Samsca (Tolvaptan Tablets )
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Samsca (Tolvaptan Tablets )

SAMSCA®
(tolvaptan) Tablets

WARNING

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 (e.g., > 12 mEq/L/24 hours) 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.

DRUG DESCRIPTION

Tolvaptan is (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-otolu-m-toluidide. The empirical formula is C26H25ClN2O3. Molecular weight is 448.94. The chemical structure is:

SAMSCA®  (tolvaptan) Structural Formula Illustration

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.

What are the possible side effects of tolvaptan (Samsca)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have any of these signs that your hyponatremia is being reversed too quickly: problems with speech or muscle control, trouble swallowing, trouble moving your arms and legs, mood changes, and seizure (convulsions).

Stop using tolvaptan and call your doctor at once if you have a serious side effect such as:

  • weakness or fainting;
  • black, bloody, or tarry...

Read All Potential Side Effects and See Pictures of Samsca »

What are the precautions when taking tolvaptan tablets (Samsca)?

Before taking tolvaptan, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: diabetes, liver disease, inability to make urine (anuria), use/abuse of alcohol.

To prevent loss of too much body water (dehydration) while taking this medication, you must be able to replace fluids by drinking. Before taking this medication, tell your doctor if you are not able to drink normally or if you cannot feel if you are thirsty. (See also How to Use section.)

This medication may infrequently make your...

Read All Potential Precautions of Samsca »

Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

SAMSCA® is indicated for the 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, cirrhosis, 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.

DOSAGE AND ADMINISTRATION

Usual Dosage in Adults

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 [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.

Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors

CYP 3A Inhibitors

Tolvaptan is metabolized by CYP 3A, and use with strong CYP 3A inhibitors causes a marked (5-fold) increase in exposure [see CONTRAINDICATIONS]. The effect of moderate CYP 3A inhibitors on tolvaptan exposure has not been assessed. Avoid co-administration of SAMSCA and moderate CYP 3A inhibitors [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

CYP 3A Inducers

Co-administration of SAMSCA with potent CYP 3A inducers (e.g., 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 AND PRECAUTIONS, DRUG INTERACTIONS].

P-gp Inhibitors

Tolvaptan is a substrate of P-gp. Co-administration of SAMSCA with inhibitors of P-gp (e.g., cyclosporine) may necessitate a decrease in SAMSCA dose [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

HOW SUPPLIED

Dosage Forms And Strengths

SAMSCA (tolvaptan) is available in 15 mg and 30 mg tablets [see Storage and Handling].

SAMSCA® (tolvaptan) tablets are available in the following strengths and packages.

SAMSCA 15 mg tablets are non-scored, blue, triangular, shallow-convex, debossed with “OTSUKA” and “15” on one side.

Blister of 10 NDC 59148-020-50

SAMSCA 30 mg tablets are non-scored, blue, round, shallow-convex, debossed with “OTSUKA” and “30” on one side.

Blister of 10 NDC 59148-021-50

Storage and Handling

Store at 25 °C (77 °F), excursions permitted between 15 °C and 30 °C (59 °F to 86 °F) [see USP controlled Room Temperature].

Keep out of reach of children.

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. Revised: 10/2012

Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Clinical Trials Experience

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 4,000 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 or more.

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 mg to 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 1 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.

Table 1: Adverse Reactions ( > 2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials

System Organ Class MedDRA Preferred Term Tolvaptan 15 mg/day-60 mg/day
(N = 223)
n (%)
Placebo
(N = 220)
n (%)
Gastrointestinal Disorders
Dry mouth 28 (13) 9 (4)
Constipation 16 (7) 4 (2)
General Disorders and Administration Site Conditions
Thirsta 35 (16) 11 (5)
Asthenia 19 (9) 9 (4)
Pyrexia 9 (4) 2 (1)
Metabolism and Nutrition Disorders
Hyperglycemiab 14 (6) 2 (1)
Anorexiac 8 (4) 2 (1)
Renal and Urinary Disorders
Pollakiuria or polyuriad 25 (11) 7 (3)
The following terms are subsumed under the referenced ADR in Table 1:
apolydipsia;
bdiabetes mellitus;
cdecreased appetite;
durine output increased, micturition urgency, nocturia

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: Prothrombin time prolonged

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

Postmarketing 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

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 vs. 0.6% of patients receiving placebo; analysis of laboratory values demonstrated an incidence of hypernatremia of 1.7% in patients receiving tolvaptan vs. 0.8% in patients receiving placebo.

Read the Samsca (tolvaptan tablets) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Effects of Drugs on Tolvaptan

Ketoconazole and Other Strong CYP 3A Inhibitors

SAMSCA is metabolized primarily by CYP 3A. Ketoconazole is a strong inhibitor of CYP 3A 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 400 mg ketoconazole daily or with other strong CYP 3A inhibitors (e.g., 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 CYP 3A inhibitors should not be co-administered [see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].

Moderate CYP 3A Inhibitors

The impact of moderate CYP 3A inhibitors (e.g., 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 coadministered with moderate CYP 3A inhibitors. Co-administration of SAMSCA with moderate CYP3A inhibitors should therefore generally be avoided [see DOSAGE AND ADMINISTRATION and 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 AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

P-gp Inhibitors

Reduction in the dose of SAMSCA may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Rifampin and Other CYP 3A Inducers

Rifampin is an inducer of CYP 3A 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 (e.g., 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 [Dosage and Administration (2.3) and WARNINGS AND PRECAUTIONS (5.5)].

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 Cmax 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 CYP 3A. 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 hour urine volume/excretion rate than does furosemide or hydrochlorothiazide. Concomitant administration of tolvaptan with furosemide or hydrochlorothiazide results in a 24 hour 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 beta-blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics. Adverse reactions of hyperkalemia were approximately 1-2% higher when tolvaptan was administered with angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.

As a V2 receptor antagonist, tolvaptan may interfere with the V2 agonist activity of desmopressin (dDAVP). In a male subject with mild Von Willebrand (vW) disease, intravenous infusion of dDAVP 2 hours after administration of oral tolvaptan did not produce the expected increases in vW Factor Antigen or Factor VIII activity. It is not recommended to administer SAMSCA with a V2 agonist.

Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae (see BOXED WARNING)

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 < 130 mEq/L had an increase in serum sodium greater than 8 mEq/L at approximately 8 hours and 2% had an increase greater than 12 mEq/L at 24 hours. Approximately 1% of placebo-treated subjects with a serum sodium < 130 mEq/L had a rise greater than 8 mEq/L at 8 hours and no patient had a rise greater than 12 mEq/L/24 hours. 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 hours of therapy with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided.

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 Interactions

Other Drugs Affecting Exposure to Tolvaptan

CYP 3A Inhibitors

Tolvaptan is a substrate of CYP 3A. CYP 3A inhibitors can lead to a marked increase in tolvaptan concentrations [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS]. Do not use SAMSCA with strong inhibitors of CYP 3A [see CONTRAINDICATIONS] and avoid concomitant use with moderate CYP 3A inhibitors.

CYP 3A Inducers

Avoid co-administration of CYP 3A inducers (e.g., 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 coadministered with CYP 3A inducers, the dose of SAMSCA may need to be increased [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].

P-gp Inhibitors

The dose of SAMSCA may have to be reduced when SAMSCA is co-administered with P-gp inhibitors, e.g., cyclosporine [see DOSAGE AND ADMINISTRATION, DRUG 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

As a part of patient counseling, healthcare providers must review the SAMSCA Medication Guide with every patient [see FDA-Approved Medication Guide].

Concomitant Medication

Advise patients to inform their 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 CYP 3A inhibitors and Pg-p inhibitors

Advise patients to inform their physician if they use strong (e.g., ketoconazole, itraconazole, clarithromycin, telithromycin, nelfinavir, saquinavir, indinavir, ritonavir) or moderate CYP 3A inhibitors (e.g., aprepitant, erythromycin, diltiazem, verapamil, fluconazol) or P-gp inhibitors (e.g., cyclosporine) [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Nursing

Advise patients not to breastfeed an infant if they are taking SAMSCA [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 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.

Use In Specific Populations

There is no need to adjust dose based on age, gender, race, or cardiac function [see CLINICAL PHARMACOLOGY].

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 embryo-fetal death occurred. SAMSCA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In embryo-fetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. Rats received 2 to 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 to 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 embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations [see Nonclinical Toxicology].

Labor and Delivery

The effect of SAMSCA on labor and delivery in humans is unknown.

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness of SAMSCA in pediatric patients have not been established.

Geriatric Use

Of the total number of hyponatremic subjects treated with SAMSCA in clinical studies, 42% were 65 and over, while 19% were 75 and over. 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 Patients with Hepatic Impairment

Moderate and severe hepatic impairment do not affect exposure to tolvaptan to a clinically relevant extent. No dose adjustment of tolvaptan is necessary.

Use in Patients with Renal Impairment

No dose adjustment is necessary based on renal function. There are no clinical trial data in patients with CrCl < 10 mL/min, and, because drug effects on serum sodium levels are likely lost at very low levels of renal function, use in patients with a CrCl < 10 mL/min is not recommended. No benefit can be expected in patients who are anuric [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

Use in Patients with Congestive Heart Failure

The exposure to tolvaptan in patients with congestive heart failure is not clinically relevantly increased. No dose adjustment is necessary.

Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

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 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 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.

CONTRAINDICATIONS

SAMSCA is contraindicated in the following conditions:

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 auto-regulate 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 such as hypotension and renal failure, outweigh possible benefits.

Concomitant use of strong CYP 3A 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 CYP 3A inhibitors such as clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, and telithromycin.

Anuric patients

In patients unable to make urine, no clinical benefit can be expected.

Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

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 V1a-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 V2-receptors compared with tolvaptan.

Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan administration.

Pharmacodynamics

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.

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 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. 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 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.

In a study in patients with creatinine clearances ranging from 10-124 mL/min administered a single dose of 60 mg tolvaptan, AUC and Cmax of plasma tolvaptan were less than doubled in patients with severe renal impairment relative to the controls. The peak increase in serum sodium was 5-6 mEq/L, regardless of renal function, but the onset and offset of tolvaptan's effect on serum sodium were slower in patients with severe renal impairment [see Use in Special Populations].

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 times the 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 times the MRHD), increased incidences of embryo-fetal 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.

Clinical Studies

Hyponatremia

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 < 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 hours of therapy to avoid overly rapid correction of serum sodium, and during the first 24 hours of therapy 87% of patients had no fluid restriction. Thereafter, patients could resume or initiate fluid restriction (defined as daily fluid intake of ≤ 1.0 liter/day) as clinically indicated.

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 (p < 0.0001) during both periods in both studies (see Table 2). 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 2). This effect was also seen across all disease etiology subsets (e.g., CHF, cirrhosis, SIADH/other).

Table 2: Effects of Treatment with Tolvaptan 15 mg/day to 60 mg/day

  Tolvaptan 15 mg/day- 60 mg/day Placebo Estimated Effect (95% CI)
Subjects with Serum Sodium < 135 mEq/L (ITT population)
Change in average daily serum [Na+] AUC baseline to Day 4 (mEq/L) Mean (SD) N 4.0 (2.8)
213
0.4 (2.4)
203
3.7 (3.3-4.2)
p < 0.0001
Change in average daily serum [Na+] AUC baseline to Day 30 (mEq/L) Mean (SD) N 6.2 (4.0)
213
1.8 (3.7)
203
4.6 (3.9-5.2)
p < 0.0001
Percent of Patients Needing Fluid Restriction* 14%
30/215
25%
51/206
p < 0.01
Subgroup with Serum Sodium < 130 mEq/L
Change in average daily serum [Na+] AUC baseline to Day 4 (mEq/L) Mean (SD) N 4.8 (3.0)
110
0.7 (2.5)
105
4.2 (3.5-5.0)
p < 0.0001
Change in average daily serum [Na+] AUC baseline to Day 30 (mEq/L) Mean (SD) N 7.9 (4.1)
110
2.6 (4.2)
105
5.5 (4.4-6.5)
p < 0.0001
Percent of Patients Needing Fluid Restriction* 19% 21/110 36% 38/106 p < 0.01
Subgroup with Serum Sodium < 125 mEq/L
Change in average daily serum [Na+] AUC baseline to Day 4 (mEq/L) Mean (SD) N 5.7 (3.8)
26
1.0 (1.8)
30
5.3 (3.8-6.9)
p < 0.0001
Change in average daily serum [Na+] AUC baseline to Day 30 (mEq/L) Mean (SD) N 10.0 (4.8)
26
4.1 (4.5)
30
5.7 (3.1-8.3)
p < 0.0001
Percent of Patients Needing Fluid Restriction* 35%
9/26
50%
15/30
p = 0.14
* Fluid Restriction defined as < 1L/day at any time during treatment period.

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 hours after the first 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.

Figure 1: Pooled SALT Studies: Analysis of Mean Serum Sodium (± SD, mEq/L) by Visit - Patients with Baseline Serum Sodium < 135 mEq/L

Analysis of Mean Serum Sodium - Illustration

*p-value < 0.0001 for all visits during tolvaptan treatment compared to placebo

Figure 2: Pooled SALT Studies: Analysis of Mean Serum Sodium (± SD, mEq/L) by Visit - Patients with Baseline Serum Sodium < 130 mEq/L

Analysis of Mean Serum Sodium (± SD, mEq/L) by Visit -  Illustration

*p-value < 0.0001 for all visits during tolvaptan treatment compared to placebo

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 to 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.

Figure 3: SALTWATER: Analysis of Mean Serum Sodium (± SD, mEq/L) by Visit

Analysis of Mean Serum Sodium (± SD, mEq/L) by Visit - Illustration

*p-value < 0.0001 for all visits during tolvaptan treatment compared to baseline

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 CV mortality or subsequent hospitalization for worsening HF [HR (95% CI): 1.0 (0.9, 1.1)].

Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

MEDICATION GUIDE

SAMSCA®
(sam-sca)
(tolvaptan) Tablets

Read the Medication Guide that comes with SAMSCA before you take it and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Share this important information with members of your household.

What is the most important information I should know about SAMSCA?

SAMSCA may make the salt (sodium) level in your blood rise too fast. This can increase your risk of a serious condition called osmotic demyelination syndrome (ODS). ODS can lead to coma or death. ODS can also cause new symptoms such as:

  • trouble speaking
  • swallowing trouble or feeling like food or liquid gets stuck while swallowing
  • drowsiness
  • confusion
  • mood changes
  • trouble controlling body movement (involuntary movement) and weakness in muscles of the arms and legs
  • seizures

You or a family member should tell your healthcare provider right away if you have any of these symptoms even if they begin later in treatment. Also tell you healthcare provider about any other new symptoms while taking SAMSCA.

You may be more at risk for ODS if you have:

  • liver disease
  • not eaten enough for a long period of time (malnourished)
  • very low sodium level in your blood
  • been drinking large amounts of alcohol for a long period of time (chronic alcoholism)

To lessen your risk of ODS while taking SAMSCA:

  • Treatment with SAMSCA should be started and re-started only in a hospital, where the sodium levels in your blood can be checked closely.
  • Do not take SAMSCA if you can not tell if you are thirsty.
  • To prevent losing too much body water (dehydration), have water available to drink at all times while taking SAMSCA. Unless your healthcare provider tells you otherwise, drink when you are thirsty.
  • If your healthcare provider tells you to keep taking SAMSCA after you leave a hospital, it is important that you do not stop and re-start SAMSCA on your own. You may need to go back to a hospital to re-start SAMSCA. Talk to your healthcare provider right away if you stop taking SAMSCA for any reason.
  • It is important to stay under the care of your healthcare provider while taking SAMSCA and follow their instructions.

What is SAMSCA?

SAMSCA is a prescription medicine used to help increase low sodium levels in the blood, in adults with conditions such as heart failure, liver disease, and certain hormone imbalances. SAMSCA helps raise salt levels in your blood by removing extra body water as urine.

It is not known if SAMSCA is safe or works in children.

Who should not take SAMSCA?

Do not take SAMSCA if:

  • the sodium level in your blood must be increased right away.
  • you can not replace fluids by drinking or you can not feel if you are thirsty.
  • you are dizzy, faint, or your kidneys are not working normally because you have lost too much body fluid.
  • you take certain medicines. These medicines could cause you to have too much SAMSCA in your blood:
    • the antibiotic medicines, clarithromycin (Biaxin, Biaxin XL) or telithromycin (Ketek)
    • the antifungal medicines, ketoconazole (Nizoral) or itraconazole (Sporonox)
    • the anti-HIV medicines, ritonavir (Kaletra, Norvir), indinavir (Crixivan), nelfinavir (Viracept), and saquinavir (Invirase)
    • the antidepressant medicine, nefazodone hydrochloride
    • your body is not able to make urine. SAMSCA will not help your condition.

What should I tell my healthcare provider before taking SAMSCA?

Tell your healthcare provider about all your medical conditions, including if you:

  • have kidney problems and your body can not make urine.
  • can not feel if you are thirsty. See “What is the most important information I should know about SAMSCA?”
  • have any allergies. See the end of this Medication Guide for a list of the ingredients in SAMSCA.
  • are pregnant or plan to become pregnant. It is not known if SAMSCA will harm your unborn baby.
  • are breast-feeding. It is not known if SAMSCA passes into your breast milk. You and your healthcare provider should decide if you will take SAMSCA or breast-feed. You should not do both.
  • are taking desmopressin (dDAVP).

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Using SAMSCA with certain medicines could cause you to have too much SAMSCA in your blood. See “Who should not take SAMSCA?”

SAMSCA may affect the way other medicines work, and other medicines may affect how SAMSCA works.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take SAMSCA?

  • See “What is the most important information I should know about SAMSCA?”
  • Take SAMSCA exactly as prescribed by your healthcare provider.
  • Take SAMSCA one time each day.
  • You can take SAMSCA with or without food.
  • Do not drink grapefruit juice during treatment with SAMSCA. This could cause you to have too much SAMSCA in your blood.
  • Certain medicines or illnesses may keep you from drinking fluids or may cause you to lose too much body fluid, such as vomiting or diarrhea. If you have these problems, call your healthcare provider right away.
  • Do not miss or skip doses of SAMSCA. If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time.
  • If you take too much SAMSCA, call your healthcare provider right away. If you take an overdose of SAMSCA, you may need to go to a hospital.
  • If your healthcare provider tells you to stop taking SAMSCA, follow their instructions about limiting the amount of fluid you should drink.

What are the possible side effects of SAMSCA?

SAMSCA can cause serious side effects including:

  • See “What is the most important information I should know about SAMSCA?”
  • Loss of too much body fluid (dehydration). Tell your healthcare provider if you:
    • have vomiting or diarrhea, and cannot drink normally.
    • feel dizzy or faint. These may be symptoms that you have lost too much body fluid.
  • Bleeding from the gastrointestinal tract in people with liver disease. Tell your healthcare provider right away if you have any of these bleeding symptoms:
    • you vomit bright red blood
    • you vomit dark blood clots, or material that looks like coffee-grounds
    • your stools are black or look like tar
    • you pass blood or stool mixed with blood
    • your stool is bright red or has maroon colored blood in it

Call your healthcare provider right away, if you have any of these symptoms.

The most common side effects of SAMSCA are:

  • thirst
  • dry mouth
  • weakness
  • constipation
  • making large amounts of urine and urinating often
  • increased blood sugar levels

These are not all the possible side effects of SAMSCA. Talk to your healthcare provider about any side effect that bothers you or that does not go away while taking SAMSCA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088.

How should I store SAMSCA?

Store SAMSCA between 59 °F to 86 °F (15 °C to 30 °C).

Keep SAMSCA and all medicines out of the reach of children.

General Information about SAMSCA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SAMSCA for a condition for which it was not prescribed. Do not give SAMSCA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about SAMSCA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about SAMSCA that is written for healthcare professionals. For more information about SAMSCA, call 1-877-726-7220 or go to www.samsca.com.

What are the ingredients in SAMSCA?

Active ingredient: tolvaptan.

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.

Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

MEDICATION GUIDE

SAMSCA®
(sam-sca)
(tolvaptan) Tablets

Read the Medication Guide that comes with SAMSCA before you take it and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Share this important information with members of your household.

What is the most important information I should know about SAMSCA?

SAMSCA may make the salt (sodium) level in your blood rise too fast. This can increase your risk of a serious condition called osmotic demyelination syndrome (ODS). ODS can lead to coma or death. ODS can also cause new symptoms such as:

  • trouble speaking
  • swallowing trouble or feeling like food or liquid gets stuck while swallowing
  • drowsiness
  • confusion
  • mood changes
  • trouble controlling body movement (involuntary movement) and weakness in muscles of the arms and legs
  • seizures

You or a family member should tell your healthcare provider right away if you have any of these symptoms even if they begin later in treatment. Also tell you healthcare provider about any other new symptoms while taking SAMSCA.

You may be more at risk for ODS if you have:

  • liver disease
  • not eaten enough for a long period of time (malnourished)
  • very low sodium level in your blood
  • been drinking large amounts of alcohol for a long period of time (chronic alcoholism)

To lessen your risk of ODS while taking SAMSCA:

  • Treatment with SAMSCA should be started and re-started only in a hospital, where the sodium levels in your blood can be checked closely.
  • Do not take SAMSCA if you can not tell if you are thirsty.
  • To prevent losing too much body water (dehydration), have water available to drink at all times while taking SAMSCA. Unless your healthcare provider tells you otherwise, drink when you are thirsty.
  • If your healthcare provider tells you to keep taking SAMSCA after you leave a hospital, it is important that you do not stop and re-start SAMSCA on your own. You may need to go back to a hospital to re-start SAMSCA. Talk to your healthcare provider right away if you stop taking SAMSCA for any reason.
  • It is important to stay under the care of your healthcare provider while taking SAMSCA and follow their instructions.

What is SAMSCA?

SAMSCA is a prescription medicine used to help increase low sodium levels in the blood, in adults with conditions such as heart failure, liver disease, and certain hormone imbalances. SAMSCA helps raise salt levels in your blood by removing extra body water as urine.

It is not known if SAMSCA is safe or works in children.

Who should not take SAMSCA?

Do not take SAMSCA if:

  • the sodium level in your blood must be increased right away.
  • you can not replace fluids by drinking or you can not feel if you are thirsty.
  • you are dizzy, faint, or your kidneys are not working normally because you have lost too much body fluid.
  • you take certain medicines. These medicines could cause you to have too much SAMSCA in your blood:
    • the antibiotic medicines, clarithromycin (Biaxin, Biaxin XL) or telithromycin (Ketek)
    • the antifungal medicines, ketoconazole (Nizoral) or itraconazole (Sporonox)
    • the anti-HIV medicines, ritonavir (Kaletra, Norvir), indinavir (Crixivan), nelfinavir (Viracept), and saquinavir (Invirase)
    • the antidepressant medicine, nefazodone hydrochloride
    • your body is not able to make urine. SAMSCA will not help your condition.

What should I tell my healthcare provider before taking SAMSCA?

Tell your healthcare provider about all your medical conditions, including if you:

  • have kidney problems and your body can not make urine.
  • can not feel if you are thirsty. See “What is the most important information I should know about SAMSCA?”
  • have any allergies. See the end of this Medication Guide for a list of the ingredients in SAMSCA.
  • are pregnant or plan to become pregnant. It is not known if SAMSCA will harm your unborn baby.
  • are breast-feeding. It is not known if SAMSCA passes into your breast milk. You and your healthcare provider should decide if you will take SAMSCA or breast-feed. You should not do both.
  • are taking desmopressin (dDAVP).

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Using SAMSCA with certain medicines could cause you to have too much SAMSCA in your blood. See “Who should not take SAMSCA?”

SAMSCA may affect the way other medicines work, and other medicines may affect how SAMSCA works.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take SAMSCA?

  • See “What is the most important information I should know about SAMSCA?”
  • Take SAMSCA exactly as prescribed by your healthcare provider.
  • Take SAMSCA one time each day.
  • You can take SAMSCA with or without food.
  • Do not drink grapefruit juice during treatment with SAMSCA. This could cause you to have too much SAMSCA in your blood.
  • Certain medicines or illnesses may keep you from drinking fluids or may cause you to lose too much body fluid, such as vomiting or diarrhea. If you have these problems, call your healthcare provider right away.
  • Do not miss or skip doses of SAMSCA. If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time.
  • If you take too much SAMSCA, call your healthcare provider right away. If you take an overdose of SAMSCA, you may need to go to a hospital.
  • If your healthcare provider tells you to stop taking SAMSCA, follow their instructions about limiting the amount of fluid you should drink.

What are the possible side effects of SAMSCA?

SAMSCA can cause serious side effects including:

  • See “What is the most important information I should know about SAMSCA?”
  • Loss of too much body fluid (dehydration). Tell your healthcare provider if you:
    • have vomiting or diarrhea, and cannot drink normally.
    • feel dizzy or faint. These may be symptoms that you have lost too much body fluid.
  • Bleeding from the gastrointestinal tract in people with liver disease. Tell your healthcare provider right away if you have any of these bleeding symptoms:
    • you vomit bright red blood
    • you vomit dark blood clots, or material that looks like coffee-grounds
    • your stools are black or look like tar
    • you pass blood or stool mixed with blood
    • your stool is bright red or has maroon colored blood in it

Call your healthcare provider right away, if you have any of these symptoms.

The most common side effects of SAMSCA are:

  • thirst
  • dry mouth
  • weakness
  • constipation
  • making large amounts of urine and urinating often
  • increased blood sugar levels

These are not all the possible side effects of SAMSCA. Talk to your healthcare provider about any side effect that bothers you or that does not go away while taking SAMSCA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088.

How should I store SAMSCA?

Store SAMSCA between 59 °F to 86 °F (15 °C to 30 °C).

Keep SAMSCA and all medicines out of the reach of children.

General Information about SAMSCA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SAMSCA for a condition for which it was not prescribed. Do not give SAMSCA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about SAMSCA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about SAMSCA that is written for healthcare professionals. For more information about SAMSCA, call 1-877-726-7220 or go to www.samsca.com.

What are the ingredients in SAMSCA?

Active ingredient: tolvaptan.

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.

Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Samsca Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

TOLVAPTAN - ORAL

(tol-VAP-tan)

COMMON BRAND NAME(S): Samsca

WARNING: Treatment with this drug should be started or restarted in a hospital for proper monitoring. Too rapid correction of low levels of sodium in the blood may rarely result in a serious (rarely fatal) condition - osmotic demyelination syndrome (ODS). Tell your doctor immediately if you notice any of the following symptoms of ODS: trouble speaking/swallowing, mental/mood changes (such as confusion), weakness/involuntary movement in the arms/legs, or seizures.

USES: This medication is used to treat low levels of salt (sodium) in the blood, which can result from conditions such as heart failure, liver disease, and certain hormone imbalances. Tolvaptan belongs to a class of drugs known as vasopressin receptor antagonists. It works by increasing the amount of urine you make, causing your body to get rid of extra water. This helps to slowly increase to normal levels of salt (sodium) in the blood.

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using tolvaptan and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth with or without food, usually once daily or as directed by your doctor. To prevent losing too much body water (dehydration), have water available to drink at all times while taking tolvaptan. Drink when you are thirsty unless otherwise directed by your doctor.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor instructs you otherwise. Grapefruit can increase the amount of this medication in your bloodstream. Consult your doctor or pharmacist for more details.

Dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day. Do not stop and restart this medication on your own. You may need to go back to a hospital to restart this medication. Tell your doctor immediately if you stop taking this medication for any reason.

Disclaimer

Samsca Consumer (continued)

SIDE EFFECTS: See also Warning section.

Thirst, dry mouth, loss of appetite, constipation, or weakness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Loss of too much body water (dehydration) can occur. The risk is increased if you have persistent vomiting or diarrhea, and cannot drink normally. Contact your doctor immediately if you notice any symptoms of dehydration, such as fast heartbeat or dizziness/lightheadedness.

People with severe liver disease (cirrhosis) may have increased risk of bleeding from the stomach or intestines while taking this medication. Tell your doctor immediately if you have any of the following symptoms: black/bloody stools, vomit that contains blood or looks like coffee grounds.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Samsca (tolvaptan tablets) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking tolvaptan, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: diabetes, liver disease, inability to make urine (anuria), use/abuse of alcohol.

To prevent loss of too much body water (dehydration) while taking this medication, you must be able to replace fluids by drinking. Before taking this medication, tell your doctor if you are not able to drink normally or if you cannot feel if you are thirsty. (See also How to Use section.)

This medication may infrequently make your blood sugar level rise, which can cause or worsen diabetes. If you have diabetes, be sure to check your blood sugar regularly. Your doctor may need to adjust your diabetes medication, exercise program, or diet.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Disclaimer

Samsca Consumer (continued)

DRUG INTERACTIONS: See also How to Use section.

The effects of some drugs can change if you take other drugs or herbal products at the same time. This can increase your risk for serious side effects or may cause your medications not to work correctly. These drug interactions are possible, but do not always occur. Your doctor or pharmacist can often prevent or manage interactions by changing how you use your medications or by close monitoring.

To help your doctor and pharmacist give you the best care, be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products) before starting treatment with this product. While using this product, do not start, stop, or change the dosage of any other medicines you are using without your doctor's approval.

Other medications can affect the removal of tolvaptan from your body, which may affect how tolvaptan works. Examples include azole antifungals (such as ketoconazole), macrolide antibiotics (such as erythromycin), rifamycins (such as rifabutin), St. John's Wort, drugs used to treat seizures (such as carbamazepine, phenytoin), among others.

This document does not contain all possible drug interactions. Keep a list of all the products you use. Share this list with your doctor and pharmacist to lessen your risk for serious medication problems.

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as levels of sodium/potassium in the blood) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your medication.

Information last revised April 2012. Copyright(c) 2012 First Databank, Inc.

Samsca Patient Information Including Side Effects

Brand Names: Samsca

Generic Name: tolvaptan (Pronunciation: tol VAP tan)

What is tolvaptan (Samsca)?

Tolvaptan reduces the level of a hormone that regulates the balance of water and salt (sodium) in the body. High levels of this hormone can cause an imbalance that results in low sodium levels and fluid retention.

Tolvaptan is used to treat hyponatremia (low levels of sodium in your blood) in people with heart failure, liver disease, and certain hormonal imbalances. Tolvaptan improves urine flow without causing the body to lose too much sodium as you urinate.

Tolvaptan may also be used for other purposes not listed in this medication guide.

What are the possible side effects of tolvaptan (Samsca)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have any of these signs that your hyponatremia is being reversed too quickly: problems with speech or muscle control, trouble swallowing, trouble moving your arms and legs, mood changes, and seizure (convulsions).

Stop using tolvaptan and call your doctor at once if you have a serious side effect such as:

  • weakness or fainting;
  • black, bloody, or tarry stools;
  • coughing up blood or vomit that looks like coffee grounds;

Less serious side effects may include:

  • dry mouth;
  • increased thirst or urination;
  • constipation; or
  • loss of appetite, fruity breath odor, drowsiness, dry skin, nausea, vomiting.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800\-FDA-1088.

Read the Samsca (tolvaptan tablets) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about tolvaptan (Samsca)?

You should not use this medication if you are allergic to tolvaptan, if you are unable to urinate, if you are unable to tell that you are thirsty, or if you are severely dehydrated and feel like you might pass out.

You should not take tolvaptan if you are using certain other medications. Before you take tolvaptan, tell your doctor about all other medications you use. Your doctor will tell you if any of your medications need to be changed while taking tolvaptan.

Also tell your doctor if you have severe liver disease or cirrhosis, if you have been drinking large amounts of alcohol, or if you are malnourished.

You will receive your first few doses of tolvaptan in a hospital setting where your heart rhythm can be monitored, in case the medication causes serious side effects.

If you stop taking tolvaptan for any length of time, do not start taking it again at home. You will need to be in a hospital under observation any time you start or restart treatment with tolvaptan.

Tell your caregivers at once if you have any of these signs that your hyponatremia is being reversed too quickly: problems with speech or muscle control, trouble swallowing, trouble moving your arms and legs, mood changes, and seizure (convulsions).

Drink plenty of fluids during the first 24 hours of treatment with tolvaptan. Avoid alcoholic drinks. Follow your doctor's instructions about the type and amount of liquids you should drink while treating hyponatremia. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

To be sure this medication is helping your condition, your blood will need to be tested on a regular basis. You may not notice any change in your symptoms, but your blood work will help your doctor determine how long to treat you with tolvaptan.

Side Effects Centers

Samsca Patient Information including How Should I Take

What should I discuss with my health care provider before taking tolvaptan (Samsca)?

You should not use this medication if you are allergic to tolvaptan, if you are unable to urinate, if you are unable to tell that you are thirsty, or if you are severely dehydrated and feel like you might pass out.

You should not take tolvaptan if you are taking any of the following medications:

  • conivaptan (Vaprisol);
  • an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), or telithromycin (Ketek);
  • antifungal medication such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), or voriconazole (Vfend);
  • an antidepressant such as nefazodone;
  • heart or blood pressure medication such as diltiazem (Cardizem, Dilacor, Tiazac), nicardipine (Cardene), quinidine (Quinaglute, Quinidex, Quin-Release), or verapamil (Calan, Covera, Isoptin, Verelan); or
  • HIV/AIDS medicine such as amprenavir (Agenerase), atazanavir (Reyataz), delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase), or ritonavir (Norvir).

Your doctor will tell you if any of your medications need to be changed while taking tolvaptan.

If you have any of these other conditions, you may need a dose adjustment or special tests to safely take tolvaptan:

  • severe liver disease (especially cirrhosis);
  • if you are malnourished; or
  • if you have been drinking large amounts of alcohol.

FDA pregnancy category C. It is not known whether tolvaptan is harmful to an unborn baby. Before taking this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether tolvaptan passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take tolvaptan (Samsca)?

Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

You will receive your first few doses of tolvaptan in a hospital setting where your heart rhythm can be monitored, in case the medication causes serious side effects.

Your doctor may occasionally change your dose to make sure you get the best results from this medication.

Tolvaptan is usually given once per day, with or without food.

Take this medication with a full glass (8 ounces) of water. Drink plenty of fluids during the first 24 hours of treatment with tolvaptan. It is best to drink something as soon as you feel thirsty, but avoid alcoholic drinks. Follow your doctor's instructions about the type and amount of liquids you should drink while treating hyponatremia. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking this medication, which can lead to serious side effects.

To be sure this medication is helping your condition, your blood will need to be tested on a regular basis. You may not notice any change in your symptoms, but your blood work will help your doctor determine how long to treat you with tolvaptan.

If you stop taking tolvaptan for any length of time, do not start taking it again at home. You will need to be in a hospital under observation any time you start or restart treatment with tolvaptan.

Store tolvaptan at room temperature away from moisture and heat.

Side Effects Centers

Samsca Patient Information including If I Miss a Dose

What happens if I miss a dose (Samsca)?

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Samsca)?

Seek emergency medical attention if you think you have used too much of this medicine. Overdose can cause dehydration (weakness, extreme thirst, increased urination, decreased sweating, hot or dry skin).

What should I avoid while taking tolvaptan (Samsca)?

Grapefruit and grapefruit juice may interact with tolvaptan and lead to potentially dangerous effects. Avoid drinking grapefruit juice while taking tolvaptan.

What other drugs will affect tolvaptan (Samsca)?

Many drugs can interact with tolvaptan. Below is just a partial list. Tell your doctor if you are using:

  • aprepitant (Emend);
  • birth control pills;
  • cyclosporine (Gengraf, Neoral, Sandimmune);
  • digoxin (digitalis, Lanoxin);
  • rifabutin (Mycobutin), rifampin (Rifadin, Rifater, Rifamate), or rifapentine (Priftin);
  • St. John's wort;
  • an antibiotic such as doxycycline (Adoxa, Doryx, Oracea, Vibramycin), metronidazole (Flagyl), norfloxacin (Noroxin), tetracycline (Ala-Tet, Brodspec, Sumycin),
  • an antidepressant such as desipramine (Norpramin) or sertraline (Zoloft);
  • a barbiturate such as phenobarbital (Solfoton) and others;
  • a diuretic (water pill) such as amiloride (Midamor), spironolactone (Aldactone, Aldactazide), triamterene (Dyrenium, Dyazide, Maxzide);
  • heart or blood pressure medication such as benazepril (Lotensin), enalapril (Vasotec), lisinopril (Prinivil, Zestril), quinapril (Accupril), and others;
  • HIV or AIDS medicine such as efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune), and others;
  • potassium supplements, potassium citrate (K-Lyte, Urocit-K, Citrolith, Polycitra), and others; or
  • seizure medication such as carbamazepine (Carbatrol, Tegretol), phenytoin (Dilantin), and others.

Where can I get more information?

Your pharmacist can provide more information about tolvaptan.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 1.04. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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