Samsca Drug Interactions

Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP3A Inhibitors: Samsca is metabolized primarily by CYP3A. Ketoconazole is a strong inhibitor of CYP3A and also an inhibitor of P-gp. Co-administration of Samsca and ketoconazole 200 mg daily results in a 5-fold increase in exposure to tolvaptan. Co-administration of Samsca with ketoconazole 400 mg daily or with other strong CYP3A inhibitors (eg, clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir and nefazodone) at the highest labeled dose would be expected to cause an even greater increase in tolvaptan exposure. Thus, Samsca and strong CYP3A inhibitors should not be co-administered (see Dosage & Administration and Contraindications).
Moderate CYP3A Inhibitors: The impact of moderate CYP3A inhibitors (eg, erythromycin, fluconazole, aprepitant, diltiazem and verapamil) on the exposure to co-administered tolvaptan has not been assessed. A substantial increase in the exposure to tolvaptan would be expected when Samsca is co-administered with moderate CYP3A inhibitors. Co-administration of Samsca with moderate CYP3A inhibitors should therefore generally be avoided (see Dosage & Administration and Precautions).
Grapefruit Juice: Co-administration of grapefruit juice and Samsca results in a 1.8-fold increase in exposure to tolvaptan (see Dosage & Administration and Precautions).
P-gp Inhibitors: Reduction in the dose of Samsca may be required in patients concomitantly treated with P-gp inhibitors eg, cyclosporine based on clinical response (see Dosage & Administration and Precautions).
Rifampin and Other CYP3A Inducers: Rifampin is an inducer of CYP3A and P-gp. Co-administration of rifampin and Samsca reduces exposure to tolvaptan by 85%. Therefore, the expected clinical effects of Samsca in the presence of rifampin and other inducers (eg, rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine and St. John’s wort) may not be observed at the usual dose levels of Samsca. The dose of Samsca may have to be increased (see Dosage & Administration and Precautions).
Lovastatin, Digoxin, Furosemide and Hydrochlorothiazide: Co-administration of lovastatin, digoxin, furosemide and hydrochlorothiazide with Samsca has no clinically relevant impact on the exposure to tolvaptan.
Effects of Tolvaptan on Other Drugs: Digoxin: Digoxin is a P-gp substrate and Samsca is a P-gp inhibitor. Co-administration of Samsca and digoxin results in a 1.3-fold increase in the exposure to digoxin.
Warfarin, Amiodarone, Furosemide and Hydrochlorothiazide: Co-administration of tolvaptan does not appear to alter the pharmacokinetics of warfarin, furosemide, hydrochlorothiazide or amiodarone (or its active metabolite, desethylamiodarone) to a clinically significant degree.
Lovastatin: Samsca is a weak inhibitor of CYP3A. Co-administration of lovastatin and Samsca increases the exposure to lovastatin and its active metabolite lovastatin-β hydroxyacid by factors of 1.4 and 1.3, respectively. This is not a clinically relevant change.
Pharmacodynamic Interactions: Tolvaptan produces a greater 24-hr urine volume/excretion rate than does furosemide or hydrochlorothiazide. Concomitant administration of tolvaptan with furosemide or hydrochlorothiazide results in a 24-hr urine volume/excretion rate that is similar to the rate after tolvaptan administration alone.
Although specific interaction studies were not performed, in clinical studies tolvaptan was used concomitantly with β-blockers, angiotensin-receptor blockers, angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diuretics. Adverse reactions of hyperkalemia were approximately 1-2% higher when tolvaptan was administered with angiotensin receptor blockers, ACE inhibitors and potassium-sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.