JINARC

What it is

JINARC contains tolvaptan in tablet strengths of 15 mg, 30 mg, 45 mg, 60 mg or 90 mg. Tolvaptan is a vasopressin antagonist that specifically blocks the binding of arginine vasopressin at the V2 receptors of the distal portions of the nephron.

Approved indications

— Slowing the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adults with chronic kidney disease (CKD) stage 1 to 3 at initiation of treatment with evidence of rapidly progressing disease.

Dosing overview

JINARC is administered twice daily in split dose regimens of 45 mg + 15 mg, 60 mg + 30 mg or 90 mg + 30 mg, with total daily doses of 60, 90, or 120 mg respectively. The initial dose is 60 mg tolvaptan per day as a split-dose regimen of 45 mg taken upon waking prior to the morning meal and 15 mg taken 8 hours later. The initial dose is titrated upward to 90 mg tolvaptan (60 mg + 30 mg) per day and then to a target of 120 mg tolvaptan (90 mg + 30 mg) per day, if tolerated, with at least weekly intervals between titrations. The morning dose is taken at least 30 minutes before the morning meal, while the second daily dose can be taken with or without food.

Key safety warnings

Tolvaptan has been associated with idiosyncratic elevations of blood alanine and aspartate aminotransferases (ALT and AST), rarely associated with concomitant elevations in bilirubin-total (BT). Blood testing for hepatic transaminases is required prior to initiation of JINARC, then continually monthly for 18 months, then every 3 months thereafter during treatment. In postmarketing experience with tolvaptan in ADPKD, acute liver failure requiring liver transplantation has been reported. Prescriber education and certification on the risk of liver injury and the importance of regular liver function monitoring is mandatory, available through the IMADJIN Program, which is run and maintained by, or for, the sponsor of JINARC. Tolvaptan may cause adverse reactions related to water loss such as thirst, polyuria, nocturia, and pollakiuria. Patients must have access to water (or other aqueous fluids) and be able to drink sufficient amounts of these fluids. Volume status must be monitored in patients taking tolvaptan because treatment may result in severe dehydration which constitutes a risk factor for renal dysfunction. If dehydration becomes evident, appropriate action may include the need to interrupt or reduce the dose of tolvaptan and increase fluid intake. In post-marketing experience, anaphylaxis (including anaphylactic shock and rash generalised) has been reported very rarely following administration of tolvaptan. This type of reaction occurred after the first administration of tolvaptan.

Contraindications

JINARC is contraindicated in hypersensitivity to the active substance, benzazepine derivatives or to any of the excipients; elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan; volume depletion; anuria; hypernatraemia; patients who cannot perceive or respond to thirst; pregnancy; and breastfeeding.

PBS listing

JINARC is listed on the PBS in multiple strengths and pack configurations with authority required and streamlined restrictions. The 15 mg tablet, 30 mg tablet, and composite packs (15 mg + 45 mg, 30 mg + 60 mg, and 30 mg + 90 mg) are listed, with individual tablet strengths at an ex-manufacturer price of A$249.38 and composite packs at A$498.75.

Regulatory history

JINARC was first listed on the ARTG on 2017-03-24 in five variants: individual tablets of 15 mg and 30 mg, and composite packs containing 15 mg + 45 mg, 30 mg + 60 mg, and 30 mg + 90 mg tablets. The AusPAR approval date was 2017-03-10. In July 2018, the PBAC recommended JINARC as an Authority Required listing for ADPKD, noting small benefit and uncertain ESKD prevention, with acceptable cost-effectiveness at a reduced price with a Risk Share Agreement for patients with stage 2–3 CKD and rapid disease progression. In November 2019, the PBAC recommended listing of two new forms (15 mg and 30 mg tablets) on a cost-minimisation basis and amended the authority level for initial treatment from written to telephone/electronic.