Pronunciation
(tol VAP
tan)
Index Terms
OPC-41061
Dosage Forms
Excipient
information presented when available (limited, particularly for generics);
consult specific product labeling.
Tablet,
Oral:
Samsca:
15 mg, 30 mg [contains fd&c blue #2 aluminum lake]
SLIDESHOW
Diabetic Nerve Pain: Symptoms And Treatment
Brand Names:U.S.
Samsca
Pharmacologic Category
Vasopressin Antagonist
Pharmacology
An
arginine vasopressin (AVP) receptor antagonist with affinity for AVP receptor
subtypes V2 and V1a in a ratio of 29:1.
Antagonism of the V2 receptor by tolvaptan promotes the
excretion of free water (without loss of serum electrolytes) resulting in net
fluid loss, increased urine output, decreased urine osmolality, and subsequent
restoration of normal serum sodium levels.
Distribution
Vd:
3 L/kg
Metabolism
Hepatic
via CYP3A4
Excretion
Feces
(19% as unchanged drug)
Onset of Action
2 to 4
hour; Peak effect: 4 to 8 hours
Time to Peak
Plasma: 2
to 4 hours
Duration of Action
60% peak
serum sodium elevation is retained at 24 hours; urinary excretion of free water
is no longer elevated
Half-Life Elimination
~12
hours; dominant half-life <12 hours
Protein Binding
99%
Use: Labeled Indications
Samsca:
Hypervolemic
and euvolemic hyponatremia: Treatment
of clinically significant hypervolemic or euvolemic hyponatremia (serum sodium
<125 mEq/L or less marked hyponatremia that is symptomatic and resistant to
fluid restriction), including patients with heart failure and Syndrome of
Inappropriate Antidiuretic Hormone (SIADH).
Limitations
of use: Not indicated for use when urgent treatment of hyponatremia is required
to prevent or treat serious neurological symptoms. It has not been established
that raising serum sodium with tolvaptan provides symptomatic benefit.
Jinarc
[Canadian product]:
Autosomal
dominant polycystic kidney disease (ADPKD): Slow the progression of kidney enlargement in patients
with ADPKD.
Limitations
of use: Clinical trials evaluated ADPKD patients having a total kidney volume ≥750
mL with relatively preserved renal function (eg, estimated creatinine clearance
≥60 mL/minute, generally corresponding to a CKD-EPI eGFR ≥30 mL/minute/1.73 m2 at
the time of therapy initiation).
Contraindications
Samsca:
Hypersensitivity (eg, anaphylactic shock, generalized rash) to tolvaptan or any
component of the formulation; hypovolemic hyponatremia; urgent need to raise
serum sodium acutely; use in patients unable to sense or appropriately respond
to thirst; anuria; concurrent use with strong CYP3A inhibitors (eg,
ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir,
nefazodone, telithromycin, clarithromycin)
Jinarc
[Canadian product]: Hypersensitivity to tolvaptan or any component of the
formulation; hypovolemia; hypernatremia; use in patients unable to sense or
appropriately respond to thirst; clinically relevant hepatic impairment;
anuria; pregnancy; breastfeeding
Dosing: Adult
Hyponatremia: Oral: Samsca: Initial: 15 mg once daily; after
at least 24 hours, may increase to 30 mg once daily to a maximum of 60 mg once
daily titrating at 24-hour intervals to desired serum sodium concentration.
Avoid fluid restriction during the first 24 hours of therapy. Do not use for
more than 30 days due to the risk of hepatotoxicity.
Autosomal
dominant polycystic kidney disease (ADPKD): Jinarc [Canadian product]: Oral: Note:Prior to
initiating therapy, restrict overnight fluid intake for 10 to 14 hours to
assess ability to concentrate urine using urine osmolality or specific gravity
(less accurate). Upon initiation of therapy fluid intake should not be
restricted.
Initial:
60 mg/day in divided doses (45 mg upon wakening and 15 mg approximately 8 hours
later); titrate per response and tolerability at intervals of at least 7 days
to 90 mg/day (60 mg upon wakening and 30 mg approximately 8 hours later) and
then to 120 mg/day (90 mg upon wakening and 30 mg approximately 8 hours later).
Downward titration may be necessary based on tolerability.
Maintenance:
Maintain patient on highest tolerated dose to decrease urine osmolality 200 to
300 mOsm/kg (preferable in most cases) from baseline. Urine osmolality or
specific gravity should be measured before morning dose. Urine osmolality
<300 mOsm/kg (corresponds to a specific gravity of 1.005) should be
maintained at all times if possible. Avoid unnecessary interruptions in
therapy; however if the ability to drink or accessibility to water is limited
therapy should be interrupted.
Dosage
adjustment with concomitant medication: Jinarc [Canadian product]:
Strong
CYP3A inhibitors (eg, ketoconazole, clarithromycin, ritonavir, saquinavir):
Patients receiving tolvaptan 120 mg/day or 90 mg/day: Reduce dose to 30 mg/day
administered upon wakening. Patients receiving tolvaptan 60 mg/day: Reduce dose
to 15 mg/day administered upon wakening. Titrate cautiously per response and
tolerability. Further downward titration or discontinuation of concurrent
therapy may be necessary based on tolerability.
Moderate
CYP3A inhibitors (eg, erythromycin, fluconazole, verapamil): Decrease daily
dose by 50% administered as split regimen with first dose upon wakening and
second dose ~8 hours later (eg, 120 mg/day [90 mg + 30 mg/day] is reduced to 60
mg/day [45 mg + 15 mg/day]). When adjusting the dose reduce the first daily
dose as needed and maintain the second daily dose at 15 mg.
Dosing: Geriatric
Refer to
adult dosing.
Dosing: Renal Impairment
CrCl ≥10
mL/minute: No dosage adjustment necessary.
CrCl
<10 mL/minute: Use not recommended (has not been studied); contraindicated
in anuria (no benefit expected).
Dosing: Hepatic Impairment
Samsca:
Avoid use in patients with underlying liver disease, including cirrhosis.
Jinarc
[Canadian product]:
Preexisting
hepatic impairment: There are no dosage adjustments provided in the
manufacturer's labeling; use with caution and monitor closely. Avoid initiation
of therapy if AST/ALT >3 times ULN. Use is contraindicated in patients with
clinically relevant impairment.
Dosage
adjustment for toxicity (during therapy): Interrupt therapy if hepatotoxicity
is suspected and promptly evaluate hepatic function; upon resolution may
consider reinitiating therapy cautiously.
ALT or
AST <3 times ULN: Continue therapy cautiously and monitor frequently.
Permanently
discontinue for any the following: ALT or AST >8 times ULN, ALT or AST >5
times ULN for >2 weeks, ALT or AST >3 times ULN and total bilirubin >2
times ULN or INR >1.5, ALT or AST >3 times ULN with persistent symptoms
of hepatic injury.
Administration
Samsca:
Oral: Treatment should be initiated or reinitiated in a hospital. May be
administered without regards to meals.
Nasogastric
(NG) tube: Administration via NG tube resulted in an ~25% reduction in AUC and
a modest reduction in Cmax in one study; 24-hour urine output
was reduced by only 2.8%. Therefore, until further studies are done to
determine a bioequivalent dose when administering via NG tube, NG tube
administration of a crushed 15 mg tablet appears to be a viable alternative
method of administration (McNeely, 2012).
Jinarc
[Canadian product]: Oral: May be administered without regards to meals.
Interrupt therapy if the ability to drink or accessibility to water is limited.
Dietary Considerations
Grapefruit
juice may increase tolvaptan serum concentrations. Management: Avoid concurrent
use with grapefruit juice.
Storage
Store at
25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).
Drug Interactions
Angiotensin
II Receptor Blockers: Tolvaptan may enhance the hyperkalemic effect of
Angiotensin II Receptor Blockers. Monitor therapy
Angiotensin-Converting
Enzyme Inhibitors: Tolvaptan may enhance the hyperkalemic effect of Angiotensin-Converting
Enzyme Inhibitors. Monitor therapy
Bosentan:
May decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers).Monitor therapy
Conivaptan:
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Avoid
combination
CYP3A4
Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates
(High risk with Inducers). Monitor therapy
CYP3A4
Inducers (Strong): May decrease the serum concentration of Tolvaptan.
Management: If concurrent use is necessary, increased doses of tolvaptan (with
close monitoring for toxicity and clinical response) may be needed. Avoid
combination
CYP3A4
Inhibitors (Moderate): May increase the serum concentration of Tolvaptan. Avoid
combination
CYP3A4
Inhibitors (Strong): May increase the serum concentration of Tolvaptan. Avoid
combination
Dabrafenib:
May decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible.
If concomitant therapy cannot be avoided, monitor clinical effects of the
substrate closely (particularly therapeutic effects). Consider therapy
modification
Dasatinib:
May increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors).Monitor therapy
Deferasirox:
May decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers).Monitor therapy
Desmopressin:
Tolvaptan may diminish the therapeutic effect of Desmopressin. Avoid
combination
Digoxin:
Tolvaptan may increase the serum concentration of Digoxin. Monitor
therapy
Fosaprepitant:
May increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors).Monitor therapy
Fusidic
Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates
(High risk with Inhibitors). Avoid combination
Idelalisib:
May increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors). Avoid combination
Palbociclib:
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor
therapy
P-glycoprotein/ABCB1
Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1
Substrates. P-glycoprotein inhibitors may also enhance the distribution of
p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein
is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor
therapy
Pitolisant:
May decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that
has a narrow therapeutic index should be avoided. Other CYP3A4 substrates
should be monitored more closely when used with pitolisant. Consider
therapy modification
Potassium-Sparing
Diuretics: Tolvaptan may enhance the hyperkalemic effect of Potassium-Sparing
Diuretics. Monitor therapy
Ranolazine:
May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor
therapy
Sarilumab:
May decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers).Monitor therapy
Siltuximab:
May decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers).Monitor therapy
Simeprevir:
May increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors).Monitor therapy
Sodium
Chloride: May enhance the adverse/toxic effect of Tolvaptan. Specifically,
Hypertonic Saline may increase the risk for too rapid of an increase in serum
sodium concentrations. Management: This interaction is specific to Hypertonic
Saline. Avoid concurrent use of Hypertonic Saline with Tolvaptan.Avoid
combination
St John'sWort: May decrease the serum concentration of
Tolvaptan. Management: If concurrent use is necessary, increased doses of
tolvaptan (with close monitoring for toxicity and clinical response) may be
needed. Avoid combination
Stiripentol:
May increase the serum concentration of CYP3A4 Substrates (High risk with
Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are
considered to have a narrow therapeutic index should be avoided due to the
increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with
stiripentol requires closer monitoring. Consider therapy modification
Tocilizumab:
May decrease the serum concentration of CYP3A4 Substrates (High risk with
Inducers).Monitor therapy
Adverse Reactions
>10%:
Endocrine
& metabolic: Increased thirst (12% to 16%)
Gastrointestinal:
Nausea (21%), xerostomia (7% to 13%)
Renal:
Polyuria (including pollakiuria, 4% to 11%)
2% to
10%:
Endocrine
& metabolic: Hyperglycemia (6%), hypernatremia (<2%)
Gastrointestinal:
Gastrointestinal hemorrhage (cirrhosis patients 10%), constipation (7%),
anorexia (4%)
Hepatic:
Hepatotoxicity (≤4%)
Neuromuscular
& skeletal: Weakness (9%)
Miscellaneous:
Fever (4%)
<2%
(Limited to important or life-threatening): Anaphylactic shock, cerebrovascular
accident, deep vein thrombosis, diabetic ketoacidosis, disseminated
intravascular coagulation, hypersensitivity reaction, increased serum ALT,
intracardiac thrombus, ischemic colitis, osmotic demyelination syndrome,
prolonged prothrombin time, pulmonary embolism, respiratory failure,
rhabdomyolysis, skin rash, urethral bleeding, vaginal hemorrhage, ventricular
fibrillation
ALERT:U.S.Boxed Warning
Treatment
initiation and monitoring:
Initiate
and reinitiate tolvaptan in patients only in a hospital where serum sodium can
be closely monitored.
Too rapid
correction of hyponatremia (eg, more than 12 mEq/L per 24 hours) can cause
osmotic demyelination, resulting in dysarthria, mutism, dysphagia, lethargy,
affective changes, spastic quadriparesis, seizures, coma, and/or death. In
susceptible patients, including those with severe malnutrition, alcoholism, or
advanced liver disease, slower rates of correction may be advisable.
Warnings/Precautions
Concerns
related to adverse effects:
• CNS
effects: Dizziness, asthenia, and/or syncope have been reported when used for
ADPKD; advise patients to use caution when performing dangerous tasks (eg,
driving, operating machinery).
•
Hepatotoxicity: Tolvaptan may increase the risk of serious hepatotoxicity,
including fatal hepatotoxicity. Cases of hepatotoxicity have been reported in patients
treated for ADPKD and have usually occurred after 3 months of therapy although
some cases occurred prior to 3 months. Therefore, treatment with Samsca should
be limited to 30 days. If hepatotoxicity is suspected, discontinue use. Avoid
use in patients with liver disease (including cirrhosis) since the ability to
recover from further liver injury may be impaired. In the treatment of ADPKD,
use of Jinarc [Canadian product] is not limited to 30 days however close
monitoring of hepatic function is recommended. Interrupt therapy for
signs/symptoms of hepatotoxicity (eg, anorexia, dark urine, jaundice, itching,
fatigue, nausea, right upper abdominal pain) and evaluate hepatic function
promptly (ie, within 48 to 72 hours) then increase the frequency of hepatic
function testing; upon resolution may consider cautious reinitiation of
therapy.
•
Hyperuricemia/Gout: Hyperuricemia and gout have been observed; in the treatment
of ADPKD, monitoring of serum uric acid is recommended (Jinarc Canadian product
monograph, 2015).
•
Hypovolemia/dehydration: Patients should ingest fluids in response to thirst
during therapy. Interrupt or discontinue therapy in patients who develop
significant signs or symptoms of hypovolemia.
• Serum
sodium monitoring/initiating in hospital: [US Boxed Warning]: Tolvaptan
should be initiated and reinitiated in patients only in a hospital where serum
sodium can be closely monitored. Too rapid correction of hyponatremia (ie,
>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. Patients with SIADH, very low baseline,
or patients who are fluid restricted during the first 24 hours of therapy may
be at greater risk of overly-rapid correction. Avoid fluid restriction during
the initial 24 hours of therapy. Discontinue or interrupt therapy if sodium
correction is too rapid and consider administration of hypotonic fluids.
Disease-related
concerns:
• Hepatic
impairment: Avoid use in patients with liver disease, including those with
cirrhosis, since the ability to recover from further liver injury may be
impaired. In addition, patients with cirrhosis have a higher risk of
gastrointestinal bleeding.
•
Hyperkalemia: Reductions in extracellular fluid volumes may cause hyperkalemia.
Patients using concomitant medications that may increase potassium levels or
with a pretreatment serum potassium >5 mEq/L should be monitored after
initiation of therapy.
• Renal
impairment: Use in patients with creatinine clearance <10 mL/minute is not
recommended; has not been studied. Use is contraindicated in patients who are
anuric.
Concurrent
drug therapy issues:
•
Drug-drug interactions: Potentially significant interactions may exist,
requiring dose or frequency adjustment, additional monitoring, and/or selection
of alternative therapy. Consult drug interactions database for more detailed
information.
Other
warnings/precautions:
•
Appropriate use: Monitor closely for rate of serum sodium increase and
neurological status; rapid serum sodium correction (>12 mEq/L/24 hours) can
lead to permanent neurological damage. Discontinue use if rate of serum sodium
increase is undesirable; fluid restriction during the first 24 hours of sodium
correction can increase the risk of overly-rapid correction and should
generally be avoided; not intended for urgent correction of serum sodium to
prevent or treat serious neurologic symptoms; it has not been demonstrated that
raising serum sodium with tolvaptan provides a symptomatic benefit. . In the
treatment of ADPKD, patients most likely to benefit from therapy are those with
rapidly progressive disease or those who are developing progressive disease but
lack extensive renal damage. Factors associated with rapid progression include
large total renal cyst mass for a given age (measured by total kidney volume),
chronic kidney disease stage 2 to 3, rapid deterioration of renal function,
systemic hypertension or albuminuria.
•
Limitations of use: SIADH: Limitations to the use of tolvaptan in SIADH may
exist due to concerns about safety, such as overly rapid correction of
hyponatremia and potential for hepatotoxicity (Spasovski, 2014). Based on
available evidence, European clinical practice guidelines recommend against the
use of vasopressin receptor antagonists in the treatment of hyponatremia in
patients with SIADH (Spasovski, 2014). Additional data may be necessary to
define the appropriate clinical role of tolvaptan in this condition.
Monitoring Parameters
Serum
sodium concentration, rate of serum sodium increase, serum potassium
concentration (if >5 mEq/L prior to administration or receiving medications
known to elevate serum potassium); volume status; hepatic function and/or signs
of drug induced hepatotoxicity (eg, anorexia, fatigue, right upper abdominal
discomfort, jaundice, dark urine, itching) as indicated.
Additional
monitoring recommendations: Jinarc [Canadian product]: Hepatic function testing
prior to therapy initiation, monthly for the first 18 months, then every 3
months for 12 months, and then every 3 to 6 months during therapy. If
signs/symptoms of hepatotoxicity, obtain ALT/AST, total bilirubin, alkaline
phosphatase promptly (ie, within 48 to 72 hours) and increase frequency of
testing until clinical/laboratory signs of resolution; urine osmolality or
specific gravity (trough level prior to morning dose); serum uric acid (prior
to initiation and as indicated during therapy.
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse
events were observed in animal reproduction studies.
Patient Education
• Discuss
specific use of drug and side effects with patient as it relates to treatment.
(HCAHPS: During this hospital stay, were you given any medicine that you had
not taken before? Before giving you any new medicine, how often did hospital
staff tell you what the medicine was for? How often did hospital staff describe
possible side effects in a way you could understand?)
• Patient
may experience increased thirst, loss of strength and energy, constipation, dry
mouth, polyuria, or nausea. Have patient report immediately to prescriber signs
of fluid and electrolyte problems (mood changes, confusion, muscle pain or
weakness, abnormal heartbeat, severe dizziness, passing out, tachycardia,
increased thirst, seizures, loss of strength and energy, lack of appetite,
urinary retention or change in amount of urine passed, dry mouth, dry eyes,
nausea, or vomiting); signs of high blood sugar (confusion, fatigue, increased
thirst, increased hunger, polyuria, flushing, fast breathing, or breath that
smells like fruit); difficulty speaking; difficulty swallowing; fatigue;
confusion; mood changes; abnormal movements; seizures; severe abdominal pain;
muscle weakness; black, tarry, bloody stools; vomiting blood; or signs of liver
problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain,
light-colored stools, vomiting, or jaundice) (HCAHPS).
• Educate
patient about signs of a significant reaction (eg, wheezing; chest tightness;
fever; itching; bad cough; blue skin color; seizures; or swelling of face,
lips, tongue, or throat). Note: This is not a comprehensive
list of all side effects. Patient should consult prescriber for additional
questions.
Intended
Use and Disclaimer: Should
not be printed and given to patients. This information is intended to serve as
a concise initial reference for healthcare professionals to use when discussing
medications with a patient. You must ultimately rely on your own discretion,
experience and judgment in diagnosing, treating and advising patients.
