What are the recommended dosing regimen, titration schedule, and monitoring parameters for Tolvaptan in treating euvolemic or hypervolemic hyponatraemia (e.g., SIADH) and autosomal dominant polycystic kidney disease?

Tolvaptan Dosing and Monitoring in Hyponatremia and ADPKD

Hyponatremia (SIADH, Heart Failure, Cirrhosis)

For euvolemic or hypervolemic hyponatremia, start tolvaptan at 15 mg once daily upon waking, titrate after at least 24 hours to 30 mg daily, then to a maximum of 60 mg daily as needed to achieve normonatremia—but only after fluid restriction has failed and only in a hospital setting with intensive sodium monitoring. 1, 2

Initiation Requirements

• Tolvaptan must be initiated and re-initiated only in a hospital where serum sodium can be monitored closely 1, 2
• This drug is indicated for clinically significant hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted fluid restriction) 2
• Do not use tolvaptan for patients requiring urgent correction of severe symptomatic hyponatremia (e.g., seizures, altered mental status)—these patients need 3% hypertonic saline instead 2

Dosing Schedule

• Starting dose: 15 mg orally once daily upon waking (no regard to meals) 1, 2
• After ≥24 hours, may increase to 30 mg once daily if serum sodium response is inadequate 1, 2
• Maximum dose: 60 mg once daily 1, 2
• Treatment duration should be limited to 30 days to minimize hepatotoxicity risk 2

Intensive Sodium Monitoring Protocol

• Check serum sodium every 2 hours during the first 8 hours after the initial dose 1
• Obtain morning blood samples before the tolvaptan dose is taken 1
• Never allow sodium correction to exceed 8–10 mmol/L in any 24-hour period to prevent osmotic demyelination syndrome 1, 2
• For patients with cirrhosis, alcoholism, or malnutrition, limit correction to 4–6 mmol/L per day due to exceptionally high risk of osmotic demyelination 1
• After the first day, continue monitoring sodium levels every 4–6 hours while on therapy 1

Special Population Adjustments

• Cirrhotic patients: Use 50% of the standard dose because metabolism is approximately 60% slower in uncompensated liver cirrhosis 1
• Avoid tolvaptan in patients with underlying liver disease whenever possible due to hepatotoxicity risk 2
• In Japan and China, lower doses (7.5–15 mg/day) are approved for ascites control 1

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Autosomal Dominant Polycystic Kidney Disease (ADPKD)

For ADPKD, initiate tolvaptan at a split-dose regimen of 45 mg upon waking and 15 mg eight hours later, then titrate weekly to a target of 90 mg AM and 30 mg PM based on tolerability—but only through the FDA-approved REMS program with monthly liver function monitoring for the first 18 months. 1, 3, 2

FDA Boxed Warning

• Tolvaptan is contraindicated for ADPKD outside of the FDA-approved REMS program due to risk of serious and potentially fatal liver injury 2
• The drug should not be used for ADPKD unless enrolled in the restricted distribution program 2

ADPKD Dosing Regimen

• Initial dose: 45 mg upon waking + 15 mg 8 hours later (total 60 mg/day split-dose) 1, 3
• Week 1 titration: Increase to 60 mg AM + 30 mg PM (total 90 mg/day) if tolerated 1, 3
• Target dose: 90 mg AM + 30 mg PM (total 120 mg/day) 1, 3
• The split-dose regimen reduces nocturia burden compared to once-daily dosing 3

Downtitration Criteria

Consider dose reduction for: 3

• Concurrent use of moderate CYP3A inhibitors (though strong inhibitors are contraindicated) 1, 3
• Intolerable aquaresis-related side effects (polyuria, thirst, nocturia) 3
• Elevated liver enzymes (see monitoring below) 3

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Mandatory Hepatotoxicity Monitoring (ADPKD Only)

Perform liver function tests (ALT, AST, bilirubin) monthly for the first 18 months, then every 3 months until discontinuation—and immediately hold tolvaptan if ALT or AST rises ≥3× ULN or if any liver injury symptoms appear. 1, 3

Monitoring Schedule

• Baseline LFTs required before initiation; do not start if ALT or AST >3× ULN 1
• Monthly LFTs for months 1–18 1, 3
• Every 3 months after month 18 until drug discontinuation 1, 3
• Within 48–72 hours if ALT/AST rises >2× ULN or >2× baseline 1

Criteria for Holding Tolvaptan

Immediately discontinue if: 1

• ALT or AST ≥3× ULN 1
• ALT or AST >2× baseline (even if <2× ULN) 1
• Any liver injury symptoms appear: fatigue, nausea, vomiting, anorexia, right-upper-quadrant pain, fever, rash, jaundice, pruritus, ascites 1

Permanent Discontinuation Rules

• Do not rechallenge unless an alternative cause for liver injury is identified and the injury has completely resolved 1
• Hepatocellular injury typically occurs between 3–18 months after initiation and is reversible within 1–4 months after stopping the drug 1

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Critical Drug Interactions and Contraindications

Avoid all strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir) and grapefruit juice—these are absolute contraindications that can cause dangerous tolvaptan accumulation. 1, 2

Absolute Contraindications

• Strong CYP3A inhibitors (antifungals, macrolide antibiotics, protease inhibitors) 1, 2
• Grapefruit juice 1
• Anuria 2
• Hypovolemic hyponatremia 1, 2
• Patients unable to sense or respond to thirst (altered mental status, impaired access to water) 1, 2
• Use for ADPKD outside FDA-approved REMS 2

Moderate CYP3A Inhibitors

• Avoid moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin, fluconazole) when possible 1, 2
• If unavoidable, reduce tolvaptan dose to 50% 1

Strong CYP3A Inducers

• Avoid rifampin, phenytoin, carbamazepine, St. John's wort—these reduce tolvaptan efficacy 1

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Management of Aquaresis-Related Side Effects

Counsel patients to expect marked polyuria, thirst, and nocturia—and instruct them to drink adequate water throughout the day (not just when thirsty) and adopt a low-sodium diet to reduce urine output. 1, 3

Common Aquaretic Effects

• Thirst and dry mouth (reported in 4.2–40.3% of patients) 4
• Polyuria and pollakiuria (0.6–31.7%) 4
• Nocturia (frequent nighttime urination disrupts sleep) 3
• Dehydration and hypernatremia if fluid intake is inadequate 1

Patient Education Strategies

• Drink water proactively throughout the day, not just in response to thirst 3
• Consume liquids without sugar or fat to avoid caloric overload 3
• Adopt a low-sodium diet (2000 mg/day) to reduce obligate water losses 3
• Take the second ADPKD dose 8 hours after the first (not at bedtime) to minimize nocturia 3
• Ensure access to bathroom facilities at work and during travel 3

When to Hold or Reduce Dose

• Dehydration with orthostatic hypotension or tachycardia 1
• Hypernatremia (sodium >145 mmol/L) 1
• Intolerable nocturia affecting quality of life 3

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Monitoring Serum Sodium in ADPKD Patients

Check serum sodium levels regularly to assess adequacy of water intake—target normal range (135–145 mmol/L) and avoid both hyponatremia and hypernatremia. 3

• Unlike hyponatremia treatment, ADPKD patients are at risk of hypernatremia if fluid intake is insufficient 1
• Monitor sodium at baseline, during titration, and periodically during maintenance therapy 3
• Hypernatremia indicates inadequate free-water intake—counsel patient to increase fluid consumption 1

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Duration of Treatment and Discontinuation

Hyponatremia

• Limit treatment to 30 days to minimize hepatotoxicity risk 2
• Effects are maintained until discontinuation (typically 30 days in studies), with sodium levels gradually returning to baseline after stopping 1
• Long-term safety beyond 30 days for hyponatremia is not established 2

ADPKD

• Continue tolvaptan until approaching kidney replacement therapy if well-tolerated 3
• Treatment can be continued in patients >55 years or eGFR <25 ml/min/1.73 m² if benefits outweigh risks 3
• Long-term safety and efficacy demonstrated in studies extending beyond 2 years 1, 5, 6
• After discontinuation, increase water intake to 2–3 liters/day and continue other renal-protective measures 3

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Efficacy Timeline

Hyponatremia

• Significant sodium increase observed by day 4 of treatment 1
• Mean sodium increase on day 4: 3.62 mmol/L vs. 0.25 mmol/L with placebo (P<0.001) 4
• Mean sodium increase on day 30: 6.22 mmol/L vs. 1.66 mmol/L with placebo (P<0.001) 4

ADPKD

• Slows eGFR decline by approximately 1.3 ml/min/1.73 m² per year compared to placebo 3
• Reduces total kidney volume growth by 2.7% per year compared to placebo 3
• Effects on kidney function are maintained for at least 2 years in extension studies 6

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Common Pitfalls to Avoid

• Never use tolvaptan as first-line therapy for hyponatremia—fluid restriction must fail first 1
• Never initiate or re-initiate tolvaptan outside a hospital for hyponatremia treatment 2
• Never use tolvaptan with hypertonic saline—this increases overcorrection risk 2
• Never ignore liver enzyme elevations—even transient rises >2× baseline require repeat testing within 48–72 hours 1
• Never apply fluid restriction during the first 24 hours of tolvaptan therapy—this increases overcorrection risk 1
• Never use tolvaptan in patients with urinary outflow obstruction until obstruction is relieved 2