Samsca Information
Samsca () Indications And Usage
Samsca () ™ is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium
Samsca () Dosage And Administration
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.
The usual starting dose for Samsca () is 15 mg administered once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 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 hours of therapy. Patients receiving Samsca () should be advised that they can continue ingestion of fluid in response to thirst
Samsca () Dosage Forms And Strengths
Samsca () (tolvaptan) is available in 15 mg and 30 mg tablets
Samsca () Contraindications
Samsca () is contraindicated in the following conditions:
Samsca () Warnings And Precautions
(see )
Osmotic demyelination syndrome is a risk associated with too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours). 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
Samsca () Overdosage
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 LD 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 first 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, 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 intravenous hypotonic fluids, while closely monitoring electrolytes and fluid balance.
ECG 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.
Samsca () Description
Tolvaptan is (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1-1-benzazepin-1-yl) carbonyl]--tolu--toluidide. The empirical formula is CHClNOMolecular weight is 448.94. The chemical structure is:
Samsca () tablets for oral use contain 15 mg or 30 mg of tolvaptan. Inactive ingredients include 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.
Samsca () Clinical Pharmacology
Tolvaptan is a selective vasopressin V‑receptor antagonist with an affinity for the V‑receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V‑receptor is 29 times greater than for the V‑receptor. When taken orally, 15 to 60 mg doses of tolvaptan 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 V‑receptors compared with tolvaptan.
Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan administration.
In healthy subjects receiving a single dose of Samsca () 60 mg, the onset of the aquaretic and sodium increasing effects occurs within 2 to 4 hours 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 hours 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 hours post-dose, but the urinary excretion rate is no longer elevated by this time. Doses above 60 mg tolvaptan do not increase aquaresis or serum sodium further. The effects of tolvaptan in the recommended dose range of 15 to 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 Day 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 ms at 2 hours after dosing on Day 1 and 17 ms at 1 hour 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.
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 curve (AUC) increases proportionally with dose. After administration of doses ≥60 mg, however, Cmax 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 unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Food does not impact the bioavailability of tolvaptan. 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 non-renal routes and mainly, if not exclusively, metabolized by CYP 3A. After oral dosing, clearance is about 4 mL/min/kg and the terminal phase half-life is about 12 hours. 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 half-life somewhat shorter than 12 hours. There is marked inter-subject 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 ranging between 79 and 10 mL/min and patients with normal renal function are not different.
Samsca () Nonclinical Toxicology
Up to two 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 times the MRHD) and to female mice at doses up to 100 mg/kg/day (8 times the MRHD) did not increase the incidence of tumors.
Tolvaptan tested negative for genotoxicity in (bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and (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.
Samsca () Clinical Studies
In two double-blind, placebo-controlled, multi-center studies (SALT‑1 and SALT‑2), a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium
The dose of tolvaptan could be increased at 24 hour 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 hours after study drug initiation and daily up to 72 hours, 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 AUC for change in serum sodium from baseline to Day 4 and baseline to Day 30 in patients with a serum sodium less than 135 mEq/L. Compared to placebo, tolvaptan caused a statistically greater increase in serum sodium (
In patients with hyponatremia (defined as
Figure 1 shows the change from baseline in serum sodium by visit in patients with serum sodium
In the open-label study SALTWATER, 111 patients, 94 of them hyponatremic (serum sodium
Samsca () How Supplied/storage And Handling
Blister of 10 NDC 59148-020-50
Blister of 10 NDC 59148-021-50
Samsca () Patient Counseling Information
As a part of patient counseling, healthcare providers must review the Samsca () Medication Guide with every patient
Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850
US Patent Nos.: 5,258,510 and 5,753,677.
Samsca () is a trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
0708L-0023 Rev. 05, 2009
©2009 Otsuka Pharmaceutical Co., Ltd.
Samsca ()
Samsca ()
Samsca ()
