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

Symdeko (tezacaftor/ivacaftor) has several clinically important drug interactions that every patient — and every prescriber — needs to know about. Because Symdeko is metabolized by an enzyme called CYP3A4, drugs that affect this enzyme can significantly change how much Symdeko is in your system. Some interactions can make Symdeko dangerously over-concentrated; others can make it ineffective. Here's a complete guide to the interactions that matter most.

Why CYP3A4 Matters for Symdeko

Tezacaftor and ivacaftor (the two active ingredients in Symdeko) are broken down by the liver enzyme CYP3A4. This enzyme acts like a traffic regulator for how quickly drugs are cleared from your body. Drugs that dramatically speed up CYP3A4 activity (called inducers) reduce Symdeko's blood levels and make it less effective. Drugs that slow down CYP3A4 (called inhibitors) increase Symdeko's blood levels, potentially causing more side effects.

Drugs You Must Avoid While Taking Symdeko (Contraindicated)

The following strong CYP3A4 inducers significantly reduce Symdeko's effectiveness and are contraindicated — meaning they should not be taken together with Symdeko:

Rifampin and rifabutin — antibiotics commonly used to treat tuberculosis (TB) and some other infections

Phenobarbital — an anti-seizure medication

Carbamazepine (Tegretol, Carbatrol, Equetro) — an anti-seizure and mood stabilizing medication

Phenytoin (Dilantin, Phenytek) — an anti-seizure medication

St. John's Wort — a common herbal supplement used for depression

If you are currently taking any of these medications and need Symdeko, talk to your CF care team and the prescribing provider for the other drug. In some cases, an alternative seizure medication or antibiotic that doesn't affect CYP3A4 may be substituted.

Drugs That Require a Dose Adjustment

The following CYP3A4 inhibitors significantly increase Symdeko blood levels. These drugs are not automatically contraindicated, but Symdeko's dosing must be reduced according to specific schedules in the prescribing information:

Strong CYP3A inhibitors (dose reduced to 1 tezacaftor/ivacaftor tablet twice weekly):

Ketoconazole, itraconazole, posaconazole, voriconazole (azole antifungals)

Clarithromycin (Biaxin) and telithromycin — macrolide antibiotics

Moderate CYP3A inhibitors (alternate-day dosing schedule):

Fluconazole (Diflucan) — a common antifungal used for yeast infections

Erythromycin — an antibiotic sometimes used for CF-related lung infections

Food and Beverage Interactions

Two specific foods must be avoided while taking Symdeko:

Grapefruit and grapefruit juice: Grapefruit contains compounds that inhibit CYP3A4 in the gut, increasing Symdeko's blood levels in an uncontrolled way. Avoid all forms of grapefruit — fresh, juice, or supplements.

Seville oranges (bitter orange) and orange marmalade: These contain the same inhibitory compounds as grapefruit. Regular navel or Valencia oranges are fine.

On the positive side: Symdeko must be taken with fat-containing food to be properly absorbed. Good choices include eggs, avocado, peanut butter, butter, whole milk, cheese, yogurt, or a peanut butter sandwich.

Hepatic Impairment: Dose Adjustment Required

Patients with moderate liver impairment (Child-Pugh Class B) should take Symdeko on an alternate-day schedule. Symdeko should be used with extreme caution in patients with severe liver impairment (Child-Pugh Class C), as exposure levels may be very high. Always tell your doctor about any history of liver disease.

Medications Commonly Used in CF That Are Generally Safe With Symdeko

Many medications commonly used in CF care do not have clinically significant interactions with Symdeko, including:

Inhaled tobramycin or aztreonam (inhaled antibiotics for Pseudomonas)

Dornase alfa (Pulmozyme) — a mucolytic used to thin airway secretions

Hypertonic saline — used for airway hydration

Pancreatic enzyme replacement therapy (PERT) — for pancreatic insufficiency

That said, always tell your CF care team and specialty pharmacy about every medication, supplement, and herbal product you take — including over-the-counter medications — before starting Symdeko.

What to Tell Your Doctor Before Starting Symdeko

Before your first Symdeko prescription, bring a complete list of:

All prescription medications (especially antibiotics, antifungals, seizure medications)

All over-the-counter medications (including pain relievers, antihistamines, antacids)

All vitamins and dietary supplements (including St. John's Wort, ginkgo, echinacea, etc.)

Any history of liver problems or kidney disease

For more on Symdeko safety, see: Symdeko Side Effects: What to Expect and When to Call Your Doctor.

Need help finding your Symdeko prescription? medfinder calls pharmacies on your behalf to confirm which ones can fill it.