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Tolvaptan (Samsca)

Tolvaptan is a medication used to treat hyponatremia (low sodium levels in the blood) and to manage fluid overload associated with conditions like heart failure and cirrhosis. It works by blocking the action of vasopressin, a hormone that regulates water retention by the kidneys. By blocking vasopressin, tolvaptan promotes the excretion of water, which can help in restoring sodium levels and reducing fluid retention.

Tolvaptan (Samsca) is an arginine vasopressin (AVP) receptor antagonist. It primarily inhibits the V2 receptors. V2-receptor inhibitor results in the excretion of free water. This results in an increase in the urine output and a reduced urinary osmolality by the excretion of water without electrolytes.

It is used in the management of the following conditions:

Autosomal dominant polycystic kidney disease:
- It slows the progression of declining kidney function in adults who are at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD)
Hypervolemic or euvolemic hyponatremia:
- It is used to treat clinically significant euvolemic or hypervolemic hyponatremia (serum sodium of less than 125 mEq/L or symptomatic patients with mild hyponatremia that is resistant to fluid restriction).
- These patients also include patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).
- It should not be used in emergency settings to prevent neurological symptoms.
- Studies have not proven any mortality benefits of raising serum sodium levels with tolvaptan.

Tolvaptan dose in Adult

Tolvaptan dose in the treatment of Autosomal dominant polycystic kidney disease (ADPKD):

For treating Autosomal Dominant Polycystic Kidney Disease (ADPKD) with a medication called Tolvaptan, also known as Jynarque or Jinarc in Canada, the starting dose is 60 mg per day.
This is divided into two doses: 45 mg when you wake up and 15 mg eight hours later.
Then, based on how you respond to the medication and how well you tolerate it, your doctor may adjust the dose.
They might increase it gradually, with at least a week between each adjustment, up to a maximum of 120 mg per day.
This would be divided into 90 mg in the morning and 30 mg eight hours later.
The goal during treatment is to keep the urine osmolality (the concentration of particles in urine) below 300 mOsm/kg if possible.
If the highest dose isn't well tolerated, your doctor might lower the dose aiming for a urine osmolality between 250 to 300 mOsm/kg.
It's important to follow your doctor's instructions closely and let them know about any side effects or concerns you have while taking this medication.

Tolvaptan (Samsca) dose in the treatment of Hypervolemic or euvolemic hyponatremia:

Start with 15 mg once daily.
After at least 24 hours, your doctor may increase the dose to 30 mg once daily.
The maximum dose is 60 mg once daily. Your doctor will adjust the dose based on your serum sodium concentration, titrating it every 24 hours until the desired level is reached.

During the first 24 hours of therapy, it's important not to restrict fluids.

However, it's crucial to note that Tolvaptan should not be used for more than 30 days due to the risk of liver damage (hepatotoxicity).

Dosage adjustment with concomitant medication:

Moderate CYP3A inhibitors: Avoid using Samsca and reduce the dose of Jynarque or Jinarc based on your current dose.
Strong CYP3A inhibitors: Both Samsca and Jynarque are contraindicated.
Strong CYP3A inducers: Avoid using Jynarque or Jinarc, and cautiously monitor if you're using Samsca.
P-gp inhibitors: Tolvaptan dose may need to be reduced if you're taking P-gp inhibitors like cyclosporine or quinidine.

Tolvaptan dose in Children

It is not approved in children less than 18 years of age.

Pregnancy Risk Factor C

Tolvaptan has been classified as Pregnancy Risk Factor C, indicating that there have been adverse events observed in animal studies related to reproduction.
This means there may be a potential risk to the fetus if taken during pregnancy, though conclusive evidence in humans is lacking.

Tolvaptan use during breastfeeding:

Tolvaptan's presence in breast milk and its impact on breastfeeding infants haven't been determined.
Due to this uncertainty, the manufacturer doesn't recommend breastfeeding while taking tolvaptan.

Tolvaptan dose in Kidney disease:

ADPKD (Jynarque, Jinarc):

For Autosomal Dominant Polycystic Kidney Disease (ADPKD) treated with Jynarque or Jinarc in Canada, the medication is not recommended for individuals who are anuric (not producing urine).
However, clinical studies have included patients with estimated glomerular filtration rate (eGFR) as low as 25 mL/minute/1.73 m².

Hypervolemic or euvolemic hyponatremia:

Regarding hypervolemic or euvolemic hyponatremia treated with Samsca, if patient creatinine clearance (CrCl) is 10 mL/minute or higher, no dosage adjustment is needed.
If patient CrCl is less than 10 mL/minute, using tolvaptan is not recommended, as its effects on serum sodium levels haven't been studied in this group, and it's contraindicated in individuals who are anuric.

Tolvaptan dose in liver disease:

ADPKD (Jynarque, Jinarc):

For Autosomal Dominant Polycystic Kidney Disease (ADPKD) treated with Jynarque or Jinarc in Canada, using the medication is not recommended for individuals with significant liver impairment or a history of liver disease.
Close monitoring for signs of liver damage (hepatotoxicity) is essential during treatment.
If liver enzyme levels (ALT, AST, or bilirubin) increase to more than twice the upper limit of normal (ULN), or if signs or symptoms of liver damage develop, treatment should be stopped immediately.
Repeat tests should be done promptly within 48 to 72 hours, and if the abnormalities stabilize or resolve, treatment may be restarted with increased monitoring, as long as ALT and AST levels remain below three times the ULN.
However, if ALT or AST levels exceed three times the ULN, treatment should not be started or restarted.

Hypervolemic or euvolemic hyponatremia (Samsca):

For hypervolemic or euvolemic hyponatremia treated with Samsca, the medication should be avoided in individuals with underlying liver disease, including cirrhosis.
Close monitoring for signs of liver damage during treatment is necessary, and if signs or symptoms of hepatotoxicity develop, the medication should be discontinued immediately.
It's important not to use Samsca for more than 30 days due to the potential risk of liver damage.

Common Side Effects of Tolvaptan (Samsca) Include:

Central Nervous System:
- Fatigue
- Dizziness
Endocrine & Metabolic:
- Increased Thirst
Gastrointestinal:
- Nausea
- Xerostomia
- Diarrhea
Renal:
- Polyuria

Less Common Side Effects of Tolvaptan (Samsca) Include:

Cardiovascular:
- Palpitations
- Cerebrovascular Accident
- Deep Vein Thrombosis
- Intracardiac Thrombus
- Pulmonary Embolism
- Ventricular Fibrillation
Dermatologic:
- Xeroderma
- Skin Rash
Endocrine & Metabolic:
- Increased Serum Sodium
- Hyperglycemia
- Hyperuricemia
- Hypernatremia
- Dehydration
- Hypovolemia
- Diabetic Ketoacidosis
Gastrointestinal:
- Gastrointestinal Hemorrhage
- Dyspepsia
- Constipation
- Decreased Appetite
- Abdominal Distention
- Anorexia
- Ischemic Colitis
Genitourinary:
- Urethral Bleeding
- Vaginal Hemorrhage
Hematologic & Oncologic:
- Disseminated Intravascular Coagulation
- Prolonged Prothrombin Time
Hepatic:
- Increased Serum Alanine Aminotransferase
Neuromuscular & Skeletal:
- Asthenia
- Rhabdomyolysis
Respiratory:
- Respiratory Failure
Miscellaneous:
- Fever

Contraindication to Tolvaptan Include:

Tolvaptan, whether as Samsca, Jynarque, or Jinarc, has several contraindications to be aware of.
These include hypersensitivity reactions (such as anaphylactic shock or generalized rash) to tolvaptan or any of its components, concurrent use with strong CYP3A inhibitors, inability to sense or appropriately respond to thirst, and anuria (not producing urine).
For Samsca, additional contraindications include hypovolemic hyponatremia, urgent need to rapidly raise serum sodium levels, and use in patients with autosomal dominant polycystic kidney disease (ADPKD) outside of the FDA-approved REMS (Risk Evaluation and Mitigation Strategy) or Health Canada Risk Management Plan (RMP), depending on the region.
For Jynarque and Jinarc, other contraindications may involve a history, signs, or symptoms of significant liver impairment or injury, uncorrected abnormal blood sodium concentrations, uncorrected urinary outflow obstruction, and hypovolemia.
Furthermore, Jinarc has additional contraindications such as a history of tolvaptan discontinuation, hypersensitivity to benzazepine or its derivatives, hypervolemia, hypernatremia, lack of access to fluids, and certain dietary intolerances like galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
It's important to discuss any existing medical conditions or concerns with your healthcare provider before starting treatment with tolvaptan.

Warnings and precautions

CNS effects

Tolvaptan, when used for autosomal dominant polycystic kidney disease (ADPKD), can lead to central nervous system (CNS) effects such as dizziness, weakness (asthenia), and fainting (syncope).
Patients should be advised to exercise caution when engaging in activities that require attention, such as driving or operating machinery.
These CNS effects can potentially impair cognitive and motor skills, so it's crucial for patients to be aware of how the medication may affect them and to take appropriate precautions to ensure their safety and the safety of others.
If these symptoms occur, patients should avoid activities that could be dangerous until they know how tolvaptan affects them individually.

Hepatotoxicity:

Tolvaptan carries a risk of hepatotoxicity, which means it may cause liver damage, potentially severe and even fatal in some cases.
ADPKD patients:
- For patients with autosomal dominant polycystic kidney disease (ADPKD), cases of liver damage have been reported, particularly within the first 18 months of treatment.
- If signs or symptoms of liver damage occur, or if liver enzyme levels (ALT, AST, or bilirubin) rise to more than twice the upper limit of normal (ULN), treatment should be stopped immediately.
- Repeat liver tests should be done within 48 to 72 hours, and if the abnormalities stabilize or resolve, treatment may be restarted with increased monitoring, as long as ALT and AST levels remain below three times the ULN.
- However, if there are signs or symptoms of liver injury or if ALT or AST levels exceed three times the ULN, treatment should not be restarted unless there's another reason for liver injury and it has resolved.
Patients with hyponatremia, hypervolemic or euvolemic:
- For patients with hypervolemic or euvolemic hyponatremia, treatment with tolvaptan should be limited to 30 days.
- It should be avoided in patients with liver disease, including cirrhosis, as their ability to recover from further liver injury may be compromised.
- If signs or symptoms of liver damage develop during treatment, tolvaptan should be discontinued immediately.

Hypovolemia and hypohydration

It's crucial for patients taking tolvaptan to maintain adequate hydration by drinking fluids as needed in response to thirst during treatment.
However, if patients experience significant signs or symptoms of hypovolemia (low blood volume) or dehydration, such as extreme thirst, dry mouth, dizziness, or decreased urine output, treatment should be interrupted or discontinued.
This ensures that patients receive appropriate medical attention and intervention to address dehydration and prevent further complications.

Start the treatment in a hospital setting to monitor the serum sodium levels. [US Boxed Warning]

Samsca, a medication containing tolvaptan, carries a serious warning.
It should only be initiated or restarted in a hospital setting where healthcare providers can closely monitor serum sodium levels.
Too rapid correction of hyponatremia (low sodium levels), defined as an increase of more than 12 mEq/L in 24 hours, can lead to osmotic demyelination syndrome, a severe neurological condition.
This syndrome can cause a range of symptoms including speech difficulties, difficulty swallowing, lethargy, changes in mood, muscle weakness, seizures, coma, and even death.
Patients with certain conditions like severe malnutrition, alcoholism, advanced liver disease, syndrome of inappropriate antidiuretic hormone secretion (SIADH), or very low baseline sodium levels may be particularly susceptible to overly rapid correction.
It's important to avoid fluid restriction during the first 24 hours of therapy.

Hepatic impairment:

ADPKD patients:
- The use of tolvaptan is contraindicated in those with significant hepatic impairment or a history of liver disease.
- This caution is due to the potential risk of exacerbating liver problems or causing further damage.
Patients with hyponatremia, hypervolemic, or euvolemic:
- For patients with hypervolemic or euvolemic hyponatremia, tolvaptan should be avoided in individuals with liver disease, including those with cirrhosis.
- This is because individuals with liver disease may have impaired liver function, and tolvaptan could potentially worsen their condition or hinder their ability to recover from further liver injury.
- Additionally, patients with cirrhosis are at a higher risk of gastrointestinal bleeding, which further necessitates caution when considering the use of tolvaptan in this population.

Hyperkalemia:

Tolvaptan treatment can lead to reductions in extracellular fluid volume, which may result in hyperkalemia (high potassium levels).
Patients who are taking medications known to increase potassium levels or who have a serum potassium level exceeding 5 mEq/L before starting tolvaptan should be closely monitored after initiating therapy.
This monitoring helps ensure that any potential increases in potassium levels are promptly identified and managed to prevent complications associated with hyperkalemia.

Renal impairment

In individuals with renal impairment, the use of tolvaptan varies depending on the condition being treated.
For patients with hypervolemic or euvolemic hyponatremia, tolvaptan is not recommended for those with a creatinine clearance (CrCl) less than 10 mL/minute.
This is because the effects of tolvaptan on serum sodium levels may be diminished at very low levels of renal function, and the medication hasn't been studied extensively in this population.
However, for patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), tolvaptan has been studied in individuals with both normal and reduced renal function.
It's important to note that the use of tolvaptan is contraindicated in patients who are anuric (not producing urine), regardless of the underlying condition.
Anuria is a condition where the kidneys are unable to produce urine, and in such cases, tolvaptan should not be used due to the lack of urine production.

Tolvaptan: Drug Interaction

Risk Factor C (Monitor therapy)
Angiotensin II Receptor Blockers	Tolvaptan may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers.
Angiotensin-Converting Enzyme Inhibitors	Tolvaptan may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Digoxin	Tolvaptan may increase the serum concentration of Digoxin.
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
P-glycoprotein/ABCB1 Inhibitors	Pglycoprotein/ABCB1 Substrates serum levels can rise. Moreover, p-glycoprotein inhibitors may improve the distribution of pglycoprotein substrates to certain cells, tissues, and organs where high levels of p-glycoprotein are present (e.g., brain, T-lymphocytes, testes, etc.).
Potassium-Sparing Diuretics	Tolvaptan may enhance the hyperkalemic effect of PotassiumSparing Diuretics.
Ranolazine	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Risk Factor D (Consider therapy modification)
BCRP/ABCG2 Substrates	Tolvaptan may increase the serum concentration of BCRP/ABCG2 Substrates.
CYP3A4 Inhibitors (Moderate)	May increase the serum concentration of Tolvaptan. Management: Jynarque dose requires adjustment when used with a moderate CYP3A4 inhibitor. See labeling or full interaction monograph for specific recommendations. Use of Samsca with moderate CYP3A4 ihibitors should generally be avoided.
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).
GlyBURIDE	Tolvaptan may increase the serum concentration of GlyBURIDE.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
OAT1/3 Substrates	Tolvaptan may increase the serum concentration of OAT1/3 Substrates. Management: Patients being treated with the Jynarque brand of tolvaptan should avoid concomitant use of OAT1/3 substrates. Concentrations and effects of the OAT1/3 substrate would be expected to increase with any combined use.
OATP1B1/1B3 (SLCO1B1/1B3) Substrates	Tolvaptan may increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
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.
Risk Factor X (Avoid combination)
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
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.
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Tolvaptan.
Desmopressin	Tolvaptan may diminish the therapeutic effect of Desmopressin.
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Grapefruit Juice	May increase the serum concentration of Tolvaptan.
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
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.
St John's Wort	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.

Monitor:

Monitoring with Tolvaptan Therapy

Serum Sodium Concentration and Rate of Increase: Regular monitoring of serum sodium levels is important to ensure they are within safe limits. Rapid increases in serum sodium levels can lead to serious neurological complications.
Serum Potassium Concentration: Patients with serum potassium levels above 5 mEq/L before starting tolvaptan or those taking medications known to increase potassium levels should be monitored closely for hyperkalemia.
Volume Status: Monitoring fluid volume status helps ensure patients maintain appropriate hydration levels during treatment.
Signs of Drug-Induced Hepatotoxicity: Watch for symptoms such as loss of appetite, fatigue, discomfort in the upper right abdomen, jaundice (yellowing of the skin or eyes), dark urine, or itching, which may indicate liver problems.
Neurologic Status: Assess neurological status at the beginning of treatment and after dose adjustments to detect any adverse effects on the nervous system.

Additional Monitoring Recommendations for Jynarque:

Hepatic Function Testing: Check liver function (ALT, AST, and bilirubin) before starting treatment, at 2 and 4 weeks after initiation, monthly for the first 18 months, and every 3 months thereafter.

Additional Monitoring Recommendations for Jinarc [Canadian Product]:

Hepatic Function Testing: Conduct hepatic function tests before starting therapy, monthly for the first 18 months, then every 3 months for the next 12 months, and then every 3 to 6 months during ongoing therapy.
Urine Osmolality or Specific Gravity: Measure urine osmolality or specific gravity before the morning dose to assess the concentration of urine.
Serum Uric Acid: Monitor serum uric acid levels before starting treatment and as needed during therapy.

How to administer Tolvaptan (Samsca)?

Oral Administration:

Tolvaptan can be taken with or without food.
It's important for patients to have water available at all times during treatment and to be encouraged to drink water regularly to prevent thirst and avoid dehydration.
If a patient's ability to drink or access to water is limited, therapy should be interrupted.

Samsca:

Treatment with Samsca should be started or restarted in a hospital setting where serum sodium levels can be closely monitored.

Nasogastric (NG) Tube Administration:

While administering tolvaptan via NG tube may result in a slight reduction in drug exposure, it's still considered a viable alternative method.
In one study, using a crushed 15 mg tablet via NG tube resulted in a 25% decrease in drug exposure and a modest reduction in drug concentration.
However, the reduction in urine output was minimal, suggesting NG tube administration can still effectively deliver the medication.
Further studies are needed to determine an equivalent dose when administering via NG tube.

Mechanism of action of Tolvaptan (Samsca):

Tolvaptan is an arginine vasopressin (AVP) receptor antagonist, meaning it blocks the action of a hormone called vasopressin.
It specifically targets two subtypes of AVP receptors, known as V1a and V2, with a ratio of 29 to 1.
By blocking the V2 receptor, tolvaptan promotes the excretion of free water without affecting the levels of electrolytes in the blood.
This leads to a net loss of fluid from the body, increased urine output, lower urine concentration, and eventually, normalization of serum sodium levels.
In simpler terms, tolvaptan helps the body get rid of excess water while keeping important electrolytes balanced, ultimately restoring sodium levels to a healthy range.

Onset of Action (Samsca):

Aquaretic and sodium-increasing effects typically start within 2 to 4 hours after administration.

Peak Effect (Samsca):

The maximum aquaretic and sodium-increasing effects are usually observed between 4 to 8 hours after taking the medication.

Duration (Samsca):

About 60% of the peak serum sodium elevation is retained at 24 hours, but urinary excretion of free water returns to normal levels by this time.

Distribution:

Tolvaptan has a volume of distribution of approximately 3 liters per kilogram of body weight.

Protein Binding:

More than 98% of tolvaptan is bound to proteins in the blood.

Metabolism:

Tolvaptan is mainly metabolized by the enzyme CYP3A4, with none of its metabolites having pharmacological activity.

Bioavailability:

The bioavailability of tolvaptan is around 56%, with some variability ranging from 42% to 80%.

Half-Life Elimination:

The half-life of tolvaptan is approximately 3 hours when given as a 15 mg dose and around 12 hours for doses of 120 mg or more. Higher doses lead to a longer half-life due to prolonged absorption.

Time to Peak Plasma Concentration: