BUSINESS CONSULT
or more within three of six provider groupings;
2. Decreased no-show rate within
three of six provider groupings;
3. Increased percentage of patients
seen within 48 hours to approximately 40% within the largest
provider grouping; and
4. Average WRVU productivity
per provider per site remained
stable.
SAMSCA® (tolvaptan) tablets for oral use
Brief Summary of Prescribing Information. Please see Full Prescribing Information for complete
product information.
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.
INDICATIONS AND USAGE: 6$06&$ LV LQGLFDWHG IRU WKH WUHDWPHQW RI FOLQLFDOO\ VLJQL¿FDQW
hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked
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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
HVWDEOLVKHGWKDWUDLVLQJVHUXPVRGLXPZLWK6$06&$SURYLGHVDV\PSWRPDWLFEHQH¿WWRSDWLHQWV
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
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FRUUHFWLRQRIVHUXPVRGLXPK\SHUQDWUHPLDDQGK\SRYROHPLD
Hypovolemic hyponatremia: 5LVNV DVVRFLDWHG ZLWK ZRUVHQLQJ K\SRYROHPLD LQFOXGLQJ
FRPSOLFDWLRQVVXFKDVK\SRWHQVLRQDQGUHQDOIDLOXUHRXWZHLJKSRVVLEOHEHQH¿WV
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
ODUJHU LQFUHDVHV LQ WROYDSWDQ H[SRVXUH7KHUH LV QRW DGHTXDWH H[SHULHQFH WR GH¿QH WKH GRVH
adjustment that would be needed to allow safe use of tolvaptan with strong CYP 3A inhibitors
VXFK DV FODULWKURP\FLQ NHWRFRQD]ROH LWUDFRQD]ROH ULWRQDYLU LQGLQDYLU QHO¿QDYLU VDTXLQDYLU
QHID]RGRQHDQGWHOLWKURP\FLQ
Anuric patients: ,QSDWLHQWVXQDEOHWRPDNHXULQHQRFOLQLFDOEHQH¿WFDQEHH[SHFWHG
Hypersensitivity: SAMSCA is contraindicated in patients with hypersensitivity (e.g. anaphylactic
VKRFNUDVKJHQHUDOL]HGWRWROYDSWDQRUDQ\FRPSRQHQWRIWKHSURGXFW[see Adverse Reactions
(6.2)].
WARNINGS AND 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
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G\VDUWKULD PXWLVP G\VSKDJLD OHWKDUJ\ DIIHFWLYH FKDQJHV VSDVWLF TXDGULSDUHVLV VHL]XUHV
FRPDRUGHDWK,QVXVFHSWLEOHSDWLHQWVLQFOXGLQJWKRVHZLWKVHYHUHPDOQXWULWLRQDOFRKROLVPRU
DGYDQFHGOLYHUGLVHDVHVORZHUUDWHVRIFRUUHFWLRQPD\EHDGYLVDEOH,QFRQWUROOHGFOLQLFDOWULDOVLQ
ZKLFKWROYDSWDQZDVDGPLQLVWHUHGLQWLWUDWHGGRVHVVWDUWLQJDWPJRQFHGDLO\RIWROYDSWDQ
treated subjects with a serum sodium <130 mEq/L had an increase in serum sodium greater than
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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
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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
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6$06&$PD\LQFUHDVHWKHOLNHOLKRRGRIRYHUO\UDSLGFRUUHFWLRQRIVHUXPVRGLXPDQGVKRXOG
generally be avoided.
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
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observed. An increased incidence of ALT greater than three times the upper limit of normal was
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serious liver injury were generally observed starting 3 months after initiation of tolvaptan although
elev ations of ALT occurred prior to 3 months. Patients with symptoms that may indicate liver
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should discontinue treatment with SAMSCA. Limit duration of therapy with SAMSCA to 30 days.
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recover from liver injury may be impaired. [see Adverse Reactions (6.1)].
Dehydration and Hypovolemia: 6$06&$ WKHUDS\ LQGXFHV FRSLRXV DTXDUHVLV ZKLFK LV
QRUPDOO\ SDUWLDOO\ RIIVHW E\ ÀXLG LQWDNH 'HK\GUDWLRQ DQG K\SRYROHPLD FDQ RFFXU HVSHFLDOO\
LQSRWHQWLDOO\YROXPHGHSOHWHGSDWLHQWVUHFHLYLQJGLXUHWLFVRUWKRVHZKRDUHÀXLGUHVWULFWHG,Q
PXOWLSOHGRVH SODFHERFRQWUROOHG WULDOV LQ ZKLFK K\SRQDWUHPLF SDWLHQWV ZHUH WUHDWHG ZLWK
WROYDSWDQ WKH LQFLGHQFH RI GHK\GUDWLRQ ZDV IRU WROYDSWDQ DQG IRU SODFHERWUHDWHG
SDWLHQWV,QSDWLHQWVUHFHLYLQJ6$06&$ZKRGHYHORSPHGLFDOO\VLJQL¿FDQWVLJQVRUV\PSWRPVRI
K\SRYROHPLDLQWHUUXSWRUGLVFRQWLQXH6$06&$WKHUDS\DQGSURYLGHVXSSRUWLYHFDUHZLWKFDUHIXO
PDQDJHPHQWRIYLWDOVLJQVÀXLGEDODQFHDQGHOHFWURO\WHV)OXLGUHVWULFWLRQGXULQJWKHUDS\ZLWK
SAMSCA may increase the risk of dehydration and hypovolemia. Patients receiving SAMSCA
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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 (2.3), Drug Interactions
(7.1)].
Do not use SAMSCA with strong inhibitors of CYP 3A [see Contraindications (4.4)] and avoid
concomitant use with moderate CYP 3A inhibitors.
CYP 3A Inducers:$YRLGFRDGPLQLVWUDWLRQRI&<3$LQGXFHUVHJULIDPSLQULIDEXWLQULIDSHQWLQ
EDUELWXUDWHVSKHQ\WRLQFDUEDPD]HSLQH6W-RKQ¶V:RUWZLWK6$06&$DVWKLVFDQOHDGWRD
reduction in the plasma concentration of tolvaptan and decreased effectiveness of SAMSCA
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increased [see Dosage and Administration (2.3), Drug Interactions (7.1)].
P-gp Inhibitors: The dose of SAMSCA may have to be reduced when SAMSCA is co-
This practice continues to improve access,
patient satisfaction, and retention as part
of implementing this strategy. Staff also
report increased satisfaction and efficiency,
largely stemming from decreases in how
often they have to disturb providers during
clinic days to request approval for work-ins.
DGPLQLVWHUHGZLWK3JSLQKLELWRUVHJF\FORVSRULQH[see Dosage and Administration (2.3), Drug
Interactions (7.1)].
Hyperkalemia or Drugs that Increase Serum Potassium: Treatment with tolvaptan is
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increased serum potassium. Serum potassium levels should be monitored after initiation of
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receiving drugs known to increase serum potassium levels.
ADVERSE REACTIONS:
Clinical Trials Experience: %HFDXVHFOLQLFDOWULDOVDUHFRQGXFWHGXQGHUZLGHO\YDU\LQJFRQGLWLRQV
adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to
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adverse events that appear to be related to drug use and for approximating rates. In multipleGRVH SODFHERFRQWUROOHG WULDOV K\SRQDWUHPLF SDWLHQWV VHUXP VRGLXP P(T/ ZHUH
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DVHUXPVRGLXPP(T/DQGSDWLHQWVKDGDVHUXPVRGLXPP(T/+\SRQDWUHPLD
ZDVDWWULEXWHGWRFLUUKRVLVLQRISDWLHQWVKHDUWIDLOXUHLQDQG6,$'+RWKHULQ2I
WKHVHSDWLHQWVZHUHWUHDWHGZLWKWKHUHFRPPHQGHGGRVHWLWUDWLRQPJWLWUDWHGWRPJ
DV QHHGHG WR UDLVH VHUXP VRGLXP 2YHUDOO RYHU SDWLHQWV KDYH EHHQ WUHDWHG ZLWK RUDO
GRVHVRIWROYDSWDQLQRSHQODEHORUSODFHERFRQWUROOHGFOLQLFDOWULDOV$SSUR[LPDWHO\RIWKHVH
SDWLHQWVKDGK\SRQDWUHPLDDSSUR[LPDWHO\RIWKHVHK\SRQDWUHPLFSDWLHQWVZHUHWUHDWHGZLWK
WROYDSWDQ IRU PRQWKV RU PRUH 7KH PRVW FRPPRQ DGYHUVH UHDFWLRQV LQFLGHQFH PRUH
WKDQSODFHERVHHQLQWZRGD\GRXEOHEOLQGSODFHERFRQWUROOHGK\SRQDWUHPLDWULDOVLQZKLFK
WROYDSWDQZDVDGPLQLVWHUHGLQWLWUDWHGGRVHVPJWRPJRQFHGDLO\ZHUHWKLUVWGU\PRXWK
DVWKHQLDFRQVWLSDWLRQSROODNLXULDRUSRO\XULDDQGK\SHUJO\FHPLD,QWKHVHWULDOV
RIWROYDSWDQWUHDWHGSDWLHQWVGLVFRQWLQXHGWUHDWPHQWEHFDXVHRIDQDGYHUVHHYHQWFRPSDUHGWR
RISODFHERWUHDWHGSDWLHQWVQRDGYHUVHUHDFWLRQUHVXOWLQJLQGLVFRQWLQXDWLRQRIWULDO
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Table 1 lists the adverse reactions reported in tolvaptan-treated patients with hyponatremia
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WZRGD\GRXEOHEOLQGSODFHERFRQWUROOHGWULDOV,QWKHVHVWXGLHVSDWLHQWVZHUHH[SRVHG
WRWROYDSWDQVWDUWLQJGRVHPJWLWUDWHGWRDQGPJDVQHHGHGWRUDLVHVHUXPVRGLXP
Adverse events resulting in deaWKLQWKHVHWULDOVZHUHLQWROYDSWDQWUHDWHGSDWLHQWVDQG
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
Constipation
General Disorders and Administration Site Conditions
a
Thirst
Asthenia
Pyrexia
Metabolism and Nutrition Disorders
b
Hyperglycemia
Anorexiac
Renal and Urinary Disorders
Pollakiuria or polyuriad
The following terms are subsumed under the referenced ADR in Table 1:
a
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ZRUVHQLQJKHDUWIDLOXUHWKHIROORZLQJDGYHUVHUHDFWLRQVRFFXUUHGLQWROYDSWDQWUHDWHGSDWLHQWV
DW D UDWH DW OHDVW JUHDWHU WKDQ SODFHER PRUWDOLW\ WROYDSWDQ SODFHER QDXVHD
WROYDSWDQSODFHERWKLUVWWROYDSWDQSODFHERGU\PRXWKWROYDSWDQ
SODFHERDQGSRO\XULDRUSROODNLXULDWROYDSWDQSODFHER
Gastrointestinal bleeding in patients with cirrhosis: In patients with cirrhosis treated with tolvaptan
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1 SODFHERRULQRISDWLHQWVLQDQXQFRQWUROOHGWULDORISDWLHQWVZLWKK\SRQDWUHPLD
1 DQGDUHQRWPHQWLRQHGHOVHZKHUHLQWKHODEHOBlood and Lymphatic System Disorders:
Disseminated intravascular coagulation; Cardiac Disorders: Intracardiac thrombus, ventricular
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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: 7KHIROORZLQJDGYHUVHUHDFWLRQVKDYHEHHQLGHQWL¿HGGXULQJSRVW
approval use of SAMSCA. Because these reactions are reported voluntarily from a population
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causal relationship to drug exposure.
Neurologic: 2VPRWLF GHP\HOLQDWLRQ V\QGURPH Investigations: Hypernatremia. Removal of
excess free body water increases serum osmolality and serum sodium concentrations. All
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should continue to be monitored to ensure serum sodium remains within normal limits. If
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GHPRQVWUDWHGDQLQFLGHQFHRIK\SHUQDWUHPLDRILQSDWLHQWVUHFHLYLQJWROYDSWDQYV
in patients receiving placebo. Immune System Disorders: Hypersensitivity reactions including