Ezetimibe (Zetia) and PPIs (Omeprazole, Pantoprazole): Drug Interaction Guide

What the Zetia label lists as interactions

Single-ingredient Zetia (ezetimibe 10 mg tablets) carries no boxed warning [1]. Its drug interactions section is a three-row table, and no PPI is in it.

• Cyclosporine: ezetimibe and cyclosporine concentrations both rise, and the rise in ezetimibe exposure may be larger in severe renal impairment; the label says to monitor cyclosporine concentrations [1].
• Fibrates: fenofibrate and ezetimibe can both increase cholesterol excretion into bile, which can lead to gallstones; combining ezetimibe with fibrates other than fenofibrate is not recommended, and suspected gallstones call for gallbladder studies [1].
• Bile acid sequestrants: cholestyramine lowers total ezetimibe exposure, which may reduce efficacy, so the label says to take ezetimibe at least 2 hours before or 4 hours after the sequestrant [1].

Omeprazole, pantoprazole, esomeprazole and the rest of the class do not appear in that table [1].

What the Nexium label lists as interactions

Nexium is esomeprazole, the S-enantiomer of omeprazole [2]. Its interaction tables cover:

• Antiretrovirals, with rilpivirine contraindicated and nelfinavir to be avoided [2]
• Warfarin, with increased INR and prothrombin time and instructions to monitor INR [2]
• Methotrexate, mainly at high dose [2]
• CYP2C19 substrates: clopidogrel (avoid the combination), citalopram (limit to 20 mg a day), cilostazol (consider 50 mg twice daily) [2]
• Digoxin and tacrolimus, with level monitoring [2]
• Drugs whose absorption depends on stomach acid, given as examples: iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole and itraconazole [2]
• Test interference with chromogranin A, the secretin stimulation test and urine THC screening [2]

Ezetimibe is not on that list [2].

Different clearance routes

Ezetimibe is conjugated in the small intestine and liver to an active glucuronide. Oxidative metabolism is minimal, the glucuronide makes up 80% to 90% of drug in plasma, and both forms have a half-life of about 22 hours [1].

PPIs differ among themselves: omeprazole is mainly cleared by CYP2C19, while lansoprazole is cleared by both CYP3A and CYP2C19.

Timing

Ezetimibe is 10 mg once daily, with or without food; a missed dose is taken as soon as possible without doubling the next one, and LDL-C can be assessed as early as 4 weeks after starting [1]. The only spacing instruction on the Zetia label is the 2-hour/4-hour rule for bile acid sequestrants [1]. The Zetia label gives no spacing rule for PPIs, and the Nexium interaction tables give none for ezetimibe [1][2]. The Nexium label does not speak for the omeprazole or pantoprazole labels.

If you also take a statin

The Zetia label does not take on the statin's risks. It says that when ezetimibe is used with a statin, fenofibrate or another LDL-C lowering therapy, the warnings and precautions of that product apply and its prescribing information should be read [1].

In controlled trials of ezetimibe started at the same time as a statin, consecutive transaminase rises of 3 times the upper limit of normal or more occurred in 1.3% of patients on ezetimibe plus a statin versus 0.4% on a statin alone [1]. Myopathy and rhabdomyolysis are listed as possible; in postmarketing reports most patients who developed rhabdomyolysis were also taking a statin or another agent such as a fibrate, and the label says to discontinue ezetimibe and other concomitant medications, as appropriate, if myopathy is suspected [1].

What each label says to watch for

On the ezetimibe side: transaminase increases, with liver enzyme testing as clinically indicated and consideration of withdrawal if ALT or AST stays at 3 times the upper limit of normal or more [1]; and myopathy, meaning muscle pain, tenderness or weakness with elevated creatine kinase [1]. Ezetimibe is not recommended in moderate or severe hepatic impairment (Child-Pugh B or C), where exposure rises about 3- to 4-fold, and severe renal impairment raises exposure about 1.5-fold [1].

On the PPI side, the Nexium label lists hypomagnesemia, reported rarely with prolonged treatment, along with low calcium or potassium in some cases [2]. Daily long-term use, for example longer than 3 years, may lead to vitamin B12 malabsorption [2]. The label bases its Clostridioides difficile diarrhea and bone fracture wording on observational studies; the fracture risk was higher with high-dose, long-term use. Fundic gland polyps are listed with risk rising beyond one year of use [2].

None of these is an ezetimibe interaction. They are the warnings each drug carries on its own [1][2].