Prometrium Drug Interactions: What You Need to Know Before Taking It

When you take Prometrium (Micronized Progesterone), it doesn't work in isolation. Other medications, supplements, and even certain foods can change how it behaves in your body — making it less effective or increasing side effects.

This guide explains the most important Prometrium drug interactions, what to avoid, and what to tell your doctor before you start taking it.

How Drug Interactions Work with Prometrium

Prometrium is processed (metabolized) in your liver by a group of enzymes called CYP3A4. This matters because many other drugs also use or affect these same enzymes.

There are two main types of interactions:

• CYP3A4 inhibitors — These drugs slow down the enzyme, which means Prometrium gets broken down more slowly. The result: higher progesterone levels in your blood, which can increase side effects like drowsiness and dizziness.
• CYP3A4 inducers — These drugs speed up the enzyme, causing Prometrium to be broken down faster. The result: lower progesterone levels, which may make the medication less effective.

Understanding this basic concept helps explain why certain combinations need to be monitored or avoided.

Medications That Interact with Prometrium

Major Interactions (Use with Caution or Avoid)

• Ketoconazole (Nizoral) — A strong antifungal that inhibits CYP3A4. Taking it with Prometrium can significantly increase progesterone levels and worsen side effects. Other strong CYP3A4 inhibitors (like itraconazole) have a similar effect.
• Rifampin (Rifadin) — An antibiotic used for tuberculosis that is a powerful CYP3A4 inducer. It can dramatically reduce Prometrium's effectiveness by speeding up how quickly your body processes it.
• Carbamazepine (Tegretol) — An anti-seizure medication and CYP3A4 inducer. It may reduce progesterone levels if taken with Prometrium.
• Phenytoin (Dilantin) — Another anti-seizure drug that induces CYP3A4, potentially decreasing Prometrium's effectiveness.
• Phenobarbital — A barbiturate and CYP3A4 inducer that can lower progesterone levels.

Moderate Interactions (Monitor Closely)

• Conjugated estrogens (Premarin) — While Prometrium is often prescribed alongside estrogen on purpose, the combination alters how both hormones are metabolized. Your doctor prescribes specific doses that account for this interaction.
• Other hormonal medications — Birth control pills, hormone patches, and other progesterone-containing products can interact. Always tell your doctor about all hormone therapies you're using.
• Other antifungal medications — Moderate CYP3A4 inhibitors like fluconazole (Diflucan) may modestly increase progesterone levels.

Supplements and Over-the-Counter Products to Watch

Some supplements and OTC products can also interact with Prometrium:

• St. John's Wort — This popular herbal supplement for mood is a known CYP3A4 inducer. It can reduce Prometrium levels, potentially making it less effective. Avoid taking St. John's Wort with Prometrium.
• Herbal supplements with estrogenic effects — Black cohosh, dong quai, red clover, and soy isoflavones can have weak estrogen-like effects that may interact with your hormone therapy. Discuss these with your doctor.
• Melatonin — Progesterone has natural sedative effects, and adding melatonin or other sleep aids can increase drowsiness. While this isn't a dangerous interaction, it's worth knowing — especially if you drive in the morning.
• Antihistamines — Over-the-counter allergy medications like diphenhydramine (Benadryl) can add to the drowsiness caused by Prometrium. Be cautious about combining them.

Food and Drink Interactions

Prometrium has a few notable food interactions:

• Food in general — Taking Prometrium with food increases its absorption. This is actually recommended — take it with a meal or snack, preferably at bedtime.
• Grapefruit and grapefruit juice — Grapefruit inhibits CYP3A4, which can increase progesterone levels. While the effect is usually modest, it's best to avoid consuming large amounts of grapefruit regularly while taking Prometrium.
• Alcohol — Alcohol doesn't directly interact with Prometrium at a metabolic level, but it can make drowsiness and dizziness significantly worse. Limit alcohol, especially in the hours around when you take your dose.

What to Tell Your Doctor Before Starting Prometrium

Before your doctor prescribes Prometrium, make sure they know about:

• All prescription medications you currently take — especially antifungals, anti-seizure drugs, antibiotics like Rifampin, and any hormone therapies
• All supplements and herbal products — particularly St. John's Wort, black cohosh, and any sleep aids
• Over-the-counter medications — including antihistamines, sleep aids, and pain relievers you use regularly
• Any changes in medications — If you start or stop a medication while taking Prometrium, tell your doctor. Adding or removing a CYP3A4 inhibitor or inducer can change your progesterone levels.
• Peanut allergy — Prometrium capsules contain peanut oil. This isn't a drug interaction, but it's critical safety information your doctor needs to know.

A good habit: bring a complete list of every medication and supplement you take to every doctor's appointment. This helps your provider catch potential interactions before they become problems.

Final Thoughts

Prometrium interacts with fewer drugs than many medications, but the interactions it does have are important. The biggest ones to watch are CYP3A4 inducers (like Rifampin, Carbamazepine, and St. John's Wort) that can make it less effective, and CYP3A4 inhibitors (like Ketoconazole) that can increase side effects.

When in doubt, always tell your doctor and pharmacist about everything you take. They can adjust your Prometrium dose or timing if needed.

For more about what Prometrium does and how to take it, read our guides on what Prometrium is and Prometrium side effects. If you need help finding Prometrium at a pharmacy, check Medfinder for real-time stock availability.