Jynarque - Drug Monograph

Introduction

Jynarque (tolvaptan) is a selective vasopressin V2-receptor antagonist approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD). It represents the first FDA-approved medication specifically designed to slow kidney function decline in adults at risk of rapidly progressing ADPKD.

Mechanism of Action

Tolvaptan competitively blocks vasopressin from binding to V2 receptors in the renal collecting ducts. This inhibition reduces the cyclic AMP-dependent signaling that promotes cystogenesis and disease progression in ADPKD. By antagonizing V2 receptors, tolvaptan:

• Reduces water reabsorption (aquaresis)
• Decreases renal epithelial cell proliferation
• Reduces chloride-driven fluid secretion into cysts
• Lowers intracellular cyclic AMP levels

These actions collectively slow cyst growth and preserve kidney function.

Indications

• Treatment of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD) in adults
• Slows the decline in kidney function as measured by estimated glomerular filtration rate (eGFR)

Dosage and Administration

• Morning dose: 45 mg + evening dose: 15 mg
• Titrate to 60 mg + 30 mg and then to 90 mg + 30 mg based on tolerability
• Doses should be taken at least 8 hours apart

• Week 1: 45 mg AM/15 mg PM
• Week 2: 60 mg AM/15 mg PM (if tolerated)
• Week 3: 90 mg AM/30 mg PM (if tolerated)

• Hepatic impairment: Contraindicated in patients with underlying liver disease
• Renal impairment: No dosage adjustment required
• Elderly: Use with caution due to increased risk of dehydration
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• History of idiosyncratic allergic reactions to tolvaptan
• Unable to sense or respond to thirst
• Volume depletion
• Hypersensitivity to any component
• Concomitant use with strong CYP3A inhibitors
• Underlying liver disease including cirrhosis
• Uncorrected abnormal serum sodium concentrations

Warnings and Precautions

• Risk of serious and potentially fatal liver injury
• Requires monitoring through the REMS program

• Dehydration and hypovolemia: Monitor volume status and serum sodium
• Hypernatremia: Monitor serum sodium frequently during initiation and titration
• Coagulation disorders: Monitor for bleeding and bruising
• Osmotic demyelination syndrome: Risk with rapid correction of hyponatremia
• Urine output and thirst: Patients must have free access to water and be able to drink sufficient amounts

Drug Interactions

Adverse Effects

• Thirst (55%)
• Polyuria (29%)
• Nocturia (25%)
• Fatigue (14%)
• Dry mouth (13%)

• Hypernatremia
• Dehydration
• Decreased appetite
• Constipation
• Dizziness
• Headache
• ALT/AST elevation

• Hepatotoxicity
• Acute liver failure
• Rhabdomyolysis
• Stevens-Johnson syndrome
• Anaphylaxis

Monitoring Parameters

• Complete metabolic panel (including sodium, potassium, creatinine)
• Liver function tests (ALT, AST, bilirubin)
• Volume status assessment
• Pregnancy test if applicable

• Serum sodium: Within first week, then monthly for first 3 months, then every 3 months
• Liver function tests: Monthly for first 18 months, then every 3 months
• Serum creatinine and eGFR: Every 3-6 months
• Volume status and symptoms of dehydration: At each visit
• Urine output and thirst perception: Regular assessment

• REMS program compliance
• Signs of hepatic injury (fatigue, anorexia, right upper quadrant discomfort, dark urine, jaundice)

Patient Education

• Must have free access to water and drink when thirsty
• Report symptoms of liver injury immediately (fatigue, nausea, vomiting, dark urine, jaundice)
• Monitor for signs of dehydration (dizziness, weakness, dry mouth)
• Take doses 8 hours apart as directed
• Do not skip doses without medical advice
• Avoid grapefruit and grapefruit juice
• Report any new medications to healthcare provider
• Participate in required monitoring and REMS program
• Use effective contraception during treatment

• Maintain adequate fluid intake, especially in hot weather
• Be aware of increased urinary frequency and nocturia
• Plan activities considering bathroom access
• Avoid alcohol due to dehydration risk

References

1. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407-2418. 2. FDA. Jynarque (tolvaptan) prescribing information. 2018. 3. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377(20):1930-1942. 4. Gansevoort RT, Arici M, Benzing T, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. Nephrol Dial Transplant. 2016;31(3):337-348. 5. Chebib FT, Perrone RD, Chapman AB, et al. A practical guide for treatment of rapidly progressive ADPKD with tolvaptan. J Am Soc Nephrol. 2018;29(10):2458-2470. 6. Otsuka Pharmaceutical Development & Commercialization Inc. JYNARQUE REMS Program. 2018. 7. Watkins PB, Lewis JH, Kaplowitz N, et al. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf. 2015;38(11):1103-1113.