Editing Modafinil (section)

== Interactions ==
Some of the drugs that frequently interact with modafinil include [[aripiprazole]] (an antipsychotic), [[amphetamine]] (including its enantiomers and salts; stimulants), [[aspirin]], [[diphenhydramine]] (an [[antihistamine]]), and others.<ref name="Modafinil Interactions Checker">{{cite web | url=https://www.drugs.com/drug-interactions/modafinil.html | title=Modafinil Interactions | work=Drugs.com | date=January 10, 2024 | access-date=February 5, 2024 | archive-date=December 15, 2023 | archive-url=https://web.archive.org/web/20231215212735/https://www.drugs.com/drug-interactions/modafinil.html | url-status=live }}</ref>

Modafinil is a weak to moderate [[enzyme inducer|inducer]] of [[CYP3A4]]<ref name="sleep-women-2016" /><ref name="FDA-2021">{{cite web | url=https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers | title=Drug Development and Drug Interactions &#124; Table of Substrates, Inhibitors and Inducers | publisher=U.S. [[Food and Drug Administration]] (FDA) | date=May 26, 2021 | access-date=April 8, 2022 | archive-date=November 4, 2020 | archive-url=https://web.archive.org/web/20201104173036/https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers | url-status=live }}</ref><ref name="UpToDate-CYP3A4">{{cite web | url = https://www.uptodate.com/contents/image?imageKey=CARD%2F76992 | title = Cytochrome P450 3A (including 3A4) inhibitors and inducers | work = UpToDate | access-date = April 8, 2022 | archive-date = April 8, 2022 | archive-url = https://web.archive.org/web/20220408220537/https://www.uptodate.com/contents/image?imageKey=CARD%2F76992 | url-status = live }}</ref> and a weak inhibitor of [[CYP2C19]],<ref name="pmid12537513"/> enzymes of the [[cytochrome P450]] group of enzymes.<ref name="pmid30285371"/> Modafinil also induces or inhibits other cytochrome P450 enzymes.<ref name="sleep-women-2016" /> One ''[[in vitro]]'' study predicts that modafinil may [[enzyme inducer|induce]] the cytochrome P450 enzymes [[CYP1A2]], CYP3A4, and [[CYP2B6]], as well as may inhibit [[CYP2C9]] and [[CYP2C19]].<ref name="pmid10820139" /> However, other in-vitro studies find no significant inhibition of [[CYP2C9]].<ref name="pmid12537513"/><ref name="pmid11831544">{{cite journal | vauthors = Robertson P, Hellriegel ET, Arora S, Nelson M | title = Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers | journal = Journal of Clinical Pharmacology | volume = 42 | issue = 2 | pages = 205–214 | date = February 2002 | pmid = 11831544 | doi = 10.1177/00912700222011120 | s2cid = 29223738 }}</ref> Modafinil may induce [[P-glycoprotein]], which may affect drugs transported by P-glycoprotein, such as [[digoxin]].<ref name="pmid17963743">{{cite journal | vauthors = Zhu HJ, Wang JS, Donovan JL, Jiang Y, Gibson BB, DeVane CL, Markowitz JS | title = Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein | journal = European Journal of Pharmacology | volume = 578 | issue = 2–3 | pages = 148–158 | date = January 2008 | pmid = 17963743 | pmc = 2659508 | doi = 10.1016/j.ejphar.2007.09.035 }}</ref>
It was clinically found that modafinil affects [[pharmacodynamics]] of drugs which are metabolized by CYP3A4 and other enzymes of the cytochrome P450 family so that interactions of modafinil with these drugs were observed in real people, rather than being predicted in a lab setting.<ref name="sleep-women-2016" /><ref name="FDA-2021"/> For instance, it was observed that induction of CYP3A4 by modafinil affects metabolism of the following [[medication]]s and [[endogenous]] substances:<ref name="Drugs.com-Interactions-2021"/>
* '''[[opioid]]s''', such as [[methadone]], [[hydrocodone]], [[oxycodone]], or [[fentanyl]] – modafinil may result in a drop in opioid plasma concentrations because of faster clearance of opioids by CYP3A4. If the patient is not monitored closely, reduced efficacy or withdrawal symptoms can occur.<ref name="Drugs.com-Interactions-2021">{{cite web |title=Modafinil drug interactions |url=https://www.drugs.com/drug-interactions/modafinil-index.html |website=Drugs.com |access-date=May 3, 2021 |archive-date=May 3, 2021 |archive-url=https://web.archive.org/web/20210503184406/https://www.drugs.com/drug-interactions/modafinil-index.html |url-status=live }}</ref>
* '''[[steroid]] hormones''', such as [[estradiol]], [[progesterone]] or [[cortisol]]. Modafinil may have an adverse effect on [[Hormonal contraception|hormonal contraceptives]] (such as [[Oral contraceptive pill|birth control pills]], [[Patch (dermatology)|patches]], etc.) for up to a month after discontinuation.<ref name="NIH-2005">{{cite web |url=https://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a602016.html | work = Medline Plus | publisher = U.S. National Library of Medicine | title = Modafinil |date=July 1, 2005 |access-date=July 21, 2007 |archive-url=https://web.archive.org/web/20070610045952/http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a602016.html |archive-date=June 10, 2007}}</ref> Both modafinil and armodafinil in the United States and the United Kingdom come with package inserts that highlight the interaction between these medications and hormonal birth control.<ref name="sleep-women-2016" /> Modafinil may induce cytochrome P450 enzymes that are involved in the clearance of steroid hormones taken as hormonal contraceptives, reducing their effectiveness, which may lead to pregnancy despite taking the birth control medication. Besides steroid hormones, modafinil may affect [[pituitary gland]] hormones. In a 2006 study, a single dose of modafinil {{Val|200|u=mg}} caused a decrease in blood [[prolactin]] levels, although it did not affect [[human growth hormone]] or [[thyroid-stimulating hormone]].<ref name="pmid17712350">{{cite journal | vauthors = Minzenberg MJ, Carter CS | title = Modafinil: a review of neurochemical actions and effects on cognition | journal = Neuropsychopharmacology | volume = 33 | issue = 7 | pages = 1477–1502 | date = June 2008 | pmid = 17712350 | doi = 10.1038/sj.npp.1301534 | publisher = Springer Science and Business Media LLC | s2cid = 13752498 | doi-access = free | title-link = doi }}</ref><ref name="pmid16401653">{{cite journal | vauthors = Samuels ER, Hou RH, Langley RW, Szabadi E, Bradshaw CM | title = Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers | journal = Journal of Psychopharmacology | volume = 20 | issue = 6 | pages = 756–770 | date = November 2006 | pmid = 16401653 | doi = 10.1177/0269881106060770 | publisher = SAGE Publications | s2cid = 8033437 }}</ref> Since modafinil induces the activity of the CYP3A4 enzyme involved in [[cortisol]] clearance,<ref name="pmid25678418">{{cite journal | vauthors = Niwa T, Murayama N, Imagawa Y, Yamazaki H | title = Regioselective hydroxylation of steroid hormones by human cytochromes P450 | journal = Drug Metabolism Reviews | volume = 47 | issue = 2 | pages = 89–110 | date = May 2015 | pmid = 25678418 | doi = 10.3109/03602532.2015.1011658 | publisher = Informa UK Limited | s2cid = 5791536 }}</ref> modafinil may reduce the bioavailability of [[hydrocortisone]]. Therefore, it may be necessary to adjust the steroid substitution dose in people receiving modafinil, which is a CYP3A4-metabolism-inducing drug.<ref name="pmid34633961">{{cite journal | vauthors = Aquinos BM, García Arabehety J, Canteros TM, de Miguel V, Scibona P, Fainstein-Day P | title = [Adrenal crisis associated with modafinil use] | language = es | journal = Medicina | volume = 81 | issue = 5 | pages = 846–849 | year = 2021 | pmid = 34633961 }}</ref>

[[Hypertensive crisis|Hypertensive crises]] have been reported when [[armodafinil]] (one of modafinil's [[enantiomer]]s) has been taken with [[monoamine oxidase inhibitor]]s (MAOIs) like [[tranylcypromine]].<ref name="KinslowShapiroGrunebaum2018">{{cite journal | vauthors = Kinslow CJ, Shapiro SD, Grunebaum MF, Miller EC | title = Acute hypertensive crisis and severe headache after concurrent use of armodafinil and tranylcypromine: Case report and review of the literature | journal = J Neurol Sci | volume = 393 | issue = | pages = 1–3 | date = October 2018 | pmid = 30077942 | pmc = 6446082 | doi = 10.1016/j.jns.2018.07.023 | url = }}</ref>