Otezla Drug Interactions: What to Avoid and What to Tell Your Doctor

Drug interactions can affect how well Otezla (apremilast) works or how safe it is to take. The most important interactions to know about involve medications that interfere with the enzyme system the body uses to metabolize Otezla. Understanding these interactions — and sharing your complete medication list with your doctor and pharmacist — is essential for safe and effective treatment. Here's what you need to know.

How Otezla Is Metabolized: The CYP3A4 Connection

Otezla is broken down in the liver primarily by an enzyme called CYP3A4, with minor contributions from CYP1A2 and CYP2A6. These are part of the cytochrome P450 (CYP450) enzyme system — a family of enzymes responsible for metabolizing hundreds of different drugs and substances. If another drug or supplement speeds up (induces) or slows down (inhibits) CYP3A4 activity, it can significantly change the levels of Otezla in your blood.

The Most Important Interactions: Strong CYP450 Inducers

The most clinically significant drug interactions with Otezla involve strong CYP450 enzyme inducers. These are drugs (and supplements) that significantly increase the activity of CYP3A4 and other enzymes, causing them to break down Otezla much faster than normal. The result is a dramatic reduction in Otezla blood levels — meaning the drug may not work as intended.

Clinical studies showed that co-administration of rifampin (a strong CYP450 inducer and antibiotic used for tuberculosis) reduced Otezla's AUC (total drug exposure) by 72% and peak concentration by 43%. This level of reduction would likely render Otezla clinically ineffective. For this reason, the Otezla prescribing information explicitly states that concomitant use with strong CYP450 inducers is not recommended.

Strong CYP450 inducers to avoid or use with extreme caution with Otezla include:

Rifampin (rifampicin): An antibiotic used for tuberculosis and other infections. The strongest known CYP450 inducer. Co-administration with Otezla is not recommended.

Carbamazepine (Tegretol): An anticonvulsant and mood stabilizer used for epilepsy and bipolar disorder. Co-administration not recommended.

Phenobarbital: A barbiturate anticonvulsant and sedative. Co-administration not recommended.

Phenytoin (Dilantin): An anticonvulsant medication. Co-administration not recommended.

Apalutamide (Erleada): A prostate cancer medication and strong CYP3A4 inducer. Avoid or use alternate drug.

St. John's Wort: An over-the-counter herbal supplement commonly used for depression. St. John's Wort is a significant CYP450 inducer and can reduce Otezla levels. Co-administration not recommended.

What About Other Antiepileptics?

Other antiepileptic medications that are moderate or strong CYP inducers — including oxcarbazepine (Trileptal), primidone (Mysoline), and felbamate — may also reduce Otezla exposure, though the magnitude of effect varies. If you take any antiseizure medication, discuss it with your doctor before starting Otezla. Some newer antiepileptics (like lamotrigine, levetiracetam, and valproate) are not significant CYP inducers and do not have this interaction.

What Is Safe to Take With Otezla?

Based on formal drug interaction studies, several commonly used medications have been shown NOT to have clinically significant pharmacokinetic interactions with Otezla:

Methotrexate: No significant PK interaction when co-administered with Otezla 30 mg. These drugs are sometimes used together in psoriatic arthritis.

Ketoconazole (CYP3A4 inhibitor): Despite being a known inhibitor of the enzyme that metabolizes Otezla, ketoconazole did not produce clinically meaningful increases in apremilast exposure in formal studies. No dose adjustment needed.

Oral contraceptives (ethinyl estradiol/norgestimate): No significant interaction. Otezla does not affect the efficacy of hormonal birth control.

Alcohol: No specific drug interaction between alcohol and Otezla has been documented. However, alcohol can worsen GI side effects (nausea, diarrhea) and can exacerbate psoriasis symptoms. Moderate alcohol consumption is generally fine; discuss with your doctor.

Food and Supplement Interactions

Food does not significantly affect the absorption of Otezla — you can take it with or without food. However, as noted above, St. John's Wort (a common herbal supplement for depression) is a significant CYP450 inducer and should be avoided during Otezla treatment.

Other herbal supplements that are weaker CYP inducers — including some formulations of ginkgo biloba and green tea extract — may have minor effects on drug levels. Always inform your doctor and pharmacist about every supplement you take, not just prescription medications.

Interactions in Special Populations

Patients with severe kidney impairment (creatinine clearance below 30 mL/min) require a dose reduction to 30 mg once daily, as the kidneys play a role in Otezla elimination. No dose adjustment is needed for liver disease. Older patients (65+) generally tolerate Otezla similarly to younger adults in clinical trials, though they may be at higher risk for complications from severe GI side effects due to dehydration.

Always Tell Your Doctor and Pharmacist Everything You Take

The most important step for avoiding drug interactions is maintaining a complete, up-to-date medication list that includes all prescription drugs, over-the-counter medications, vitamins, and herbal supplements. Give this list to every provider who treats you. For a full overview of Otezla's safety profile, see our guide on Otezla Side Effects: What to Expect. If you need help finding your specialty pharmacy, medfinder can locate pharmacies that can fill your Otezla prescription.