Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Otsuka Pharmaceutical Netherlands B.V., Herikerbergweg 292, 1101 CT, Amsterdam, Netherlands
Tolvaptan has not been studied in a setting of urgent need to raise serum sodium acutely. For such patients, alternative treatment has to be considered.
Tolvaptan may cause adverse reactions related to water loss such as thirst, dry mouth and dehydration (see section 4.8). Therefore, patients must have access to water and be able to drink sufficient amounts of water. If fluid restricted patients are treated with tolvaptan, extra caution has to be exercised to ensure that patients do not become overly dehydrated.
Volume status must be monitored in patients taking tolvaptan because treatment with tolvaptan may result in severe dehydration, which constitutes a risk factor for renal dysfunction. If dehydration becomes evident, take appropriate action which may include the need to interrupt or reduce the dose of tolvaptan and increase fluid intake.
Urinary output must be secured. Patients with partial obstruction of urinary outflow, for example patients with prostatic hypertrophy or impairment of micturition, have an increased risk of developing acute retention.
Fluid and electrolyte status has to be monitored in all patients and particularly in those with renal and hepatic impairment. Administration of tolvaptan may cause too rapid increases in serum sodium (≥12 mmol/L per 24 hours, please see below); therefore, monitoring of serum sodium in all patients must start no later than 4-6 hours after treatment initiation. During the first 1-2 days and until the tolvaptan dose is stabilised serum sodium and volume status must be monitored at least every 6 hours.
Patients with very low baseline serum sodium concentrations may be at greater risk for too rapid correction of serum sodium.
Too rapid correction of hyponatremia (increase ≥12 mmol/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. Therefore after initiation of treatment, patients have to be closely monitored for serum sodium and volume status (see above).
In order to minimise the risk of too rapid correction of hyponatremia the increase of serum sodium should be less than 10-12 mmol/L/24 hours and less than 18 mmol/L/48 hours. Therefore, more precautionary limits apply during the early treatment phase.
If sodium correction exceeds 6 mmol/L during the first 6 hours of administration or 8 mmol/L during the first 6-12 hours, respectively, the possibility that serum sodium correction may be overly rapid should be considered. These patients should be monitored more frequently regarding their serum sodium and administration of hypotonic fluid is recommended. In case serum sodium increases ≥12 mmol/L within 24 hours or ≥18 mmol/L within 48 hours, tolvaptan treatment is to be interrupted or discontinued followed by administration of hypotonic fluid.
In patients at higher risk of demyelination syndromes, for example those with hypoxia, alcoholism or malnutrition, the appropriate rate of sodium correction may be lower than that in patients without risk factors; these patients should be very carefully managed.
Patients who received other treatment for hyponatremia or medicinal products which increase serum sodium concentration (see section 4.5) prior to initiation of treatment with Samsca must be managed very cautiously. These patients may be at higher risk for developing rapid correction of serum sodium during the first 1-2 days of treatment due to potential additive effects. Co-administration of Samsca with other treatments for hyponatremia, and medicinal products that increase serum sodium concentration, is not recommended during initial treatment or for other patients with very low baseline serum sodium concentrations (see section 4.5).
Diabetic patients with an elevated glucose concentration (e.g. in excess of 300 mg/dL) may present with pseudo-hyponatremia. This condition should be excluded prior and during treatment with tolvaptan.
Tolvaptan may cause hyperglycemia (see section 4.8). Therefore, diabetic patients treated with tolvaptan should be managed cautiously. In particular this applies to patients with inadequately controlled type II diabetes.
Liver injury induced by tolvaptan was observed in clinical trials investigating a different indication (autosomal dominant polycystic kidney disease [ADPKD]) with long-term use of tolvaptan at higher doses than for the approved indication (see section 4.8).
In post-marketing experience with tolvaptan in ADPKD, acute liver failure requiring liver transplantation has been reported (see section 4.8).
In these clinical trials, clinically significant increases (greater than 3 × Upper Limit of Normal) in serum alanine aminotransferase (ALT), along with clinically significant increases (greater than 2 × Upper Limit of Normal) in serum total bilirubin were observed in 3 patients treated with tolvaptan. In addition, an increased incidence of significant elevations of ALT was observed in patients treated with tolvaptan [4.4% (42/958)] compared to those receiving placebo [1.0% (5/484)]. Elevation (>3 × ULN) of serum aspartate aminotransferase (AST) was observed in 3.1% (30/958) of patients on tolvaptan and 0.8% (4/484) patients on placebo. Most of the liver enzyme abnormalities were observed during the first 18 months of treatment. The elevations gradually improved after discontinuation of tolvaptan. These findings may suggest that tolvaptan has the potential to cause irreversible and potentially fatal liver injury.
In a post-authorisation safety study of tolvaptan in hyponatremia secondary to SIADH, several cases of hepatic disorders and elevated transaminases were observed (see section 4.8).
Liver function tests must be promptly performed in patients taking tolvaptan who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. If liver injury is suspected, tolvaptan must be promptly discontinued, appropriate treatment has to be instituted, and investigations have to be performed to determine the probable cause. Tolvaptan must not be re-initiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with tolvaptan.
In post-marketing experience, anaphylaxis (including anaphylactic shock and generalised rash) has been reported very rarely following administration of tolvaptan. Patients have to be carefully monitored during treatment. Patients with known hypersensitivity reactions to benzazepine or benzazepine derivatives (e.g. benazepril, conivaptan, fenoldopam mesylate or mirtazapine) may be at risk for hypersensitivity reaction to tolvaptan (see section 4.3 Contraindications).
If an anaphylactic reaction or other serious allergic reactions occur, administration of tolvaptan must be discontinued immediately and appropriate therapy initiated. Since hypersensitivity is a contraindication (see section 4.3) treatment must never be restarted after an anaphylactic reaction or other serious allergic reactions.
Samsca contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
There is no experience from controlled clinical trials with concomitant use of Samsca and other treatments for hyponatremia such as hypertonic sodium chloride solution, oral sodium formulations, and medicinal products that increase serum sodium concentration. Medicinal products with high sodium content such as effervescent analgesic preparations and certain sodium containing treatments for dyspepsia may also increase serum sodium concentration. Concomitant use of Samsca with other treatments for hyponatremia or other medicinal products that increase serum sodium concentration may result in a higher risk for developing rapid correction of serum sodium (see section 4.4) and is therefore not recommended during initial treatment or for other patients with very low baseline serum sodium concentrations where rapid correction may represent a risk for osmotic demyelination (see section 4.4).
Tolvaptan plasma concentrations have been increased by up to 5.4-fold area under time-concentration curve (AUC) after the administration of strong CYP3A4 inhibitors. Caution should be exercised in coadministering CYP3A4 inhibitors (e.g. ketoconazole, macrolide antibiotics, diltiazem) with tolvaptan (see section 4.4). Co-administration of grapefruit juice and tolvaptan resulted in a 1.8-fold increase in exposure to tolvaptan. Patients taking tolvaptan should avoid ingesting grapefruit juice.
Tolvaptan plasma concentrations have been decreased by up to 87% (AUC) after the administration of CYP3A4 inducers. Caution has to be exercised in co-administering CYP3A4 inducers (e.g. rifampicin, barbiturates) with tolvaptan.
In healthy subjects, tolvaptan, a CYP3A4 substrate, had no effect on the plasma concentrations of some other CYP3A4 substrates (e.g. warfarin or amiodarone). Tolvaptan increased plasma levels of lovastatin by 1.3- to 1.5-fold. Even though this increase has no clinical relevance, it indicates tolvaptan can potentially increase exposure to CYP3A4 substrates.
While there does not appear to be a synergistic or additive effect of concomitant use of tolvaptan with loop and thiazide diuretics, each class of agent has the potential to lead to severe dehydration, which constitutes a risk factor for renal dysfunction. If dehydration or renal dysfunction becomes evident, take appropriate action which may include the need to interrupt or reduce doses of tolvaptan and/or diuretics, increase fluid intake, evaluate and address other potential causes of renal dysfunction or dehydration.
Steady state digoxin concentrations have been increased (1.3-fold increase in maximum observed plasma concentration [Cmax] and 1.2-fold increase in area under the plasma concentration-time curve over the dosing interval [AUCτ]) when co administered with multiple once daily 60 mg doses of tolvaptan. Patients receiving digoxin should therefore be evaluated for excessive digoxin effects when treated with tolvaptan.
In addition to its renal aquaretic effect, tolvaptan is capable of blocking vascular vasopressin V2-receptors involved in the release of coagulation factors (e.g., von Willebrand factor) from endothelial cells. Therefore, the effect of vasopressin analogues such as desmopressin may be attenuated in patients using such analogues to prevent or control bleeding when co-administered with tolvaptan.
There are no or limited amount of data from the use of tolvaptan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Samsca is contraindicated during pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during tolvaptan treatment.
It is unknown whether tolvaptan is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of tolvaptan in breast milk (for details see 5.3). The potential risk for humans is unknown. Samsca is contraindicated during breast-feeding (see section 4.3).
Studies in animals showed effects on fertility (see section 5.3). The potential risk for humans is unknown.
Samsca has no or negligible influence on the ability to drive or use machines. However, when driving or using machines it should be taken into account that occasionally dizziness, asthenia or syncope may occur.
The adverse reaction profile of tolvaptan in SIADH is based on a clinical trials database of 3,294 tolvaptan-treated patients and is consistent with the pharmacology of the active substance. The pharmaco-dynamically predictable and most commonly reported adverse reactions are thirst, dry mouth and pollakiuria occurring in approximately 18%, 9% and 6% of patients.
The frequencies of the adverse reactions from clinical trials correspond with very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse reactions is qualified as “not known”.
Not known: Anaphylactic shock, Generalised rash
Common: Polydipsia, Dehydration, Hyperkalemia, Hyperglycemia, Hypoglycemia1, Hypernatremia1, Hyperuricemia1, Decreased appetite
Common: Syncope1, Headache1, Dizziness1
Uncommon: Dysgeusia
Common: Orthostatic hypotension
Very common: Nausea
Common: Constipation, Diarrhoea1, Dry mouth
Common: Ecchymosis, Pruritus
Uncommon: Pruritic rash1
Common: Pollakiuria, Polyuria
Uncommon: Renal impairment
Very common: Thirst
Common: Asthenia, Pyrexia, Malaise1
Not known: Hepatic disorders2, Acute hepatic failure3
Common: Blood urine present1, Alanine aminotransferase increased (see section 4.4)1, Aspartate aminotransferase increased (see section 4.4)1, Blood creatinine increased
Uncommon: Bilirubin increased (see section 4.4)1
Not known: Elevated transaminases2
Very common: Rapid correction of hyponatremia, sometimes leading to neurological symptoms
1 observed in clinical trials investigating other indications
2 from post-authorisation safety study in hyponatremia secondary to SIADH
3 observed in post-marketing with tolvaptan in ADPKD. Liver transplantation was necessary.
In a post-authorisation safety study of tolvaptan in hyponatremia secondary to SIADH, including a high proportion of patients with tumours (especially Small Cell Lung Cancer), patients with low baseline serum sodium as well as patients with concomitant use of diuretics and/or sodium chloride solution the incidence of rapid correction of hyponatremia was found to be higher than in clinical trials.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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