Tolvaptan

Tolvaptan comes as a tablet to take by mouth. It is usually taken once a day with or without food for no longer than 30 days. At the beginning of your treatment, you will be given tolvaptan at a regularly scheduled time in the hospital. If you are told to take tolvaptan at home after you are discharged, you should take it at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tolvaptan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will probably start you on a low dose of tolvaptan and gradually increase your dose, not more often than once every 24 hours.

Talk to your doctor about what you should do after you stop taking tolvaptan. You will probably need to limit the amount of fluid you drink, and your doctor will monitor you carefully during this time.

Mechanism of Action

Selective vasopressin V2-receptor antagonist that causes an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentration

Pharmacokinetics

Half-Life, Terminal: 12 hr

Absorption: >40%

Pgp substrate and inhibitor

Peak effect: 4-8 hr

Duration: At 24 hr 60% of peak serum sodium elevation is retained

Peak Plasma Time: 2-4 hr

Vd: 3 L/kg  

Protein Bound: 99%

Metabolism: Hepatic through CYP3A4

Excretion: Feces

Tolvaptan is a prescription medication used in adults to help increase low sodium levels in the blood.

Tolvaptan belongs to a group of drugs called vasopressin receptor blockers. It works by raising salt levels in the blood by removing extra body water as urine.

This medication comes in tablet form and is taken once daily with or without food.

Common side effects of tolvaptan include thirst, dry mouth and constipation.

Tolvaptan is part of the drug class:

• Vasopressin antagonists

The usual starting dose for tolvaptan is 15 mg taken once daily with or without food.

Your healthcare provider may decide to increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium. To minimize the risk of liver problems, you should not take tolvaptan for more than 30 days.

Tolvaptan reduces the level of a hormone that regulates the balance of water and salt (sodium) in the body. High levels of this hormone can cause an imbalance that results in low sodium levels and fluid retention.

Tolvaptan is used to treat hyponatremia (low levels of sodium in your blood) in people with heart failure, and certain hormonal imbalances. Tolvaptan improves urine flow without causing the body to lose too much sodium as you urinate.

Tolvaptan may also be used for purposes not listed in this medication guide.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Avoid alcoholic drinks.

Grapefruit and grapefruit juice may interact with tolvaptan and lead to unwanted side effects. Avoid the use of grapefruit products while taking tolvaptan.

Euvolemic or Hypervolemic Hyponatremia

Treatment of clinically important euvolemic or hypervolemic hyponatremia (serum sodium concentration of <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including cases in patients with heart failure or SIADH.1 2 6 9

Not indicated for the treatment of hypovolemic hyponatremia.1

Do not use in patients who require urgent intervention to raise serum sodium concentrations to prevent or treat serious neurologic manifestations.1

Use of tolvaptan to increase serum sodium concentrations has not been established to provide symptomatic benefit to patients.1

In the U.S.

• Samsca

Available Dosage Forms:

• Tablet

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Vasopressin Receptor Antagonist, V2

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%

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.

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.

Applies to tolvaptan: oral tablet

Along with its needed effects, tolvaptan may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking tolvaptan:

• Abdominal or stomach pain
• blurred vision
• dry mouth
• flushed, dry skin
• frequent urination
• fruit-like breath odor
• increased hunger
• increased thirst
• increased urination
• increased volume of pale, dilute urine
• nausea
• sweating
• thirst
• troubled breathing
• unexplained weight loss
• unusual tiredness or weakness
• vomiting

• Abdominal or stomach tenderness
• anxiety
• blood in the urine
• bloody stools
• blue lips, fingernails, or skin
• bruising
• chest pain
• confusion
• cough
• coughing or vomiting blood
• dark-colored urine
• dizziness or lightheadedness
• fainting
• fast, slow, irregular or shallow heartbeat
• fever
• irregular, fast or slow, or shallow breathing
• loss of consciousness
• muscle cramps or spasms
• muscle pain or stiffness
• pain, redness, or swelling in the arm or leg
• persistent bleeding or oozing from puncture sites, mouth, or nose
• pink or red urine
• rash
• rectal bleeding
• shortness of breath
• sudden shortness of breath or troubled breathing
• sweating
• vaginal bleeding

Some side effects of tolvaptan may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Difficulty having a bowel movement (stool)
• lack or loss of strength

• Loss of appetite
• weight loss

Applies to tolvaptan: oral tablet

Cardiovascular

Common (1% to 10%): Intracardiac thrombus, ventricular fibrillation, orthostatic hypotension[Ref]

Gastrointestinal

Very common (10% or more): Dry mouth (up to 13%), nausea
Common (1% to 10%): Constipation, ischemic colitis, gastrointestinal bleeding, diarrhea[Ref]

General

The most frequently reported side effects included thirst, dry mouth (up to 13%), asthenia, constipation, pollakiuria or polyuria and hyperglycemia.[Ref]

Genitourinary

Common (1% to 10%): Blood in urine
Uncommon (0.1% to 1%): Urethral hemorrhage, vaginal hemorrhage[Ref]

Hematologic

Common (1% to 10%): Prolonged prothrombin time, disseminated intravascular coagulation[Ref]

Musculoskeletal

Common (1% to 10%): Rhabdomyolysis

Nervous system

Common (1% to 10%): Cerebrovascular accident, syncope, dizziness, headache
Uncommon (0.1% to 1%): Dysgeusia
Postmarketing reports: Osmotic demyelination syndrome[Ref]

Renal

Very common (10% or more): Pollakiuria and polyuria (11%)
Uncommon (0.1% to 1%): Renal impairment[Ref]

Respiratory

Common (1% to 10%): Pulmonary embolism, respiratory failure[Ref]

Metabolic

Common (1% to 10%): Hyperglycemia, anorexia, diabetic ketoacidosis, dehydration, hyperkalemia, decreased appetite, creatinine increased, hypernatremia, hypoglycemia, hyperuricemia[Ref]

Dermatologic

Common (1% to 10%): Ecchymosis, pruritus
Uncommon (0.1% to 1%): Pruritic rash[Ref]

Hepatic

Common: Alanine aminotransferase increased, aspartate aminotransferase increased, bilirubin increased

Hypersensitivity

Postmarketing reports: Hypersensitivity reactions including anaphylactic shock and generalized rash

Other

Very common (10% or more): Thirst (up to 18%)
Common (1% to 10%): Asthenia, pyrexia, malaise

Some side effects of tolvaptan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Data not available