Vaptan

Approved Indications:

• Clinically Significant Hyponatremia:
• Due to Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
• Associated with Heart Failure (hypervolemic hyponatremia)
• Associated with Cirrhosis (hypervolemic hyponatremia)
• In euvolemic hyponatremia where fluid restriction is ineffective
• Autosomal Dominant Polycystic Kidney Disease (ADPKD):
• To slow progression of kidney function decline in adults at risk of rapidly progressing disease (e.g., based on age, total kidney volume, and eGFR trends)

Off-Label/Clinically Accepted Uses:

• Severe refractory hyponatremia in ICU settings
• Hyponatremia in postoperative neurosurgical or traumatic brain injury patients (specialist-supervised)
• Acute heart failure cases with dilutional hyponatremia unresponsive to loop diuretics

Route of Administration: Oral
Available Dosage Forms: Tablets – 15 mg, 30 mg, 45 mg, 60 mg, 90 mg

Hyponatremia (Adults):

• Initial dose: 15 mg once daily
• Titration: May increase to 30 mg, then to 60 mg at ≥24-hour intervals, based on serum sodium and patient response
• Duration: Use is recommended for ≤30 days to minimize risk of hepatotoxicity

ADPKD (Adults):

• Initial dose: 60 mg/day in two divided doses
• 45 mg in the morning + 15 mg 8 hours later
• Titration: May escalate to 90/30 mg/day in weekly increments based on tolerance and labs
• Administration: On an empty stomach with water, morning dose at least 8 hours before bedtime to reduce nocturia

Elderly:

• Same dosing as adults; careful monitoring for dehydration and hypotension is required

Pediatric Use:

• Not approved for use in children or adolescents

Renal Impairment:

• Contraindicated in anuria
• Not recommended in severe renal impairment or ESRD (eGFR <15 mL/min/1.73 m²)

Hepatic Impairment:

• Contraindicated in active liver disease
• Use with caution in mild to moderate impairment; close LFT monitoring is essential

Tolvaptan is a selective vasopressin V2 receptor antagonist. It blocks the action of vasopressin on the V2 receptors located in the distal nephron, specifically in the collecting ducts of the kidney. This inhibition prevents the insertion of aquaporin-2 channels into the tubular membrane, reducing water reabsorption and promoting aquaresis—the excretion of free water without electrolyte loss. This action raises serum sodium levels in hyponatremia. In ADPKD, Tolvaptan lowers intracellular cyclic AMP (cAMP) levels, thereby reducing cyst epithelial proliferation and fluid secretion into cysts, slowing cyst growth and delaying kidney function decline.

• Absorption: Oral bioavailability ~56%; peak plasma concentration in 2–4 hours
• Distribution: Highly protein-bound (~99%)
• Metabolism: Primarily metabolized by hepatic CYP3A4
• Half-life: 3 to 12 hours (dose-dependent)
• Excretion: ~59% via feces, ~33% via urine (as metabolites)
• Steady-State: Reached within 2 days of once-daily dosing
• Food Effect: Minor; does not significantly affect pharmacokinetics

Pregnancy:

• FDA Pregnancy Category: Not assigned (formerly Category D)
• Animal studies suggest embryotoxicity and fetal harm
• Not recommended during pregnancy unless no alternatives are available and benefits outweigh risks

Lactation:

• Unknown if Tolvaptan is excreted in human breast milk
• Animal data show presence in milk; potential for adverse effects in breastfed infants
• Breastfeeding not recommended during and for 1 month after discontinuation of therapy

• Primary Class: Vasopressin Antagonist
• Subclass: Selective Vasopressin V2 Receptor Antagonist (“Vaptan” class)

• Known hypersensitivity to Tolvaptan or any excipients
• Urgent need for rapid correction of hyponatremia
• Inability to perceive or respond to thirst
• Anuria (complete absence of urine output)
• Hypovolemic hyponatremia
• Use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir)
• Active liver disease or significant liver enzyme elevations (especially in ADPKD)

• Black Box Warning: Risk of serious liver injury, including hepatic failure; monthly liver function monitoring is essential in ADPKD
• Overcorrection of Sodium: Risk of osmotic demyelination syndrome (ODS) if serum sodium rises too rapidly
• Volume Depletion/Dehydration: Monitor volume status regularly, especially in elderly or diuretic users
• Polyuria and Nocturia: Advise patients to maintain fluid intake and avoid nighttime dosing
• CYP3A4 Metabolism: Drug levels can be altered significantly by inhibitors or inducers
• Monitoring: Regular assessment of serum sodium, volume status, and liver function tests is mandatory

Common (≥10%):

• General: Thirst, dry mouth, fatigue
• Renal/Urinary: Polyuria, nocturia, increased urinary frequency
• Gastrointestinal: Nausea, diarrhea
• Neurologic: Dizziness, headache

Less Common to Rare:

• Liver Function: Elevated ALT/AST, hepatotoxicity
• Electrolyte Imbalance: Hypernatremia, dehydration
• Neurologic: Osmotic demyelination (rare, with rapid Na+ correction)
• Hypotension: Especially in volume-depleted patients

Timing of Onset:

• Polyuria and thirst typically occur within hours
• Liver injury may develop after weeks to months

Major Interactions:

• CYP3A4 Inhibitors (↑ Tolvaptan levels – avoid use):
• Ketoconazole, itraconazole, clarithromycin, ritonavir
• CYP3A4 Inducers (↓ efficacy):
• Rifampin, carbamazepine, phenytoin, St. John's Wort
• Loop or Thiazide Diuretics:
• Additive effect → monitor for dehydration

Food/Herbal Interactions:

• Grapefruit juice: Inhibits CYP3A4 → avoid due to increased drug exposure

Alcohol:

• Increases dehydration and hepatic strain; best avoided

• FDA (2023): Reiterated liver injury risk in ADPKD; mandatory monthly LFTs in first 18 months of use
• EMA & NICE: Recommend Tolvaptan only in rapidly progressing ADPKD (age-adjusted TKV + eGFR decline criteria)
• KDIGO 2023 Guidelines: Support Tolvaptan as a disease-modifying therapy in ADPKD with early intervention strategies
• Hyponatremia Management Consensus: Reaffirms use in SIADH and heart failure when fluid restriction fails

• Storage Temperature: 20°C to 25°C (68°F to 77°F)
• Permissible Range: 15°C to 30°C allowed for short periods
• Humidity Protection: Store in a dry area
• Light Protection: Store in original container to protect from light
• Handling Precautions:
• Do not crush or split tablets
• Keep out of reach of children
• Protect from freezing
• Reconstitution/Refrigeration: Not applicable