Depo-Provera Drug Interactions: What to Avoid and What to Tell Your Doctor

Depo-Provera (medroxyprogesterone acetate) is not a controlled substance and doesn't have the long list of dangerous drug interactions that some other medications carry—but several drugs and supplements can affect how well it works or how it behaves in your body. Knowing about these interactions helps protect both your contraceptive effectiveness and your overall health.

How Depo-Provera Is Metabolized (Why Interactions Happen)

Medroxyprogesterone acetate (MPA) is primarily metabolized by the liver enzyme CYP3A4 (part of the cytochrome P450 enzyme system). Drugs that affect CYP3A4 activity can change how quickly your body breaks down MPA:

CYP3A4 inducers speed up MPA metabolism, lowering blood levels and potentially reducing contraceptive effectiveness.

CYP3A4 inhibitors slow down MPA metabolism, increasing blood levels and potentially intensifying side effects.

Interactions That May Reduce Depo-Provera's Effectiveness

The following drugs are CYP3A4 inducers that may reduce MPA levels in your blood. While the injectable depot formulation is more resistant to these interactions than oral progestins (due to its much higher dose), caution is still warranted with long-term use:

Rifampin (rifampicin): An antibiotic used for tuberculosis. A strong CYP3A4 inducer that can significantly lower MPA levels.

Anticonvulsants/seizure medications: Carbamazepine (Tegretol), phenytoin (Dilantin), phenobarbital, primidone, and oxcarbazepine are CYP3A4 inducers. Women on these medications who use Depo-Provera should discuss this with both their prescriber and their contraceptive provider.

Apalutamide (Erleada): A prostate cancer drug that is a potent CYP3A4 inducer. Marked as an avoid/major interaction.

Enzalutamide (Xtandi): Another cancer drug and CYP3A4 inducer. Contraceptive failure is possible; use an alternative if available.

Eslicarbazepine (Aptiom): An anticonvulsant that may reduce MPA levels via CYP3A4 induction.

Acitretin (Soriatane): A retinoid used for severe psoriasis. Reduces medroxyprogesterone's effects via an unknown mechanism. Contraceptive failure possible — use an alternative contraceptive method.

Aminoglutethimide: May significantly suppress MPA serum concentrations. Not commonly used but occasionally prescribed for Cushing's syndrome.

Herbal Supplements to Be Aware Of

St. John's Wort: A widely used herbal supplement for mood support. It is a CYP3A4 inducer that is known to reduce blood levels of oral hormonal contraceptives. The effect on injectable DMPA is less studied but worth mentioning to your provider.

Interactions That May Increase Depo-Provera's Effect or Cause Side Effects

Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): These may increase MPA concentrations, potentially intensifying side effects such as irregular bleeding, mood changes, or hormonal effects.

Interactions That May Cause Separate Risks

Etrasimod (Velsipity): A drug used for ulcerative colitis. Combined use with medroxyprogesterone may produce additive immunosuppressive effects, increasing infection risk. Avoid combining these medications.

What Doesn't Interact with Depo-Provera

Unlike oral hormonal contraceptives, Depo-Provera is not affected by common antibiotics such as amoxicillin, doxycycline, or azithromycin. There is no clinical evidence that standard antibiotics reduce injectable DMPA effectiveness. Antifungal fluconazole (Diflucan) at single standard doses also does not clinically affect MPA levels.

Important Note About Lab Tests

Depo-Provera can affect certain lab test results. When having blood work done, tell your provider and the lab you're using Depo-Provera. Affected tests include thyroid hormone tests (T3-uptake may be decreased), certain clotting factors (Factors VII, VIII, IX, X may be increased), liver function tests, and blood glucose tests in diabetics.

What to Tell Your Doctor

Before receiving your Depo-Provera injection, tell your provider:

All prescription medications, including anticonvulsants, antibiotics, cancer medications, and immunosuppressants

All herbal supplements, especially St. John's Wort

Any history of meningioma, blood clots, liver disease, or breast cancer

Any plans to become pregnant in the near future (important for fertility planning)

For more information on Depo-Provera side effects, see: Depo-Provera Side Effects: What to Expect and When to Call Your Doctor. To find a pharmacy with your next injection in stock, use medfinder.