Oral Contraceptives and Oral Contraceptives and GeneMedRxGeneMedRx

Christopher E. StephensChristopher E. StephensUW Doctor of Pharmacy UW Doctor of Pharmacy

Candidate 2007Candidate 2007

July 26July 26thth 2006 2006

Why I chose oral Why I chose oral contraceptivescontraceptives

Oral contraceptives are a fact of life for a Oral contraceptives are a fact of life for a large portion of the population that a large portion of the population that a pharmacist will encounter. pharmacist will encounter.

Men, even male medical practitioners, Men, even male medical practitioners, often feel uncomfortable talking to often feel uncomfortable talking to women about contraception, and women about contraception, and women often have less confidence that women often have less confidence that a man can answer their questions on a man can answer their questions on the topic. the topic.

Why I chose oral Why I chose oral contraceptivescontraceptives

I want to be able to serve all of my patients,I want to be able to serve all of my patients,not shy away from a topic because I amnot shy away from a topic because I amunfamiliar with it, or come off as unfamiliar with it, or come off as

uneducateduneducatedto my female patients.to my female patients.

Nothing in life is to be feared.Nothing in life is to be feared. It is only to be understood. It is only to be understood.

Marie CurieMarie Curie

What’s in an oral What’s in an oral contraceptive?contraceptive?

Oral contraceptives contain either a Oral contraceptives contain either a combination of estrogen and progestin combination of estrogen and progestin or a progestin alone. or a progestin alone.

Estrogen, usually as ethinyl estradiol, Estrogen, usually as ethinyl estradiol, prevents the development of follicles prevents the development of follicles by suppressing FSH; increases the by suppressing FSH; increases the effect of progestins; and stabilizes the effect of progestins; and stabilizes the endometrial lining. endometrial lining.

Progestins block ovulation by Progestins block ovulation by suppressing the LH surge and suppressing the LH surge and contributes to contraception by contributes to contraception by thickening cervical mucusthickening cervical mucus

What is GeneMedRx?What is GeneMedRx?

GeneMedRx is a software tool designed GeneMedRx is a software tool designed toto

help physicians predict whether or not help physicians predict whether or not

drugs are safe and effective for drugs are safe and effective for patients.patients.11

11http://www.genemedrx.com/public/home.htmlhttp://www.genemedrx.com/public/home.html

How does it work? How does it work?

GeneMedRx is designed to predict drug GeneMedRx is designed to predict drug interactions based upon how drugs are interactions based upon how drugs are metabolized and what enzymes or metabolized and what enzymes or transporters are usually involved in that transporters are usually involved in that metabolism. metabolism.

The program can take into account a person’s The program can take into account a person’s genetics, the genes that affect each genetics, the genes that affect each person’s ability to make specific enzymes or person’s ability to make specific enzymes or express transporters, in predicting these express transporters, in predicting these drug interactions. drug interactions.

If you do not know your genetic information, If you do not know your genetic information, Genelex, the company that created Genelex, the company that created GeneMedRx, offers genetic testingGeneMedRx, offers genetic testing

Contraceptive Drug Contraceptive Drug InteractionInteraction

A search of PubMed was conducted using A search of PubMed was conducted using the keywords “Contraceptive Drug the keywords “Contraceptive Drug Interaction”Interaction”

692 results were found that were accessible 692 results were found that were accessible through the University of Washington. through the University of Washington.

100 of those summaries were reviewed100 of those summaries were reviewed

41 Abstracts were evaluated41 Abstracts were evaluated

31 Full text articles were selected31 Full text articles were selected

Sixty Five Drug Interactions Sixty Five Drug Interactions were Identified and processed were Identified and processed

through GeneMedRxthrough GeneMedRx

35

12

18

Predicted by GeneMed Rx

Not Predicted

Needed changes

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

54%

18%

28%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Total

Not already entered

Entered but changed

Already entered

Keeping GeneMedRx Keeping GeneMedRx CurrentCurrent

The most recent article suggesting a drug The most recent article suggesting a drug interaction was only published Mar 2006interaction was only published Mar 2006

Sixty five potential interactions were found Sixty five potential interactions were found on PubMed and this translated into over on PubMed and this translated into over 30 new notes added to GeneMedRx to 30 new notes added to GeneMedRx to ensure that all drug/drug, drug/class and ensure that all drug/drug, drug/class and drug/enzyme interactions were updated. drug/enzyme interactions were updated.

Oral contraceptives and Oral contraceptives and GeneMedRxGeneMedRx

Estrogen Estrogen metabolizmetabolizeded by:by:

EstrogeEstrogen n InhibitsInhibits::

EstrogeEstrogen n InducesInduces::

ProgestiProgestin n metabolizmetabolized by:ed by:

somesome

ProgestiProgestins ns Inhibit:Inhibit:

UGT1A1UGT1A1

CYP3A…CYP3A…

CYP1A2CYP1A2

CYP1A2CYP1A2

CYP2C9CYP2C9

CYP2C1CYP2C199

CYP2B6CYP2B6

CYP3ACYP3A……

UGT1AUGT1A44

CYP2C9CYP2C9

CYP2C19CYP2C19

CYP3A…CYP3A…

CYP2C9CYP2C9

CYP2C19CYP2C19

CYP3A…CYP3A…

Beneficial MetabolismBeneficial Metabolism

Estrogen increases the effect of progestins; as Estrogen increases the effect of progestins; as you can see from the previous table, you can see from the previous table, progestins are metabolized by the CYP’s 2C9,progestins are metabolized by the CYP’s 2C9,

2C19, and the 3A series, but estrogen 2C19, and the 3A series, but estrogen inhibits those same enzymes, this means inhibits those same enzymes, this means that progestins are not metabolized as that progestins are not metabolized as quickly in the presence of estrogen and quickly in the presence of estrogen and therefore have more time to act in the body. therefore have more time to act in the body.

When interactions go badWhen interactions go bad

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

Drugs that may have increased Drugs that may have increased plasma levels because of oral plasma levels because of oral

contraceptivescontraceptives

CaffeineCaffeineCarisoprodolCarisoprodol

ChlorpromazineChlorpromazineClozapineClozapine

NaratriptanNaratriptanOmeprazoleOmeprazoleTizanidineTizanidine

Dose reduction may be required for these medications while on Dose reduction may be required for these medications while on contraceptivescontraceptives

Drugs that may have Drugs that may have decreased plasma levels from decreased plasma levels from

oral contraceptivesoral contraceptives

DextromethorphanDextromethorphanLamotrigineLamotrigineValproic acidValproic acid

Warfarin Warfarin

Dose adjustments may be required for these medications while on oral contraceptivesDose adjustments may be required for these medications while on oral contraceptives

Drugs that can decrease the Drugs that can decrease the effectiveness of oral effectiveness of oral

contraceptivescontraceptivesAntibiotics Antibiotics CarbamazepineCarbamazepine

FelbamateFelbamate GriseofulvinGriseofulvin

Kaletra®Kaletra® LamotrigineLamotrigine

NelfinavirNelfinavir NevirapineNevirapine

OxcarbazepineOxcarbazepinePhenobarbitolPhenobarbitol

Phenytoin Phenytoin RifampinRifampin

RitonavirRitonavir St. John’s WortSt. John’s Wort

TegaserodTegaserod TopiramateTopiramateAlternate methods of contraception should be suggested while on these Alternate methods of contraception should be suggested while on these

medications. medications.

Drug Interaction TrendsDrug Interaction Trends

0

5

10

15

20

25No Change in either drug

Increase in OC levels

Increase in non-OC drug

Decrease in OC

Decrease in non-OC

Other

Culprits and VictimsCulprits and Victims

The ethinyl estradiol component of oral The ethinyl estradiol component of oral contraceptives was the primary culprit/victim contraceptives was the primary culprit/victim in most drug interactions; 46 of the 65 drug in most drug interactions; 46 of the 65 drug interactions found involved ethinyl estradiol!interactions found involved ethinyl estradiol!

The drug class most often the culprit/victim of The drug class most often the culprit/victim of drug interactions were the anticonvulsant drug interactions were the anticonvulsant drugs, such as topiramate, lamotrigine and drugs, such as topiramate, lamotrigine and phenobarbital.phenobarbital.

So what does this mean?So what does this mean?

A decrease in the efficacy of oral A decrease in the efficacy of oral contraceptives was the primary result of contraceptives was the primary result of many drug interactions, leading to unplanned many drug interactions, leading to unplanned pregnancies.pregnancies.

Increased toxicity or side effects of some Increased toxicity or side effects of some medications was another potential drug/drug medications was another potential drug/drug interaction probleminteraction problem

A third problem is sub-therapeutic doses being A third problem is sub-therapeutic doses being given because the OC is causing a decrease given because the OC is causing a decrease in the levels of treatment drug; for example, in the levels of treatment drug; for example, when dosing lamotrigine and OC’s.when dosing lamotrigine and OC’s.

So what can we do? So what can we do?

Practitioners should be aware of all Practitioners should be aware of all medications that their patients are medications that their patients are taking and not forget to or feel taking and not forget to or feel uncomfortable with inquiring about uncomfortable with inquiring about contraception.contraception.

Patients should be sure to tell their Patients should be sure to tell their doctor/pharmacist all of the drugs that doctor/pharmacist all of the drugs that they are taking, including they are taking, including contraceptives or herbal products. The contraceptives or herbal products. The one drug you forget to mention will one drug you forget to mention will probably be the one that causes probably be the one that causes problems! problems!

How can GeneMedRx help?How can GeneMedRx help?

The list of drugs that exist and can potentially The list of drugs that exist and can potentially interact is long and keeps growing. New interact is long and keeps growing. New studies are being done and new articles are studies are being done and new articles are published frequently that tell of new drugs or published frequently that tell of new drugs or new interactions. new interactions.

The GeneMedRx program is useful in actually The GeneMedRx program is useful in actually predicting these interactions before they occur predicting these interactions before they occur and thereby informing the patient/practitioner and thereby informing the patient/practitioner before a drug interaction may occur.before a drug interaction may occur.

The program also provides notes about and The program also provides notes about and references to articles that list specific drug references to articles that list specific drug interactions.interactions.

Learn more about Learn more about GeneMedRxGeneMedRx

httphttp://://

www.genemedrx.com/demo.htmlwww.genemedrx.com/demo.html

Special thanks to Genelex, Special thanks to Genelex, SeattleSeattle

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2006 Jun;107(6):1453-72.PMID: 167381832006 Jun;107(6):1453-72.PMID: 16738183