Jynarque

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

• Recommended dosage (
  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.
  )

  Initial Dosage		Titration Step		Target Dosage
  1st Dose	45 mg	1st Dose	60 mg	1st Dose	90 mg
  2nd Dose (8 hours later)	15 mg	2nd Dose (8 hours later)	30 mg	2nd Dose (8 hours later)	30 mg
  Total Daily Dose	60 mg	Total Daily Dose	90 mg	Total Daily Dose	120 mg

• Dose adjustment is recommended for patients taking moderate CYP3A inhibitors (
  2.4 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.

  Table 1: Dose adjustment for patients taking moderate CYP3A inhibitors

  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
  ,
  5.4 Co-Administration with Inhibitors of CYP3A

  Concomitant use of JYNARQUE with drugs that are moderate or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, ritonavir, and conivaptan) increases tolvaptan exposure

  [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)]

  . Use with strong CYP3A inhibitors is contraindicated; dose reduction of JYNARQUE is recommended for patients while taking moderate CYP3A inhibitors

  [see Dosage and Administration (2.4)and Contraindications (4)].
  ,
  7.1 CYP3A Inhibitors and Inducers

  CYP3A 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

  [see Warnings and Precautions (5.4)and Clinical Pharmacology (12.3)]

  . Larger doses of the strong CYP3A inhibitor would be expected to produce larger increases in tolvaptan exposure. Concomitant use of tolvaptan with strong CYP3A inhibitors is contraindicated

  [see Contraindications (4)].

  Dose reduction of JYNARQUE is recommended for patients while taking moderate CYP3A inhibitors

  [see Dosage and Administration (2.4)].

  Patients should avoid grapefruit juice beverages while taking JYNARQUE.

  Strong CYP3A Inducers

  Co-administration of JYNARQUE with strong CYP3A inducers reduces exposure to JYNARQUE

  [see Clinical Pharmacology (12.3)].

  Avoid concomitant use of JYNARQUE with strong CYP3A inducers

  [see Dosage and Administration (2.4)].
  )

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:

• Pregnancy: May cause fetal harm (
  8.1 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 (AUC_24h6570 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 C_maxvalues 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: Breastfeeding not recommended (
  8.2 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.
  )