Nomegestrol and Amitriptyline: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Nomegestrol
No brand names on record
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
You're taking amitriptyline (an antidepressant) along with a hormone medicine called nomegestrol. In some people, hormones like this can change how the body handles amitriptyline. This can lead to something a little confusing: your antidepressant may work less well, while at the same time you feel more side effects like drowsiness, dizziness when standing up, or restlessness.
This tends to show up slowly, not right away, and it seems more likely when a hormone is added after you've been stable on your antidepressant. The good news is your care team can manage this by adjusting your doses and keeping an eye on how you feel. Let them know if your mood dips or you notice new side effects.
Effect: Estrogen/progestin therapy may alter tricyclic (amitriptyline) response, producing paradoxical loss of antidepressant efficacy alongside signs of TCA toxicity (sedation, orthostatic hypotension, akathisia).
- Mechanism: Possible estrogen-mediated changes in hepatic microsomal metabolism (enzyme induction or inhibition); effect appears dose-related.
- Direction: Bidirectional/unpredictable; efficacy may fall while toxicity rises. Neither agent is a prodrug requiring activation.
- Onset: Delayed. Evidence: Probable, isolated cases.
- Management: Monitor mood and TCA toxicity, especially when adding hormone to a stabilized patient. Downward dose adjustment of either component may restore balance; withdrawal occasionally required.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have, in isolated instances, been reported to either heighten or diminish the pharmacologic actions of tricyclic antidepressants3, with a paradoxical situation in which antidepressant efficacy is lost while tricyclic toxicity emerges at the same time1. This interaction seems to depend on the estrogen dose2 and is likely to carry clinical significance chiefly among patients who had already been stabilized on tricyclic therapy and are then beginning estrogen treatment6.
Why it happens (mechanism)
Possible estrogen-enhanced hepatic metabolism of the tricyclic antidepressant or estrogen inhibition of hepatic microsomal enzymes
How to manage this interaction
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is manageable with attention from your care team.
- Watch for signs your antidepressant is working less well (returning low mood) or new tricyclic side effects (drowsiness, lightheadedness on standing, restlessness).
- The dose of either the amitriptyline or the hormone may need to be adjusted and individualized by your care team to restore benefit or ease side effects.
- Your team may monitor you more closely, especially right after starting the hormone.
- Report any changes to your pharmacist or prescriber rather than changing doses yourself.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) A study assessed the qualitative outcomes of giving estrogen together with tricyclic antidepressants (TCAs). In one trial, 30 depressed female prisoners were randomized into 4 treatment groups. Ten patients were given placebo, 10 received imipramine (150 milligrams/day) plus placebo, 5 patients received imipramine (150 milligrams/day) plus ethinyl estradiol (50 micrograms/day), and 5 patients received imipramine (150 milligrams/day) plus ethinyl estradiol (25 micrograms/day). The 10 patients on placebo showed no improvement across the 6 weeks of the study. The 10 patients receiving estrogen and imipramine showed a significantly greater symptom improvement than the 10 patients receiving imipramine alone. Nevertheless, after 2 weeks, the 5 patients given imipramine and high-dose estrogen had not improved as much as those given imipramine and low-dose estrogen. The only side effect reported was drowsiness, which affected only the patients taking imipramine. After ethinyl estradiol was stopped, a period of 2 weeks was needed for the high-dose estrogen group to match the performance of the low-dose group. This was attributed to residual estrogen remaining in the high-dose group. In another group, 5 women who received imipramine 150 milligrams and ethinyl estradiol 50 micrograms daily did not improve as much as 10 patients on imipramine alone. In addition, the patients on the combination experienced severe side effects, including lethargy, coarse tremor, and systolic hypotension 1.
b) A case report described an interaction in a 32-year-old woman taking conjugated estrogens 2.5 milligrams and imipramine 100 milligrams. She developed lethargy, tremors, and signs of depersonalization. After 2 years of treatment, the patient raised her estrogen dose to 5 milligrams and then to 7.5 milligrams daily. She became nauseated, experienced constant headaches, and had low normal blood pressure. All laboratory results were normal. When the estrogen was discontinued, the side effects subsided 2. Some investigators have suggested that the side effects arose from increased tricyclic antidepressant effects secondary to estrogen inhibition of hepatic microsomal enzymes 3.
c) A study evaluated women who received clomipramine along with oral contraceptives or clomipramine by itself. At the study's outset, 30 women were taking the combination, but 12 later withdrew. The 18 patients on the combination were matched with 18 patients on clomipramine alone. No significant difference was observed in the patients' responses to clomipramine. It was proposed that there was no significant difference in side effects between the groups; however, the groups were matched after patients had already dropped out of the study. If the patients had been matched before the study began, different conclusions might have been reached 4.
d) A study examined the effects of oral contraceptives on clomipramine in 42 women aged between 18 and 40 years. Twenty-three women took clomipramine 25 milligrams at bedtime, while 19 took clomipramine 25 milligrams at bedtime together with oral contraceptives. Over the 4-week study, 3 patients in the control group (2 because of side effects) and 5 in the experimental group (2 because of side effects) withdrew. Venous blood samples were collected weekly to measure serum clomipramine concentrations. No difference in serum concentrations was found between the groups. However, this finding may be partly attributable to the low dose of clomipramine used 5.
e) Three patients taking conjugated estrogens and tricyclic antidepressants concurrently developed akathisia. A 24-year-old patient taking clomipramine 120 milligrams/day for anorexia nervosa and conjugated estrogens 1.25 milligrams/day for amenorrhea developed restless legs and a persistent urge to keep moving. Estrogen was stopped and benztropine 2 milligrams was given, producing marked reduction and resolution within 48 hours. Akathisia and disorientation developed in a 55-year-old patient on conjugated estrogens 1.25 milligrams/day who was prescribed amitriptyline 50 milligrams/day for depression. Within hours of taking amitriptyline, the patient was confused, restless, and had an inner urge to move continuously. The symptoms disappeared after amitriptyline was discontinued. A positive rechallenge occurred at one week with doxepin 100 milligrams, with resolution after doxepin was stopped. A third case of akathisia was reported in a 35-year-old patient who received conjugated estrogens 1.25 milligrams/day and amitriptyline 50 milligrams/day. Akathisia developed within a few hours after the first dose of amitriptyline and resolved within 48 hours after the antidepressant was discontinued 6.
f) The absolute bioavailability of imipramine rose in women who received low-dose oral contraceptives (50 micrograms or less of ethinyl estradiol) from 27% to 44% (p less than 0.05), as shown by an increase in the AUC 7.
g) Estrogens may inhibit the oxidation of tricyclic antidepressants (TCAs) by acting on hepatic microsomal enzymes 8. Many TCAs are metabolized through oxidation and conjugation pathways. Inhibiting the oxidation of TCAs could lead to accumulation and toxicity resulting from reduced clearance. Estrogens are also suspected of having other central nervous system effects that produce an antidepressant effect 9.
Common questions
Can I take Nomegestrol and Amitriptyline together?
Adding this hormone can throw off your amitriptyline, sometimes weakening its antidepressant effect while increasing side effects like drowsiness or dizziness. Tell your care team about any mood or side-effect changes so they can adjust your dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Nomegestrol and Amitriptyline interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Nomegestrol and Amitriptyline interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is manageable with attention from your care team. Watch for signs your antidepressant is working less well (returning low mood) or new tricyclic side effects (drowsiness, lightheadedness on standing, restlessness). The dose of either the amitriptyline or the hormone may need to be adjusted and ind… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Nomegestrol or Amitriptyline need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (9)
- Prange AJ Jr: Estrogens may well affect response to antidepressants. JAMA 1972; 219:143-144.
- Khurana RC: Estrogen-imipramine interaction (letter). JAMA 1972; 222:702-703. PubMed
- Somani SM & Khurana RC: Mechanism of estrogen-imipramine interaction (letter). JAMA 1973; 223:560. DOI
- Beaumont G: Drug interactions with clomipramine. J Int Med Res 1973; 1:480-484.
- Luscombe DK & John V: Influences of age, cigarette smoking and the oral contraceptive on plasma concentrations of clomipramine. Postgrad Med J 1980; 56(suppl 1):99-102.
- Krishnan KR, France RD, & Ellinwood EH: Tricyclic-induced akathisia in patients taking conjugated estrogens. Am J Psychiatry 1984; 141:696-697. PubMed
- Abernethy DR, Greenblatt DJ, & Shader RI: Imipramine disposition in users of oral contraceptive steroids. Clin Pharmacol Ther 1984; 35:792-797. PubMed
- John VA, Luscombe DK, & Kemp H: Effects of age, cigarette smoking and the oral contraceptive on the pharmacokinetics of clomipramine and its desmethyl metabolite during chronic dosing. J Int Med Res 1980; 8(suppl 3):88-95.
- Oppenheim G: Estrogens in the treatment of depression: neuropharmacological mechanisms. Biol Psychiatry 1983; 18:721-725.
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