Jynarque Drug Information
Generic name: TOLVAPTAN
Vasopressin V2 Receptor Antagonist [EPC]
Uses of Jynarque
is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). JYNARQUE is a selective vasopressin V 2 -receptor antagonist indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD)
Dosage & Administration of Jynarque
| 1st Dose | 45 mg |
|---|---|
| 2nd Dose (8 hours later) | 15 mg |
| 60 mg |
Side Effects of Jynarque
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. TEMPO 3:4: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Trial in Early, Rapidly-Progressing ADPKD The TEMPO 3:4 (NCT00428948) trial employed a two-arm, 2:1 randomization to tolvaptan or placebo, titrated to a maximally-tolerated total daily dose of 60 to 120 mg.
A total of 961 subjects with rapidly progressing ADPKD were randomized to JYNARQUE. Of these, 742 (77%) subjects who were treated with JYNARQUE remained on treatment for at least 3 years. The average daily dose in these subjects was 96 mg daily. Adverse events that led to discontinuation were reported for 15.4% (148/961) of subjects in the JYNARQUE group and 5.0% (24/483) of subjects in the placebo group.
Aquaretic effects were the most common reasons for discontinuation of JYNARQUE. These included pollakiuria, polyuria, or nocturia in 63 (6.6%) subjects treated with JYNARQUE compared to 1 subject (0.2%) treated with placebo. Table 2 lists the adverse reactions that occurred in at least 3% of ADPKD subjects treated with JYNARQUE and at least 1.5% more than on placebo. Table 2: TEMPO 3:4, Treatment Emergent Adverse Reactions in ≥3% of JYNARQUE Treated Subjects with Risk Difference ≥1.5%, Randomized Period Adverse Reaction Tolvaptan (N=961) Placebo (N=483) Number of Subjects Proportion (%) 100× (Number of subjects with an adverse event/N) Annualized Rate 100× (Number of subjects with an adverse event/Total subject years of drug exposure) Number of Subjects Proportion (%) Annualized Rate Increased urination Increased urination includes micturition urgency, nocturia, pollakiuria, polyuria 668 69.5 28.6 135 28.0
Thirst Thirst includes polydipsia and thirst 612 63.7 26.2 113 23.4 8.7
Dry mouth 154 16.0 6.6 60 12.4
Fatigue 131 13.6 5.6 47 9.7 3.6 Diarrhea 128 13.3 5.5 53
11.0
Dizziness 109 11.3 4.7 42 8.7 3.2 Dyspepsia 76 7.9 3.3 16
3.3
Decreased appetite 69 7.2 3.0 5 1.0 0.4 Abdominal distension 47 4.9
2.0 16 3.3
Dry skin 47 4.9 2.0 8 1.7 0.6 Rash 40 4.2 1.7
9 1.9
Hyperuricemia 37 3.9 1.6 9 1.9 0.7 Palpitations 34 3.5 1.5 6
1.2
REPRISE
A Phase 3, Randomized-Withdrawal, Placebo-Controlled, Double-Blind, Trial in Late Stage 2 to Early Stage 4 ADPKD The REPRISE (NCT02160145) trial employed a 5-week single-blind titration and run-in period for JYNARQUE prior to the randomized double-blind period. During the JYNARQUE titration and run-in period, 126 (8.4%) of the 1496 subjects discontinued the study, 52 (3.5%) were due to aquaretic effects and 10 (0.7%) were due to liver test findings. Because of this run-in design, the adverse reaction rates observed during the randomized period are not described.
Liver Injury In the two double-blind, placebo-controlled trials, ALT elevations >3 times ULN were observed at an increased frequency with JYNARQUE compared with placebo (4.9% versus 1.1%, respectively) within the first 18 months after initiating treatment and increases usually resolved within 1 to 4 months after discontinuing the drug.
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 reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary Disorders: Liver failure requiring transplant Immune System Disorders: Anaphylaxis
Warnings & Cautions for Jynarque
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 the upper limit of normal 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 the 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 the 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 the ULN, 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.
Tolvaptan for
ADPKD Shared System REMS 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, because of the risks of liver injury . Notable requirements of the Tolvaptan for ADPKD Shared System REMS 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.
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.TolvaptanADPKDSharedREMS.com or by telephone at 1-866-244-9446.
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.
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 . Use with strong CYP3A inhibitors is contraindicated; dose reduction of JYNARQUE is recommended for patients while taking moderate CYP3A inhibitors.
Drug Interactions with Jynarque
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 . 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. Dose reduction of JYNARQUE is recommended for patients while taking moderate CYP3A inhibitors.
Patients should avoid grapefruit juice beverages while taking JYNARQUE. Strong CYP3A Inducers Co-administration of JYNARQUE with strong CYP3A inducers reduces exposure to JYNARQUE. Avoid concomitant use of JYNARQUE with strong CYP3A inducers.
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.
Pregnancy Safety for Jynarque
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 24h 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 C max 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.
Pediatric Use of Jynarque
Pediatric Use Safety and effectiveness of JYNARQUE in pediatric patients have not been established.
Contraindications for 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 Taking strong CYP3A inhibitors With uncorrected abnormal blood sodium concentrations Unable to sense or respond to thirst Hypovolemia Hypersensitivity (e.g., anaphylaxis, rash) to tolvaptan or any component of the product Uncorrected urinary outflow obstruction Anuria History of signs or symptoms of significant liver impairment or injury, does not include uncomplicated polycystic liver disease Concomitant use of strong CYP3A inhibitors is contraindicated Uncorrected abnormal blood sodium concentrations Unable to sense or respond to thirst Hypovolemia Hypersensitivity to tolvaptan or any of its components Uncorrected urinary outflow obstruction Anuria
Overdosage Information for Jynarque
Single oral doses up to 480 mg (4 times the maximum recommended daily dose) and multiple doses up to 300 mg once daily for 5 days have been well tolerated in trials in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia.
No mortality was observed in rats or dogs following single oral doses of 2000 mg/kg (maximum feasible dose). A single oral dose of 2000 mg/kg was lethal in mice, and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia. In patients with suspected JYNARQUE overdosage, assessment of vital signs, electrolyte concentrations, ECG and fluid status is recommended. Continue replacement of water and electrolytes until aquaresis abates.
Dialysis may not be effective in removing JYNARQUE because of its high binding affinity for human plasma protein (>98%).
Clinical Studies of Jynarque
was shown to slow the rate of decline in renal function in adult patients at risk of rapidly progressing ADPKD in two trials: TEMPO 3:4 in patients at earlier stages of disease and REPRISE in patients at later stages. The findings from these trials, when taken together, suggest that JYNARQUE slows the loss of renal function progressively through the course of the disease. TEMPO 3:4: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Trial in Early, Rapidly-Progressing ADPKD In TEMPO 3:4 (NCT00428948), 1445 adult patients (age >18 years) with early (estimated creatinine clearance ≥60 mL/min), rapidly-progressing (total kidney volume ≥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 to 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 to 89 mL/min/1.73 m 2, 14% had an eGFR of 45 to 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. Event Tolvaptan Placebo Hazard Ratio, 95% CI Total Number of Events (Events per 100 person-years) Number of Subjects with an Event (percentage) Total Number of Events (Events per 100 person-years) Number of Subjects with an Event (percentage) Composite 1049 572 665 341 0.87 Worsening Kidney Function 44 42 64 61 0.39 Kidney Pain 113 95 97 78 0.64 Onset or Progression of Hypertension 734 426 426 244 0.94 Worsening Albuminuria 195 195 103 101 1.04 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. 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: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Withdrawal Trial in Later-Stage ADPKD REPRISE (NCT02160145) was a double-blind, placebo-controlled randomized withdrawal trial in adult patients (age 18 to 65 years) with chronic kidney disease (CKD) with an eGFR between 25 and 65 mL/min/1.73m 2 if younger than age 56 years, 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 to 65 years.
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 to 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 to 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.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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