Ethinyl Estradiol; Norethindrone with Licorice Interaction Details
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 12, 2023
Interaction Effect
Increased risk of fluid retention and elevated blood pressure
Interaction Summary
Elevated blood pressure and fluid retention has been associated with concomitant use of licorice and oral contraceptives in case reports, which may be related to estrogen and/or progesterone. The glycyrrhetinic acid component of licorice is metabolized to 3-monoglucuronyl-glycyrrhetinic acid (3MGA), which inhibits 11-beta-hydroxysteroid dehydrogenase and reduces cortisol breakdown, resulting in a hypermineralocorticoid effect .
Severity
Moderate
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Caution is advised if licorice is used with oral contraceptives. If the patient develops fluid retention or hypertension, discontinue licorice.
Mechanism Of Interaction
Increased mineralocorticoid effect
Literature Reports
A) A 21-year-old female developed headache and hypertension (190/120 mmHg), associated with licorice consumption (100 grams daily) along with an oral contraceptive. She was advised to discontinue eating licorice. Blood pressure remained elevated with treatment combining atenolol, lisinopril, hydrochlorothiazide, and amlodipine. Drug treatment was discontinued, and 2 weeks later blood pressure was 180/110 mmHg, potassium 2.6 mmol/L (normal, 3.8 to 5 mmol/L), bicarbonate 35.9 mmol/L (normal, 23 to 29 mmol/L). Plasma aldosterone was 160 picomoles/liter (pmol/L) (normal, 320 to 2000 pmol/L). The patient then admitted to replacing her licorice intake with two packets of Stimerolol Sugar Free(R) chewing gum per day. This chewing gum contains 585 mg licorice in each 15-gram packet, which equals 8% to 12% glycyrrhizinic acid. Her glycyrrhizinic acid intake was calculated to be 120 mg daily. Within 3 weeks of discontinuing the gum, her blood pressure and potassium level normalized .
B) A 35-year-old woman taking an oral contraceptive and chlorothiazide experienced hypokalemia (2.2 mmol/L). Her blood pressure was 140/80 mmHg. Chlorothiazide was stopped and potassium chloride 600 mg three times daily was started. After one week, potassium remained abnormal at 2 mmol/L; after 2 weeks, it decreased further to 1.5 mmol/L. Intravenous potassium supplementation was started. Although she denied licorice use, it was discovered that she used BenBits Cool Mint(R) chewing gum (Leaf, United Kingdom), 3 packets daily. This product contained 160 mg licorice in each 16-gram packet, of which 10% was glycyrrhizinic acid. After 2 days of intravenous potassium and 15 days of oral potassium, and within 3 weeks of discontinuing the chewing gum, edema disappeared, blood pressure decreased to 110/80 mmHg and potassium increased to 4.2 mmol/L. The authors attributed the hypokalemia to the licorice intake .
C) In a study of 4 groups of 6 healthy volunteers administered varying doses of licorice root, the group administered 814 mg of glycyrrhizin experienced a decrease in serum potassium from 4.25 millimoles/liter (mmol/L) to 3.53 mmol/L (p=0.014) after one week. Two of the subjects were taking oral contraceptives concomitantly; all others were taking no other medications. One of the subjects taking an oral contraceptive developed headache, peripheral edema, borderline arterial hypertension (144/91 mmHg), and hypokalemia (2.6 mmol/L) and discontinued treatment. Kaliuresis was noted as well, though not statistically significant. After one week, plasma renin activity significantly decreased in groups taking 380 mg and 814 mg glycyrrhizin (p=0.025 and p=0.045, respectively). Plasma aldosterone decreased significantly in the group taking 814 mg glycyrrhizin (p=0.04). This indicates that volume expansion occurred; however, renal sodium retention was not found to be significant .
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Definitions
Severity Categories
Contraindicated
These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.
Major
This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.
Moderate
This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.
Minor
While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.
Onset
Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.
Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.
Evidence
Level of documentation of the interaction.
Established: The interaction is documented and substantiated in peer-reviewed medical literature.
Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.
How To Manage The Interaction
Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.
It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.
Mechanism Of Interaction
The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.
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