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

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 48-72 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 (48-72 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.

5.4 Co-Administration with Inhibitors of CYP 3A

Concomitant use of JYNARQUE with drugs that are moderate or strong CYP 3A 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 CYP 3A inhibitors is contraindicated; dose reduction of JYNARQUE is recommended for patients while taking moderate CYP 3A inhibitors [see Dosage and Administration (2.4) and Contraindications (4)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. JYNARQUE has been studied in over 3000 patients with ADPKD. Long-term, placebo-controlled safety information of JYNARQUE in ADPKD is principally derived from two trials where 1,413 subjects received tolvaptan and 1,098 received placebo for at least 12 months across both studies.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tolvaptan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.

Hepatobiliary Disorders: Liver failure requiring transplant

Immune System Disorders: Anaphylaxis

7.1 CYP 3A Inhibitors and Inducers

7.2 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 [see Clinical Pharmacology (12.3)] .

7.3 BCRP Transporter Substrates

Tolvaptan is an inhibitor of BCRP. Patients who take JYNARQUE should avoid concomitant use with BCRP substrates (e.g., rosuvastatin) [see Clinical Pharmacology (12.3)] .

7.4 V 2-Receptor Agonist

As a V 2-receptor antagonist, tolvaptan will interfere with the V 2-agonist activity of desmopressin (dDAVP). Avoid concomitant use of JYNARQUE with a V 2-agonist.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of JYNARQUE in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of tolvaptan did not include sufficient numbers of subjects aged 65 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.

8.6 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)].

8.7 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 eGFR CKD-Epi 25 to 65 mL/min/1.73m 2.

12.1 Mechanism of Action

Tolvaptan is a selective vasopressin V 2-receptor antagonist with an affinity for the V 2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2-receptor is 29 times that for the V 1a-receptor. Decreased binding of vasopressin to the V 2-receptor in the kidney lowers adenylate cyclase activity resulting in a decrease in intracellular adenosine 3', 5'-cyclic monophosphate (cAMP) concentrations. Decreased cAMP concentrations prevent aquaporin 2 containing vesicles from fusing with the plasma membrane, which in turn causes an increase in urine water excretion, an increase in free water clearance (aquaresis) and a decrease in urine osmolality. In human ADPKD cyst epithelial cells, tolvaptan inhibited AVP-stimulated in vitro cyst growth and chloride-dependent fluid secretion into cysts. In animal models, decreased cAMP concentrations were associated with decreases in the rate of growth of total kidney volume and the rate of formation and enlargement of kidney cysts. Tolvaptan metabolites have no or weak antagonist activity for human V 2-receptors compared with tolvaptan.

12.2 Pharmacodynamics

In healthy subjects or patients with eGFRs as low as 10 mL/min/1.73m 2 receiving a single dose of tolvaptan, the onset of the aquaretic effects occurs within 1 to 2 hours post-dose. In healthy subjects, single doses of 60 mg and 90 mg produce a peak effect of about a 9 mL/min increase in urine excretion rate is observed between 4 and 8 hours post-dose. Higher doses of tolvaptan do not increase the peak effect in urine excretion rate but sustain the effect for a longer period of time.

Urine excretion rate returns to baseline within 24 hours following the maximum recommended 90 mg dose of tolvaptan.

Changes in free water clearance mirror the changes in urine excretion rate. Increased free water clearance causes an increase in serum sodium concentration unless fluid intake is increased to match urine output.

Increases in urine excretion rate and free water clearance are positively correlated with baseline glomerular filtration rate with increases in both values observed in patients with creatinine clearance as low as 15 mL/min.

With the recommended split-dose regimens, tolvaptan inhibits vasopressin from binding to the V 2-receptor in the kidney for the entire day, as indicated by increased urine output and decreased urine osmolality. Following a 90/30 mg split-dose regimen in patients with eGFR >60 mL/min/1.73 m 2, the change in mean daily urine volume was about 4 L for a mean total daily volume of about 7 L. In patients with eGFR <30 mL/min/1.73 m 2, the mean change in daily urine volume was about 2 L for a total daily urine volume of about 5 L.

Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan treatment and return to baseline levels when treatment is stopped.

During tolvaptan treatment, small changes in renal function are expected and the changes are independent of baseline renal function. Glomerular filtration rate is decreased about 6%-10% and uric acid clearance is decreased about 20%-25%. Percent changes in renal plasma flow are highly correlated to percent changes in GFR. These changes are reversed upon discontinuation of tolvaptan.

12.3 Pharmacokinetics

In healthy subjects, the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been studied. In ADPKD patients, single doses up to 120 mg and multiple split-doses up to 90/30 mg have been studied.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

TEMPO 3:4 -NCT00428948: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Trial in Early, Rapidly-Progressing ADPKD

In TEMPO 3:4, 1445 adult patients (age >18 years) with early (estimated creatinine clearance [eCrCl] ≥60 mL/min), rapidly-progressing (total kidney volume [TKV] ≥750 mL and age <51 years) ADPKD (diagnosed by modified Ravine criteria) were randomized 2:1 to treatment with tolvaptan or placebo. Patients were treated for up to 3 years; patients who discontinued medication prematurely were only required to attend clinic visits to assess renal function for up to 42 days after treatment withdrawal and to attend telephone visits at all scheduled visits for up to 36 months. Patients who completed treatment at the 3‑year visit had treatment interrupted for 2-6 weeks to assess renal function post treatment. Patients received treatment twice a day (first dose on waking, second dose approximately 9 hours later). Patients were initiated on 45 mg/15 mg, and up-titrated weekly to 60 mg/30 mg and then to 90 mg/30 mg as tolerated. Patients were to maintain the highest tolerated dose for 3 years, but could interrupt, decrease and/or increase as clinical circumstances warranted within the range of titrated doses. All patients were encouraged to drink adequate water to avoid thirst or dehydration and before bedtime.

The primary endpoint was the intergroup difference for rate of change of TKV normalized as a percentage. The key secondary composite endpoint (ADPKD progression) was time to multiple clinical progression events of: 1) worsening kidney function (defined as a persistent 25% reduction in reciprocal serum creatinine during treatment from end of titration to last on-drug visit); 2) medically significant kidney pain (defined as requiring prescribed leave, last-resort analgesics, narcotic and anti-nociceptive, radiologic or surgical interventions); 3) worsening hypertension (defined as a persistent increase in blood pressure category or an increased anti-hypertensive prescription); 4) worsening albuminuria (defined as a persistent increase in albumin/creatinine ratio category).

At baseline, average estimated glomerular filtration rate (eGFR) was 82 mL/min/1.73 m 2 (CKD-Epidemiology formula) and mean TKV was 1692 mL (height adjusted 972 mL/m). Approximately 35% had an eGFR of 90 mL/min/1.73 m 2 or greater, 48% had an eGFR between 60-89 mL/min/1.73 m 2, 14% had an eGFR of 45-60 mL/min/1.73 m 2, and 3% had an eGFR of <45 mL/min/1.73 m 2. The subjects' mean age was 39 years, 48% were female, 84% were Caucasian, 13% were Asian, and 1.7% were Black or African-American. Approximately 80% had hypertension and approximately 71% were taking an agent that acts on the renin-angiotensin system. Of the 770 subjects who submitted to genetic analysis in TEMPO 3:4's open-label extension, 749 (97%) had an identifiable mutation in the PKD1 (656 or 88%), or PKD2 (93 or 12%) gene.

The trial met its prespecified primary endpoint of 3‑year change in TKV (p<0.0001). The difference in TKV between treatment groups mostly developed within the first year, the earliest assessment, with little further difference in years two and three. In years 4 and 5 during the TEMPO 3:4 extension trial, both groups received JYNARQUE and the difference between the groups in TKV was not maintained. Tolvaptan has little effect on kidney size beyond what accrues during the first year of treatment.

The relative rate of ADPKD-related events was decreased by 13.5% in tolvaptan-treated patients, (44 vs. 50 events per 100 person-years; hazard ratio, 0.87; 95% CI, 0.78 to 0.97; p=0.0095). As shown in the table below, the result of the key secondary composite endpoint was driven by effects on worsening kidney function and kidney pain events. In contrast, there was no effect of tolvaptan on either progression of hypertension or albuminuria. Few subjects in either arm required a radiologic or surgical intervention for kidney pain. Most kidney pain events reflected use of a medication to treat pain such as use of paracetamol, tricyclic antidepressants, narcotics and other non-narcotic agents.

The third endpoint (kidney function slope) was assessed as slope of eGFR during treatment (from end of titration to last on-drug visit). The estimated difference in the annual rate of change in those who contributed to the analysis was 1.0 mL/min/1.73m 2/year with a 95% confidence interval of (0.6, 1.4). Of the subjects enrolled in the trial, 5% of subjects in the tolvaptan arm and 2% in the placebo arm either had missing baseline data or discontinued from treatment prior to the end of the titration visit and hence were excluded from the analysis. In the extension trial, eGFR differences produced by the third year of the TEMPO 3:4 trial were maintained over the next 2 years of JYNARQUE treatment.

The efficacy profile was generally consistent across subgroups of interest for this indication; few Black or African-American patients were enrolled in the trial.

REPRISE-NCT02160145: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Withdrawal Trial in Later-Stage ADPKD

REPRISE was a double-blind, placebo-controlled randomized withdrawal trial in adult patients (age 18-65) with chronic kidney disease (CKD) with an eGFR between 25 and 65 mL/min/1.73m 2 if younger than age 56; or eGFR between 25 and 44 mL/min/1.73m 2, plus eGFR decline >2.0 mL/min/1.73m 2/year if between age 56-65. Subjects were to be treated for 12 months; after completion of treatment, patients entered a 3‑week follow-up period to assess renal function. The primary endpoint was the treatment difference in the change of eGFR from pre-treatment baseline to post-treatment follow-up, annualized by dividing by each subject's treatment duration.

Prior to randomization, patients were required to complete sequential single-blind run-in periods during which they received placebo for 1 week, followed by tolvaptan titration for 2 weeks, and then treatment with tolvaptan at the highest tolerated dose achieved during titration for 3 weeks. During the titration period, tolvaptan was up-titrated every 3-4 days from a daily oral dose of 30 mg/15 mg to 45 mg/15 mg, 60 mg/30 mg and up to a maximum dose of 90 mg/30 mg. Only patients who could tolerate the two highest doses of tolvaptan (60 mg/30 mg or 90 mg/30 mg) for the subsequent 3 weeks were randomized 1:1 to treatment with tolvaptan or placebo.

Patients were maintained on their highest tolerated dose for a period of 12 months but could interrupt, decrease and/or increase as clinical circumstances warranted within the range of titrated doses. All patients were encouraged to start drinking an adequate amount of water at screening and continuing through the end of the trial to avoid thirst or dehydration.

A total of 1519 subjects were enrolled in the study. Of these, 1370 subjects successfully completed the pre-randomization period and were randomized and treated during the 12‑month double-blind period. Because 57 subjects did not complete the off-treatment follow-up period, 1313 subjects were included in the primary efficacy analysis.

For subjects randomized, the baseline, average estimated glomerular filtration rate (eGFR) was 41 mL/min/1.73 m 2 (CKD-Epidemiology formula) and historical TKV, available in 318 (23%) of subjects, averaged 2026 mL. Approximately 5%, 75% and 20% had an eGFR 60 mL/min/1.73 m 2 or greater, between 30-59 mL/min/1.73 m 2, and between 25 and 29 mL/min/1.73 m 2, respectively. The subjects' mean age was 47 years, 50% were female, 92% were Caucasian, 4% Black or African-American and 3% were Asian, 93% had hypertension, and 87% of subjects were taking antihypertensive agents affecting the angiotensin converting enzyme or receptor. Of the 115 (8%) of subjects who had prior genetic tests, only 54 (47%) knew their results with 48 (89%) of these having PKD1 and 6 (11%) having PKD2 mutations.

In the randomized period, the change of eGFR from pretreatment baseline to post-treatment follow-up was –2.3 mL/min/1.73 m 2/year with tolvaptan as compared with –3.6 mL/min/1.73 m 2/year with placebo, corresponding to a treatment effect of 1.3 mL/min/1.73 m 2/year (p <0.0001). The key secondary endpoint (eGFR slope in ml/min/1.73 m 2/year assessed using a linear mixed effect model of annualized eGFR (CKD-EPI)) showed a difference between treatment groups of 1.0 ml/min/ m 2/year that was also statistically significant (p <0.0001).

The efficacy profile was generally consistent across subgroups of interest for this indication; few Black or African-American patients were enrolled in the trial.

16.1 How Supplied

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 (tolvaptan) 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.

JYNARQUE (tolvaptan) tablets are supplied as:

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP controlled Room Temperature].

Serious Liver Injury

Advise patients that blood testing is required before starting JYNARQUE, at 2 weeks and 4 weeks after initiation, then monthly during the first 18 months of therapy and every 3 months thereafter as a requirement to reduce the risk of serious liver injury [see Boxed Warning and Warning and Precautions (5.1)].

Advise patients to immediately stop taking JYNARQUE and notify their healthcare provider if they have symptoms or signs (e.g., abnormal transaminase elevations) of hepatic injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort or tenderness, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice) [see Warning and Precautions (5.1)].

JYNARQUE REMS Program

Advise patients that JYNARQUE is only available through a restricted program called the JYNARQUE REMS Program [see Warning and Precautions (5.2)]. Inform the patient of the following notable requirement:

• Patients must enroll in the program and comply with ongoing monitoring requirements [see Warning and Precautions (5.1)]

Advise patients that JYNARQUE is only available only through restricted distribution from certified specialty pharmacies participating in the JYNARQUE REMS program. Therefore, provide patients with the telephone number and web site for information on how to obtain the product [see Warning and Precautions (5.2)].

Hypernatremia, Dehydration and Hypovolemia

Advise patients to drink water to avoid thirst, throughout the day and night. Patients should stop taking JYNARQUE and notify their healthcare provider if they have symptoms or signs of sodium imbalance or dehydration (e.g., dizziness, fainting, weight loss, palpitations, confusion, weakness, gait instability) [see Warning and Precautions (5.3)]. Advise the patient that if they cannot drink enough water for any reason (no access to water, cannot sense thirst, unable to maintain hydration due to vomiting, diarrhea) they should stop taking JYNARQUE and inform their health care provider right away [see Warning and Precautions (5.3)] .

Pregnancy

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed during treatment with JYNARQUE [see Use in Specific Populations (8.2)].