Nextstellis 28 Day Drug Interactions: What to Avoid and What to Tell Your Doctor

Nextstellis 28 Day contains two active ingredients — drospirenone and estetrol — that can interact with other medications, supplements, and herbal products. Some of these interactions can reduce the effectiveness of Nextstellis, increasing the risk of unintended pregnancy. Others can increase the risk of side effects. Understanding these interactions is essential to using Nextstellis safely.

Category 1: Drugs That May Reduce Nextstellis Effectiveness (CYP3A Inducers)

The most clinically important Nextstellis drug interactions involve CYP3A enzyme inducers. These medications speed up the breakdown of drospirenone and estetrol in your liver, which can lower their levels in your blood enough to reduce contraceptive effectiveness and potentially cause contraceptive failure.

Strong CYP3A inducers — avoid if possible:

• Rifampin (rifampicin): Used for tuberculosis and other bacterial infections. A potent CYP3A inducer that can significantly reduce Nextstellis hormone levels.
• Anti-seizure medications: Carbamazepine (Tegretol), phenytoin (Dilantin), phenobarbital, primidone, and oxcarbazepine are all CYP3A inducers that can reduce Nextstellis effectiveness.
• HIV/antiviral medications: Ritonavir, lopinavir, and other HIV protease inhibitors or non-nucleoside reverse transcriptase inhibitors may affect Nextstellis hormone levels.

Moderate and weak CYP3A inducers (use backup contraception):

• St. John's Wort (Hypericum perforatum): A common herbal supplement for depression that is a moderate CYP3A inducer. Avoid taking with Nextstellis.
• Modafinil (Provigil): Used for narcolepsy and shift work disorder. Moderate CYP3A inducer.

If you must take a CYP3A inducer, use an alternative or backup non-hormonal contraceptive during co-administration and for up to 28 days after stopping the inducer.

Category 2: Drugs That May Increase Drospirenone Levels (CYP3A4 Inhibitors)

Strong CYP3A4 inhibitors slow the breakdown of drospirenone, which can raise its blood levels and increase the risk of side effects — particularly hyperkalemia (elevated potassium). Examples include:

• Azole antifungals: Fluconazole (Diflucan), itraconazole, ketoconazole — often prescribed for vaginal yeast infections or systemic fungal infections.
• Macrolide antibiotics: Clarithromycin (Biaxin), erythromycin. Note: Most short-course antibiotics (e.g., penicillin, amoxicillin) do NOT interact with Nextstellis.
• Grapefruit juice: Large amounts of grapefruit or grapefruit juice can inhibit CYP3A4 and raise drospirenone levels.

Category 3: Potassium-Raising Medications (Hyperkalemia Risk)

Because drospirenone has anti-mineralocorticoid activity (comparable to 25 mg spironolactone), it can raise potassium levels. Taking Nextstellis with other medications that also raise potassium can be dangerous. These include:

• ACE inhibitors: Lisinopril (Zestril), enalapril (Vasotec) — prescribed for high blood pressure and heart failure.
• ARBs (angiotensin receptor blockers): Losartan (Cozaar), valsartan (Diovan) — used for hypertension.
• Potassium-sparing diuretics: Spironolactone (Aldactone), eplerenone, triamterene — important because spironolactone is commonly prescribed alongside hormonal therapy for PCOS.
• NSAIDs (nonsteroidal anti-inflammatory drugs): Ibuprofen (Advil), naproxen (Aleve) — occasional use is generally fine, but chronic daily use may raise potassium levels.

Your provider should check your potassium levels if you are taking any of these medications long-term alongside Nextstellis.

Category 4: Absolute Contraindication — Hepatitis C Drug Combinations

Nextstellis is absolutely contraindicated for use with hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir — e.g., Viekira Pak, Technivie). This combination causes a significant increase in liver enzymes (ALT elevation). Nextstellis must be stopped prior to starting this hepatitis C regimen and can be restarted approximately 2 weeks after completing treatment.

Category 5: Drugs That May Be Affected by Nextstellis

Nextstellis can also affect the way some drugs work in your body:

• Antidiabetic drugs: Nextstellis may reduce the blood glucose-lowering effect of insulin and oral diabetes medications. Monitor blood glucose more carefully if you have diabetes.
• Thyroid medications: Nextstellis may increase thyroxine-binding globulin (TBG) levels, which can affect thyroid function tests. If you are on thyroid replacement therapy, your provider may need to adjust your dose.

What to Tell Your Doctor and Pharmacist

Before starting Nextstellis, give your provider a complete list of everything you take — including prescription drugs, over-the-counter medications, vitamins, minerals, and herbal supplements. Be especially sure to mention:

• Any seizure medications
• St. John's Wort supplements
• Blood pressure medications (ACE inhibitors, ARBs, diuretics)
• Any antifungal medications (fluconazole, itraconazole)
• Diabetes medications (insulin, metformin, etc.)
• Any HIV antivirals or hepatitis C treatments

The Bottom Line

The most important Nextstellis drug interactions involve CYP3A inducers (which can make it less effective), CYP3A4 inhibitors (which can raise hormone levels), and potassium-raising medications (which can cause dangerous hyperkalemia). Always disclose your full medication list to your prescriber and pharmacist. To learn about side effects in detail, read our Nextstellis side effects guide. And when you're ready to fill your prescription, medfinder can help you find it in stock near you.