Sign Out
Effect of other medicinal products on the pharmacokinetics of JINARC: 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 JINARC exposure.
Co-administration of JINARC and ketoconazole resulted in a 440% increase in area under time-concentration curve (AUC) and 248% increase in maximum observed plasma concentration (Cmax) for JINARC.
Co-administration of JINARC and fluconazole, a moderate CYP3A inhibitor, produced a 200% and 80% increase in JINARC AUC and Cmax, respectively.
Co-administration of JINARC with grapefruit juice, a moderate to strong CYP3A inhibitor, produced a doubling of peak JINARC concentrations (Cmax).
Dose reduction of JINARC 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 JINARC exposure and efficacy. Co-administration of JINARC with rifampicin reduces Cmax and AUC for JINARC by about 85%. Therefore, concomitant administration of JINARC with potent CYP3A inducers (e.g. rifampicin, rifabutin, rifapentine, 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 JINARC 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 JINARC 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: JINARC 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 JINARC 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 JINARC and/or diuretics and increased fluid intake. Other potential causes of renal dysfunction or dehydration must be evaluated and addressed.
Effect of JINARC on the pharmacokinetics of other products: CYP3A substrates: In healthy subjects, JINARC, a CYP3A substrate, had no effect on the plasma concentrations of some other CYP3A substrates (e.g. warfarin or amiodarone). JINARC increased plasma levels of lovastatin by 1.3- to 1.5-fold. Even though this increase has no clinical relevance, it indicates JINARC can potentially increase exposure to CYP3A4 substrates.
Transporter substrates: P-glycoprotein substrates: In-vitro studies indicate that JINARC is a substrate and competitive inhibitor of P-glycoprotein (P-gp). Steady state digoxin concentrations were increased (1.3-fold in maximum observed plasma concentration [Cmax] 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 JINARC. 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 JINARC.
OATP1B1/OAT3/BCRP and OCT1: In-vitro studies indicate that JINARC or its oxobutyric metabolite may have the potential to inhibit OATP1B1, OAT3, BCRP and OCT1 transporters. Co-administration of JINARC (90 mg) with rosuvastatin (5 mg), a BCRP substrate, increased rosuvastatin Cmax and AUCτ of 54% and 69%, respectively. If BCRP substrates (e.g. sulfasalazine) are co-administered with JINARC, patients must be managed cautiously and evaluated for excessive effects of these medicinal products.
Administration of rosuvastatin (OATP1B1 substrate) or furosemide (OAT3 substrate) to healthy subjects with elevated oxobutyric acid metabolite (inhibitor of OATP1B1 and OAT3) plasma concentrations did not meaningfully alter the pharmacokinetics of rosuvastatin or furosemide. Statins commonly used in the tolvaptan phase 3 pivotal trial (e.g. rosuvastatin and pitavastatin) are OATP1B1 or OATP1B3 substrates, however no difference in adverse events profile were observed during the phase 3 pivotal trial for tolvaptan in ADPKD.
If 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 JINARC cannot be excluded.
Co-administration with vasopressin analogues: In addition to its renal aquaretic effect, JINARC 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 JINARC. It is not recommended to administer 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 JINARC.
