2.1 Recommended Dosage

The initial dosage for tolvaptan tablets 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 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 tablets 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.

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 >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 for ADPKD Shared System REMS

Tolvaptan tablets are 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 [see Warnings and Precautions (5.1)].

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 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.TolvaptanADPKDSharedREMS.com or by telephone at 1-866-244-9446.

5.3 Hypernatremia, Dehydration and Hypovolemia

Tolvaptan tablets increase 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% 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 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)].

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 3000 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.

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 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 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

7.1 CYP 3A Inhibitors and Inducers

CYP 3A 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 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 V2-Receptor Agonist

As a V2-receptor antagonist, tolvaptan will interfere with the V2-agonist activity of desmopressin (dDAVP). Avoid concomitant use of tolvaptan tablets with a V2-agonist.

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 1000 mg/kg, which is approximately 17-times the exposure in humans at the 90/30 mg dose (AUC24h 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 Cmax 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.

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/1.73 m2.

12.1 Mechanism of Action

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times that for the V1a- receptor. Decreased binding of vasopressin to the V2-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 V2-receptors compared with tolvaptan.

12.2 Pharmacodynamics

In healthy subjects or patients with eGFRs as low as 10 mL/min/1.73 m2 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 V2-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 m2, 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 m2, 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 to 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% to 10% and uric acid clearance is decreased about 20% to 25%. Percent changes in renal plasma flow are highly correlated to percent changes in GFR. These changes are reversed upon discontinuation of tolvaptan.

Cardiac Electrophysiology

No prolongation of the QT interval was observed with tolvaptan following multiple doses of 300 mg/day for 5 days.

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.

Absorption

In healthy subjects, peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Peak concentrations increase less than dose proportionally with doses greater than 240 mg.

The absolute bioavailability of tolvaptan decreases with increasing doses. The absolute bioavailability of tolvaptan following an oral dose of 30 mg is 56% (range 42 to 80%).

Co-administration of 90 mg tolvaptan tablets with a high-fat meal (~1000 calories, of which 50% are from fat) doubles peak concentrations but has no effect on the AUC of tolvaptan; tolvaptan may be administered with or without food.

Distribution

Tolvaptan binds to both albumin and α1-acid glycoprotein and the overall protein binding is >98%; binding is not affected by disease state. The volume of distribution of tolvaptan is about 3 L/kg. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. When administered as multiple once-daily 300 mg doses to healthy subjects or as split-dose regimens to patients with ADPKD, tolvaptan's accumulation factor is <1.2. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.

Metabolism and Elimination

Tolvaptan is metabolized almost exclusively by CYP 3A. Fourteen metabolites have been identified in plasma, urine and feces; all but one were also metabolized by CYP 3A and none are pharmacodynamically active. After oral administration of radiolabeled tolvaptan, tolvaptan was a minor component in plasma representing 3% of total plasma radioactivity; the oxobutyric acid metabolite was present at 52.5% of total plasma radioactivity with all other metabolites present at lower concentrations than tolvaptan. The oxobutyric acid metabolite shows a plasma half-life of ~180 h. About 40% of radioactivity was recovered in urine (<1% as unchanged tolvaptan) and 59% in feces (19% as unchanged tolvaptan). Following intravenous infusion, tolvaptan half-life is approximately 3 hours. Following single oral doses to healthy subjects, the estimated half-life of tolvaptan increases from 3 hours for a 15 mg dose to approximately 12 hours for 120 mg and higher doses due to more prolonged absorption of tolvaptan at higher doses; apparent clearance is approximately 4 mL/min/kg and does not appear to change with increasing dose.

Specific Populations:

Age, Gender and Race

Age, gender and race have no effect on tolvaptan pharmacokinetics.

Hepatic Impairment

In studies involving patients with hepatic impairment (Child-Pugh class A-C), but without ADPKD; moderate (class A, B) or severe (class C) hepatic impairment decreases the clearance and increases the volume of distribution of tolvaptan.

Renal Impairment

In subjects with creatinine clearances ranging from 10 to 124 mL/min administered a single dose of 60 mg tolvaptan, the AUC and Cmax of plasma tolvaptan was increased 90% and 10%, respectively, for subjects with clearances of <30 mL/min compared to subjects with clearances >60 mL/min [see Use in Special Populations (8.7)].

In ADPKD patients with estimated creatinine clearance >60 mL/min, pharmacokinetics were similar to healthy subjects.

Drug Interaction Studies

Impact of Other Drugs on Tolvaptan:

Strong CYP 3A Inhibitors

Tolvaptan's Cmax and AUC were, respectively, 3.5 times and 5.4 times as high following ketoconazole 200 mg given one day prior to and concomitantly with 30 mg tolvaptan.

Moderate CYP 3A4 Inhibitors

Fluconazole: Fluconazole 400 mg given one day prior and 200 mg given concomitantly produced an 80% and 200% increase in tolvaptan Cmax and AUC, respectively.

Grapefruit Juice: When 60 mg tolvaptan was taken with 240 mL regular strength grapefruit juice, tolvaptan Cmax and AUC increased 90% and 60%, respectively.

CYP 3A Inducers

Rifampin: Rifampin 600 mg once daily for 7 days followed by a single 240 mg dose of tolvaptan decreased both tolvaptan Cmax and AUC about 85%.

Other Drugs

Co-administration of lovastatin, digoxin, furosemide, and hydrochlorothiazide with tolvaptan has no clinically relevant impact on the exposure to tolvaptan.

Impact of Tolvaptan on Other Drugs: 

CYP 3A Substrates

Co-administration of lovastatin and tolvaptan increases the AUC of lovastatin and its active metabolite lovastatin-β hydroxy acid by 40% and 30%, respectively. These are non-clinically significant increases in exposure.

P-gp Substrates

Digoxin: Digoxin 0.25 mg was administered once daily for 12 days. Tolvaptan 60 mg, was co-administered once daily on Days 8 to 12. Digoxin Cmax and AUC were increased 30% and 20%, respectively.

Transporter Substrates

Tolvaptan is a substrate of P-gp and an inhibitor of P-gp and BCRP. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1 and OAT3. Co-administration of tolvaptan with rosuvastatin (BCRP substrate) did not have a clinically significant effect on rosuvastatin exposure. Rosuvastatin Cmax and AUCt increased 54% and 69%, respectively.

Administration of rosuvastatin (OATP1B1 substrate) or furosemide (OAT3 substrate) to healthy subjects with elevated oxobutyric acid metabolite plasma concentrations did not meaningfully alter the pharmacokinetics of rosuvastatin or furosemide.

Other Drugs

Co-administration of tolvaptan did not meaningfully alter the pharmacokinetics of warfarin, furosemide, hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of tolvaptan tablets was assessed in 2-year carcinogenicity studies in mice and rats. Tolvaptan was not tumorigenic in male or female rats at doses up to 1000 mg/kg/day (1.9 to 5.1 times the human exposure at the 90/30 mg dose), in male mice at doses up to 60 mg/kg/day (0.4 times the human exposure at the 90/30 mg dose) and to female mice at doses up to 100 mg/kg/day (0.7 times the human exposure at the 90/30 mg dose).

Mutagenesis

Tolvaptan was not clastogenic in the in vitro chromosomal aberration test in Chinese hamster lung fibroblast cells or the in vivo rat micronucleus assay and was not mutagenic in the in vitro bacterial reverse mutation assay.

Impairment of Fertility

In a fertility study in which male and female rats were administered tolvaptan orally at 100, 300 or 1000 mg/kg/day, altered estrous cycles due to prolongation of diestrus were observed in dams given 300 and 1000 mg/kg/day (9.7 and 17.3 times the human exposure at the 90/30 mg dose). Tolvaptan had no effect on copulation or fertility indices. There were also no effects on the incidences of early or late resorption, dead fetuses, pre- or post-implantation loss, external anomalies, or fetal body weights.

16.1 How Supplied

Tolvaptan tablets, 15 mg are pink to light pink coloured, capsule shape, mottled tablets debossed with "F05" on one side and "LU" on other side.

Tolvaptan tablets, 30 mg are pink to light pink coloured, round shaped, flat faced bevelled edge mottled tablets debossed with "F06" on one side and "LU" on other side.

Tolvaptan tablets, 45 mg are pink to light pink coloured, octagonal shape, mottled tablets debossed with "LU" on one side and "F07" on other side.

Tolvaptan tablets, 60 mg are pink to light pink coloured, almond shaped, flat faced bevelled edge mottled tablets debossed with "LU" on one side and "F08" on other side.

Tolvaptan tablets, 90 mg are pink to light pink coloured, capsule shaped, biconvex mottled tablets debossed with "LU" on one side and "F09" on other side.

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 to 30°C (59°F to 86°F) [see USP controlled Room Temperature].