Jynarque

JYNARQUE- tolvaptan
JYNARQUE- tolvaptan tablet
Otsuka America Pharmaceutical, Inc.

WARNING: RISK OF SERIOUS LIVER INJURY

JYNARQUE (tolvaptan) can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported [see Warnings and Precautions (5.1)].

Measure ALT, AST and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, then monthly for the first 18 months and every 3 months thereafter [see Warnings and Precautions (5.1)]. Prompt action in response to laboratory abnormalities, signs, or symptoms indicative of hepatic injury can mitigate, but not eliminate, the risk of serious hepatotoxicity.

Because of the risks of serious liver injury, JYNARQUE is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the JYNARQUE REMS Program [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The initial dosage for JYNARQUE is 60 mg orally per day as 45 mg taken on waking and 15 mg taken 8 hours later. Titrate 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 down-titrate based on tolerability. Encourage patients to drink enough water to avoid thirst or dehydration.

2.2 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 [see Warnings and Precautions (5.1)].

2.3 Missed Doses

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

2.4 Co-Administration with CYP 3A Inhibitors

CYP 3A Inhibitors

Concomitant use of strong CYP 3A inhibitors is contraindicated [see Contraindications (4) and Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.4) and Drug Interactions (7.1)]. 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
Standard Morning and Afternoon Dose (mg) Dose (mg) with Moderate CYP 3A Inhibitors
90 mg and 30 mg 45 mg and 15 mg
60 mg and 30 mg 30 mg and 15 mg
45 mg and 15 mg 15 mg and 15 mg

3 DOSAGE FORMS AND STRENGTHS

JYNARQUE (tolvaptan) is supplied as non-scored, blue, shallow-convex, immediate release tablets, debossed with “OTSUKA” and the tablet strength (mg) on one side.

JYNARQUE 15 mg tablets are triangular, 30 mg tablets are round, 45 mg tablets are square, 60 mg tablets are rectangular, and 90 mg tablets are pentagonal.

4 CONTRAINDICATIONS

JYNARQUE is contraindicated in patients:

5 WARNINGS AND PRECAUTIONS

5.1 Serious Liver Injury

JYNARQUE can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported in the post-marketing ADPKD experience. Discontinuation in response to laboratory abnormalities or signs or symptoms of liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice) can reduce the risk of severe hepatotoxicity.

In a 3-year placebo-controlled trial and its open-label extension (in which patients’ liver tests were monitored every 4 months), evidence of serious hepatocellular injury (elevations of hepatic transaminases of at least 3 times ULN combined with elevated bilirubin at least 2 times the ULN) occurred in 0.2% (3/1487) of tolvaptan treated patients compared to none of the placebo treated patients.

To reduce the risk of significant or irreversible liver injury, assess ALT, AST and bilirubin prior to initiation of JYNARQUE, at 2 weeks and 4 weeks after initiation, then monthly for 18 months and every 3 months thereafter.

At the onset of signs or symptoms consistent with hepatic injury or if ALT, AST, or bilirubin increase to >2 times ULN, immediately discontinue JYNARQUE, obtain repeat tests as soon as possible (within 48 to 72 hours), and continue testing as appropriate. If laboratory abnormalities stabilize or resolve, JYNARQUE may be reinitiated with increased frequency of monitoring as long as ALT and AST remain below 3 times ULN.

Do not restart JYNARQUE in patients who experience signs or symptoms consistent with hepatic injury or whose ALT or AST ever exceeds 3 times ULN during treatment with tolvaptan, unless there is another explanation for liver injury and the injury has resolved.

In patients with a stable, low baseline AST or ALT, an increase above 2 times baseline, even if less than 2 times upper limit of normal, may indicate early liver injury. Such elevations may warrant treatment suspension and prompt (48 to 72 hours) re-evaluation of liver test trends prior to reinitiating therapy with more frequent monitoring.

5.2 JYNARQUE REMS Program

JYNARQUE is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the JYNARQUE REMS Program, because of the risks of liver injury [see Warnings and Precautions (5.1)].

Notable requirements of the JYNARQUE REMS Program include the following:

  • Prescribers must be certified by enrolling in the REMS program.
  • Prescribers must inform patients receiving JYNARQUE about the risk of hepatotoxicity associated with its use and how to recognize the signs and symptoms of hepatotoxicity and the appropriate actions to take if it occurs.
  • Patients must enroll in the REMS program and comply with ongoing monitoring requirements [see Warnings and Precautions (5.1)].
  • Pharmacies must be certified by enrolling in the REMS program and must only dispense to patients who are authorized to receive JYNARQUE.

Further information, including a list of qualified pharmacies/distributors, is available at www.JYNARQUEREMS.com or by telephone at 1-877-726-7220.

5.3 Hypernatremia, Dehydration and Hypovolemia

JYNARQUE increases free water clearance and, as a result, may cause dehydration, hypovolemia and hypernatremia. Therefore, ensure abnormalities in sodium concentrations are corrected prior to initiation of therapy.

Instruct patients to drink water when thirsty, and throughout the day and night if awake. Monitor for weight loss, tachycardia and hypotension because they may signal dehydration.

In the two double-blind, placebo-controlled trials of patients with ADPKD, hypernatremia (defined as any serum sodium concentration >150 mEq/L) was observed in 4.0% versus 0.6% and 1.4% versus 0% of tolvaptan-treated versus placebo-treated patients, respectively. The rate of dehydration and hypovolemia in the two studies was 2.1% versus 0.7% and 2.3% versus 0.4% for tolvaptan-treated versus placebo-treated patients, respectively.

During JYNARQUE therapy, if serum sodium increases above normal range or the patient becomes hypovolemic or dehydrated and fluid intake cannot be increased, then suspend JYNARQUE until serum sodium, hydration status and volume status is within the normal range.

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