JYNARQUE SIDE EFFECTS
- Generic Name: tolvaptan tablets for oral use
- Brand Name: Jynarque
SIDE EFFECTS
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Serious Liver Injury
- Hypernatremia, Dehydration and Hypovolemia
- Drug Interactions with Inhibitors of CYP 3A
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 -NCT00428948: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Trial In Early, Rapidly-Progressing ADPKD
The TEMPO 3:4 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 1 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 1: 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) |
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| Number of Subjects | Proportion (%)* | Annualized Rate† | Number of Subjects | Proportion (%)* | Annualized Rate† | |
| Increased urination‡ | 668 | 69.5 | 28.6 | 135 | 28.0 | 10.3 |
| Thirst§ | 612 | 63.7 | 26.2 | 113 | 23.4 | 8.7 |
| Dry mouth | 154 | 16.0 | 6.6 | 60 | 12.4 | 4.6 |
| Fatigue | 131 | 13.6 | 5.6 | 47 | 9.7 | 3.6 |
| Diarrhea | 128 | 13.3 | 5.5 | 53 | 11.0 | 4.1 |
| Dizziness | 109 | 11.3 | 4.7 | 42 | 8.7 | 3.2 |
| Dyspepsia | 76 | 7.9 | 3.3 | 16 | 3.3 | 1.2 |
| Decreased appetite | 69 | 7.2 | 3.0 | 5 | 1.0 | 0.4 |
| Abdominal distension | 47 | 4.9 | 2.0 | 16 | 3.3 | 1.2 |
| Dry Skin | 47 | 4.9 | 2.0 | 8 | 1.7 | 0.6 |
| Rash | 40 | 4.2 | 1.7 | 9 | 1.9 | 0.7 |
| Hyperuricemia | 37 | 3.9 | 1.6 | 9 | 1.9 | 0.7 |
| Palpitations | 34 | 3.5 | 1.5 | 6 | 1.2 | 0.5 |
| * 100x (Number of subjects with an adverse event/N) † 100x (Number of subjects with an adverse event/Total subject years of drug exposure) ‡ Increased urination includes micturition urgency, nocturia, pollakiuria, polyuria § Thirst includes polydipsia and thirst |
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REPRISE-NCT02160145: A Phase 3, Randomized-Withdrawal, Placebo-Controlled, Double-Blind, Trial In Late Stage 2 To Early Stage 4 ADPKD
The REPRISE 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% [80/1637] versus 1.1% [13/1166], 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 estimate their frequency reliably or establish a causal relationship to drug exposure.
Hepatobiliary Disorders: Liver failure requiring transplant
Immune System Disorders: Anaphylaxis.
SRC: NLM .