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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 K\SRQDWUHPLD WKDW LV V\PSWRPDWLF DQG KDV UHVLVWHG FRUUHFWLRQ ZLWK ÀXLG UHVWULFWLRQ  LQFOXGLQJ SDWLHQWVZLWKKHDUWIDLOXUHDQG6\QGURPHRI,QDSSURSULDWH$QWLGLXUHWLF+RUPRQH 6,$'+  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 WR DXWRUHJXODWH ÀXLG EDODQFH DUH DW VXEVWDQWLDOO\ LQFUHDVHG ULVN RI LQFXUULQJ DQ RYHUO\ UDSLG 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]HG WRWROYDSWDQRUDQ\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 FRUUHFWLRQ RI K\SRQDWUHPLD HJ ! P(T/ KRXUV  2VPRWLF GHP\HOLQDWLRQ UHVXOWV LQ 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 P(T/DWDSSUR[LPDWHO\KRXUVDQGKDGDQLQFUHDVHJUHDWHUWKDQP(T/DWKRXUV $SSUR[LPDWHO\  RI SODFHERWUHDWHG VXEMHFWV ZLWK D VHUXP VRGLXP  P(T/ KDG D ULVH JUHDWHU WKDQ  P(T/ DW  KRXUV DQG QR SDWLHQW KDG D ULVH JUHDWHU WKDQ  P(T/ KRXUV 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 VRGLXP FRQFHQWUDWLRQV DQG QHXURORJLF VWDWXV HVSHFLDOO\ GXULQJ LQLWLDWLRQ DQG DIWHU WLWUDWLRQ 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 UDSLG D ULVH LQ VHUXP VRGLXP GLVFRQWLQXH RU LQWHUUXSW WUHDWPHQW ZLWK 6$06&$ DQG FRQVLGHU DGPLQLVWUDWLRQ RI K\SRWRQLF ÀXLG )OXLG UHVWULFWLRQ GXULQJ WKH ¿UVW  KRXUV RI WKHUDS\ ZLWK 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 GRPLQDQW SRO\F\VWLF NLGQH\ GLVHDVH FDVHV RI VHULRXV OLYHU LQMXU\ DWWULEXWHG WR WROYDSWDQ ZHUH observed. An increased incidence of ALT greater than three times the upper limit of normal was DVVRFLDWHG ZLWK WROYDSWDQ  RU   FRPSDUHG WR SODFHER  RU   &DVHV RI 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 LQMXU\ LQFOXGLQJ IDWLJXH DQRUH[LD ULJKW XSSHU DEGRPLQDO GLVFRPIRUW GDUN XULQH RU MDXQGLFH should discontinue treatment with SAMSCA. Limit duration of therapy with SAMSCA to 30 days. $YRLG XVH LQ SDWLHQWV ZLWK XQGHUO\LQJ OLYHU GLVHDVH LQFOXGLQJ FLUUKRVLV EHFDXVH WKH DELOLW\ WR 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 VKRXOGFRQWLQXHLQJHVWLRQRIÀXLGLQUHVSRQVHWRWKLUVW 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:$YRLGFRDGPLQLVWUDWLRQRI&<3$LQGXFHUV HJULIDPSLQULIDEXWLQULIDSHQWLQ EDUELWXUDWHVSKHQ\WRLQFDUEDPD]HSLQH6W-RKQ¶V:RUW ZLWK6$06&$DVWKLVFDQOHDGWRD reduction in the plasma concentration of tolvaptan and decreased effectiveness of SAMSCA WUHDWPHQW ,I FRDGPLQLVWHUHG ZLWK &<3 $ LQGXFHUV WKH GRVH RI 6$06&$ PD\ QHHG WR EH 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 DVVRFLDWHG ZLWK DQ DFXWH UHGXFWLRQ RI WKH H[WUDFHOOXODU ÀXLG YROXPH ZKLFK FRXOG UHVXOW LQ increased serum potassium. Serum potassium levels should be monitored after initiation of WROYDSWDQ WUHDWPHQW LQ SDWLHQWV ZLWK D VHUXP SRWDVVLXP ! P(T/ DV ZHOO DV WKRVH ZKR DUH 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 UDWHVLQWKHFOLQLFDOWULDOVRIDQRWKHUGUXJDQGPD\QRWUHÀHFWWKHUDWHVREVHUYHGLQSUDFWLFH7KH DGYHUVHHYHQWLQIRUPDWLRQIURPFOLQLFDOWULDOVGRHVKRZHYHUSURYLGHDEDVLVIRULGHQWLI\LQJWKH adverse events that appear to be related to drug use and for approximating rates. In multiple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• PRUH WKDQSODFHER VHHQLQWZRGD\GRXEOHEOLQGSODFHERFRQWUROOHGK\SRQDWUHPLDWULDOVLQZKLFK WROYDSWDQZDVDGPLQLVWHUHGLQWLWUDWHGGRVHV PJWRPJRQFHGDLO\ ZHUHWKLUVWGU\PRXWK DVWKHQLDFRQVWLSDWLRQSROODNLXULDRUSRO\XULDDQGK\SHUJO\FHPLD,QWKHVHWULDOV   RIWROYDSWDQWUHDWHGSDWLHQWVGLVFRQWLQXHGWUHDWPHQWEHFDXVHRIDQDGYHUVHHYHQWFRPSDUHGWR   RISODFHERWUHDWHGSDWLHQWVQRDGYHUVHUHDFWLRQUHVXOWLQJLQGLVFRQWLQXDWLRQRIWULDO PHGLFDWLRQRFFXUUHGDWDQLQFLGHQFHRI!LQWROYDSWDQWUHDWHGSDWLHQWV Table 1 lists the adverse reactions reported in tolvaptan-treated patients with hyponatremia VHUXPVRGLXPP(T/ DQGDWDUDWHDWOHDVWJUHDWHUWKDQSODFHERWUHDWHGSDWLHQWVLQ WZRGD\GRXEOHEOLQGSODFHERFRQWUROOHGWULDOV,QWKHVHVWXGLHVSDWLHQWVZHUHH[SRVHG WRWROYDSWDQ VWDUWLQJGRVHPJWLWUDWHGWRDQGPJDVQHHGHGWRUDLVHVHUXPVRGLXP  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 SRO\GLSVLDbGLDEHWHVPHOOLWXV cGHFUHDVHGDSSHWLWHdXULQHRXWSXWLQFUHDVHGPLFWXULWLRQ XUJHQF\QRFWXULD ,QDVXEJURXSRISDWLHQWVZLWKK\SRQDWUHPLD 1 VHUXPVRGLXPP(T/ HQUROOHGLQD GRXEOHEOLQGSODFHERFRQWUROOHGWULDO PHDQGXUDWLRQRIWUHDWPHQWZDVPRQWKV RISDWLHQWVZLWK ZRUVHQLQJKHDUWIDLOXUHWKHIROORZLQJDGYHUVHUHDFWLRQVRFFXUUHGLQWROYDSWDQWUHDWHGSDWLHQWV DW D UDWH DW OHDVW  JUHDWHU WKDQ SODFHER PRUWDOLW\  WROYDSWDQ  SODFHER  QDXVHD WROYDSWDQSODFHER WKLUVW WROYDSWDQSODFHER GU\PRXWK WROYDSWDQ SODFHER DQGSRO\XULDRUSROODNLXULD WROYDSWDQSODFHER  Gastrointestinal bleeding in patients with cirrhosis: In patients with cirrhosis treated with tolvaptan LQWKHK\SRQDWUHPLDWULDOV JDVWURLQWHVWLQDOEOHHGLQJZDVUHSRUWHGLQRXWRI  WROYDSWDQWUHDWHGSDWLHQWVDQGRXW RI  SODFHERWUHDWHGSDWLHQWV 7KHIROORZLQJDGYHUVHUHDFWLRQVRFFXUUHGLQRIK\SRQDWUHPLFSDWLHQWVWUHDWHGZLWKSAMSCA DQGDWDUDWHJUHDWHUWKDQSODFHERLQGRXEOHEOLQGSODFHERFRQWUROOHGWULDOV 1 WROYDSWDQ 1 SODFHER RULQRISDWLHQWVLQDQXQFRQWUROOHGWULDORISDWLHQWVZLWKK\SRQDWUHPLD 1  DQGDUHQRWPHQWLRQHGHOVHZKHUHLQWKHODEHOBlood and Lymphatic System Disorders: Disseminated intravascular coagulation; Cardiac Disorders: Intracardiac thrombus, ventricular ¿EULOODWLRQ ,QYHVWLJDWLRQV 3URWKURPELQ WLPH SURORQJHG *DVWURLQWHVWLQDO 'LVRUGHUV ,VFKHPLF 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 RIDQXQNQRZQVL]HLWLVQRWDOZD\VSRVVLEOHWRUHOLDEO\HVWLPDWHWKHLUIUHTXHQF\RUHVWDEOLVKD 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 SDWLHQWVWUHDWHGZLWKWROYDSWDQHVSHFLDOO\WKRVHZKRVHVHUXPVRGLXPOHYHOVEHFRPHQRUPDO should continue to be monitored to ensure serum sodium remains within normal limits. If K\SHUQDWUHPLD LV REVHUYHG PDQDJHPHQW PD\ LQFOXGH GRVH GHFUHDVHV RU LQWHUUXSWLRQ RI WROYDSWDQWUHDWPHQWFRPELQHGZLWKPRGL¿FDWLRQRIIUHHZDWHULQWDNHRULQIXVLRQ'XULQJFOLQLFDO WULDOV RI K\SRQDWUHPLF SDWLHQWV K\SHUQDWUHPLD ZDV UHSRUWHG DV DQ DGYHUVH HYHQW LQ  RI SDWLHQWVUHFHLYLQJWROYDSWDQYVRISDWLHQWVUHFHLYLQJSODFHERDQDO\VLVRIODERUDWRU\YDOXHV GHPRQVWUDWHGDQLQFLGHQFHRIK\SHUQDWUHPLDRILQSDWLHQWVUHFHLYLQJWROYDSWDQYV in patients receiving placebo. Immune System Disorders: Hypersensitivity reactions including