Tolvaptan

1 INDICATIONS AND USAGE Tolvaptan tablets are 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 )

2 DOSAGE AND ADMINISTRATION Recommended dosage ( 2.1 ) Initial Dosage Titration Step Target Dosage 1 st Dose 45 mg 1 st Dose 60 mg 1 st Dose 90 mg 2 nd Dose (8 hours later) 15 mg 2 nd Dose (8 hours later) 30 mg 2 nd 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 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. 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

3 DOSAGE FORMS AND STRENGTHS Tolvaptan tablets are supplied as: 15 mg: pink to light pink coloured, capsule shape, mottled tablets debossed with "F05" on one side and "LU" on other side. 30 mg: pink to light pink coloured, round shaped, flat faced bevelled edge mottled tablets debossed with "F06" on one side and "LU" on other side. 45 mg: pink to light pink coloured, octagonal shape, mottled tablets debossed with "LU" on one side and "F07" on other side. 60 mg: pink to light pink coloured, almond shaped, flat faced bevelled edge mottled tablets debossed with "LU" on one side and "F08" on other side. 90 mg: pink to light pink coloured, capsule shaped, biconvex mottled tablets debossed with "LU" on one side and "F09" on other side. Tablets: 15 mg, 30 mg, 45 mg, 60 mg and 90 mg ( 3 )

4 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 tablets 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 tablets or any of its components ( 4 ) Uncorrected urinary outflow obstruction ( 4 ) Anuria ( 4 )

6 ADVERSE REACTIONS 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 >10% and at least twice that for placebo) were thirst, polyuria, nocturia, pollakiuria and polydipsia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 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. 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 (%) 100x (Number of subjects with an adverse event/N) Annualized Rate 100x (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 10.3 Thirst Thirst includes polydipsia and 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 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 …

7 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.

8 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 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 mg/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 mg/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 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 mg/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 mg/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 mg/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 mg/30 mg dose. 8.4 Pediatric Use Safety and effectivene …

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.

11 DESCRIPTION Tolvaptan tablets contain 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 N-(4-(7-chloro-5-hydroxy-2, 3, 4, 5 - tetrahydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide. The empirical formula is C 26 H 25 ClN 2 O 3 . Molecular weight is 448.9. The chemical structure is: Inactive ingredients include corn starch, hydroxy propyl cellulose, lactose monohydrate, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose and red iron oxide. Image

10 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 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 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 (>98%).

16 HOW SUPPLIED/STORAGE AND HANDLING 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: 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 70748-240-11 70748-240-13 30 mg and 15 mg 70748-241-11 70748-241-13 45 mg and 15 mg 70748-242-11 70748-242-13 60 mg and 30 mg 70748-243-11 70748-243-13 90 mg and 30 mg 70748-244-11 70748-244-13 30 Count Bottles NDC 15 mg 70748-238-06 30 mg 70748-239-06 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].

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: 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 70748-240-11 70748-240-13 30 mg and 15 mg 70748-241-11 70748-241-13 45 mg and 15 mg 70748-242-11 70748-242-13 60 mg and 30 mg 70748-243-11 70748-243-13 90 mg and 30 mg 70748-244-11 70748-244-13 30 Count Bottles NDC 15 mg 70748-238-06 30 mg 70748-239-06