Tolvaptan

In-vitro studies indicate that tolvaptan is a substrate and competitive inhibitor of P-glycoprotein (P-gp). In vitro studies indicate that tolvaptan or its oxobutyric metabolite may have the potential to inhibit OATP1B1, OATP1B3, OAT3, BCRP and OCT1 transporters. Steady state digoxin concentrations were increased (1.3-fold in maximum observed plasma concentration [C_max] and 1.2-fold in area under the plasma concentration-time curve over the dosing interval [AUC_τ]) when co-administered with multiple once daily 60 mg doses of tolvaptan. Patients receiving digoxin or other narrow therapeutic P-gp substrates (e.g. dabigatran) must therefore be managed cautiously and evaluated for excessive effects when treated with tolvaptan. Statins commonly used in the tolvaptan phase 3 pivotal trial (e.g. rosuvastatin and pitavastatin) are OATP1B1 or OATP1B3 substrates, however no difference in adverse events profile was observed during the phase 3 pivotal trial for tolvaptan in ADPKD. If OATP1B1 and OATP1B3 substrates (e.g. statins such as rosuvastatin and pitavastatin), OAT3 substrates (e.g. methotrexate, ciprofloxacin), BCRP substrates (e.g. sulfasalazine) or OCT1 substrates (e.g. metformin) are co-administered with tolvaptan, patients must be managed cautiously and evaluated for excessive effects of these medicinal products.

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.

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 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.

No information is available in patients with severe hepatic impairment (Child-Pugh class C). In these patients dosing has to be managed cautiously and electrolytes and volume status must be monitored.

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.

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.

Studies in animals showed effects on fertility. The potential risk for humans is unknown.

Steady state digoxin concentrations have been increased (1.3-fold increase in maximum observed plasma concentration [C_max] and 1.2-fold increase in area under the plasma concentration-time curve over the dosing interval [AUC_τ]) 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.

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.

In post-marketing experience with tolvaptan in ADPKD, acute liver failure requiring liver transplantation has been reported.

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.

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.

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 treatment must never be restarted after an anaphylactic reaction or other serious allergic reactions.

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.

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. Therefore, diabetic patients treated with tolvaptan should be managed cautiously. In particular this applies to patients with inadequately controlled type II diabetes.

There are no or limited amount of data from the use of tolvaptan in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Tolvaptan is contraindicated during pregnancy. 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. The potential risk for humans is unknown. Tolvaptan is contraindicated during breast-feeding.

Fertility

Studies in animals showed effects on fertility. The potential risk for humans is unknown.

Tolvaptan 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.

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.

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”.

Immune system disorders

Not known: Anaphylactic shock, Generalised rash

Metabolism and nutrition disorders

Common: Polydipsia, Dehydration, Hyperkalemia, Hyperglycemia, Hypoglycemia¹, Hypernatremia¹, Hyperuricemia¹, Decreased appetite

Nervous system disorders

Common: Syncope¹, Headache¹, Dizziness¹

Uncommon: Dysgeusia

Vascular disorders

Common: Orthostatic hypotension

Gastrointestinal disorders

Very common: Nausea

Common: Constipation, Diarrhoea¹, Dry mouth

Skin and subcutaneous tissue disorders

Common: Ecchymosis, Pruritus

Uncommon: Pruritic rash¹

Renal and urinary disorders

Common: Pollakiuria, Polyuria

Uncommon: Renal impairment

General disorders and administration site conditions

Very common: Thirst

Common: Asthenia, Pyrexia, Malaise¹

Hepatobiliary disorders

Not known: Hepatic disorders², Acute hepatic failure³

Investigations

Common: Blood urine present¹, Alanine aminotransferase increased¹, Aspartate aminotransferase increased¹, Blood creatinine increased

Uncommon: Bilirubin increased¹

Not known: Elevated transaminases²

Surgical and medical procedures

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.

Description of selected adverse reactions

Rapid correction of hyponatremia

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.