Tolvaptan

Adjunct Treatment of Volume Overload in Heart Failure: Volume overload in heart failure when adequate response is not obtained with other diuretics (eg, loop diuretics).

Important Limitations: Tolvaptan should be used in combination with other diuretics eg, loop diuretics, thiazides and aldosterone antagonists.

Hyponatremia: Treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).

Important Limitations: Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with Tolvaptan.

It has not been established that raising serum sodium with Tolvaptan provides a symptomatic benefit to patients.

This medication guide provides information about the Tolvaptan brand of Tolvaptan. Tolvaptan is another brand of Tolvaptan that is not covered in this medication guide.

Tolvaptan (Tolvaptan) is used to slow the decline in kidney function in adults who have autosomal dominant polycystic kidney disease.

Tolvaptan is available only under a special program. You must be registered in the program and understand the risks and benefits of Tolvaptan.

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

Usual Dosage In Adults

Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response and because too rapid correction of hyponatremia can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.

The usual starting dose for Tolvaptan is 15 mg administered once daily without regard to meals. 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. Do not administer Tolvaptan for more than 30 days to minimize the risk of liver injury.

During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Avoid fluid restriction during the first 24 hours of therapy. Patients receiving Tolvaptan should be advised that they can continue ingestion of fluid in response to thirst.

Drug Withdrawal

Following discontinuation from Tolvaptan, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium and volume status.

Co-Administration With CYP 3A Inhibitors, CYP 3A Inducers And P-gp Inhibitors

CYP 3A Inhibitors

Tolvaptan is metabolized by CYP 3A, and use with strong CYP 3A inhibitors causes a marked (5-fold) increase in exposure. The effect of moderate CYP 3A inhibitors on Tolvaptan exposure has not been assessed. Avoid co-administration of Tolvaptan and moderate CYP 3A inhibitors.

CYP 3A Inducers

Co-administration of Tolvaptan with potent CYP 3A inducers (e.g., rifampin) reduces Tolvaptan plasma concentrations by 85%. Therefore, the expected clinical effects of Tolvaptan may not be observed at the recommended dose. Patient response should be monitored and the dose adjusted accordingly.

P-gp Inhibitors

Tolvaptan is a substrate of P-gp. Co-administration of Tolvaptan with inhibitors of P-gp (e.g., cyclosporine) may necessitate a decrease in Tolvaptan dose.

How supplied

Dosage Forms And Strengths

Tolvaptan (Tolvaptan) is available in 15 mg and 30 mg tablets.

Tolvaptan® (Tolvaptan) tablets are available in the following strengths and packages.

Tolvaptan 15 mg tablets are non-scored, blue, triangular, shallow-convex, debossed with “OTSUKA” and “15” on one side.

Blister of 10 NDC 59148-020-50

Tolvaptan 30 mg tablets are non-scored, blue, round, shallow-convex, debossed with “OTSUKA” and “30” on one side.

Blister of 10 NDC 59148-021-50

Storage and Handling

Store at 25 °C (77 °F), excursions permitted between 15 °C and 30 °C (59 °F to 86 °F).

Keep out of reach of children.

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. Revised: Feb 2014

See also:
What is the most important information I should know about Tolvaptan?

Tolvaptan is contraindicated in the following conditions:

Urgent need to raise serum sodium acutely

Tolvaptan 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 to auto-regulate fluid balance are at substantially increased risk of incurring an overly rapid correction of serum sodium, hypernatremia and hypovolemia.

Hypovolemic hyponatremia

Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits.

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 larger increases in Tolvaptan exposure. There is not adequate experience to define the dose adjustment that would be needed to allow safe use of Tolvaptan with strong CYP 3A inhibitors such as clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, and telithromycin.

Anuric patients

In patients unable to make urine, no clinical benefit can be expected.

Hypersensitivity

​Tolvaptan is contraindicated in patients with hypersensitivity (e.g. anaphylactic shock, rash generalized) to Tolvaptan or any component of the product.

Use Tolvaptan as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Tolvaptan comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Tolvaptan refilled.
• Take Tolvaptan by mouth with or without food.
• Do not eat grapefruit or drink grapefruit juice while you are taking Tolvaptan.
• Continue to take Tolvaptan even if you feel well. Do not miss any doses.
• If you miss a dose of Tolvaptan, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once. If you miss several doses of Tolvaptan, contact your doctor for instructions.

Ask your health care provider any questions you may have about how to use Tolvaptan.

This medication is used to treat low levels of salt (sodium) in the blood, which can result from conditions such as heart failure and certain hormone imbalances. Tolvaptan belongs to a class of drugs known as vasopressin receptor antagonists. It works by increasing the amount of urine you make, causing your body to get rid of extra water. This helps to slowly increase to normal levels of salt (sodium) in the blood.

How to use Tolvaptan

Read the Medication Guide provided by your pharmacist before you start using Tolvaptan and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth with or without food, usually once daily or as directed by your doctor. You should not take Tolvaptan for longer than 30 days.

To prevent losing too much body water (dehydration), have water available to drink at all times while taking Tolvaptan. Drink when you are thirsty unless otherwise directed by your doctor.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day. Do not stop and restart this medication on your own. You may need to go back to a hospital to restart this medication. Tell your doctor right away if you stop taking this medication for any reason.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor instructs you otherwise. Grapefruit can increase the amount of this medication in your bloodstream. Consult your doctor or pharmacist for more details.

Dosage is based on your medical condition and response to treatment.

See also:
What other drugs will affect Tolvaptan?

Effects Of Drugs On Tolvaptan

Ketoconazole and Other Strong CYP 3A Inhibitors

Tolvaptan is metabolized primarily by CYP 3A. Ketoconazole is a strong inhibitor of CYP 3A and also an inhibitor of P-gp. Co-administration of Tolvaptan and ketoconazole 200 mg daily results in a 5-fold increase in exposure to Tolvaptan. Co-administration of Tolvaptan with 400 mg ketoconazole daily or with other strong CYP 3A inhibitors (e.g., clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir and nefazodone) at the highest labeled dose would be expected to cause an even greater increase in Tolvaptan exposure. Thus, Tolvaptan and strong CYP 3A inhibitors should not be co-administered.

Moderate CYP 3A Inhibitors

The impact of moderate CYP 3A inhibitors (e.g., erythromycin, fluconazole, aprepitant, diltiazem and verapamil) on the exposure to co-administered Tolvaptan has not been assessed. A substantial increase in the exposure to Tolvaptan would be expected when Tolvaptan is coadministered with moderate CYP 3A inhibitors. Co-administration of Tolvaptan with moderate CYP3A inhibitors should therefore generally be avoided.

Grapefruit Juice

Co-administration of grapefruit juice and Tolvaptan results in a 1.8-fold increase in exposure to Tolvaptan.

P-gp Inhibitors

Reduction in the dose of Tolvaptan may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response.

Rifampin and Other CYP 3A Inducers

Rifampin is an inducer of CYP 3A and P-gp. Co-administration of rifampin and Tolvaptan reduces exposure to Tolvaptan by 85%. Therefore, the expected clinical effects of Tolvaptan in the presence of rifampin and other inducers (e.g., rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine and St. John's Wort) may not be observed at the usual dose levels of Tolvaptan.

The dose of Tolvaptan may have to be increased [Dosage and Administration (2.3) and WARNINGS AND PRECAUTIONS (5.5)].

Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide

Co-administration of lovastatin, digoxin, furosemide, and hydrochlorothiazide with Tolvaptan has no clinically relevant impact on the exposure to Tolvaptan.

Effects Of Tolvaptan On Other Drugs

Digoxin

Digoxin is a P-gp substrate. Co-administration of Tolvaptan with digoxin increased digoxin AUC by 20% and Cmax by 30%.

Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide

Co-administration of Tolvaptan does not appear to alter the pharmacokinetics of warfarin, furosemide, hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone) to a clinically significant degree.

Lovastatin

Tolvaptan is a weak inhibitor of CYP 3A. Co-administration of lovastatin and Tolvaptan increases the exposure to lovastatin and its active metabolite lovastatin-β hydroxyacid by factors of 1.4 and 1.3, respectively. This is not a clinically relevant change.

Pharmacodynamic Interactions

Tolvaptan produces a greater 24 hour urine volume/excretion rate than does furosemide or hydrochlorothiazide. Concomitant administration of Tolvaptan with furosemide or hydrochlorothiazide results in a 24 hour urine volume/excretion rate that is similar to the rate after Tolvaptan administration alone.

Although specific interaction studies were not performed, in clinical studies Tolvaptan was used concomitantly with beta-blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics. Adverse reactions of hyperkalemia were approximately 1-2% higher when Tolvaptan was administered with angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.

As a V2 receptor antagonist, Tolvaptan may interfere with the V2 agonist activity of desmopressin (dDAVP). In a male subject with mild Von Willebrand (vW) disease, intravenous infusion of dDAVP 2 hours after administration of oral Tolvaptan did not produce the expected increases in vW Factor Antigen or Factor VIII activity. It is not recommended to administer Tolvaptan with a V2 agonist.

See also:
What are the possible side effects of Tolvaptan?

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

In multiple-dose, placebo-controlled trials, 607 hyponatremic patients (serum sodium < 135 mEq/L) were treated with Tolvaptan. The mean age of these patients was 62 years; 70% of patients were male and 82% were Caucasian. One hundred eighty nine (189) Tolvaptan-treated patients had a serum sodium < 130 mEq/L, and 52 patients had a serum sodium < 125 mEq/L. Hyponatremia was attributed to cirrhosis in 17% of patients, heart failure in 68% and SIADH/other in 16%. Of these patients, 223 were treated with the recommended dose titration (15 mg titrated to 60 mg as needed to raise serum sodium).

Overall, over 4,000 patients have been treated with oral doses of Tolvaptan in open-label or placebo-controlled clinical trials. Approximately 650 of these patients had hyponatremia; approximately 219 of these hyponatremic patients were treated with Tolvaptan for 6 months or more.

The most common adverse reactions (incidence ≥ 5% more than placebo) seen in two 30-day, double-blind, placebo-controlled hyponatremia trials in which Tolvaptan was administered in titrated doses (15 mg to 60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. In these trials, 10% (23/223) of Tolvaptan-treated patients discontinued treatment because of an adverse event, compared to 12% (26/220) of placebo-treated patients; no adverse reaction resulting in discontinuation of trial medication occurred at an incidence of > 1% in Tolvaptan-treated patients.

Table 1 lists the adverse reactions reported in Tolvaptan-treated patients with hyponatremia (serum sodium < 135 mEq/L) and at a rate at least 2% greater than placebo-treated patients in two 30-day, double-blind, placebo-controlled trials. In these studies, 223 patients were exposed to Tolvaptan (starting dose 15 mg, titrated to 30 and 60 mg as needed to raise serum sodium). Adverse events resulting in death in these trials were 6% in Tolvaptan-treated-patients and 6% in placebo-treated patients.

Table 1: Adverse Reactions ( > 2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials

In a subgroup of patients with hyponatremia (N = 475, serum sodium < 135 mEq/L) enrolled in a double-blind, placebo-controlled trial (mean duration of treatment was 9 months) of patients with worsening heart failure, the following adverse reactions occurred in Tolvaptan-treated patients at a rate at least 2% greater than placebo: mortality (42% Tolvaptan, 38% placebo), nausea (21% Tolvaptan, 16% placebo), thirst (12% Tolvaptan, 2% placebo), dry mouth (7% Tolvaptan, 2% placebo) and polyuria or pollakiuria (4% Tolvaptan, 1% placebo).

Gastrointestinal bleeding in patients with cirrhosis

In patients with cirrhosis treated with Tolvaptan in the hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) Tolvaptan-treated patients and 1 out of 57 (2%) placebo treated patients.

The following adverse reactions occurred in < 2% of hyponatremic patients treated with Tolvaptan and at a rate greater than placebo in double-blind placebo-controlled trials (N = 607 Tolvaptan; N = 518 placebo) or in < 2% of patients in an uncontrolled trial of patients with hyponatremia (N = 111) and are not mentioned elsewhere in the label.

Blood and Lymphatic System Disorders: Disseminated intravascular coagulation

Cardiac Disorders: Intracardiac thrombus, ventricular fibrillation

Investigations: Prothrombin time prolonged

Gastrointestinal Disorders: Ischemic 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

The following adverse reactions have been identified during post-approval use of Tolvaptan. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Neurologic: Osmotic demyelination syndrome

Investigations: Hypernatremia

Removal of excess free body water increases serum osmolality and serum sodium concentrations. All patients treated with Tolvaptan, especially those whose serum sodium levels become normal, should continue to be monitored to ensure serum sodium remains within normal limits. If hypernatremia is observed, management may include dose decreases or interruption of Tolvaptan treatment, combined with modification of free-water intake or infusion. During clinical trials of hyponatremic patients, hypernatremia was reported as an adverse event in 0.7% of patients receiving Tolvaptan vs. 0.6% of patients receiving placebo; analysis of laboratory values demonstrated an incidence of hypernatremia of 1.7% in patients receiving Tolvaptan vs. 0.8% in patients receiving placebo.

Immune System Disorders

Hypersensitivity reactions including anaphylactic shock and rash generalized.

Each tablet also contains the following inactive ingredients: Corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose, and FD&C blue no. 2 aluminum lake as colorant.

Tolvaptan is (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-o-tolu-m-toluidide. The empirical formula is C₂₆H₂₅ClN₂O₃ with a molecular weight of 448.94.