Tolvamac

Uses

Tolvamac is used for-

• Hypervolemic or euvolemic hyponatremia.
• Autosomal dominant polycystic kidney disease.

Tolvamac is also used to associated treatment for these conditions: Autosomal Dominant Polycystic Kidney Disease （ADPKD), Symptomatic euvolemic Hyponatremia, Symptomatic hypervolemic Hyponatremia

How Tolvamac works

Tolvamac is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvamac is especially useful for heart failure patients as they have higher serum levels of vasopressin.

Dosage

Tolvamac dosage

Hypervolemic or euvolemic hyponatremia: The usual starting dose for Tolvamac 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 use for more than 30 days due to the risk of hepatotoxicity.

Autosomal dominant polycystic kidney disease (ADPKD):

• Initially: 60 mg/day in divided doses (given as 45 mg upon wakening and 15 mg 8 hours later);
• Titrate per response and tolerability at intervals of at least 7 days between titrations to 90 mg/day in divided doses (given as 60 mg upon wakening and 30 mg 8 hours later) followed by 120 mg/day in divided doses (given as 90 mg upon wakening and 30 mg 8 hours later).
• Maintain urine osmolality of <300 mOsm/kg if possible; if the maximum dose is not tolerated, administration of a lower dose with the goal of achieving urine osmolality of 250 to 300 mOsm/kg is reasonable.

Side Effects

The most common side effects of Tolvamac are: thirst, dry mouth, weakness, constipation, making large amounts of urine and urinating often & increased blood sugar levels.

Toxicity

The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia.

Precaution

Too rapid correction of serum sodium can cause serious neurologic sequelae.

Interaction

Other Drugs Affecting Exposure to Tolvamac:

• CYP 3A Inhibitors: Tolvamac is a substrate of CYP 3A. CYP 3A inhibitors can lead to a marked increase in Tolvamac concentrations. Do not use Tolvamac with strong inhibitors of CYP 3A and avoid concomitant use with moderate CYP 3A inhibitors.
• CYP 3A Inducers: Avoid co-administration of CYP 3A inducers (e.g., Rifampin, Rifabutin, Rifapentin, Barbiturates, Phenytoin, Carbamazepine) with Tolvamac, as this can lead to a reduction in the plasma concentration of Tolvamac and decreased effectiveness of Tolvamac treatment. If co-administered with CYP 3A inducers, the dose of Tolvamac may need to be increased.
• P-gp Inhibitors: The dose of Tolvamac may have to be reduced when Tolvamac is co-administered with P-gp inhibitors, e.g., Cyclosporine.

Food Interaction

• Avoid excessive or chronic alcohol consumption. This may increase the risk of developing osmotic demyelination syndrome.
• Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of tolvaptan, which may increase its serum concentration.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of tolvaptan and may reduce its serum concentration.
• Take with or without food.

[Moderate] GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of tolvaptan.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

According to the product labeling, administration of tolvaptan with grapefruit juice resulted in a 1.8-fold increase in tolvaptan systemic exposure.

The clinical significance is unknown, although increased pharmacologic effects may be expected.

Too rapid correction of hyponatremia increases the risk of osmotic demyelination syndrome, which is associated with dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death.

MANAGEMENT: Patients treated with tolvaptan should avoid consumption of grapefruits and grapefruit juice.

Tolvamac Drug Interaction

Moderate: spironolactone, sulfamethoxazole / trimethoprim, sacubitril / valsartan, heparinUnknown: aspirin, epinephrine, aspirin, calcium / vitamin d, citalopram, albuterol / ipratropium, carvedilol, levothyroxine, omega-3 polyunsaturated fatty acids, fluticasone nasal, insulin lispro, furosemide, atorvastatin, metoprolol, acetaminophen, cholecalciferol

Tolvamac Disease Interaction

Major: liver impairment, renal impairmentModerate: liver disease/alcoholism

Volume of Distribution

Healthy subjects: 3L/kg; slightly higher in heart failure patients.

Elimination Route

Tmax, Healthy subjects: 2 - 4 hours; Cmax, Healthy subjects, 30 mg: 374 ng/mL; Cmax, Healthy subjects, 90 mg: 418 ng/mL; Cmax, heart failure patients, 30 mg: 460 ng/mL; Cmax, heart failure patients, 90 mg: 723 ng/mL; AUC(0-24 hours), 60 mg: 3.71 μg·h/mL; AUC(∞), 60 mg: 4.55 μg·h/mL; The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan.

Half Life

Terminal half life, oral dose = 12 hours.

Clearance

4 mL/min/kg (post-oral dosing).

Elimination Route

Fecal- very little renal elimination (<1% is excreted unchanged in the urine)

Pregnancy & Breastfeeding use

There are no or limited amount of data from the use of Tolvamac in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Tolvamac is contraindicated during pregnancy. Women of childbearing potential have to use effective contraception during Tolvamac treatment. It is unknown whether Tolvamac is excreted in human milk.

Contraindication

Hypersensitivity to the active substance or to any of the excipients, anuria, volume depletion, hypovolemic hyponatremia, hypernatremia, Patients who cannot perceive thirst, pregnancy, breast-feeding.

Acute Overdose

Single doses up to 480 mg and multiple doses up to 300 mg per day for 5 days have been well tolerated in clinical trials in healthy volunteers. There is no specific antidote for Tolvamac intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst and dehydration/ hypovolemia (profuse and prolonged aquaresis). In patients with suspected Tolvamac overdose, assessment of vital signs, electrolyte concentrations, ECG and fluid status is recommended. Appropriate replacement of water and/or electrolytes must continue until aquaresis abates. Dialysis may not be effective in removing Tolvamac because of its high binding affinity for human plasma protein (>98%).

Storage Condition

Store at below 25°C in a dry place, protected from light. Keep out of reach of children.

Innovators Monograph

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