Tolvaptan
Tablet · Oral
Uses
Tolvaptan tablet is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan tablet 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) ( 1 )
Dosage and administration
Recommended dosage ( 2.1 ) 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 CYP 3A inhibitors ( 2.4 , 5.4 , 7.1 ) 2.1 Recommended Dosage The initial dosage for tolvaptan tablets are 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 tolvaptan tablets, 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 tolvaptan tablet is not taken at the scheduled time, take the next dose at its scheduled time. 2.4 Co-Administration with CYP 3A Inhibitors CYP 3A Inhibitors Concomitant use of strong CYP 3A inhibitors is contraindicated [see Contraindications ( 4 ) and Warnings and Precautions ( 5.4 )] . In patients taking concomitant moderate CYP 3A inhibitors, reduce the dose of tolvaptan tablets 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 tolvaptan tablets temporarily for short term therapy with moderate CYP 3A inhibitors if the recommended reduced doses are not available. Table 1: Dose adjustment for patients taking moderate CYP 3A inhibitors Standard Morning and Afternoon Dose (mg) Dose (mg) with Moderate CYP 3A 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
Dosage forms and strengths
Tolvaptan tablets are supplied as Light blue to blue colored, mottled appearance, uncoated tablets, debossed with “TOL” on one side and the tablet strength (mg) on other side. Tolvaptan 15 mg tablets are round, 30 mg tablets are round, 45 mg tablets are square, 60 mg tablets are rectangular, and 90 mg tablets are pentagonal. Tablets: 15 mg, 30 mg, 45 mg, 60 mg and 90 mg ( 3 )
Contraindications
Tolvaptan tablets are 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 CYP 3A 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 History of signs or symptoms of significant liver impairment or injury, does not include uncomplicated polycystic liver disease ( 4 ) Concomitant use of strong CYP 3A inhibitors is contraindicated ( 4 ) Uncorrected abnormal blood sodium concentrations ( 4 , 5.3 ) Unable to sense or respond to thirst ( 4 ) Hypovolemia ( 4 ) Hypersensitivity to tolvaptan or any of its components ( 4 ) Uncorrected urinary outflow obstruction ( 4 ) Anuria ( 4 )
Warnings and precautions
Hypernatremia, dehydration and hypovolemia: May require intervention ( 5.3 ) 5.1 Serious Liver Injury Tolvaptan tablets 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 tolvaptan tablets, 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 greater than 2 times ULN, immediately discontinue tolvaptan tablets, obtain repeat tests as soon as possible (within 48 to 72 hours), and continue testing as appropriate. If laboratory abnormalities stabilize or resolve, tolvaptan tablets may be reinitiated with increased frequency of monitoring as long as ALT and AST remain below 3 times ULN. Do not restart tolvaptan tablets 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 to 72 hours) re-evaluation of liver test trends prior to reinitiating therapy with more frequent monitoring. 5.2 Tolvaptan Tablets REMS Program Tolvaptan tablets are available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the tolvaptan tablets REMS Program, because of the risks of liver injury [see Warnings and Precautions ( 5.1 )] . Notable requirements of the tolvaptan tablets REMS Program include the following: Prescribers must be certified by enrolling in the REMS program. Prescribers must inform patients receiving tolvaptan tablets 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 tolvaptan tablets. Further information, including a list of qualified pharmacies/distributors, is available at www.ascendlaboratories.com or by telephone at 1-877-272-7901. 5.3 Hypernatremia, Dehydration and Hypovolemia Tolvaptan tablets 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 greater than 150 mEq/L) was observed in 4% versus 0.6% and 1.4% versus 0% of tolvaptantreated 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 tolvaptan tablets therapy, if serum sodium increases above normal range or the patient becomes hypovolemic or dehydrated and fluid intake cannot be increased, then suspend tolvaptan tablets 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 tolvaptan tablets 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 tolvaptan tablets are recommended for patients while taking moderate CYP 3A inhibitors [see Dosage and Administration ( 2.4 ) and Contraindications ( 4 )].
Side effects
The following adverse reactions are discussed in more detail in other sections of the labeling: Serious Liver Injury [see Boxed Warning and Warnings and Precautions ( 5.1 )] Hypernatremia, Dehydration and Hypovolemia [see Warnings and Precautions ( 5.3 )] Drug Interactions with Inhibitors of CYP 3A [see Warnings and Precautions ( 5.4 )] Most common observed adverse reactions with tolvaptan tablets (incidence greater than 10% and at least twice that for placebo) were thirst, polyuria, nocturia, pollakiuria and polydipsia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Tolvaptan tablets have been studied in over 3,000 patients with ADPKD. Long-term, placebo-controlled safety information of tolvaptan tablets 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 tolvaptan tablets. Of these, 742 (77%) subjects who were treated with tolvaptan tablets 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 tolvaptan tablets group and 5% (24/483) of subjects in the placebo group. Aquaretic effects were the most common reasons for discontinuation of tolvaptan tablets. These included pollakiuria, polyuria, or nocturia in 63 (6.6%) subjects treated with tolvaptan tablets 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 tolvaptan tablets and at least 1.5% more than on placebo. Table 2: TEMPO 3:4, Treatment Emergent Adverse Reactions in ≥3% of Tolvaptan Tablets Treated Subjects with Risk Difference ≥ 1.5%, Randomized Period Adverse Reaction Tolvaptan (N=961) Placebo (N=483) Number of Subjects Proportion (%) * Annualized Rate † Number of Subjects Proportion (%) * Annualized Rate † Increased urination ‡ 668 69.5 28.6 135 28 10.3 Thirst § 612 63.7 26.2 113 23.4 8.7 Dry mouth 154 16 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 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 5 1 0.4 Abdominal distension 47 4.9 2 16 3.3 1.2 Dry skin 47 4.9 2 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 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 tolvaptan tablets prior to the randomized double-blind period. During the tolvaptan tablets titration and run-in period, 126 (8.4%) of the 1,496 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 greater than 3 times ULN were observed at an increased frequency with tolvaptan tablets 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. 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
Drug interactions
Avoid concomitant use with: Strong CYP 3A Inducers ( 7.1 ) V 2 -Receptor Agonists ( 7.2 ) 7.1 CYP 3A Inhibitors and Inducers CYP 3A Inhibitors Tolvaptan’s AUC was 5.4 times as large and C max 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 CYP 3A inhibitor would be expected to produce larger increases in tolvaptan exposure. Concomitant use of tolvaptan with strong CYP 3A inhibitors is contraindicated [see Contraindications ( 4 )]. Dose reduction of tolvaptan tablets is recommended for patients while taking moderate CYP 3A inhibitors [see Dosage and Administration ( 2.4 )]. Patients should avoid grapefruit juice beverages while taking tolvaptan tablets. Strong CYP 3A Inducers Co-administration of tolvaptan tablets with strong CYP 3A inducers reduces exposure to tolvaptan tablets [see Clinical Pharmacology ( 12.3 )]. Avoid concomitant use of tolvaptan tablets with strong CYP 3A inducers [see Dosage and Administration ( 2.4 )]. 7.2 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 tolvaptan tablets with a V 2 -agonist.
Use in specific populations
Pregnancy: May cause fetal harm ( 8.1 ) Lactation: Breastfeeding not recommended ( 8.2 ) 8.1 Pregnancy Risk Summary Available data with tolvaptan tablets 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 estimated 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 1,000 mg/kg, which is approximately 17-times the exposure in humans at the 90/30 mg dose (AUC 24h 6,570 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 1,000 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 1,000 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. 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 tolvaptan tablets. 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. 8.4 Pediatric Use Safety and effectiveness of tolvaptan tablets in pediatric patients have not been established. 8.5 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. 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 eGFRCKD-Epi 25 to 65 mL/min/1.73m 2 .
Pregnancy
8.1 Pregnancy Risk Summary Available data with tolvaptan tablets 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 estimated 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 1,000 mg/kg, which is approximately 17-times the exposure in humans at the 90/30 mg dose (AUC 24h 6,570 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 1,000 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 1,000 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
8.4 Pediatric Use Safety and effectiveness of tolvaptan tablets in pediatric patients have not been established.
Geriatric use
8.5 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.
Overdosage
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 2,000 mg/kg (maximum feasible dose). A single oral dose of 2,000 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 tolvaptan tablets 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 tolvaptan tablets because of its high binding affinity for human plasma protein (greater than 98%).
Description
Tolvaptan tablets contains tolvaptan, a selective vasopressin V 2 -receptor antagonist in immediate release tablets for oral administration available in 15 mg, 30 mg, 45 mg, 60 mg and 90 mg strengths. Tolvaptan is (±)-4’-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1 H -1-benzazepin-1-yl) carbonyl]- o -tolu- m -toluidide. The molecular formula is C 26 H 25 ClN 2 O 3 . Molecular weight is 448.94. The chemical structure is: Inactive ingredients include croscarmellose sodium, corn starch, FD&C Blue No. 2 Aluminium lake, hypromellose 2910, lactose monohydrate, magnesium stearate and microcrystalline cellulose. tolvaptan-structure
Mechanism of action
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 AVPstimulated 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.
How supplied
16.1 How Supplied Tolvaptan tablets are supplied as Light blue to blue colored, mottled appearance, uncoated tablets, debossed with “TOL” on one side and the tablet strength (mg) on other side. Tolvaptan 15 mg tablets are round, 30 mg tablets are round, 45 mg tablets are square, 60 mg tablets are rectangular, and 90 mg tablets are pentagonal. Tolvaptan tablets are supplied as: Morning and Afternoon Doses NDC 7-Day Blister Card (Containing 14 Tablets) 28-Day Carton (4 Blister Cards Containing a Total of 56 Tablets) 15 mg and 15 mg 67877-920-14 67877-920-54 30 mg and 15 mg 67877-921-14 67877-921-54 45 mg and 15 mg 67877-922-14 67877-922-54 60 mg and 30 mg 67877-923-14 67877-923-54 90 mg and 30 mg 67877-924-14 67877-924-54 30 Count Bottles NDC 15 mg 67877-915-30 30 mg 67877-916-30 45 mg 67877-917-30 60 mg 67877-918-30 90 mg 67877-919-30 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Patient information
As part of patient counseling, healthcare providers must review the tolvaptan tablets Medication Guide with every patient [see Medication Guide]. Serious Liver Injury Advise patients that blood testing is required before starting tolvaptan tablets, 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 Warnings and Precautions ( 5.1 )]. Advise patients to immediately stop taking tolvaptan tablets 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 Warnings and Precautions ( 5.1 ) ]. Tolvaptan tablets REMS Program Advise patients that tolvaptan tablets is only available through a restricted program called the tolvaptan tablets REMS Program [see Warnings 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 Warnings and Precautions ( 5.1 )] Advise patients that tolvaptan tablets is only available only through restricted distribution from certified specialty pharmacies participating in the tolvaptan tablets REMS program. Therefore, provide patients with the telephone number and web site for information on how to obtain the product [see Warnings 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 tolvaptan tablets 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 Warnings 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 tolvaptan tablets and inform their health care provider right away [see Warnings 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 tolvaptan tablets [se e Use in Specific Populations ( 8.2 )]. Manufactured by: Alkem Laboratories Ltd., Mumbai - 400 013, INDIA. Distributed by: Ascend Laboratories, LLC Bedminster, NJ 07921
Label text from the FDA structured product label by Ascend Laboratories, LLC (revised Aug 26, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Tolvaptan in 20 products
Tolvaptan NDC products (35)
Frequently asked questions
What is Tolvaptan used for?
Tolvaptan tablet is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan tablet 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) ( 1 )
What are the side effects of Tolvaptan?
The following adverse reactions are discussed in more detail in other sections of the labeling: Serious Liver Injury [see Boxed Warning and Warnings and Precautions ( 5.1 )] Hypernatremia, Dehydration and Hypovolemia [see Warnings and Precautions ( 5.3 )] Drug Interactions with Inhibitors of CYP 3A [see Warnings and Precautions ( 5.4 )] Most common observed adverse reactions with tolvaptan… See the full label for the complete list.
Who makes Tolvaptan?
Tolvaptan is listed by 8 labelers in the FDA NDC directory, including Apotex Corp., Ascend Laboratories, LLC, Camber Pharmaceuticals, Inc., Lupin Pharmaceuticals, Inc..