonavirSt. Johns Wort TegaserodTopiramate Alternate methods of contraception should be suggested while on these medications.

17 Drug Interaction Trends

18 Culprits and Victims The ethinyl estradiol component of oral contraceptives was the primary culprit/victim in most drug interactions; 46 of the 65 drug interactions found involved ethinyl estradiol! The drug class most often the culprit/victim of drug interactions were the anticonvulsant drugs, such as topiramate, lamotrigine and phenobarbital.

19 So what does this mean? A decrease in the efficacy of oral contraceptives was the primary result of many drug interactions, leading to unplanned pregnancies. Increased toxicity or side effects of some medications was another potential drug/drug interaction problem A third problem is sub-therapeutic doses being given because the OC is causing a decrease in the levels of treatment drug; for example, when dosing lamotrigine and OCs.

20 So what can we do? Practitioners should be aware of all medications that their patients are taking and not forget to or feel uncomfortable with inquiring about contraception. Patients should be sure to tell their doctor/pharmacist all of the drugs that they are taking, including contraceptives or herbal products. The one drug you forget to mention will probably be the one that causes problems!

21 How can GeneMedRx help? The list of drugs that exist and can potentially interact is long and keeps growing. New studies are being done and new articles are published frequently that tell of new drugs or new interactions. The GeneMedRx program is useful in actually predicting these interactions before they occur and thereby informing the patient/practitioner before a drug interaction may occur. The program also provides notes about and references to articles that list specific drug interactions.

22 Learn more about GeneMedRx http ://

23 Special thanks to Genelex, Seattle

24 References Wadelius M, Darj E, Frenne G, Rane A. Induction of CYP2D6 in pregnancy.Clin Pharmacol Ther Oct;62(4): PMID: Laine K, Tybring G, Bertilsson L. No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin Pharmacol Ther Aug;68(2): PMID: Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res Nov;47(1-2): PMID: Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16(4): PMID: Koke SC, Brown EB, Miner CM. Safety and efficacy of fluoxetine in patients who receive oral contraceptive therapy. Am J Obstet Gynecol Sep;187(3): PMID: Olubodun JO, Ochs HR, Truten V, Klein A, von Moltke LL, Harmatz JS, Shader RI, Greenblatt DJ. Zolpidem pharmacokinetic properties in young females: influence of smoking and oral contraceptive use. J Clin Pharmacol Oct;42(10): PMID: Kouri EM, Lundahl LH, Borden KN, McNeil JF, Lukas SE. Effects of oral contraceptives on acute cocaine response in female volunteers. Pharmacol Biochem Behav Dec;74(1): PMID: Gabbay V, O'Dowd MA, Mamamtavrishvili M, Asnis GM. Clozapine and oral contraceptives: a possible drug interaction. J Clin Psychopharmacol Dec;22(6): PMID: Moore KH, McNeal S, Britto MR, Bye C, Sale M, Richardson MS. The pharmacokinetics of sumatriptan when administered with norethindrone 1 mg/ethinyl estradiol mg in healthy volunteers. Clin Ther Nov;24(11): PMID: Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology Aug 26;61(4): PMID: Brown D, Goosen TC, Chetty M, Hamman JH. Effect of oral contraceptives on the transport of chlorpromazine across the CACO-2 intestinal epithelial cell line. Eur J Pharm Biopharm Sep;56(2): PMID: Burt VK, Rasgon N. Special considerations in treating bipolar disorder in women.Bipolar Disord Feb;6(1):2-13. PMID: Frohlich M, Burhenne J, Martin-Facklam M, Weiss J, von Wolff M, Strowitzki T, Walter-Sack I, Haefeli WE. Oral contraception does not alter single dose saquinavir pharmacokinetics in women. Br J Clin Pharmacol Mar;57(3): PMID: Simonson SG, Martin PD, Warwick MJ, Mitchell PD, Schneck DW. The effect of rosuvastatin on oestrogen & progestin pharmacokinetics in healthy women taking an oral contraceptive. Br J Clin Pharmacol Mar;57(3): PMID: Lea R, Whorwell PJ. Benefit-risk assessment of tegaserod in irritable bowel syndrome.Drug Saf. 2004;27(4): PMID: Dienel A, Klement S, Muller F. Influence of losigamone on the pharmacokinetics of a combined oral contraceptive in healthy female volunteers. Arzneimittelforschung. 2004;54(3): PMID: Hendrix CW, Jackson KA, Whitmore E, Guidos A, Kretzer R, Liss CM, Shah LP, Khoo KC, McLane J, Trapnell CB. The effect of isotretinoin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone. Clin Pharmacol Ther May;75(5): PMID: Baisini O, Benini F, Petraglia F, Kuhnz W, Scalia S, Marschall HU, Brunetti G, Tauschel HD, Lanzini A. Ursodeoxycholic acid does not affect ethinylestradiol bioavailability in women taking oral contraceptives. Eur J Clin Pharmacol Sep;60(7): PMID: Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clinical Pharmacokinetics. 2004;43(11): PMID: Koch K, Campanella C, Baidoo CA, Manzo JA, Ameen VZ, Kersey KE. Pharmacodynamics and pharmacokinetics of oral contraceptives co-administered with alosetron (Lotronex).Dig Dis Sci Aug;49(7-8): PMID: Legnani C, Cini M, Cosmi B, Poggi M, Boggian O, Palareti G. Risk of deep vein thrombosis: interaction between oral contraceptives and high factor VIII levels. Haematologica Nov;89(11): PMID: Izzo AA. Herb-drug interactions: an overview of the clinical evidence.Fundam Clin Pharmacol Feb;19(1):1-16 PMID: Griffith SG, Dai Y. Effect of zonisamide on the pharmacokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women. Clin Ther Dec;26(12): PMID: Charles JA, Pullicino PM, Stoopack PM, Shroff Y. Ischemic colitis associated with naratriptan and oral contraceptive use. Headache Apr;45(4): PMID: Catanzaro LM, Morse GD. Data from clinical trials. J Acquir Immune Defic Syndr Mar;38 Suppl 1:S26-9. PMID: Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception Jun;71(6): PMID: Winston A, Boffito M. The management of HIV-1 protease inhibitor pharmacokinetic interactions. J Antimicrob Chemother Jul;56(1):1-5. Epub 2005 Jun 7.PMID: Herzog AG, Farina EL, Blum AS. Serum valproate levels with oral contraceptive use. Epilepsia Jun;46(6): PMID: Bramness JG, Skurtveit S, Gulliksen M, Breilid H, Steen VM, Morland J. The CYP2C19 genotype and the use of oral contraceptives influence the pharmacokinetics of carisoprodol in healthy human subjects. Eur J Clin Pharmacol Aug;61(7): Epub 2005 Jul 15. PMID: Williamson L, Yein K. Potential failure of contraceptive efficacy in a patient taking methotrexate. Rheumatology (Oxford) Nov;44(11): Epub 2005 Aug 16. PMID: Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations. Epilepsia Sep;46(9): PMID: Gittes EB, Strickland JL. Contraceptive choices for chronically ill adolescents. Adolesc Med Clin Oct;16(3): PMID: Granfors MT, Backman JT, Laitila J, Neuvonen PJ. Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2. Clin Pharmacol Ther Oct;78(4): PMID: Shelepova T, Nafziger AN, Victory J, Kashuba AD, Rowland E, Zhang Y, Sellers E, Kearns G, Leeder JS, Gaedigk A, Bertino JS Jr. Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+1 cocktail. J Clin Pharmacol Dec;45(12): PMID: Bauer KL, Wolf D, Patel M, Vinson DC. Clinical inquiries. Do antibiotics interfere with the efficacy of oral contraceptives? J Fam Pract Dec;54(12): PMID: Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol Mar;61(3): PMID: Zupanc ML. Antiepileptic drugs and hormonal contraceptives in adolescent women with epilepsy. Neurology Mar 28;66(6 Suppl 3):S PMID: ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol Jun;107(6): PMID:

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