Tolvaptan Accord

HOS-100311 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile 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. Tabulated list of adverse reactions 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". System Organ Frequency Class Very common Common Uncommon Not known Immune system Anaphylactic disorders shock, Generalised rash Metabolism and Polydipsia, nutrition disorders Dehydration, Hyperkalemia, Hyperglycemia, Hypoglycemia1, Hypernatremia1, Hyperuricemia1, Decreased appetite Nervous system Syncope1, Dysgeusia disorders Headache1, Dizziness1 Vascular Orthostatic disorders hypotension Gastrointestinal Nausea Constipation, disorders Diarrhoea1, Dry mouth

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HOS-100307 · has-contraindication-information · PDF-Seite 3

3 • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to benzazepine or benzazepine derivatives (see section 4.4) • Anuria • Volume depletion • Hypovolemic hyponatremia • Hypernatremia • Patients who cannot perceive thirst • Pregnancy (see section 4.6) • Breast-feeding (see section 4.6)

HOS-100306 · has-indication-information · PDF-Seite 2

Tolvaptan is indicated in adults for the treatment of hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). 2

HOS-100309 · has-interaction-information · PDF-Seite 6

Co-administration with other treatments for hyponatremia and medicinal products that increase serum sodium concentration There is no experience from controlled clinical trials with concomitant use of tolvaptan 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 tolvaptan 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). Effect of other medicinal products on the pharmacokinetics of tolvaptan CYP3A4 inhibitors 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 co-administering CYP3A4 inhibitors (e.g. ketoconazole, macrolide antibiotics, diltiazem) with tolvaptan. 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. CYP3A4 inducers 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 and St. John’s wort) with tolvaptan. Effect of tolvaptan on the pharmacokinetics of other products CYP3A4 substrates 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 6 lovastatin by 1.3-fold to 1.5-fold. Even though this increase has no clinical relevance, it indicates tolvaptan can potentially increase exposure to CYP3A4 substrates. Transporter substrates P-glycoprotein substrates In-vitro studies indicate that tolvaptan is a substrate and competitive inhibitor

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HOS-100310 · has-pregnancy-information · PDF-Seite 7

Pregnancy 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. Tolvaptan is contraindicated during pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during tolvaptan treatment. Breast-feeding 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. Tolvaptan is contraindicated during breast-feeding (see section 4.3). 7 Fertility Studies in animals showed effects on fertility (see section 5.3). The potential risk for humans is unknown.

HOS-100308 · has-warning-information · PDF-Seite 4

Urgent need to raise serum sodium acutely 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. Access to water 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. Dehydration 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 outflow obstruction 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 balance 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 to 6 hours after treatment initiation. During the first 1 to 2 days and until the tolvaptan dose is stabilised serum sodium and volume status must be monitored at least every 6 hours. Too rapid correction of serum sodium 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 mmol/L/24 hours to 12 mmol/L/24 hours and less than 18 mmol/L/48 hours. Therefore, more precautionary limits apply during the early treatment

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