Samsca

Tolvaptan.

Each tablet also contains the following inactive ingredients: Corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C blue no. 2 aluminum lake as colorant.
Tolvaptan is (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-o-tolu-m-toluidide. Its empirical formula is C₂₆H₂₅ClN₂O₃ and molecular weight is 448.94.

Pharmacology: Pharmacodynamics: In healthy subjects receiving a single dose of Samsca 60 mg, the onset of the aquaretic and sodium increasing effects occurs within 2-4 hrs post-dose. A peak effect of about a 6-mEq increase in serum sodium and about 9 mL/min increase in urine excretion rate is observed between 4 and 8 hrs post-dose; thus, the pharmacological activity lags behind the plasma concentrations of tolvaptan. About 60% of the peak effect on serum sodium is sustained at 24 hrs post-dose, but the urinary excretion rate is no longer elevated by this time. Tolvaptan doses >60 mg do not increase aquaresis or serum sodium further. The effects of tolvaptan in the recommended dose range of 15-60 mg once daily appear to be limited to aquaresis and the resulting increase in sodium concentration.
In a parallel-arm, double-blind (for tolvaptan and placebo), placebo- and positive-controlled, multiple-dose study of the effect of tolvaptan on the QTc interval, 172 healthy subjects were randomized to tolvaptan 30 mg, tolvaptan 300 mg, placebo or moxifloxacin 400 mg once daily. At both, the 30-mg and 300-mg doses, no significant effect of administering tolvaptan on the QTc interval was detected on day 1 and 5. At the 300-mg dose, peak tolvaptan plasma concentrations were approximately 4-fold higher than the peak concentrations following a 30-mg dose. Moxifloxacin increased the QT interval by 12 millisec at 2 hrs after dosing on day 1 and 17 millisec at 1 hr after dosing on day 5, indicating that the study was adequately designed and conducted to detect tolvaptan's effect on the QT interval, had an effect been present.
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 greater than for the V_1a-receptor. When taken orally, tolvaptan 15-60 mg doses antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality and a resulting increase in serum sodium concentrations. Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V₂-receptors compared with tolvaptan.
Plasma concentrations of native AVP may increase (average 2-9 pg/mL) with tolvaptan administration.
Clinical Studies: Hyponatremia: In 2 double-blind, placebo-controlled, multicenter studies (SALT-1 and SALT-2), a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) resulting from a variety of underlying causes [heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone (SIADH) and others] were treated for 30 days with tolvaptan or placebo, then followed for an additional 7 days after withdrawal. Symptomatic patients, patients likely to require saline therapy during the course of therapy, patients with acute and transient hyponatremia associated with head trauma or postoperative state and patients with hyponatremia due to primary polydipsia, uncontrolled adrenal insufficiency or uncontrolled hypothyroidism were excluded. Patients were randomized to receive either placebo (N=220) or tolvaptan (N=223) at an initial oral dose of 15 mg once daily. The mean serum sodium concentration at study entry was 129 mEq/L. Fluid restriction was to be avoided if possible during the first 24 hrs of therapy to avoid overly rapid correction of serum sodium and during the first 24 hrs of therapy, 87% of patients had no fluid restriction. Thereafter, patients could resume or initiate fluid restriction (defined as daily fluid intake of ≤1 L/day) as clinically indicated.
The dose of tolvaptan could be increased at 24-hr intervals to 30 mg once daily, then to 60 mg once daily, until either the maximum dose of 60 mg or normonatremia (serum sodium >135 mEq/L) was reached. Serum sodium concentrations were determined at 8 hrs after study drug initiation and daily up to 72 hrs, within which time titration was typically completed. Treatment was maintained for 30 days with additional serum sodium assessments on days 11, 18, 25 and 30. On the day of study discontinuation, all patients resumed previous therapies for hyponatremia and were reevaluated 7 days later. The primary endpoint for these studies was the average daily area under the concentration-time curve (AUC) for change in serum sodium from baseline to day 4 and baseline to day 30 in patients with a serum sodium <135 mEq/L. Compared to placebo, tolvaptan caused a statistically greater increase in serum sodium (p<0.0001) during both periods in both studies (see Table 1). For patients with a serum sodium of <130 mEq/L or <125 mEq/L, the effects at day 4 and day 30 remained significant (see Table 1). This effect was also seen across all disease etiology subsets [eg, congestive heart failure (CHF), cirrhosis, SIADH/other].

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In patients with hyponatremia (defined as <135 mEq/L), serum sodium concentration increased to a significantly greater degree in tolvaptan-treated patients compared to placebo-treated patients as early as 8 hrs after the 1st dose and the change was maintained for 30 days. The percentage of patients requiring fluid restriction (defined as ≤1 L/day at any time during the treatment period) was also significantly less (p<0.0017) in the tolvaptan-treated group (30/215, 14%) as compared with the placebo-treated group (51/206, 25%).
Figure 1 shows the change from baseline in serum sodium by visit in patients with serum sodium <135 mEq/L. Within 7 days of tolvaptan discontinuation, serum sodium concentrations in tolvaptan-treated patients declined to levels similar to those of placebo-treated patients.

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Click on icon to see table/diagram/image

In the open-label study SALTWATER, 111 patients, 94 of them hyponatremic (serum sodium <135 mEq/L), previously on tolvaptan or placebo therapy were given tolvaptan as a titrated regimen (15-60 mg once daily) after having returned to standard care for at least 7 days. By this time, their baseline mean serum sodium concentration had fallen to between their original baseline and post-placebo therapy level. Upon initiation of therapy, average serum sodium concentrations increased to approximately the same levels as observed for those previously treated with tolvaptan and were sustained for at least a year. Figure 3 shows results from 111 patients enrolled in the SALTWATER Study.

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Heart Failure: In a phase 3 double-blind, placebo-controlled study (EVEREST), 4133 patients with worsening heart failure were randomized to tolvaptan or placebo as an adjunct to standard of care. Long-term tolvaptan treatment (mean duration of treatment of 0.75 years) had no demonstrated effect, either favorable or unfavorable, on all-cause mortality [HR (95% CI): 0.98 (0.9, 1.1)] or the combined endpoint of cardiovascular mortality or subsequent hospitalization for worsening heart failure [HR (95% CI): 1 (0.9, 1.1)].
Adjunct Treatment of Volume Overload in Heart Failure (Japanese Data): The efficacy of oral administration of Samsca at 15 mg for 7 days in congestive heart failure patients with volume overload despite the use of a conventional diuretic was evaluated in a double-blind phase 3 study. Changes in body weight from baseline at the end of treatment, the primary efficacy endpoint, were -1.54±1.61 kg (mean±SD) in the Samsca 15-mg group (baseline: 59.42±12.3 kg, n=53) and -0.45±0.93 kg in the placebo group (baseline: 55.68±12.6 kg, n=57), showing that Samsca 15 mg significantly decreased body weight compared with placebo (p<0.0001, t-test). A marked reduction in body weight was observed in the Samsca 15-mg group on day 1, with subsequent decrease during the treatment period (see Figure 4). Signs and symptoms associated with cardiac edema, including jugular venous distention, hepatomegaly and lower limb edema, were also improved at the end of treatment (see Table 2).

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Click on icon to see table/diagram/image

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 examined. Area under the concentration-time curve increases proportionally with dose. After administration of doses ≥60 mg, however, maximum plasma concentration (C_max) increases less than proportionally with dose. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is approximately 56%. At least 40% of the dose is absorbed as tolvaptan or metabolites. Peak concentrations of tolvaptan are observed between 2 and 4 hrs post-dose. Food does not impact the bioavailability of tolvaptan. In vitro data indicate that tolvaptan is a substrate and inhibitor of P-gp. Tolvaptan is highly plasma protein bound (99%) and distributed into an apparent volume of distribution of about 3 L/kg. Tolvaptan is eliminated entirely by nonrenal routes and mainly, if not exclusively, metabolized by CYP3A. After oral dosing, clearance is about 4 mL/min/kg and the terminal phase half-life (t_½) is about 12 hrs. The accumulation factor of tolvaptan with the once-daily regimen is 1.3 and the trough concentrations amount to ≤16% of the peak concentrations, suggesting a dominant t_½ somewhat shorter than 12 hrs. There is marked intersubject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30% and 60%.
In patients with hyponatremia of any origin, the clearance of tolvaptan is reduced to about 2 mL/min/kg. Moderate or severe hepatic impairment or congestive heart failure decrease the clearance, and increase the volume of distribution of tolvaptan, but the respective changes are not clinically relevant. Exposure and response to tolvaptan in subjects with creatinine clearance (CrCl) ranging between 79 and 10 mL/min and patients with normal renal function are not different.
Special Populations: Use in Patients with Hepatic Impairment: In a population pharmacokinetic analysis in patients with hyponatremia of various origin, moderate to severe hepatic impairment did not affect exposure to tolvaptan to a clinically relevant extent.
In a population pharmacokinetic analysis in patients with hepatic edema, AUC of tolvaptan in severely (Child-Pugh class C) and moderately (Child-Pugh classes A and B) hepatic impaired patients were 3.1 and 2.3 times higher than that in healthy subjects.
Use in Patients with Renal Impairment: Samsca has been studied in subjects with varying degrees of renal function following a single 60-mg dose. Samsca AUC in subjects with CrCl <30 mL/min was approximately 1.9 times higher than that in subjects with CrCl >60 mL/min but there was no correlation between Samsca AUC and changes in pharmacodynamic endpoints (urine volume, fluid intake, creatinine and free water clearances, urinary excretions of creatinine, Na⁺ and K⁺). No dose adjustment is necessary. Exposure and response to tolvaptan in patients with a CrCl <10 mL/min or in patients on chronic dialysis have not been studied. No benefit can be expected in patients who are anuric (see Contraindications).
Use in Patients with Congestive Heart Failure: In a population pharmacokinetic analysis in patients with hyponatremia of various origin, there was no clinically relevant increase in exposure to tolvaptan in patients with hyponatremia secondary to congestive heart failure.
In a clinical pharmacology study, AUC of tolvaptan in patients with cardiac edema (congestive heart failure) was 3.4 times higher than that in healthy subjects.
Toxicology: Nonclinical Toxicology: Carcinogenicity, Mutagenicity and Impairment of Fertility: Up to 2 years of oral administration of tolvaptan to male and female rats at doses up to 1000 mg/kg/day [162 times the maximum recommended human dose (MRHD) on a body surface area basis], to male mice at doses up to 60 mg/kg/day (5 x MRHD) and to female mice at doses up to 100 mg/kg/day (8 x MRHD) did not increase the incidence of tumors.
Tolvaptan tested negative for genotoxicity in in vitro (bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and in vivo (rat micronucleus assay) test systems.
In a fertility study in which male and female rats were orally administered, tolvaptan at 100, 300 or 1000 mg/kg/day, the highest dose level was associated with significantly fewer corpora lutea and implants than control.
Reproductive and Developmental Toxicology: In pregnant rats, oral administration of tolvaptan at 10, 100 and 1000 mg/kg/day during organogenesis was associated with a reduction in maternal body weight gain and food consumption at 100 and 1000 mg/kg/day and reduced fetal weight and delayed ossification of fetuses at 1000 mg/kg/day (162 x MRHD on a body surface area basis). Oral administration of tolvaptan at 100, 300 and 1000 mg/kg/day to pregnant rabbits during organogenesis was associated with reductions in maternal body weight gain and food consumption at all doses and abortions at mid- and high-doses. At 1000 mg/kg/day (324 x MRHD), increased incidences of embryofetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations were observed. There are no adequate and well-controlled studies of Samsca in pregnant women. Samsca should be used in pregnancy only if the potential benefit justifies the risk to the fetus.

Adjunct Treatment of Volume Overload in Heart Failure: Volume overload in heart failure when adequate response is not obtained with other diuretics (eg, loop diuretics).
Important Limitations: Samsca should be used in combination with other diuretics eg, loop diuretics, thiazides and aldosterone antagonists.
Hyponatremia: Treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).
Important Limitations: Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with Samsca.
It has not been established that raising serum sodium with Samsca provides a symptomatic benefit to patients.

Adults: Adjunct Treatment of Volume Overload in Heart Failure: Adjunct therapy to other diuretics (loop or thiazide diuretics, aldosterone antagonists, etc).
Usual Dose: 15 mg once daily but it is recommended to start from 7.5 mg/day for patients whose serum sodium is <125 mEq/L or for whom rapid volume decrease is considered inappropriate. In order to avoid nocturnal urination, it is recommended to take Samsca in the morning. Treatment with Samsca should be initiated in hospital and patients should be frequently monitored for serum sodium especially during the 1st day of treatment.
Hyponatremia: Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response and because too rapid correction of hyponatremia can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.
Usual Starting Dose: 15 mg once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hrs. Maximum: 60 mg once daily, as needed to achieve the desired level of serum sodium.
During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Avoid fluid restriction during the first 24 hrs of therapy. Patients receiving Samsca should be advised that they can continue ingestion of fluid in response to thirst (see Warnings and Precautions).
Drug Withdrawal: Following discontinuation from Samsca, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium and volume status.
Special Populations: There is no need to adjust dose based on age, gender, race, cardiac or hepatic function (see Pharmacology under Actions and Precautions).
Renal Impairment: There is no need to adjust the dose in patients with mild to severe renal impairment; tolvaptan has not been evaluated in patients with CrCl <10 mL/min or in patients undergoing dialysis. No benefit can be expected in patients who are anuric (see Pharmacology under Actions and Contraindications).
Co-Administration with CYP3A Inhibitors, CYP3A Inducers and P-gp Inhibitors: CYP3A Inhibitors: Tolvaptan is metabolized by CYP3A and use with strong CYP3A inhibitors causes a marked (5-fold) increase in exposure (see Contraindications). The effect of moderate CYP3A inhibitors on tolvaptan exposure has not been assessed. Avoid co-administration of Samsca and moderate CYP3A inhibitors (see Warnings, Precautions and Interactions).
CYP3A Inducers: Co-administration of Samsca with potent CYP3A inducers (eg, rifampin) reduces tolvaptan plasma concentrations by 85%. Therefore, the expected clinical effects of Samsca may not be observed at the recommended dose. Patient response should be monitored and the dose adjusted accordingly (see Warnings, Precautions and Interactions).
P-gp Inhibitors: Tolvaptan is a substrate of P-gp. Co-administration of Samsca with inhibitors of P-gp (eg, cyclosporine) may necessitate a decrease in Samsca dose (see Warnings, Precautions and Interactions).
Co-Administration with Vasopressin Analogs: In addition to its renal aquaretic effect, Samsca is capable of blocking vasopressin V₂ receptors involved in the release of coagulation factors (eg, von Willebrand's factor) from endothelial cells. Therefore, the effect of vasopressin analogs eg, DDAVP may be attenuated in patients using such analogs to prevent or control bleeding when co-administered with Samsca.

Single oral doses up to 480 mg and multiple doses up to 300 mg once daily for 5 days have been well tolerated in studies 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.
The oral lethal dose 50% (LD₅₀) of tolvaptan in rats and dogs is >2000 mg/kg. 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.
If overdose occurs, estimation of the severity of poisoning is an important 1st step. A thorough history and details of overdose should be obtained and a physical examination should be performed. The possibility of multiple drug involvement should be considered.
Treatment should involve symptomatic and supportive care, with respiratory, electrocardiogram (ECG) and blood pressure monitoring and water/electrolyte supplements as needed. A profuse and prolonged aquaresis should be anticipated, which, if not matched by oral fluid ingestion, should be replaced with IV hypotonic fluids, while closely monitoring electrolytes and fluid balance.
Electrocardiogram monitoring should begin immediately and continue until ECG parameters are within normal ranges. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (>99%). Close medical supervision and monitoring should continue until the patient recovers.

History of hypersensitivity to tolvaptan or to any of the excipients of Samsca or to benzazepine derivatives.
Urgent Need to Raise Serum Sodium Acutely: Samsca has not been studied in a setting of urgent need to raise serum sodium acutely.
Inability of the Patient to Sense or Appropriately Respond to Thirst: Patients who are unable to autoregulate fluid balance are at substantially increased risk of incurring an overly rapid correction of serum sodium, hypernatremia and hypovolemia.
Hypovolemic Hyponatremia: Risks associated with worsening hypovolemia, including complications eg, hypotension and renal failure, outweigh possible benefits.
Concomitant Use of Strong CYP3A Inhibitors: Ketoconazole 200 mg administered with tolvaptan increased tolvaptan exposure by 5-fold. Larger doses would be expected to produce larger increases in tolvaptan exposure. There is not adequate experience to define the dose adjustment that would be needed to allow safe use of tolvaptan with strong CYP3A inhibitors eg, clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone and telithromycin.
Anuric Patients: In patients unable to make urine, no clinical benefit can be expected.
Patients with hypernatremia.

Initiate and Re-Initiate in a Hospital and Monitor Serum Sodium: Samsca should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.
Too rapid correction of hyponatremia (eg, >12 mEq/L/24 hrs) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.
Potent aquaresis (free water clearance), especially in normonatremic patients treated with Samsca for heart failure, may induce hypernatremia which can lead to disturbed consciousness. If serum sodium increases above normal range, Samsca should be discontinued, serum sodium should be carefully monitored and appropriate measures should be taken if necessary.

Too Rapid Correction of Serum Sodium can Cause Serious Neurologic Sequelae (see Warnings): Osmotic demyelination syndrome is a risk associated with too rapid correction of hyponatremia (eg, >12 mEq/L/24 hrs). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. In controlled clinical trials, in which tolvaptan was administered in titrated doses starting at 15 mg once daily, 7% of tolvaptan-treated subjects with a serum sodium <130 mEq/L had an increase in serum sodium >8 mEq/L at approximately 8 hrs and 2% had an increase >12 mEq/L at 24 hrs. Approximately 1% of placebo-treated subjects with a serum sodium <130 mEq/L had a rise >8 mEq/L at 8 hrs and no patient had a rise >12 mEq/L/24 hrs. Osmotic demyelination syndrome has been reported in association with Samsca therapy (see Adverse Reactions). Patients treated with Samsca should be monitored to assess serum sodium concentrations and neurologic status, especially during initiation and after titration. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving Samsca who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with Samsca and consider administration of hypotonic fluid. Fluid restriction during the first 24 hrs of therapy with Samsca may increase the likelihood of overly-rapid correction of serum sodium and should generally be avoided.
Hypernatremia (see Warnings): Hemoconcentration associated with rapid diuresis may induce hypernatremia, possibly accompanied by consciousness disturbance. In patients being treated with Samsca, fluid intake, urine volume, serum sodium level and the occurrence of clinical symptoms eg, thirst and dehydration should be carefully monitored. If clinical symptoms eg, persistent thirst and dehydration are observed, Samsca should be discontinued or the dosage reduced and appropriate measures eg, fluid replenishment, including fluid therapy, should be taken in accordance with the symptoms. If serum sodium level is increased above the normal range, administration of Samsca should be discontinued immediately and appropriate measures eg, fluid replenishment, including fluid therapy, should be taken.
Liver Injury: Drug-induced liver injury has been observed in clinical trials investigating a different indication with long-term use of Samsca at higher doses than for the approved indication. In these clinical trials, clinically significant increases [>3 x upper limit of normal (ULN)] in serum alanine aminotransferase (ALT), along with clinically significant increases (>2 x ULN) in serum total bilirubin were observed in 3 patients treated with Samsca. In addition, an increased incidence of significant elevations of ALT was observed in patients treated with Samsca [4.4% (42/958)] compared to those receiving placebo [1% (5/484)]. Most of the liver enzyme abnormalities were observed during the first 18 months of treatment. The elevations gradually improved after discontinuation of Samsca. These findings may suggest that Samsca has the potential to cause irreversible and potentially fatal liver injury.
In other clinical trials of Samsca, including the trials supporting the approved indications, an increased incidence of liver injury relative to placebo has not been observed. However, these data are not adequate to exclude the possibility that patients receiving Samsca for its indicated use are at a potential of a similar risk for liver injury.
To mitigate the risk of significant or irreversible liver injury, blood testing for hepatic transaminases and bilirubin is required prior to initiation of Samsca. For short-term use (ie, <30 days) of Samsca for the treatment of volume overload in heart failure, liver function test should be performed prior to initiation and frequently at least for the first 2 weeks while the patient is on Samsca treatment. (See Adverse Reactions.) After completion of treatment, liver function test is not required, however, if the patient reports symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice, liver function test should be promptly initiated.
For long-term use (ie, >30 days), blood testing for hepatic transaminases and bilirubin is required prior to initiation of Samsca and continuing monthly for 18 months and at regular intervals (eg, 3-6 months), thereafter. Liver function tests should be promptly performed in patients taking Samsca who report symptoms of liver injury. If liver injury is suspected, Samsca should be promptly discontinued, appropriate treatment should be instituted and investigations should be performed to determine the probable cause. Samsca should not be re-initiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with Samsca.
Gastrointestinal Bleeding in Patients with Cirrhosis: In patients with cirrhosis treated with tolvaptan in hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) tolvaptan-treated patients and 1 out of 57 (2%) placebo-treated patients. Samsca should be used in cirrhotic patients only when the need to treat outweighs this risk.
Dehydration and Hypovolemia: Samsca therapy induces copious aquaresis, which is normally partially offset by fluid intake. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In multiple-dose, placebo-controlled trials in which 607 hyponatremic patients were treated with tolvaptan, the incidence of dehydration was 3.3% for tolvaptan and 1.5% for placebo-treated patients. In patients receiving Samsca who develop medically significant signs or symptoms of hypovolemia, interrupt or discontinue Samsca therapy and provide supportive care with careful management of vital signs, fluid balance and electrolytes. Fluid restriction during therapy with Samsca may increase the risk of dehydration and hypovolemia. Patients receiving Samsca should continue ingestion of fluid in response to thirst.
Co-Administration with Hypertonic Saline: Concomitant use with hypertonic saline is not recommended.
Drug Interaction: Other Drugs Affecting Exposure to Tolvaptan: CYP3A Inhibitors: Tolvaptan is a substrate of CYP3A. CYP3A inhibitors can lead to a marked increase in tolvaptan concentrations (see Dosage & Administration and Interactions). Do not use Samsca with strong inhibitors of CYP3A (see Contraindications) and avoid concomitant use with moderate CYP3A inhibitors.
CYP3A Inducers: Avoid co-administration of CYP3A inducers (eg, rifampin, rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine, St. John's wort) with Samsca, as this can lead to a reduction in the plasma concentration of tolvaptan and decreased effectiveness of Samsca treatment. If co-administered with CYP3A inducers, the dose of Samsca may need to be increased (see Dosage & Administration and Interactions).
P-gp Inhibitors: The dose of Samsca may have to be reduced when Samsca is co-administered with P-gp inhibitors eg, cyclosporine (see Dosage & Administration and Interactions).
Hyperkalemia or Drugs that Increase Serum Potassium: Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume which could result in increased serum potassium. Serum potassium levels should be monitored after initiation of tolvaptan treatment in patients with a serum potassium >5 mEq/L as well as those who are receiving drugs known to increase serum potassium levels.
Patient Counseling Information: Concomitant Medication: Advise patients to inform the physician if they are taking or plan to take any prescription or over-the-counter drugs since there is a potential for interactions.
Strong and Moderate CYP3A Inhibitors and P-gp Inhibitors: Advise patients to inform the physician if they use strong (eg, ketoconazole, itraconazole, clarithromycin, telithromycin, nelfinavir, saquinavir, indinavir, ritonavir) or moderate CYP3A inhibitors (eg, aprepitant, erythromycin, diltiazem, verapamil, fluconazole) or P-gp inhibitors (eg, cyclosporine) (see Dosage & Administration, Contraindications, Warnings and Interactions).
Nursing: Advise patients not to breastfeed an infant if they are taking Samsca (see Use in lactation).
Use in pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies of Samsca use in pregnant women. In animal studies, cleft palate, brachymelia, microphthalmia, skeletal malformations, decreased fetal weight, delayed fetal ossification and embryofetal death occurred. Samsca should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryofetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. Rats received 2-162 times the maximum recommended human dose (MRHD) of tolvaptan (on a body surface area basis). Reduced fetal weights and delayed fetal ossification occurred at 162 times the MRHD. Signs of maternal toxicity (reduction in body weight gain and food consumption) occurred at 16 and 162 times the MRHD. When pregnant rabbits received oral tolvaptan at 32-324 times the MRHD (on a body surface area basis), there were reductions in maternal body weight gain and food consumption at all doses and increased abortions at the mid- and high-doses (about 97 and 324 times the MRHD). At 324 times the MRHD, there were increased rates of embryofetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations (see Toxicology: Nonclinical Toxicology under Actions).
Labor and Delivery: The effect of Samsca on labor and delivery in humans is unknown.
Use in lactation: It is not known whether Samsca is excreted into human milk. Tolvaptan is excreted into the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Samsca, a decision should be made to discontinue nursing or Samsca, taking into consideration the importance of Samsca to the mother.
Use in children: Safety and effectiveness of Samsca in pediatric patients have not been established.
Use in the elderly: Of the total number of hyponatremic subjects treated with Samsca in clinical studies, 42% were ≥65, while 19% were ≥75. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Increasing age has no effect on tolvaptan plasma concentrations.

Use in pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies of Samsca use in pregnant women. In animal studies, cleft palate, brachymelia, microphthalmia, skeletal malformations, decreased fetal weight, delayed fetal ossification and embryofetal death occurred. Samsca should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryofetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. Rats received 2-162 times the maximum recommended human dose (MRHD) of tolvaptan (on a body surface area basis). Reduced fetal weights and delayed fetal ossification occurred at 162 times the MRHD. Signs of maternal toxicity (reduction in body weight gain and food consumption) occurred at 16 and 162 times the MRHD. When pregnant rabbits received oral tolvaptan at 32-324 times the MRHD (on a body surface area basis), there were reductions in maternal body weight gain and food consumption at all doses and increased abortions at the mid- and high-doses (about 97 and 324 times the MRHD). At 324 times the MRHD, there were increased rates of embryofetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations (see Toxicology: Nonclinical Toxicology under Actions).
Labor and Delivery: The effect of Samsca on labor and delivery in humans is unknown.
Use in lactation: It is not known whether Samsca is excreted into human milk. Tolvaptan is excreted into the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Samsca, a decision should be made to discontinue nursing or Samsca, taking into consideration the importance of Samsca to the mother.

Clinical Trials Experience: Hyponatremia: Because clinical trials are conducted under widely varying conditions, adverse reactions 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. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
In multiple-dose, placebo-controlled trials, 607 hyponatremic patients (serum sodium <135 mEq/L) were treated with Samsca. The mean age of these patients was 62 years; 70% of patients were male and 82% were Caucasian. One hundred eighty-nine (189) tolvaptan-treated patients had a serum sodium <130 mEq/L and 52 patients had a serum sodium <125 mEq/L. Hyponatremia was attributed to cirrhosis in 17% of patients, heart failure in 68% and SIADH/other in 16%. Of these patients, 223 were treated with the recommended dose titration (15 mg titrated to 60 mg as needed to raise serum sodium).
Overall, over 4000 patients have been treated with oral doses of tolvaptan in open-label or placebo-controlled clinical trials. Approximately 650 of these patients had hyponatremia; approximately 219 of these hyponatremic patients were treated with tolvaptan for ≥6 months.
The most common adverse reactions (incidence ≥5% more than placebo) seen in two 30-day, double-blind, placebo-controlled hyponatremia trials in which tolvaptan was administered in titrated doses (15-60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. In these trials, 10% (23/223) of tolvaptan-treated patients discontinued treatment because of an adverse event, compared to 12% (26/220) of placebo-treated patients; no adverse reaction resulting in discontinuation of trial medication occurred at an incidence of >1% in tolvaptan-treated patients.
Table 3 lists the adverse reactions reported in tolvaptan-treated patients with hyponatremia (serum sodium <135 mEq/L) and at a rate at least 2% greater than placebo-treated patients in two 30-day, double-blind, placebo-controlled trials. In these studies, 223 patients were exposed to tolvaptan (starting dose 15 mg, titrated to 30 and 60 mg as needed to raise serum sodium). Adverse events resulting in death in these trials were 6% in tolvaptan-treated patients and 6% in placebo-treated patients.

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In a subgroup of patients with hyponatremia (N=475, serum sodium <135 mEq/L) enrolled in a double-blind, placebo-controlled trial (mean duration of treatment was 9 months) of patients with worsening heart failure, the following adverse reactions occurred in tolvaptan-treated patients at a rate at least 2% greater than placebo: Mortality (42% tolvaptan, 38% placebo), nausea (21% tolvaptan, 16% placebo), thirst (12% tolvaptan, 2% placebo), dry mouth (7% tolvaptan, 2% placebo) and polyuria or pollakiuria (4% tolvaptan, 1% placebo).
The following adverse reactions occurred in <2% of hyponatremic patients treated with Samsca and at a rate greater than placebo in double-blind placebo-controlled trials (N=607 tolvaptan; N=518 placebo) or in <2% of patients in an uncontrolled trial of patients with hyponatremia (N=111) and are not mentioned elsewhere in the label.
Blood and Lymphatic System Disorders: Disseminated intravascular coagulation.
Cardiac Disorders: Intracardiac thrombus, ventricular fibrillation.
Investigations: Prolonged prothrombin time.
Gastrointestinal Disorders: Ischemic colitis.
Metabolism and Nutrition Disorders: Diabetic ketoacidosis.
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.
Nervous System: Cerebrovascular accident.
Renal and Urinary Disorders: Urethral hemorrhage.
Reproductive System and Breast Disorders (Female): Vaginal hemorrhage.
Respiratory, Thoracic and Mediastinal Disorders: Pulmonary embolism, respiratory failure.
Vascular Disorder: Deep vein thrombosis.
Adjunct Treatment of Volume Overload in Heart Failure (Japanese Data): Of 213 patients included in safety evaluations in Japanese clinical trials for volume overload in heart failure, 143 patients (67.1%) had adverse drug reactions, including abnormal laboratory values. The most common adverse drug reactions were 65 cases of thirst (30.5%), 28 cases of increased blood urea nitrogen (BUN) (13.1%) and 20 cases of increased blood uric acid (9.4%).
Clinically Significant Adverse Reactions: Renal failure (0.1% to <5%): Since severe renal impairment including renal failure, may occur in patients being treated with Samsca, patients should be carefully monitored during treatment. If any abnormalities are observed, Samsca should be discontinued and appropriate measures should be taken.
Thromboembolism (0.1% to <6%): Hemoconcentration associated with rapid diuresis may induce thrombosis or thromboembolism. Patients should be carefully monitored during treatment. If any abnormalities are observed, Samsca should be discontinued and appropriate measures should be taken.

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Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of Samsca. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Neurologic: Osmotic demyelination syndrome.
Investigations: Hypernatremia.
Immune System Disorders: Anaphylactic shock, generalized rash.
Removal of excess free body water increases serum osmolality and serum sodium concentrations. All patients treated with tolvaptan, especially those whose serum sodium levels become normal, should continue to be monitored to ensure serum sodium remains within normal limits. If hypernatremia is observed, management may include dose decreases or interruption of tolvaptan treatment, combined with modification of free-water intake or infusion. During clinical trials of hyponatremic patients, hypernatremia was reported as an adverse event in 0.7% of patients receiving tolvaptan versus 0.6% of patients receiving placebo; analysis of laboratory values demonstrated an incidence of hypernatremia of 1.7% in patients receiving tolvaptan versus 0.8% in patients receiving placebo.
In post-marketing experience, anaphylaxis (including anaphylactic shock and generalized rash) has been reported very rarely following administration of tolvaptan. This type of reaction occurred after the 1st administration of tolvaptan. If an anaphylactic reaction or other serious allergic reactions occur, administration of tolvaptan should be discontinued immediately and appropriate therapy initiated.

Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP3A Inhibitors: Samsca is metabolized primarily by CYP3A. Ketoconazole is a strong inhibitor of CYP3A and also an inhibitor of P-gp. Co-administration of Samsca and ketoconazole 200 mg daily, results in a 5-fold increase in exposure to tolvaptan. Co-administration of Samsca with ketoconazole 400 mg daily or with other strong CYP3A inhibitors (eg, clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir and nefazodone) at the highest labeled dose would be expected to cause an even greater increase in tolvaptan exposure. Thus, Samsca and strong CYP3A inhibitors should not be co-administered (see Dosage & Administration and Contraindications).
Moderate CYP3A Inhibitors: The impact of moderate CYP3A inhibitors (eg, erythromycin, fluconazole, aprepitant, diltiazem and verapamil) on the exposure to co-administered tolvaptan has not been assessed. A substantial increase in the exposure to tolvaptan would be expected when Samsca is co-administered with moderate CYP3A inhibitors. Co-administration of Samsca with moderate CYP3A inhibitors should therefore generally be avoided (see Dosage & Administration, Warnings and Precautions).
Grapefruit Juice: Co-administration of grapefruit juice and Samsca results in a 1.8-fold increase in exposure to tolvaptan (see Dosage & Administration, Warnings and Precautions).
P-gp Inhibitors: Reduction in the dose of Samsca may be required in patients concomitantly treated with P-gp inhibitors eg, cyclosporine, based on clinical response (see Dosage & Administration, Warnings and Precautions).
Rifampin and Other CYP3A Inducers: Rifampin is an inducer of CYP3A and P-gp. Co-administration of rifampin and Samsca reduces exposure to tolvaptan by 85%. Therefore, the expected clinical effects of Samsca in the presence of rifampin and other inducers (eg, rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine and St. John's wort) may not be observed at the usual dose levels of Samsca. The dose of Samsca may have to be increased (see Dosage & Administration, Warnings and Precautions).
Lovastatin, Digoxin, Furosemide and Hydrochlorothiazide: Co-administration of lovastatin, digoxin, furosemide and hydrochlorothiazide with Samsca has no clinically relevant impact on the exposure to tolvaptan.
Effects of Tolvaptan on Other Drugs: Digoxin: Digoxin is a P-gp substrate. Co-administration of Samsca with digoxin increased digoxin AUC by 20% and C_max by 30%.
Warfarin, Amiodarone, Furosemide and Hydrochlorothiazide: Co-administration of tolvaptan does not appear to alter the pharmacokinetics of warfarin, furosemide, hydrochlorothiazide or amiodarone (or its active metabolite, desethylamiodarone) to a clinically significant degree.
Lovastatin: Samsca is a weak inhibitor of CYP3A. Co-administration of lovastatin and Samsca increases the exposure to lovastatin and its active metabolite lovastatin-β hydroxyacid by factors of 1.4 and 1.3, respectively. This is not a clinically relevant change.
Pharmacodynamic Interactions: Tolvaptan produces a greater 24-hr urine volume/excretion rate than does furosemide or hydrochlorothiazide. Concomitant administration of tolvaptan with furosemide or hydrochlorothiazide results in a 24-hr urine volume/excretion rate that is similar to the rate after tolvaptan administration alone.
Although specific interaction studies were not performed, in clinical studies, tolvaptan was used concomitantly with β-blockers, angiotensin receptor blockers, angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diuretics. Adverse reactions of hyperkalemia were approximately 1-2% higher when tolvaptan was administered with angiotensin receptor blockers, ACE inhibitors and potassium-sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.

Store at temperature not exceeding 30°C.

Diuretics

C03XA01 - tolvaptan ; Belongs to the class of vasopressin antagonists. Used as diuretics.

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