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Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP 3A Inhibitors: SAMSCA is metabolized primarily by CYP 3A. Ketoconazole is a strong inhibitor of CYP 3A 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 400 mg ketoconazole daily or with other strong CYP 3A inhibitors (e.g., 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 CYP 3A inhibitors should not be co-administered [see Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors under Dosage & Administration and Concomitant use of strong CYP 3A inhibitors under Contraindications].
Moderate CYP 3A Inhibitors: The impact of moderate CYP 3A inhibitors (e.g., 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 CYP 3A inhibitors. Co-administration of SAMSCA with moderate CYP3A inhibitors should therefore generally be avoided [see Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors under Dosage & Administration and Drug Interactions under Precautions].
Grapefruit Juice: Co-administration of grapefruit juice and SAMSCA results in a 1.8-fold increase in exposure to tolvaptan [see Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors under Dosage & Administration and Drug Interactions under Precautions].
P-gp Inhibitors: Reduction in the dose of SAMSCA may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response [see Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors under Dosage & Administration and Drug Interactions under Precautions].
Rifampin and Other CYP 3A Inducers: Rifampin is an inducer of CYP 3A 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 (e.g., 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 Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors under Dosage & Administration and Drug Interactions under 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. Co-administration of SAMSCA with digoxin increased digoxin AUC by 20% and Cmax by 30%.
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 CYP 3A. 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 hour urine volume/excretion rate than does furosemide or hydrochlorothiazide. Concomitant administration of tolvaptan with furosemide or hydrochlorothiazide results in a 24 hour 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 beta-blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics. Adverse reactions of hyperkalemia were approximately 1-2% higher when tolvaptan was administered with angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.
As a V2-receptor antagonist, tolvaptan may interfere with the V2-agonist activity of desmopressin (dDAVP). In a male subject with mild Von Willebrand (vW) disease, intravenous infusion of dDAVP 2 hours after administration of oral tolvaptan did not produce the expected increases in vW Factor Antigen or Factor VIII activity. It is not recommended to administer SAMSCA with a V2-agonist.
