Jinarc Drug Interactions

Effect of other medicinal products on the pharmacokinetics of Tolvaptan: CYP3A inhibitors: Concomitant use of medicinal products that are moderate CYP3A inhibitors (e.g. amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) or strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, ritonavir, clarithromycin) increase tolvaptan exposure.
Co-administration of tolvaptan and ketoconazole resulted in a 440 % increase in area under time-concentration curve (AUC) and 248 % increase in maximum observed plasma concentration (C_max) for tolvaptan.
Co-administration of tolvaptan and fluconazole, a moderate CYP3A inhibitor, produced a 200% and 80% increase in tolvaptan AUC and C_max, respectively.
Co-administration of tolvaptan with grapefruit juice, a moderate to strong CYP3A inhibitor, produced a doubling of peak tolvaptan concentrations (C_max).
Dose reduction of tolvaptan is recommended for patients while taking moderate or strong CYP3A inhibitors (see Dosage & Administration). Patients taking moderate or strong CYP3A inhibitors must be managed cautiously, in particular if the inhibitors are taken more frequently than once a day.
CYP3A inducers: Concomitant use of medicinal products that are potent CYP3A inducers (e.g., rifampicin) will decrease tolvaptan exposure and efficacy. Co-administration of tolvaptan with rifampicin reduces C_max and AUC for tolvaptan by about 85 %. Therefore, concomitant administration of tolvaptan with potent CYP3A inducers (e.g., rifampicin, rifabutin, rifapentin, phenytoin, carbamazepine, and St. John's Wort) is to be avoided.
Co-administration with medicinal products that increase serum sodium concentration: There is no experience from controlled clinical trials with concomitant use of tolvaptan and hypertonic sodium chloride solution, oral sodium formulations, and medicinal products that increase serum sodium concentration. Medicinal products with high sodium content such as effervescent analgesic preparations and certain sodium containing treatments for dyspepsia may also increase serum sodium concentration. Concomitant use of tolvaptan with medicinal products that increase serum sodium concentration may result in a higher risk for developing hypernatraemia (see Precautions) and is therefore not recommended.
Diuretics: Tolvaptan has not been extensively studied in ADPKD in combination with diuretics. While there does not appear to be a synergistic or additive effect of concomitant use of tolvaptan with loop and thiazide diuretics, each class of agent has the potential to lead to severe dehydration, which constitutes a risk factor for renal dysfunction. If dehydration or renal dysfunction becomes evident, appropriate action must be taken which may include the need to interrupt or reduce doses of tolvaptan and/or diuretics and increased fluid intake. Other potential causes of renal dysfunction or dehydration must be evaluated and addressed.
Effect of tolvaptan on the pharmacokinetic of other products: CYP3A substrates: In healthy subjects, tolvaptan, a CYP3A substrate, had no effect on the plasma concentrations of some other CYP3A substrates (e.g. warfarin or amiodarone). Tolvaptan increased plasma levels of lovastatin by 1.3- to l.5-fold. Even though this increase has no clinical relevance, it indicates tolvaptan can potentially increase exposure to CYP3A4 substrates.
Transporter substrates: In-vitro studies indicate that tolvaptan is a substrate and competitive inhibitor of P-glycoprotein (P-gp). In-vitro studies indicate that tolvaptan or its oxobutyric metabolite may have the potential to inhibit OATP1B1, OATP1B3, OAT3, BCRP and OCT1 transporters. Steady state digoxin concentrations were increased (1.3-fold in maximum observed plasma concentration [C_max] and 1.2-fold in area under the plasma concentration-time curve over the dosing interval [AUCτ]) when co-administered with multiple once daily 60 mg doses of tolvaptan. Patients receiving digoxin or other narrow therapeutic P-gp substrates (e.g., dabigatran) must therefore be managed cautiously and evaluated for excessive effects when treated with tolvaptan. Statins commonly used in the tolvaptan phase 3 pivotal trial (e.g., rosuvastatin and pitavastatin) are OATP1B1 or OATP1B3 substrates, however no difference in AE profile was observed during the phase 3 pivotal trial for tolvaptan in ADPKD. If OATP1B1 and OATP1B3 substrates (e.g., statins such as rosuvastatin and pitavastatin), OAT3 substrates (e.g., methotrexate, ciprofloxacin), BCRP substrates (e.g. sulfasalazine) or OCT1 substrates (e.g. metformin) are co-administered with tolvaptan, patients must be managed cautiously and evaluated for excessive effects of these medicinal products.
Diuretics or non-diuretic anti-hypertensive medicinal product(s): Standing blood pressure was not routinely measured in ADPKD trials, therefore a risk of orthostatic/postural hypotension due to a pharmacodynamic interaction with tolvaptan cannot be excluded.
Co-administration with vasopressin analogues: In addition to its renal aquaretic effect, tolvaptan is capable of blocking vascular vasopressin V2 receptors involved in the release of coagulation factors (e.g., von Willebrand factor) from endothelial cells. Therefore, the effect of vasopressin analogues such as desmopressin may be attenuated in patients using such analogues to prevent or control bleeding when co-administered with tolvaptan. It is not recommended to administer Tolvaptan (JINARC^®) with vasopressin analogues.
Smoking and alcohol: Data related to smoking or alcohol history in ADPKD trials are too limited to determine possible interactions of smoking or alcohol with efficacy and safety of ADPKD treatment with tolvaptan.