Hormonal Therapy, Birth Control & Menstruation
Considerations for People Who Have Hypersomnias
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:
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:
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 (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/
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 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.
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 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.
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.
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.
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.
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.
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.
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.
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 pitolisant, the following approaches may be considered to increase the hormone dose by 50%:
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).
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 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.
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.
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.
Reviewed and approved by Hypersomnia Foundation’s Board of Directors and Medical Advisory Board.