Why Drug Interactions Matter With Progesterone

Progesterone is metabolized by an enzyme in your liver called CYP3A4. This is important because many other medications either speed up or slow down this same enzyme. When that happens, the amount of Progesterone in your body can change — making it either less effective or causing stronger side effects.

If you're taking Progesterone for hormone therapy, fertility support, or another condition, knowing these interactions can help you stay safe and get the most from your treatment.

Major Drug Interactions (High Risk)

These interactions can significantly affect how Progesterone works in your body. Your doctor needs to know about all of these:

Strong CYP3A4 Inhibitors — Can Increase Progesterone Levels

These medications slow down the enzyme that breaks down Progesterone. The result is higher Progesterone levels in your blood, which can increase side effects like drowsiness, dizziness, and nausea.

• Ketoconazole — an antifungal medication
• Itraconazole — another antifungal
• Clarithromycin — an antibiotic used for respiratory and skin infections

If you need one of these medications while taking Progesterone, your doctor may adjust your Progesterone dose or monitor you more closely for side effects.

Strong CYP3A4 Inducers — Can Decrease Progesterone Levels

These medications speed up the enzyme that breaks down Progesterone. The result is lower Progesterone levels, which can make your treatment less effective — a serious concern if you're relying on Progesterone for fertility support or endometrial protection.

• Rifampin — an antibiotic used for tuberculosis and certain other infections
• Carbamazepine — an anti-seizure medication (brand name Tegretol)
• Phenytoin — another anti-seizure medication (brand name Dilantin)
• St. John's Wort — an herbal supplement commonly used for depression

Important: St. John's Wort is available without a prescription and many people don't think of it as a "drug." But it's a potent CYP3A4 inducer that can significantly reduce Progesterone levels. Always tell your doctor if you're taking it.

Anticoagulants (Blood Thinners)

• Warfarin (Coumadin) — Progesterone may alter how your blood clots, which can change your INR levels. If you're on Warfarin and start Progesterone, your doctor will likely need to check your INR more frequently and may adjust your Warfarin dose.

Moderate Drug Interactions

These interactions are less likely to cause serious problems but are still worth monitoring:

Moderate CYP3A4 Inhibitors

These can moderately increase Progesterone levels:

• Erythromycin — a common antibiotic
• Fluconazole — an antifungal often prescribed for yeast infections
• Verapamil — a calcium channel blocker used for blood pressure and heart conditions

Other Hormonal Medications

• Estrogens: Progesterone is often intentionally combined with estrogen in menopausal hormone therapy. This isn't a harmful interaction — it's the intended use. But both hormones together carry the cardiovascular and breast cancer risks described in the boxed warning.
• Oral contraceptives: Taking Progesterone with hormonal birth control may alter the effectiveness of either medication. Talk to your doctor about whether this combination is appropriate.

Diabetes Medications

Progesterone may affect glucose tolerance, which means it can change how well your diabetes medications work. If you have diabetes and start taking Progesterone, monitor your blood sugar more frequently at first. Your doctor may need to adjust your diabetes medication dose.

Food and Beverage Interactions

Grapefruit and Grapefruit Juice

Grapefruit inhibits the CYP3A4 enzyme in the gut, which can increase how much Progesterone is absorbed into your bloodstream. While this interaction is moderate, it's best to avoid large amounts of grapefruit or grapefruit juice while taking oral Progesterone.

Food and Oral Progesterone

Taking oral Progesterone with food increases its bioavailability (the amount that gets into your bloodstream). While this might sound helpful, higher absorption can also mean stronger side effects — particularly drowsiness and nausea. That's why the prescribing information recommends taking oral Progesterone capsules on an empty stomach at bedtime.

Alcohol

Alcohol isn't listed as a formal drug interaction, but it increases the sedative effects of Progesterone. Combining the two can cause excessive drowsiness, dizziness, and impaired coordination. It's best to avoid alcohol around the time you take your Progesterone dose.

Supplements and Herbal Interactions

Many patients don't think to mention supplements to their doctor, but several can interact with Progesterone:

• St. John's Wort: As mentioned above, this is a strong CYP3A4 inducer that can significantly lower Progesterone levels. Avoid it while on Progesterone therapy.
• Chasteberry (Vitex): This herbal supplement affects hormone levels and may interfere with Progesterone therapy. Discuss with your doctor before combining.
• Black cohosh: Sometimes used for menopausal symptoms, it may have hormonal effects that could interact with Progesterone therapy.

The Peanut Oil Factor: Prometrium

This isn't a drug interaction, but it's a critical safety concern. Prometrium brand oral capsules contain peanut oil. If you have a peanut allergy, you cannot take Prometrium. This is a contraindication — not just a precaution.

If you have a peanut allergy and need oral Progesterone, your doctor can prescribe a generic version that doesn't contain peanut oil or switch to a vaginal formulation. Always check the inactive ingredients of your specific prescription.

How to Tell Your Doctor About Your Medications

Before starting Progesterone, give your doctor a complete list of everything you take, including:

• All prescription medications
• Over-the-counter medications (including NSAIDs, allergy meds, etc.)
• Herbal supplements and vitamins
• Any medications you take occasionally (like antifungals for yeast infections)

If you start a new medication while already taking Progesterone, check with your pharmacist or doctor about potential interactions before combining them.

What If You Need a Medication That Interacts With Progesterone?

Having a drug interaction doesn't always mean you can't use both medications. Your doctor may:

• Adjust your Progesterone dose to compensate for the interaction
• Monitor you more closely for side effects or reduced effectiveness
• Switch your Progesterone formulation — vaginal forms bypass liver metabolism and may be less affected by CYP3A4 interactions
• Choose an alternative medication — see our guide on Progesterone alternatives
• Time the medications strategically to minimize the interaction

Quick Reference: Progesterone Interaction Summary

• Avoid: St. John's Wort, large amounts of grapefruit juice, alcohol around dosing time
• Tell your doctor about: Ketoconazole, Itraconazole, Clarithromycin, Rifampin, Carbamazepine, Phenytoin, Warfarin, Erythromycin, Fluconazole, Verapamil, diabetes medications, hormonal birth control
• Critical allergy alert: Prometrium contains peanut oil — contraindicated with peanut allergy

The Bottom Line

Progesterone is generally a safe medication, but like all drugs, it interacts with certain other medications, foods, and supplements. The most important interactions involve CYP3A4 inhibitors and inducers, blood thinners, and the often-overlooked herbal supplement St. John's Wort. Always keep your doctor and pharmacist informed about everything you're taking.

If you're currently looking for Progesterone and having trouble finding it in stock, MedFinder can help you check pharmacy availability near you.