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SAMSCA (tolvaptan) tablets
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use SAMSCA safely and effectively. See full prescribing information for SAMSCA.
SAMSCA ® (tolvaptan) tablets for oral use
Initial U.S. Approval: 05/2009
WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM
See full prescribing information for complete boxed warning.
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SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.
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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.
RECENT MAJOR CHANGES
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Contraindications |
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Hypersensitivity (4.6) |
02/2014 |
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Warnings and Precautions |
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Liver Injury (5.2) |
04/2013 |
INDICATIONS AND USAGE
SAMSCA is a selective vasopressin V2-receptor antagonist 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 and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) (1)
Important Limitations:
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Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA (1)
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It has not been established that SAMSCA provides a symptomatic benefit to patients (1)
DOSAGE AND ADMINISTRATION
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SAMSCA should be initiated and re-initiated in a hospital (2.1)
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The recommended starting dose is 15 mg once daily. Dosage may be increased at intervals ≥24 hr to 30 mg once daily, and to a maximum of 60 mg once daily as needed to raise serum sodium. (2.1)
DOSAGE FORMS AND STRENGTHS
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Tablets: 15 mg and 30 mg (3)
CONTRAINDICATIONS
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Need to raise serum sodium acutely (4.1)
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Patients who are unable to respond appropriately to thirst (4.2)
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Hypovolemic hyponatremia (4.3)
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Concomitant use of strong CYP 3A inhibitors (4.4)
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Anuria (4.5)
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Hypersensitivity (4.6)
WARNINGS AND PRECAUTIONS
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Liver injury: Limit treatment duration to 30 days. If hepatic injury is suspected, discontinue SAMSCA. Avoid use in patients with underlying liver disease. (5.2)
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Dehydration and hypovolemia may require intervention (5.3)
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Avoid use with hypertonic saline (5.4)
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Avoid use with CYP 3A inducers and moderate CYP 3A inhibitors (5.5)
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Consider dose reduction if co-administered with P-gp inhibitors (5.5)
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Monitor serum potassium in patients with potassium >5 mEq/L or on drugs known to increase potassium (5.6)
ADVERSE REACTIONS
Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Otsuka at 1-877-726-7220 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).
USE IN SPECIFIC POPULATIONS
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Pregnancy: Based on animal data, may cause fetal harm (8.1)
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Nursing mothers: Discontinue drug or nursing taking into consideration importance of drug to mother (8.3)
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Pediatric Use: There are no studies (8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 2/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
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 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.
2 DOSAGE AND ADMINISTRATION
2.1 Usual Dosage in Adults
Patients should be in a hospital for initiation and re-initiation of therapy to eva luate 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. Do not administer SAMSCA for more than 30 days to minimize the risk of liver injury [see Warnings and Precautions (5.2)].
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 (5.1)].
2.2 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.
2.3 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 (4.4)]. 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 (5.5), Drug Interactions (7.1)].
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 (5.5), Drug Interactions (7.1)].
3 DOSAGE FORMS AND STRENGTHS
SAMSCA (tolvaptan) is available in 15 mg and 30 mg tablets [see How Supplied/Storage and Handling (16)].
4 CONTRAINDICATIONS
SAMSCA is contraindicated in the following conditions:
4.1 Urgent need to raise serum sodium acutely
SAMSCA has not been studied in a setting of urgent need to raise serum sodium acutely.
4.2 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.
4.3 Hypovolemic hyponatremia
Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits.
4.4 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.
4.5 Anuric patients
In patients unable to make urine, no clinical benefit can be expected.
4.6 Hypersensitivity
SAMSCA is contraindicated in patients with hypersensitivity (e.g. anaphylactic shock, rash generalized) to tolvaptan or any component of the product [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
5.1 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 (6.2)]. 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.
5.2 Liver Injury
SAMSCA can cause serious and potentially fatal liver injury. In a placebo-controlled and open label extension study of chronically administered tolvaptan in patients with autosomal dominant polycystic kidney disease, cases of serious liver injury attributed to tolvaptan were observed. An increased incidence of ALT greater than three times the upper limit of normal was associated with tolvaptan (42/958 or 4.4%) compared to placebo (5/484 or 1.0%). Cases of serious liver injury were generally observed starting 3 months after initiation of tolvaptan although elevations of ALT occurred prior to 3 months.
Patients with symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice should discontinue treatment with SAMSCA.
Limit duration of therapy with SAMSCA to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover from liver injury may be impaired [see Adverse Reactions (6.1)].
5.3 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.
5.4 Co-administration with Hypertonic Saline
Concomitant use with hypertonic saline is not recommended.
5.5 Drug Interactions
Other Drugs Affecting Exposure to Tolvaptan
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 co-administered with CYP 3A inducers, the dose of SAMSCA may need to be increased [see Dosage and Administration (2.3), Drug Interactions (7.1)].
5.6 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.
6 ADVERSE REACTIONS
6.1 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.
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).
Gastrointestinal bleeding in patients with cirrhosis
In patients with cirrhosis treated with tolvaptan in the hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) tolvaptan-treated patients and 1 out of 57 (2%) placebo treated patients.
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
6.2 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
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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.
Immune System Disorders: Hypersensitivity reactions including anaphylactic shock and rash generalized [see Contraindications (4.6)].
7 DRUG INTERACTIONS
7.1 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 (2.3) and Contraindications (4.4)].
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 co-administered with moderate CYP 3A inhibitors. Co-administration of SAMSCA with moderate CYP3A inhibitors should therefore generally be avoided [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)].
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.
7.2 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.
8 USE IN SPECIFIC POPULATIONS
There is no need to adjust dose based on age, gender, race, or cardiac function [see Clinical Pharmacology (12.3)].
8.1 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 (13.3)].
8.2 Labor and Delivery
The effect of SAMSCA on labor and delivery in humans is unknown.
8.3 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.
8.4 Pediatric Use
Safety and effectiveness of SAMSCA in pediatric patients have not been established.
8.5 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.
8.6 Use in Patients with Hepatic Impairment
Moderate and severe hepatic impairment do not affect exposure to tolvaptan to a clinically relevant extent. Avoid use of tolvaptan in patients with underlying liver disease.
8.7 Use in Patients with Renal Impairment
No dose adjustment is necessary based on renal function. There are no clinical tria |
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