Continued from page 52
ment of obesity and obesity-related disorders is increasingly recognized. Fecal transplantation studies in germ-free mice have provided insights into the causality of the
microbiome in development of obesity-related disorders. Several randomized controlled
trials have looked directly at the effect of probiotics on metabolic control and found
promising but mixed results.
More specific to cardiology: a study just published in JACC Heart Failure that measured the
presence of pathogenic gut flora in patients with chronic heart failure (CHF).7 Compared with
normal control subjects, the “entire” CHF population had “massive quantities of pathogenic
bacteria and Candida.” (TABLE on page 50) They also showed increased levels of inflammation. Commenting on the study, W.H. Wilson Tang, MD, said, “Further investigations are
unquestionably warranted to investigated if specific intestinal microbioal pathways can serve
as therapeutic targets to prevent the development and progression of HF.”8
REFERENCES:
1. Mundstock E, Sarria EE, Zatti H, et al. Obesity (Silver Spring). 2015;23:2165-74.
2. Crous-Bou M, Fung TT, Prescott J, et al. BMJ. 2014;349:g6674.
3. Laimer M, Melmer A, Lamina C, et al. Int J Obes (Lond). 2015 Nov. 26. [Epub ahead of print]
4. Ashburner JM, Go AS, Chang Y, et al. J Am Coll Cardiol. 2016;67:39-247.
5. Bloomgarden Z, Bansilal S. J Am Coll Cardiol. 2016;67:248-50.
6. Khodneva Y, Shalev A, Frank SJ, et al. Diabetes Res Clin Pract. 2016 Jan. 15. [Epub before print]
7. Pasini E, Aquilani R, Testa C, et al. JACC Heart Fail. 2015 Dec. 9. [Epub before print].
8. Tang W. JACC Heart Fail. 2016 Feb. 10. [Epub before print]
SAMSCA® (tolvaptan) tablets for oral use
Brief Summary of Prescribi ng 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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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
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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
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
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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
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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\
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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:$YRLGFRDGPLQLVWUDWLRQRI&<3$LQGXFHUV HJULIDPSLQULIDEXWLQULIDSHQWLQ
EDUELWXUDWHVSKHQ\WRLQFDUEDPD]HSLQH6W-RKQ¶V:RUW ZLWK6$06&$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-
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
WUHDWHGZLWK6$06&$7KHPHDQDJHRIWKHVHSDWLHQWVZDV\HDUV RISDWLHQWVZHUH
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DVHUXPVRGLXP P(T/DQGSDWLHQWVKDGDVHUXPVRGLXP P(T/+\SRQDWUHPLD
ZDVDWWULEXWHGWRFLUUKRVLVLQRISDWLHQWVKHDUWIDLOXUHLQDQG6,$'+RWKHULQ2I
WKHVHSDWLHQWVZHUHWUHDWHGZLWKWKHUHFRPPHQGHGGRVHWLWUDWLRQ PJWLWUDWHGWRPJ
DV QHHGHG WR UDLVH VHUXP VRGLXP 2YHUDOO RYHU SDWLHQWV KDYH EHHQ WUHDWHG ZLWK RUDO
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WROYDSWDQ IRU PRQWKV RU PRUH 7KH PRVW FRPPRQ DGYHUVH UHDFWLRQV LQFLGHQFH PRUH
WKDQSODFHER VHHQLQWZRGD\GRXEOHEOLQGSODFHERFRQWUROOHGK\SRQDWUHPLDWULDOVLQZKLFK
WROYDSWDQZDVDGPLQLVWHUHGLQWLWUDWHGGRVHV PJWRPJRQFHGDLO\ ZHUHWKLUVWGU\PRXWK
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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
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
Thirsta
Asthenia
Pyrexia
Metabolism and Nutrition Disorders
Hyperglycemiab
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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SODFHER DQGSRO\XULDRUSROODNLXULD WROYDSWDQSODFHER
Gastrointestinal bleeding in patients with cirrhosis: In patients with cirrhosis treated with tolvaptan
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1 DQGDUHQRWPHQWLRQHGHOVHZKHUHLQWKHODEHO Blood and Lymphatic System Disorders:
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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.
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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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in patients receiving placebo. Immune System Disorders: Hypersensitivity reactions including