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Oral contraceptives: 50 years ago introduction of Enovid (mestranol and norethynodrel) Jessica Oesterheld, MD. Vignette.

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  1. Oral contraceptives: 50 years ago introduction of Enovid (mestranol and norethynodrel)Jessica Oesterheld, MD

  2. Vignette • A 25 year old woman with several prior depressive episodes has a first hypomanic episode. You wish to treat her with a mood stabilizer. She does not wish to become pregnant and takes oral contraceptives (OC). What mood stabilizers would you consider? What should you avoid?

  3. ORAL CONTRACEPTIVES • In use by more than 1/4th of women • Introduced 50 years ago as “Enovid” • Contain an estrogen (17-alpha ethinyl estradiol, EE) and progestin (PG) • EE supresses ovulation, PG supresses LH and limits endometrial hyperplasia, reduce endometrial carcinoma

  4. ORAL CONTRACEPTIVES • Usually 35-50 ug of ethinyl estradiol (EE) • Low dose OC contain 20ug EE to reduce EE side effects, headaches and thrmoboembolic events (Alesse, Mircette etc) • Only a few contain mestranol, a pro-drug of EE (Nelova 1/50, Ortho-Novum 1/50)

  5. Many formulations of contraceptives Oral: • Monophasic- same amount of EE and progestin-taken for 21 days • Biphasic and triphasic: progestin is reduced and the effects similar to hormonal influences during natural menstrual cycles • Continuous daily regimens of ethinyl estradiol (10 and 30 ug) and a progestin-allow withdrawal-bleeding periods only 4 times a year (Seasonale, Seasonique). A yearly no cycling version of levonorgestrel and EE (Lybrel)

  6. Many formulations of contraceptives Transdermal- OrthoEvra (norelgestromin and ethinyl estradiol) Transvaginal- Nuva-Ring (3-ketodesogestrel or etonogestrel and ethinyl estradiol)

  7. Progestin-only Contraceptives • the minipill containing norethindrone, norgestrel or levonorgestrel (POPs) • a subdermal implant (Implanon) • intramuscular and subcutaneous preparations of medroxyprogesterone acetate administered every 3 months • intrauterine devices that release progesterone and levonorgestrel.

  8. Non-CYP Drug Interactions from other metabolic pathways • Conjugated EEs • chewed up by gut bactria (Clostria)---> free EEs and if Rx ampicillin, neomycin-->more EE conjugates in feces, less EE in plasma • Unclear interaction - better to be safe than sorry • Drugs that compete for sulfation • in gut wall and raise EE levels (e.g., acetaminophen, vitamin C)

  9. Metabolism of EE/Progestins • Extremely complicated- 50% reach systemic circulation • Major pathway: CYP3A4 • Minor pathway: CYP2C9 • Conjugated by UGT1A1, possibly UGT1A8 and UGT1A9 • Mestranol is a pro-drug metabolized by CYP2C9 • Progestins metabolized by CYP3A4 including desogestrel which is a pro-drug (Korhonen et al 2005)

  10. Inactivation of EE Phase 1Phase 2 EE 2-OH EE conjugation CYP3A4UGT1A1 Sulfation

  11. CYP-based drug interactions1 How other drugs affect OCs2 How OCs affect other drugs

  12. How other drugs affect OCs: • Drugs that induceCYP3A4/ UGT1A1: • may lead to increased clearance of EE and/or progestins and loss of clinical efficacy. • drug interactions resulting in spotting, breakthrough bleeding, or unwanted pregnancy

  13. How other drugs affect OCs: CYP 3A4 Inducers • Aprepitant-long term Bosentan • Carbamazepine Felbamate • Griseofulvin • Nelfinavir Nevirapine • Oxcarbazepine Phenobarbital • Phenytoin Primidone • Rifabutin/Rifampin Ritonavir/ “boosteds” • St Johns wort Topiramate (200mg/d) Modafinil (200mg/d)

  14. What to do for contraception if must take a 3A4 inducer? • Barrier contraception • Increase OC to 50-100 mg-some support • Switch to depo medroxyproesterone acetate as a contraceptive, since it does not seem to be affected by inducing anticonvulsants • Remember that induction continues 2-4 weeks after inducing drug is discontinued • Phenytoin different----- show you in a minute

  15. How other drugs affect OCs: CYP 3A4 Inhibitors (increase OC availability/activity) Amprenavir Atazanavir Atorvastatin Dapsone ? 1984 study Delavirdine Efavirenz-1 neg study Erythromycin et al Fluconazole ?Fluoxetine ?Fluvoxamine ?Gestodene GF Juice Indinavir Itraconazole Ketoconazole Nefazodone Voriconazole

  16. Special issue of very low dose OCs • Mircette, Asesse, Levlite, Loestrin • have 20 mcg of EE • If inhibited by CYP3A4 inhibitors----EE concentrations increases and shift them to “high dose EE” ( lead to adverse events e.g., breast tenderness, bloating, weight gain) • Case report with nefazodone

  17. Remember desogestrel OCs • Apri, Cesia, Cyclessa, Desogen, Kariva, Mircette, Ortho-Cept, Solia, Velivet • Desogestrel is a pro-drug metabolized via CYP3A4 to become active (has other pathways)

  18. Remember mestranol • Pro-drug that is metabolized via CYP2C9 to EE • Vulnerable to CYP2C9 inhibitors to not be converted to active metabolite • Sulfaphenazole (check the CYP2C9 potent inhibitor list)

  19. How OCs affect other drugs: CYP and UGT-based DDIs

  20. OCs Effect Other Drugs - Inhibition OCs are moderate inhibitors of 1A2, 2C19 and mild inhibitors of 2B6 and 3A4: Amitriptyline Bupropion Caffeine Carisoprodol ?Chlordiazepoxide Chlorpromazine Clozapine Cyclosporine Diazepam Imipramine ?Olanzapine Omeprazole Phenytoin Prednisolone Proguanil (pro-drug) Selegiline ?Tacrine Tizanidine Theophylline Voriconazole

  21. OCs Effect Other Drugs - Inhibition • CYP 1A2 • theophylline (30% decrease in clearance), olanzapine, CLZ, tacrine • CYP 2C19 • special case of phenytoin, ? proton pump inhibitors • CYP 3A4 • How potent is it: documented cyclosporine, prednisolone, <not midazolam> • 2C19 and 3A4 • imipramine, amitriptyline, diazepam, chlordiazepoxide (via nordiazepam intermediate)

  22. Phenytoin and OCs • Remember I said phenytoin will induceCYP3A4, but OCs increase levels of phenytoin through CYP2C19 inhibition- thus the strategy of increasing OC dosage to overcome phenytoin induction will lead to phenytoin toxicity

  23. OCs Effect Other Drugs – Induction of CYP2A6 and some UGTs • EE induces CYP2A6- nicotine- woman have higher rates of lung CA • Induce UGTs: acetaminophen, clofibrate, diflunisal, lamotrigine and valproate • During OC wash out week levels increase 84% for lamotrigine (Contin et al. 2006; Christensen et al. 2007) • Consider continuous regimens of OCs, dose reduction of 25% during pill-free weeks or progestin only OCs

  24. Clearance changes in each trimester-pregnancy (Increase in Clearance-> reduced blood levels) (Tracy et al 2005, Anderson 2005, Hebert et al 2008)

  25. Clearance changes in each trimester-pregnancy (Increase in Clearance-> reduced blood levels)

  26. Drug levels decrease in late pregnancy • Lamotrigine levels decrease 50% (Brodtkorb & Reimers 2007) : do monthly levels (Harden& Sethi 2008) • Levetiracetam levels decrease 50% (Westin et al 2008) • Oxcarbazepine decrease 30-40% (Brodtkorb & Reimers 2007) • Labetalol decreased (UGT1A1, Jeong et al 2008) • Others that also may be decreased phenytoin, phenobarbital (Pennell & Hovinga 2008) • Carbamazepine may be least affected (Harden& Sethi 2008 )

  27. Medroxyprogesterone and HIV drugs • IM medroxyprogesterone but not oral progestins increased clearance of prednisolone 25% (Tsunoda et al 1998) • On nelfinavir, nevirapine, efavirenz HIV regimens no ovulation, no change CD4+ , minor pk changes in increasing clearance of nelfinavir and decreased Cx nevirapine not clinically significant- none for efavirenz and no changes in medroxyprogesterone (Cohn et al 2007) • Effects of HIV antiretrovirals on the pharmacokinetics of hormonal contraceptives.

  28. Medroxyprogesterone and HIV drugs • Women on zidovudine/lamivudine/efavirenz showed no pk changes in medroxyprogesterone (Nanda et al 2008)

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