Tolvaptan
Regulatory sources consulted
Approved indications
- Slow the progression of cyst development and renal insufficiency associated with autosomal dominant polycystic kidney disease in adults with chronic kidney disease stages 1–4 at treatment initiation and signs of rapid progression.
Contraindications
Absolute
- Hypersensitivity to tolvaptan, other benzazepine derivatives or excipients; anuria, hypovolemia, hypernatremia, inability to perceive or respond to thirst, pregnancy or breastfeeding.
- Elevated liver enzymes or signs or symptoms of liver injury before initiation that meet permanent discontinuation criteria.
Clinical warnings
- Major warning · Jinarc may cause serious liver injury. Measure ALT, AST, and bilirubin before treatment, monthly for 18 months, and every 3 months thereafter. Stop and repeat testing within 48–72 hours if symptoms or abnormalities occur. — https://cima.aemps.es/cima/dochtml/ft/1151000007/FT_1151000007.html
- Major warning · Permanently discontinue Jinarc if ALT/AST exceeds 8 times ULN, exceeds 5 times ULN for more than 2 weeks, exceeds 3 times ULN with bilirubin above 2 times ULN or INR above 1.5, or exceeds 3 times ULN with persistent symptoms. — https://cima.aemps.es/cima/dochtml/ft/1151000007/FT_1151000007.html
- Major warning · Ensure continuous access to water and monitor thirst, osmolality, sodium, weight, and hydration status; discontinue if adequate hydration cannot be maintained. — https://cima.aemps.es/cima/dochtml/ft/1151000007/FT_1151000007.html
Drug interactions
- HighCYP3A inhibitors
Mechanism: They markedly increase tolvaptan exposure; ketoconazole increased AUC by 440% and Cmax by 248%, fluconazole increased AUC by 200% and Cmax by 80%, and grapefruit approximately doubled Cmax.
Recommendation: Apply the specified dose reductions with moderate or strong CYP3A inhibitors and avoid grapefruit juice.
https://cima.aemps.es/cima/dochtml/ft/1151000007/FT_1151000007.html
- HighStrong CYP3A inducers
Mechanism: They reduce tolvaptan exposure by approximately 85% and may negate efficacy.
Recommendation: Avoid concomitant administration.
https://cima.aemps.es/cima/dochtml/ft/1151000007/FT_1151000007.html
- HighDiuretics or sodium-raising medicines
Mechanism: Diuretics increase dehydration and renal impairment; sodium-raising medicines increase hypernatremia risk.
Recommendation: Avoid sodium-raising medicines; with diuretics, closely monitor hydration, sodium, and renal function.
https://cima.aemps.es/cima/dochtml/ft/1151000007/FT_1151000007.html
- ModerateP-gp substrates such as digoxin or dabigatran
Mechanism: Tolvaptan may increase exposure to P-gp substrates.
Recommendation: Monitor substrate effects and toxicity.
https://cima.aemps.es/cima/dochtml/ft/1151000007/FT_1151000007.html
Adverse events
Common (≥1%)
Thirst · Polyuria · Nocturia · Pollakiuria · Polydipsia · Dry mouth · Diarrhea · Increased ALT or AST · Asthenia · Constipation · Hyperglycemia
Rare but serious
Acute liver failure
Pregnancy and lactation
Jinarc is contraindicated during pregnancy and breastfeeding; women of reproductive potential must use effective contraception during treatment.
Recent literature (PubMed)
Hyponatraemia is the most common electrolyte disorder in hospital patients associated with increased morbidity, mortality, hospital stay and financial burden. The speed of a correction with 3% sodium chloride as a 100- to 150-ml intravenous bolus or continuous infusion depends on the severity and persistence of the symptoms and needs frequent biochemical monitoring. The rapid intermittent administration of hypertonic saline is preferred for treatment of symptomatic hyponatraemia. In asymptomatic mild hyponatraemia, an adequate solute intake with an initial fluid restriction (FR) of 500 ml/day adjusted according to the serum sodium (sNa) levels is preferred. Almost half of the syndrome of inappropriate antidiuretic hormone (SIADH) patients do not respond to FR as first-line therapy. At present, urea and tolvaptan are considered the most effective second-line therapies in SIADH. However, the evidence for guidance on the choice of second-line therapy of hypotonic hyponatraemia is lacking. Oral urea is considered to be a very effective and safe treatment. Mild and asymptomatic hyponatraemia is treated with adequate solute intake (salt and protein) and initial FR with adjustments based on sNa levels. Specific treatment with vaptans may be considered in either euvolaemic or hypervolaemic patients with high ADH activity. In order to ensure optimal patient outcome, close monitoring and readiness for administration of either hypotonic fluids or desmopressin may be crucial in the decision-making process for specific treatment and eventual overcorrection consequences. According to the guidelines, gradual correction and clinical evaluation is preferable over rapid normalization of sNa towards the laboratory reference ranges.
Hyponatremia is the most common electrolyte disorder, affecting more than 15% of patients in the hospital. Syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hypotonic hyponatremia, mediated by nonosmotic release of arginine vasopressin (AVP, previously known as antidiuretic hormone), which acts on the renal V2 receptors to promote water retention. There are a variety of underlying causes of SIAD, including malignancy, pulmonary pathology, and central nervous system pathology. In clinical practice, the etiology of hyponatremia is frequently multifactorial and the management approach may need to evolve during treatment of a single episode. It is therefore important to regularly reassess clinical status and biochemistry, while remaining alert to potential underlying etiological factors that may become more apparent during the course of treatment. In the absence of severe symptoms requiring urgent intervention, fluid restriction (FR) is widely endorsed as the first-line treatment for SIAD in current guidelines, but there is considerable controversy regarding second-line therapy in instances where FR is unsuccessful, which occurs in around half of cases. We review the epidemiology, pathophysiology, and differential diagnosis of SIAD, and summarize recent evidence for therapeutic options beyond FR, with a focus on tolvaptan, urea, and sodium-glucose cotransporter 2 inhibitors.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and is the most common inherited kidney disorder worldwide. ADPKD accounts for 5% to 10% of kidney failure in the US and Europe, and its prevalence in the US is 9.3 per 10 000 individuals. ADPKD is typically diagnosed in individuals aged 27 to 42 years and is primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes. Most persons with ADPKD have an affected parent, but de novo disease is suggested in 10% to 25% of families. More than 90% of patients older than 35 years have hepatic cysts, which may cause abdominal discomfort and occasionally require medical or surgical intervention. Hypertension affects 70% to 80% of patients with ADPKD, and approximately 9% to 14% develop intracranial aneurysms, which have a rupture rate of 0.57 per 1000 patient-years. Approximately 50% of individuals with ADPKD require kidney replacement therapy by 62 years of age. The severity of kidney disease can be quantified using the Mayo Imaging Classification (MIC), which stratifies patients based on total kidney volume adjusted for height and age and ranges from 1A to 1E. Patients with MIC 1C to MIC 1E have larger kidneys because of more rapid growth (6%-10% per year) compared with those with MIC 1A and 1B (1%-5% per year) and have earlier progression to kidney replacement therapy, which occurs at a mean age of 58.4 years for MIC 1C, 52.5 years for MIC 1D, and 43.4 years for MIC 1E. Optimal management of ADPKD includes systolic blood pressure lower than 120 mm Hg for most patients, but lower than 110/75 mm Hg for patients with MIC 1C to 1E who have an estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m2 and are younger than 50 years, dietary sodium restriction (<2000 mg/d), weight management, and adequate hydration (>2.5 L daily). The vasopressin type 2 receptor antagonist tolvaptan reduces the annual rate of eGFR decline by 0.98 to 1.2
Hyponatremia is the most common electrolyte disturbance seen in clinical practice, affecting up to 30% of acute hospital admissions, and is associated with significant adverse clinical outcomes. Acute or severe symptomatic hyponatremia carries a high risk of neurological morbidity and mortality. In contrast, chronic hyponatremia is associated with significant morbidity including increased risk of falls, osteoporosis, fractures, gait instability, and cognitive decline; prolonged hospital admissions; and etiology-specific increase in mortality. In this Approach to the Patient, we review and compare the current recommendations, guidelines, and literature for diagnosis and treatment options for both acute and chronic hyponatremia, illustrated by 2 case studies. Particular focus is concentrated on the diagnosis and management of the syndrome of inappropriate antidiuresis. An understanding of the pathophysiology of hyponatremia, along with a synthesis of the duration of hyponatremia, biochemical severity, symptomatology, and blood volume status, forms the structure to guide the appropriate and timely management of hyponatremia. We present 2 illustrative cases that represent common presentations with hyponatremia and discuss the approach to management of these and other causes of hyponatremia.
Drug-induced hyponatremia caused by renal water retention is mainly due to syndrome of inappropriate antidiuresis (SIAD). SIAD can be grouped into syndrome of inappropriate antidiuretic hormone secretion (SIADH) and nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The former is characterized by uncontrolled hypersecretion of arginine vasopressin (AVP), and the latter is produced by intrarenal activation for water reabsorption and characterized by suppressed plasma AVP levels. Desmopressin is useful for the treatment of diabetes insipidus because of its selective binding to vasopressin V2 receptor (V2R), but it can induce hyponatremia when prescribed for nocturnal polyuria in older patients. Oxytocin also acts as a V2R agonist and can produce hyponatremia when used to induce labor or abortion. In current clinical practice, psychotropic agents, anticancer chemotherapeutic agents, and thiazide diuretics are the major causes of drug-induced hyponatremia. Among these, vincristine and ifosfamide were associated with sustained plasma AVP levels and are thought to cause SIADH. However, others including antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics may induce hyponatremia by intrarenal mechanisms for aquaporin-2 (AQP2) upregulation, compatible with NSIAD. In these cases, plasma AVP levels are suppressed by negative feedback. In rat inner medullary collecting duct cells, haloperidol, sertraline, carbamazepine, and cyclophosphamide upregulated V2R mRNA and increased cAMP production in the absence of vasopressin. The resultant AQP2 upregulation was blocked by a V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors, suggestive of the activation of V2R-cAMP-PKA signaling. Hydrochlorothiazide can also upregulate AQP2 in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway. In brief, nephrogenic antidiuresis, or NSIAD, is the major mechanism for drug-induced hyponatremia. The ass