Jynarque (tolvaptan)

Jynarque is a prescription medicine used to slow kidney function decline in adults who are at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).

It is not known if Jynarque is safe and effective in children.

Jynarque can cause serious side effects, including:

• Serious liver problems. Jynarque can cause serious liver problems that can lead to the need for a liver transplant or can lead to death. Stop taking Jynarque and call your healthcare provider right away if you get any of the following symptoms:
  • feeling tired
  • loss of appetite
  • nausea
  • right upper stomach (abdomen) pain or tenderness
  • vomiting
  • fever
  • rash
  • itching
  • yellowing of the skin and white part of the eye (jaundice)
  • dark urine

  To help reduce your risk of liver problems, your healthcare provider will do a blood test to check your liver:

  • before you start taking Jynarque
  • at 2 weeks and 4 weeks after you start treatment with Jynarque
  • then monthly for 18 months during treatment with Jynarque
  • and every 3 months from then on

It is important to stay under the care of your healthcare provider during treatment with Jynarque.

Because of the risk of serious liver problems Jynarque is only available through a restricted distribution program called the Jynarque Risk Evaluation and Mitigation Strategy (REMS) Program.

• Before you start treatment with Jynarque, you must enroll in the Jynarque REMS Program. Talk to your healthcare provider about how to enroll in the program.
• Jynarque can only be dispensed by a certified pharmacy that participates in the Jynarque REMS Program. Your healthcare provider can give you information on how to find a certified pharmacy.

Jynarque may cause serious side effects, including:

• Too much sodium in your blood (hypernatremia) and loss of too much body fluid (dehydration). In some cases, dehydration can lead to extreme loss of body fluid called hypovolemia. You should drink water when you are thirsty and throughout the day and night. Stop taking Jynarque and call your healthcare provider if you cannot drink enough water for any reason, such as not having access to water, or vomiting or diarrhea. Tell your healthcare provider if you get any of the following symptoms:
  • dizziness
  • fainting
  • weight loss
  • a change in the way your heart beats
  • feel confused or weak

The most common side effects of Jynarque include:

• thirst and drinking more fluid than normal
• making large amounts of urine, urinating often and urinating at night

These are not all the possible side effects of Jynarque.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Recommended Dosage

• The initial dosage for Jynarque is a total of 60 mg taken orally per day.
  • This dosage includes taking 45 mg on waking and then taking 15 mg 8 hours later.
• The dosage may be increased to 60 mg plus 30 mg, then to 90 mg plus 30 mg per day, if tolerated with at least weekly intervals between titrations.
• Patients may also decrease the dosage based on tolerability.
• Patients should drink enough water to avoid thirst or dehydration.

Monitoring

To mitigate the risk of significant or irreversible liver injury, perform blood testing for ALT, AST and bilirubin prior to initiation of Jynarque, at 2 and 4 weeks after initiation, monthly for 18 months and every 3 months thereafter. Monitor for concurrent symptoms that may indicate liver injury.

Missed Doses

If a dose of Jynarque is not taken at the scheduled time, take the next dose at its scheduled time.

Co-Administration With CYP 3A Inhibitors

CYP 3A Inhibitors

Concomitant use of strong CYP 3A inhibitors is contraindicated.

In patients taking concomitant moderate CYP 3A inhibitors, reduce the dose of Jynarque per Table 1. Consider further reductions if patients cannot tolerate the reduced dose. Interrupt Jynarque temporarily for short term therapy with moderate CYP 3A inhibitors if the recommended reduced doses are not available.

Table 1: Dose adjustment for patients taking moderate CYP 3A inhibitors

CYP 3A Inhibitors And Inducers

CYP 3A Inhibitors

• Tolvaptan's AUC was 5.4 times as large and Cmax was 3.5 times as large after co-administration of tolvaptan and 200 mg ketoconazole.
• Larger doses of the strong CYP 3A inhibitor would be expected to produce larger increases in tolvaptan exposure. Concomitant use of tolvaptan with strong CYP 3A inhibitors is contraindicated.
• Dose reduction of Jynarque is recommended for patients while taking moderate CYP 3A inhibitors.
• Patients should avoid grapefruit juice beverages while taking Jynarque.

Strong CYP 3A Inducers

• Co-administration of Jynarque with strong CYP 3A inducers reduces exposure to Jynarque.
• Avoid concomitant use of Jynarque with strong CYP 3A inducers.

OATP1B1/3 And OAT3 Transporter Substrates

• The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1/B3 and OAT3 in vitro.
• Patients who take Jynarque should avoid concomitant use with OATP1B1/B3 and OAT3 substrates (e.g., statins, bosentan, glyburide, nateglinide, repaglinide, methotrexate, furosemide), as the plasma concentrations of these substrates may be increased.

BCRP Transporter Substrates

• Tolvaptan is an inhibitor of BCRP. Patients who take Jynarque should avoid concomitant use with BCRP substrates (e.g., rosuvastatin).

V₂-Receptor Agonist

• As a V₂-receptor antagonist, tolvaptan will interfere with the V₂-agonist activity of desmopressin (dDAVP).
• Avoid concomitant use of Jynarque with a V₂-agonist.

• Available data with Jynarque use in pregnant women are insufficient to determine if there is a drug associated risk of adverse developmental outcomes.
• There are no data on the presence of tolvaptan in human milk, the effects on the breastfed infant, or the effects on milk production.
• Because of the potential for serious adverse reactions, including liver toxicity, electrolyte abnormalities (e.g., hypernatremia), hypotension, and volume depletion in breastfed infants, women should not breastfeed during treatment with Jynarque.