What tuberculosis (TB), human immunodeficiency virus (HIV) medications, such as antiretroviral therapy (ART), and seizure medications should not be given with estrogen therapy?

Drug Interactions Between Estrogen and TB/HIV/Seizure Medications

Rifamycins (rifampin and rifabutin) should not be given with estrogen-containing hormonal contraceptives due to significant drug interactions that reduce estrogen efficacy, requiring dose adjustments or alternative contraceptive methods. 1

Tuberculosis Medications That Interact with Estrogen

Rifamycins (Primary Concern)

• Rifampin and rifabutin both cause clinically significant interactions with hormonal contraceptives through CYP450 enzyme induction, requiring either dose adjustments or alternative contraceptive methods 1

• Rifampin is the most potent CYP450 inducer among rifamycins and markedly reduces serum levels of estrogen-containing medications 1

• Rifabutin has substantially less CYP450 induction activity than rifampin but still affects hormonal contraceptive metabolism 1

• The enzyme-inducing effect of rifampin continues for at least 2 weeks after discontinuation, so contraceptive efficacy remains compromised during this washout period 1

• Research demonstrates that rifampin enhances estrone sulfate metabolism and reduces plasma estrone sulfate levels by approximately 25%, while paradoxically increasing estradiol and estrone through secondary mechanisms 2, 3

Non-Rifamycin TB Medications (No Contraindication)

• Isoniazid, pyrazinamide, ethambutol, and streptomycin do not induce CYP450 enzymes and have no contraindication with estrogen therapy 1

HIV Medications That Interact with Estrogen

Protease Inhibitors

• All protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir, amprenavir) are CYP450 inhibitors and can affect estrogen metabolism, though the primary concern is when combined with rifamycins rather than direct estrogen interaction 1

• Ritonavir is the most potent CYP450 inhibitor, followed by amprenavir, indinavir, and nelfinavir with approximately equal potencies, and saquinavir as the least potent 1

• When rifampin is coadministered with any protease inhibitor, this combination is absolutely contraindicated due to markedly decreased antiretroviral serum levels 1

• Rifabutin coadministration with ritonavir or hard-gel saquinavir (Invirase) is also contraindicated 1

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Delavirdine is contraindicated with rifabutin due to CYP450 inhibition effects 1

• Nevirapine (CYP450 inducer) and efavirenz (both inducer and inhibitor) can be used with rifabutin with dose adjustments but are contraindicated with rifampin 1

• Rifampin is contraindicated with all NNRTIs due to marked reduction in antiretroviral drug levels 1

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• NRTIs (zidovudine, didanosine, zalcitabine, stavudine, lamivudine) are NOT metabolized by CYP450 and have no contraindication with estrogen or rifamycins 1

• Rifampin slightly decreases zidovudine concentrations through glucuronidation, but this effect is not clinically important 1

Seizure Medications (Anticonvulsants) That Interact with Estrogen

• Phenytoin and carbamazepine have significant interactions with both rifamycins and estrogen through CYP450 enzyme systems 1

• Isoniazid is a potent inhibitor of CYP2C9, CYP2C19, and CYP2E1, which can increase phenytoin and carbamazepine concentrations to toxic levels 1

• The inductive effect of rifampin outweighs the inhibitory effect of isoniazid, resulting in an overall decrease in phenytoin concentrations when both drugs are given together 1

• Rifamycins require dose adjustments or alternative therapies when used with anticonvulsants due to bidirectional enzyme induction effects 1

Clinical Management Approach

When Rifamycins Are Required

• Consider rifabutin instead of rifampin when patients require hormonal contraception, as rifabutin has less potent CYP450 induction 1

• Recommend barrier contraceptive methods or non-hormonal intrauterine devices during rifamycin therapy and for 2 weeks after discontinuation 1

• If hormonal contraception must continue, consider increasing estrogen doses or switching to depot medroxyprogesterone acetate with appropriate counseling about reduced efficacy 1

Alternative TB Regimens

• Streptomycin-based regimens without rifamycins can be considered for patients requiring protease inhibitors, NNRTIs, or reliable hormonal contraception 1

• These regimens avoid CYP450 interactions entirely but require longer treatment duration 1

Critical Pitfalls to Avoid

• Never assume contraceptive efficacy is maintained during rifamycin therapy without implementing backup methods 1

• Do not start protease inhibitors or NNRTIs until at least 2 weeks after the last rifampin dose to allow enzyme activity normalization 1

• When managing HIV-TB coinfection, rifabutin with dose-adjusted antiretrovirals is preferred over rifampin, which is absolutely contraindicated with protease inhibitors and NNRTIs 1

• Monitor for contraceptive failure and counsel patients about pregnancy risk throughout rifamycin therapy and the 2-week washout period 1