Hormonal Therapy, Birth Control & Menstruation

Considerations for People Who Have Hypersomnias

Published May 18, 2021
Revised May 10, 2022

Vetted by Our Medical Advisory Board

This content was developed by the Hypersomnia Foundation for use by person(s) who have hypersomnias (PWH), such as idiopathic hypersomnia (IH) or narcolepsy, in conjunction with their doctors. It is based on consultation with gynecology and sleep medicine experts and review of clinical findings in publications and at professional conferences. 

We recommend that PWH and their doctors each familiarize themselves with the content in advance of an appointment to discuss specific concerns and questions. (For the clinician unfamiliar with IH, we also recommend review of our IH Summary and About IH web page.) It is always appropriate for the healthcare provider to be sensitive to their patient and their comfort regarding how they want to talk about their body. A simple way to begin that conversation is in introductions: “Hi, I’m Dr. X. I use ”she” and “her” pronouns. How would you like to be addressed?”

PWH confront many questions and challenges when making decisions about their health. The purpose of this content is to provide them and their doctors with information to help make informed choices about birth control and hormonal therapy. Some medications commonly used in the management of hypersomnias may interact with hormonal medications and require doctor-patient discussion.  

See also our related page, “Parenthood & Pregnancy: Considerations for People Who Have Hypersomnias,” which covers the following topics:

  • Inheritance/Risk to Offspring
  • Medical/Parental Leave & Accommodations
  • Treatment During Conception & Pregnancy
  • Role for Maternal-Fetal Medicine
  • Delivery
  • Human Milk Feeding
  • Infant Care

Continuous Hormonal Therapy to Reduce Fatigue From Iron Deficiency Anemia

If iron-deficiency anemia is causing or worsening fatigue, continuous hormonal therapy may reduce that fatigue by preventing or limiting menstruation and therefore related iron deficiency as a consequence of heavy menstrual flow. Methods include:

  • Combined oral contraceptives
  • Progestin-only “mini-pill” 
  • Progestin-containing IUD or implant
  • Transdermal patch
  • Vaginal ring

For all these methods, treatment is taken continuously, with no days of placebo or skipped treatment. PWH may experience spotting or breakthrough bleeding with any of these continuous methods, so treatment options for breakthrough bleeding may need to be discussed. 

Modafinil/Armodafinil/Pitolisant & Hormonal Therapy (Estrogen/Progesterone/Testosterone)

Modafinil (e.g., Provigil), armodafinil (e.g., Nuvigil) and pitolisant (Wakix) are all commonly used to treat IH and narcolepsy. They are also all P450 inducers, having the potential to reduce the effectiveness of hormonal medications by inducing cytochrome P450 3A4 (CYP3A4) enzymes in the liver. These liver enzymes inactivate numerous hormones, including ethinyl estradiol (estrogen), progestins and testosterone, and this inactivation is increased by P450 inducers, decreasing the bioavailability (or effective dose) of the hormones.*

Estrogen and/or progestins may be taken for menopausal symptoms or gender affirming therapy. The doses are usually lower than those used for birth control pills. P450 inducers, such as modafinil/armodafinil and pitolisant, decrease the effective doses of these hormones, as they do for hormonal birth control (discussed in detail below). One can consider increasing the hormone doses to counteract the effects of the P450 inducer. For modafinil/armodafinil, the hormone doses should be increased up to double. For pitolisant, the hormone doses should be increased up to 50%. Titrating to symptom control may be prudent, so as to use the lowest dose of hormone needed. However, studies have not yet been done to inform these recommendations.

Testosterone supplements may be taken by older men for replacement or by younger people for gender affirming therapy. These supplements are also metabolized by cytochrome P450 34A. Therefore, the testosterone dose could be reduced similarly to estrogen and progesterone when someone is also taking a P450 inducer. According to drugs.com, pharmacologic response to these testosterone supplements “may be altered and should be monitored more closely whenever modafinil or armodafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.” Similarly, according to expert endocrinologists at WPATH, there are no specific data available, so the standard approach is to recheck testosterone levels when there has been a change in a potentially interfering medication.

  • Many medications for other disorders have similar interactions with hormonal medications, including birth control. For some of these other disorders, such as epilepsy, there are recommendations for how to choose and adjust birth control when using P450-inducing medications. Providers interested in more detail on management of these types of interactions may find recommendations such as the following useful: Reimers 2016; Schwenkhagen 2008. 
  • Other medications can also be inactivated at an increased rate when taken with P450 inducers such as modafinil, armodafinil or pitolisant, and doctors may find it prudent to discuss this further with pharmacists. In general, it is very important for doctors and patients to review together the patient’s entire medication list (including over-the-counter medications and herbal treatments) for interactions whenever starting any new medications.
  • Clarithromycin (e.g., Biaxin), which is also used as a long-term treatment for IH, is a CYP3a inhibitor, having the opposite effect—hormones are broken down less quickly. Although on its own, this should not affect the efficacy of hormonal birth control, the addition of clarithromycin or any other P450 inducing or inhibiting medication (or substance, such as grapefruit juice) must be done with great care and attention to the various enzyme effects. (Read more HERE.)
  • Keep in mind that even when one stops taking a P450-inducing medication, the effects, including the reduction of hormonal birth control effectiveness, will persist for up to several weeks. This is because inducers increase CYP450 enzyme activity by a slow process—increasing the rate of enzyme production and/or stabilization of the enzyme (which slows degradation). For CYP3A specifically, studies indicate that deinduction (the undoing of the induction) takes several weeks, with a deinduction half-life of approximately 4 days. After 5 half-lives (or 20 days), the enzyme activity is essentially back to normal. (Read more HERE.) Modafinil and armodafinil’s FDA labels indicate that hormonal contraception may be reduced for one month after discontinuation of modafinil. Pitolisant’s FDA label indicates 21 days. 
  • An unpublished study by the manufacturer of pitolisant has suggested that the interaction with hormonal birth control may be less substantial than initially thought. However, more data are needed to provide more sufficient assurance. (See Abstract 6-035.)

Modafinil/Armodafinil/Pitolisant & Birth Control (Including Emergency Contraception)

Many medications commonly used to treat IH and narcolepsy (such as methylphenidate, oxybates or amphetamines) do not appear to interact with any method of birth control. However, as discussed above, modafinil, armodafinil and pitolisant are P450 inducers, having the potential to reduce the effectiveness of hormonal birth control. This does not mean that it isn’t safe to take modafinil/etc. if one is also on hormonal birth control. It means that the effectiveness rates quoted for the various methods may be reduced when P450 inducers are used. This may impact the choice of birth control method, as effectiveness is one of several factors that inform each person’s decision of which method of birth control to use. It is also important to keep in mind the safety profile of each medication during a potential pregnancy when choosing a birth control method.

Shared decision-making is critical to choosing what type of contraception is best for each individual, after weighing the risks and benefits with the provider. With the exception of abstinence, the risk of pregnancy with any contraceptive is never zero, and each person metabolizes medications differently, which can further affect this risk. If PWH want to reduce their pregnancy risk closer to zero than the efficacy rate of their chosen contraceptive method, then a backup barrier method should be added.

  • Birth Control Methods: The Three Tiers of Efficacy

The general efficacy of birth control methods is often described using the tier system, with 3 tiers of efficacy. See Figure 1: CDC’s Effectiveness of Family Planning Methods.

For example, a 1% typical-use failure rate means that 1 out of every 100 women using the birth control method typically (i.e., not perfectly) over the course of 1 year will become pregnant. A 6% typical use failure rate means that 6 out of every 100 women using the birth control method typically (i.e., not perfectly) over the course of 1 year will become pregnant.

    • The Top Tier: IUDs; Implants; Sterilization

The good news is that the top tier of most effective forms of birth control, with typical use failure rates less than 1%, are not significantly affected by P450 inducers. These include intrauterine devices (IUDs, both hormonal and copper), and sterilization (via vasectomy or tubal ligation). Hormonal implants are also included in this tier, but they may be somewhat affected by P450 inducers, as discussed below. These top-tier birth control methods are also the ones associated with the lowest complications, highest satisfaction, lowest cost over time, and highest rate of continuous use.

Intrauterine Devices (IUDs)
Neither copper nor hormonal IUDs (intrauterine devices) are significantly affected by P450 inducers.

  • Copper IUDs don’t have any hormones to interact.
  • Hormonal IUDs contain progestin, which works through local absorption to thicken cervical mucus and thin the uterine lining, thereby preventing pregnancy. (Although the progestin does also work systemically to decrease ovulation somewhat, this inhibition is not relied upon for the contraceptive effect). Because the main contraceptive effects are local, liver metabolism should not affect the efficacy.

Hormonal Implants
These implants have a 0.05% typical use failure rate. The very small daily dose of progestin (etonogestrel) released by these implants will be reduced somewhat by P450 inducers, leading immediately to the possibility of reduced efficacy (the amount of this reduction is unknown). Until studies are performed that quantify the actual reduction in contraceptive efficacy among these patients, patients can be counseled that efficacy may be decreased by P450 inducers, but according to expert recommendation, this efficacy is still likely to be higher than lower tier methods, such as barrier methods, progestin-only pills, and combined oral contraceptives (COCs). (Read more HERE.) If greater contraceptive efficacy is desired, it is prudent to add a barrier method, such as a diaphragm or condom, to the implant.

There is consistent data that the implant can last up to 5 years when not taking P450 inducers. Therefore, when also taking P450 inducers, it is reasonable to replace the implant at the typically-advised 3 years, although this has not been studied.

    • The Second Tier: Depo; Combined Oral Contraceptives (COCs); Progesterone-Only Mini Pills; Patches/Rings; Diaphragms

If, for whatever reason, doctor and patient together decide that none of the top tier contraceptive methods are the best choice, the second tier contraceptives may be considered. These have a typical use failure rate of 6-12% and include injectable hormones (such as depo-provera), pills, patches, rings, and the diaphragm.

Depo-Provera
For depo-provera, which has a 6% typical use failure rate, the progestin dose is considerably higher than for all other methods in tier 2. Because of its very high progestin dose, when taking P450-inducing anti-seizure medications, depo is “considered to provide effective contraception in most publications, although clinical trials to support this are lacking. Some authors recommend shortening the interval between each injection (e.g. from 12 to 10 weeks)” (Schwenkhagen 2008). It is also helpful to work toward perfect use, which reduces the failure rate, as compared to typical-use (considering missed or late doses). It is recommended to use a smartphone app (medicine-reminder) or other measures to help ensure timely dosing.

Diaphragms
Although these are not affected by P450 inducers, their typical use failure rate of 12% is the highest in this tier. Again, working toward perfect use can help improve the efficacy.

COCs, Mini-Pills and Patches/Rings
The other hormonal methods in the second tier have typical use failure rates of 9% and are all affected negatively by P450 inducers. (Of note, progestin metabolism can be quite variable from person to person.) However, according to expert recommendations, it is still likely more effective to use a method in tier 2, even with a P450 inducer reducing its efficacy, than to use a method from tier 3 alone. And, a tier 2 method with one or more of the methods to increase efficacy (below) will be more effective than a tier 2 method alone.

COCs
Although estrogen used to be the primary method for ovulation suppression (and contraceptive efficacy), in modern COCs the progestins have been changed and their dose increased, and the dose of estrogen has been reduced. Given this, the progestins are now the primary method of ovulation suppression, and estrogen is just there to balance the hormones and potentiate the effect. Modern COCs typically contain about 1.5–2 times the ovulation-inhibiting progestin dose. (Read more HERE).

For COCs, there are several methods that are highly recommended to improve efficacy that is reduced by P450 inducers. And these methods can and should be combined to further improve efficacy.

  1. Add a barrier method, such as a diaphragm or condom.
  2. Use an extended or continuous regimen. 
  3. Work toward perfect use, which has closer to a 1% failure rate, as opposed to typical-use (considering missed doses). It is recommended to use a smartphone app (pill-reminder), digital tablet dispenser, or other measures to minimize the number of missed pills.
  4. Choose a highly-effective pill.
  5. Consider increasing the dose. 

Extended or Continuous Use
There is data that pills containing 20 mcg or less of ethinyl estradiol (“low-dose pills”) when taken cyclically (3 weeks on; 1 week off/placebo) have a higher risk of ovulation during use versus combined oral contraceptives used in extended (e.g., 3 months on; 1 week off) or continuous regimens, suggesting that the risk of contraceptive failure is lower with extended/continuous use. Note that if one chooses extended/continuous contraception, management of possible breakthrough bleeding should also be discussed.

Highly-Effective Pills
For combined oral-contraceptives, there is data that “low-dose pills” when taken cyclically (i.e., not continuously) have a higher risk of ovulation during use versus higher dose pills, suggesting that the risk of contraceptive failure is higher with the lower dose. Therefore, a pill with higher ethinyl estradiol, such as a 35 mcg pill is likely to be more effective.

Increasing the Dose
Although increasing the dose of oral hormonal contraceptives has not been studied as a method to improve the efficacy reduction caused by P450 inducers, it is theoretically effective. Older guidelines based on expert opinion recommended use of 50 mcg of ethinyl estradiol when using P450 inducers. Given that progestin is now the primary method of ovulation suppression in modern COCs, ensuring a higher progestin dose is also important. As discussed above, modern COCs typically already include 1.5-2 times the ovulation-suppression dose of progestin. However, given the variability in individual metabolization, it remains prudent to further increase the progestin as well as the estrogen.

It is known that modafinil/armodafinil increases inactivation of hormonal contraception (both estrogen and progestins) by 30-50%, while pitolisant increases inactivation by 10-32%. Therefore, doubling the hormone doses when taking modafinil/armodafinil should increase the dose enough to improve the contraceptive efficacy closer to the typical-use range. For pitolisant, the hormone dose should be increased by 50%. 

When taking modafinil/armodafinil, the following approaches may be considered to double the hormone dose:

  • Take 2 “low-dose” pills per day, each containing 20 mcg of ethinyl estradiol and a progestin. 
  • Take custom compounded pills (or separate prescriptions) for ethinyl estradiol and a progestin at double their standard dosages (e.g., with 40 mcg of ethinyl estradiol and a doubled progestin dose). 

When taking pitolisant, the following approaches may be considered to increase the hormone dose by 50%:

  • Take custom compounded pills (or separate prescriptions) with a 50% increase in both the standard 20 microgram of ethinyl estradiol and a 50% increase in the progestin. 
  • Take 2 “low-dose” pills per day, each containing 20 mcg of ethinyl estradiol and a progestin. Although this doubles the hormones and may therefore provide more hormone than necessary, it remains a reasonable approach.

For all of the above approaches, the pill-free interval should be reduced to 4 days (instead of 7) or more preferably skipped completely (continuous/extended contraception). 

Custom compounding or separate prescriptions may not be easily available. One must also keep in mind that there is possibly more variability in dosage inherent with custom compounding, which may also affect the contraceptive efficacy. (Note that in the U.S., insurance coverage may also be limited for compounded medications and/or for doubled doses.) 

It is important to note that there is safety data to confirm that cardiovascular complications (including stroke, heart attack, and venous thromboembolism) are increased with ethinyl estradiol doses of 50 mcg or higher, so those should be avoided. Although P450 inducers will reduce the available dose of estrogen, it remains prudent to avoid this higher dosing.

The higher doses of hormones may increase the likelihood of side effects. Patients should make their provider aware of any such concerns. Patients should also discuss with their provider any variability in their usage of modafinil, armodafinil, or pitolisant (such as medication holidays to prevent tolerance), since that variability in usage may further complicate hormone dosing. As long as the ethinyl estradiol dose is not higher than 40 mcg, there shouldn’t be increased safety concerns, even on days that the P450-inducing medications are skipped, but there may be increased side effects. If that is the case, one could consider reducing the hormone dose (e.g., taking a typical dose) during medication holidays. However, given that the effects of the P450 inducers are slow to start and stop (see *Notes above), altering the hormone dose on days the P450 inducers are skipped may not significantly improve any side effects. 

Hormonal Patches and Rings
There are several methods to improve efficacy that is reduced by P450 inducers. And these methods can be combined to further improve efficacy. However, unlike COCs, the dose of the patch/ring cannot be increased to counteract the effects of P450 inducers; therefore, between these two, COCs would likely be the more effective option (assuming an increased oral dose were used).

  1. Add a barrier method, such as a diaphragm or condom.
  2. Use an extended or continuous regimen.
  3. Work toward perfect use, which has closer to a 1% failure rate, as opposed to typical-use (considering late doses). It is recommended to use a smartphone app (medicine-reminder) or other measures to ensure timely ring/patch replacement.

Progesterone-Only Mini-Pill
The progesterone-only mini-pill is much less preferred for use with P450 inducers because there are so many various progestins and they also have more variable metabolism than estrogen. Additionally, one is then relying only on a single mechanism for ovulation suppression, as opposed to the dual hormones in the COCs.

However, if the mini-pill is chosen, all the methods discussed in detail above to improve efficacy of COCs should also be strongly considered here. When choosing a highly-effective pill, there is evidence that the drospirenone-only pill now available is more potent/effective than one like micronor (norethindrone).

To increase the dose for use with modafinil/armodafinil, take 2 progestin-only “mini-pills”. To increase the dose for use with pitolisant, take custom compounded pills with a 50% increase in the progestin dose or take 2 “mini-pills”.

    • The Third Tier

The third tier includes condoms, withdrawal, spermicides, and rhythm (fertility-awareness based methods). Their typical use failure rate is 18-28% (out of 100 women over 1 year, 18-28 will have unintended pregnancies with these methods). Although none of these methods interact with P450 inducing medications such as modafinil and pitolisant, their typical-use efficacy is very likely lower than that of using a hormonal contraceptive along with a P450 inducer.

  • Emergency Contraception

The effectiveness of emergency hormonal contraception is also reduced by P450 inducers such as modafinil. However, the most effective emergency contraception, insertion of a copper IUD within 5 days of unprotected vaginal intercourse, is not affected by P450 inducers.

If hormonal emergency contraception is chosen, there are some methods to improve the effectiveness when used with P450 inducers.

  • Use the most effective method.
  • Consider increasing the dose.
  • Take it as soon as possible (for levonorgestrel*).

Ulipristal acetate (Ella) is twice as effective as levonorgestrel emergency contraception for obese people and  can be taken up to 5 days after unprotected vaginal intercourse with no loss of effectiveness. It is a progesterone receptor modulator; although P450 inducers could theoretically reduce effectiveness, this hasn’t yet been studied. Regardless, one could consider a double-dose to counteract the possible effects of the P450 inducer; however, studies have also not yet been done to inform this recommendation. In the U.S., a prescription is required.

*Levonorgestrel emergency contraception (such as “Plan B”) is available over-the-counter, without a prescription, in the U.S. The sooner you take it, the better it works, but it can be taken up to 5 days after the unprotected intercourse. Doubling the dose should theoretically counteract the effects of P450 inducers, but again, studies have not yet been done to confirm this.

Acknowledgements

  • Based on the 2018 HF Conference Presentation by Isabelle Arnulf, MD, PhD, HF Medical Advisory Board Member
  • OB/GYN review and vetting by Elezabeth Young, MD and Carrie Cwiak, MD, MPH, Director of the Family Planning Division at Emory University School of Medicine
  • Sleep Medicine review and vetting by Lynn Marie Trotti, MD, MSc and Isabelle Arnulf, MD, PhD, Members, HF Medical Advisory Board
  • Contributions by Christopher T. Lang, MD
  • Contributions by Valerie Vanderlip, IBCLC

Reviewed and approved by Hypersomnia Foundation’s Board of Directors and Medical Advisory Board.

  1. Brodie, Martin J, et al. “Enzyme Induction with Antiepileptic Drugs: Cause for Concern?” Epilepsia, vol. 54, no. 1, 2012, pp. 11–27, doi:10.1111/j.1528-1167.2012.03671.x. Free Full Text.
  2. “CDC Contraceptive Guidance.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 13 Aug. 2020, www.cdc.gov/reproductivehealth/contraception/contraception_guidance.htm.
  3. “DailyMed – MODAFINIL Tablet.” U.S. National Library of Medicine, National Institutes of Health, dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c634b7a-cce6-4c3d-9c49-63593755f49c. Accessed June 5, 2020.
  4. “DailyMed – WAKIX- Pitolisant Hydrochloride Tablet, Film Coated.” U.S. National Library of Medicine, National Institutes of Health, dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8daa5562-824e-476c-9652-26ceef3d4b0e. Accessed June 5, 2020.
  5. Hatcher, Robert A. Contraceptive Technology. Ayer Company Publishers, Inc, 2018.
  6. Hypersomniafoundation. “Dr. Isabelle Arnulf: Women and IH.” YouTube, 14 Apr. 2019, www.youtube.com/watch?v=L7TG5Z5rf3s.
  7. Lange, Jill, et al. “Decreased Efficacy of an Etonogestrel Implant in a Woman on Antiepileptic Medications: a Case Report.” Journal of Medical Case Reports, vol. 8, no. 1, 2014, doi:10.1186/1752-1947-8-43. Free Full Text.
  8. Lynch, et al. “The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects.” American Family Physician. 2007 Aug 1;76(3):391-396. Free Full Text.
  9. Mignot, Emmanuel J. M. “A Practical Guide to the Therapy of Narcolepsy and Hypersomnia Syndromes.” Neurotherapeutics, vol. 9, no. 4, 2012, pp. 739–752, doi:10.1007/s13311-012-0150-9. Free Full Text.
  10. “Provigil and Testosterone Interactions.” Drugs.com, www.drugs.com/drug-interactions/provigil-with-testosterone-1647-1020-2167-0.html?professional=1. Accessed Feb. 12, 2022.
  11. Reimers, Arne. “Contraception for women with epilepsy: counseling, choices, and concerns.” Open Access Journal of Contraception, vol. 7, 2016, pp. 69-76, doi: 10.2147/OAJC.S85541. Free Full Text.
  12. Robert, P. “Hormonal Contraceptive and Pitolisant CYP3A4 Induction.” 71st Annual Meeting of the American Academy of Neurology (AAN), May 4-10, 2019; Philadelphia, PA. Poster 4354. Free Abstract.
  13. Robertson, P. “Effect of Modafinil on the Pharmacokinetics of Ethinyl Estradiol and Triazolam in Healthy Volunteers.” Clinical Pharmacology & Therapeutics, vol. 71, no. 1, 2002, pp. 46–56, doi:10.1067/mcp.2002.121217. Abstract & Request Full Text.
  14. Schwenkhagen, Anneliese M., and Stefan R.g. Stodieck. “Which Contraception for Women with Epilepsy?” Seizure, vol. 17, no. 2, 2008, pp. 145–150, doi:10.1016/j.seizure.2007.11.013. Free Full Text.
  15. Zhang, Nan, et al. “Role of CYP3A in Oral Contraceptives Clearance.” Clinical and Translational Science, vol. 11, no. 3, 2017, pp. 251–260, doi:10.1111/cts.12499. Free Full Text.
  16. “Wakix: Highlights of Prescribing Information” U.S. FDA, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211150s000lbl.pdf. Accessed June 5, 2020.
Disclaimer

The contents of this website, including text, graphics and other material, are for informational purposes only. This website is not intended to be a substitute for professional legal or medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Always consult your own attorney or other legal advisor with any legal questions you may have. The Hypersomnia Foundation does not recommend or endorse any specific tests, physicians, lawyers, legal advisors, products, procedures, opinions or other information referenced on this website. Reliance on any information on this website is solely at your own risk.

The Hypersomnia Foundation makes no representations or warranties about the satisfaction of any government regulations requiring disclosure of information on prescription drug products. In no event shall The Hypersomnia Foundation be liable for any damages (including without limitation incidental and consequential damages) or costs (including without limitation attorney’s fees) based on any claim arising from the use of this website and/or its content.