Dosage & Administration
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Jynarque Prescribing Information
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 Tolvaptan for ADPKD Shared System REMS [see Warnings and Precautions (5.2)].
JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).
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.
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)].
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 CYP3A Inhibitors
CYP3A Inhibitors
Concomitant use of strong CYP3A inhibitors is contraindicated [see Contraindications (4) and Warnings and Precautions (5.4)].
In patients taking concomitant moderate CYP3A 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 CYP3A inhibitors if the recommended reduced doses are not available.
| Standard Morning and Afternoon Dose (mg) | Dose (mg) with Moderate CYP3A 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 |
JYNARQUE (tolvaptan) is supplied as non-scored, blue, shallow-convex, immediate release tablets, debossed with "OTSUKA" and the tablet strength (mg) on one side as follows:
| Strength | Shape |
|---|---|
| 15 mg | triangular |
| 30 mg | round |
| 45 mg | square |
| 60 mg | rectangular |
| 90 mg | pentagonal |
Pregnancy
Risk Summary
Available data with JYNARQUE use in pregnant women are insufficient to determine if there is a drug associated risk of adverse developmental outcomes. In embryo-fetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. At maternally non-toxic doses, tolvaptan did not cause any developmental toxicity in rats or in rabbits at exposures approximately 4- and 1-times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 90/30 mg. However, effects on embryo-fetal development occurred in both species at maternally toxic doses. In rats, reduced fetal weights and delayed fetal ossification occurred at 17 times the human exposure. In rabbits, increased abortions, embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations occurred at approximately 3 times the human exposure (see Data). Advise pregnant women of the potential risk to the fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.
Data
Animal Data
Oral administration of tolvaptan during the period of organogenesis in Sprague-Dawley rats produced no evidence of teratogenesis at doses up to 100 mg/kg/day. Lower body weights and delayed ossification were seen at 1000 mg/kg, which is approximately 17 times the human exposure at the 90/30 mg dose (AUC24h 6570 h∙ng/mL). The fetal effects are likely secondary to maternal toxicity (decreased food intake and low body weights). In a prenatal and postnatal study in rats, tolvaptan had no effect on physical development, reflex function, learning ability or reproductive performance at doses up to 1000 mg/kg/day.
In New Zealand White rabbits, placental transfer was demonstrated with Cmax values in the yolk sac fluid approximating 22.7% of the value in maternal rabbit serum. In embryo-fetal studies, teratogenicity (microphthalmia, embryo-fetal mortality, cleft palate, brachymelia and fused phalanx) was evident in rabbits at 1000 mg/kg (approximately 3 times the exposure at the 90/30 mg dose). Body weights and food consumption were lower in dams at all doses, equivalent to 0.6 to 3 times the human exposure at the 90/30 mg dose.
Lactation
Risk Summary
There are no data on the presence of tolvaptan in human milk, the effects on the breastfed infant, or the effects on milk production. Tolvaptan is present in rat milk. When a drug is present in animal milk, it is possible that the drug will be present in human milk, but relative levels may vary (see Data). Because of the potential for serious adverse reactions, including liver toxicity, electrolyte abnormalities (e.g., hypernatremia), hypotension, and volume depletion in breastfed infants, advise women not to breastfeed during treatment with JYNARQUE.
Data
In lactating rats administration of radiolabeled tolvaptan, lacteal radioactivity concentrations reached the highest level at 8 hours after administration and then decreased gradually with time with a half-life of 27.3 hours. The level of activity in milk ranged from 1.5- to 15.8-fold those in blood over the period of 72 hours post-dose. In a prenatal and postnatal study in rats, maternal toxicity was noted at 100 mg/kg/day or higher (≥4.4 times the human exposure at the 90/30 mg dose). Increased perinatal death and decreased body weight of the offspring were observed during the lactation period and after weaning at approximately 17.3 times the human exposure at the 90/30 mg dose.
Pediatric Use
Safety and effectiveness of JYNARQUE in pediatric patients have not been established.
Geriatric Use
Clinical studies of tolvaptan did not include sufficient numbers of subjects aged 65 years old and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Use in Patients with Hepatic Impairment
Because of the risk of serious liver injury, use is contraindicated in patients with a history, signs or symptoms of significant liver impairment or injury. This contraindication does not apply to uncomplicated polycystic liver disease which was present in 60% and 66% of patients in TEMPO 3:4 and REPRISE, respectively. No specific exclusion for hepatic impairment was implemented in TEMPO 3:4. However, REPRISE excluded patients with ADPKD who had hepatic impairment or liver function abnormalities other than that expected for ADPKD with typical cystic liver disease [see Contraindications (4)].
Use in Patients with Renal Impairment
Efficacy studies included patients with normal and reduced renal function [see Clinical Studies (14)]. TEMPO 3:4 required patients to have an estimated creatinine clearance ≥60 mL/min, while REPRISE included patients with eGFRCKD-Epi 25 to 65 mL/min/1.73m2.
JYNARQUE is contraindicated in patients:
- With a history, signs or symptoms of significant liver impairment or injury. This contraindication does not apply to uncomplicated polycystic liver disease [see Warnings and Precautions (5.1)]
- Taking strong CYP3A inhibitors
- With uncorrected abnormal blood sodium concentrations [see Warnings and Precautions (5.3)]
- Unable to sense or respond to thirst [see Warnings and Precautions (5.3)]
- Hypovolemia [see Warnings and Precautions (5.3)]
- Hypersensitivity (e.g., anaphylaxis, rash) to tolvaptan or any component of the product [see Adverse Reactions (6)]
- Uncorrected urinary outflow obstruction
- Anuria