Tolvaptan Drug Interactions You Need to Know About

Tolvaptan (sold as Samsca and Jynarque) is a powerful medication — and it interacts with a significant number of other drugs, supplements, and even foods. Some of these interactions are dangerous enough to be listed as contraindications, meaning you absolutely cannot take them together. Others require dose adjustments or extra monitoring.

If you're taking Tolvaptan or about to start, here's what you and your doctor need to watch for.

How Drug Interactions Work With Tolvaptan

Tolvaptan is primarily broken down in your liver by an enzyme called CYP3A4. It's also transported through your body by a protein called P-glycoprotein (P-gp). Any medication that speeds up, slows down, or blocks these pathways can change how much Tolvaptan ends up in your bloodstream — making it either too strong (risking serious side effects) or too weak (reducing its effectiveness).

Understanding this is important because the list of medications that affect CYP3A4 is long. Your doctor and pharmacist will screen for interactions, but you should know the major ones too.

Medications That Interact With Tolvaptan

Major Interactions — Contraindicated

These medications must not be taken with Tolvaptan. They are strong CYP3A4 inhibitors that can dramatically increase Tolvaptan levels in your blood, raising the risk of serious side effects including liver injury and severe dehydration:

• Ketoconazole (Nizoral) — antifungal
• Itraconazole (Sporanox) — antifungal
• Clarithromycin (Biaxin) — antibiotic
• Ritonavir (Norvir) — HIV protease inhibitor

If you need treatment for a fungal infection or bacterial infection while on Tolvaptan, your doctor must choose an alternative medication that doesn't strongly inhibit CYP3A4.

Major Interactions — Dose Reduction Required

These moderate CYP3A4 inhibitors increase Tolvaptan levels enough that your dose may need to be reduced:

• Fluconazole (Diflucan) — antifungal
• Erythromycin (E-Mycin, Ery-Tab) — antibiotic
• Diltiazem (Cardizem) — calcium channel blocker for blood pressure/heart conditions
• Verapamil (Calan, Verelan) — calcium channel blocker

If you're prescribed any of these, your doctor should adjust your Tolvaptan dose and monitor you more closely.

Major Interactions — Reduced Tolvaptan Effectiveness

These strong CYP3A4 inducers speed up the breakdown of Tolvaptan, potentially making it ineffective:

• Rifampin (Rifadin) — antibiotic used for tuberculosis
• Phenytoin (Dilantin) — anti-seizure medication
• Carbamazepine (Tegretol) — anti-seizure medication

If you take any of these, Tolvaptan may not work well enough to control your condition. Your doctor needs to know.

Moderate Interactions — Monitor Closely

• Digoxin (Lanoxin) — Tolvaptan increases Digoxin levels in the blood. If you take both, your doctor should monitor your Digoxin concentration and watch for signs of toxicity (nausea, visual changes, irregular heartbeat).
• Cyclosporine (Sandimmune, Neoral) — A P-glycoprotein inhibitor that can increase Tolvaptan levels.
• Other diuretics (Furosemide/Lasix, Hydrochlorothiazide, Spironolactone) — Using Tolvaptan alongside other diuretics can cause additive fluid loss, increasing the risk of dehydration and electrolyte imbalances.
• Hypertonic saline — Should not be used with Samsca. Combining them risks overly rapid sodium correction, which can cause osmotic demyelination syndrome.
• ACE inhibitors / ARBs (Lisinopril, Losartan, etc.) — Potential additive risk of hyperkalemia (high potassium). Your potassium levels should be monitored.
• Desmopressin (DDAVP) — Tolvaptan and Desmopressin have opposite effects. Desmopressin tells the kidneys to hold water; Tolvaptan tells them to release it. Taking both would be pharmacologic antagonism — they'd cancel each other out.

Supplements and Over-the-Counter Medications to Watch

Some OTC products and supplements can also interact with Tolvaptan:

• St. John's Wort — This popular herbal supplement is a strong CYP3A4 inducer. It can significantly reduce Tolvaptan levels in your blood, making the drug less effective. Avoid it.
• Potassium supplements — Since Tolvaptan can increase potassium levels (hyperkalemia risk), adding potassium supplements on top could push levels dangerously high. Only take potassium if your doctor specifically prescribes it and monitors your labs.
• NSAIDs (Ibuprofen/Advil, Naproxen/Aleve) — While not a direct Tolvaptan interaction, NSAIDs can affect kidney function and fluid balance, potentially complicating your treatment. Use with caution and inform your doctor.

Food and Drink Interactions

Grapefruit Juice — Avoid

Grapefruit juice is a well-known CYP3A4 inhibitor. Drinking it while taking Tolvaptan can significantly increase the amount of drug in your system, raising your risk of side effects. This includes grapefruit, Seville oranges, and pomelos. Avoid grapefruit juice entirely while on Tolvaptan.

Alcohol

While there's no specific labeled interaction between Tolvaptan and alcohol, alcohol can affect liver function, fluid balance, and sodium levels — all of which are relevant when you're on Tolvaptan. Discuss alcohol use with your doctor, especially if you're taking Jynarque (which requires liver monitoring).

Water

This isn't an "interaction" per se, but it's critical: Tolvaptan causes your body to excrete large amounts of water. You must drink adequate fluids — especially with Jynarque, where dehydration is a real risk. Don't restrict fluids unless your doctor specifically tells you to.

What to Tell Your Doctor Before Starting Tolvaptan

Before your first dose, make sure your doctor knows about:

1. All prescription medications you're taking — especially antifungals, antibiotics, HIV medications, blood pressure drugs, and seizure medications
2. All OTC medications — including pain relievers, antacids, and allergy medications
3. All supplements and herbal products — especially St. John's Wort, potassium, and any herbal teas or extracts
4. Your diet — specifically if you regularly eat grapefruit or drink grapefruit juice
5. Liver and kidney history — any past liver problems, hepatitis, or kidney disease beyond your current diagnosis
6. Other health conditions — diabetes, heart rhythm problems, or anything that affects fluid balance

Your pharmacist is also a valuable resource. When you fill your Tolvaptan prescription, they'll screen for interactions against your medication profile. If anything gets added or changed later, let them know you're on Tolvaptan.

Final Thoughts

Tolvaptan has a meaningful list of drug interactions because of how it's metabolized in the liver. The most important ones to remember: no strong CYP3A4 inhibitors (like Ketoconazole or Clarithromycin), no St. John's Wort, and no grapefruit juice. For everything else, your doctor and pharmacist can help determine whether a dose adjustment or extra monitoring is needed. Be thorough when sharing your medication list — even supplements matter.

For more on Tolvaptan, read our guides on what Tolvaptan is, side effects to watch for, and how to save money on your prescription. Need help finding it? Visit Medfinder.