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

Vaprena is indicated to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adults with chronic kidney disease (CKD) stage 1 to 4 at initiation of treatment with evidence of rapidly progressing disease (see section 5.1).

Due to the need for a dose titration phase with close monitoring of serum sodium and volume status, treatment with Vaprena has to be initiated in hospital.

Tolvaptan treatment must be initiated and monitored under the supervision of physicians with expertise in managing ADPKD and a full understanding of the risks of tolvaptan therapy including hepatic toxicity and monitoring requirements (see section 4.4).

Posology

For correction of hyponatremia:

Tolvaptan has to be initiated at a dose of 15 mg once daily. The dose may be increased to a maximum of 60 mg once daily as tolerated to achieve the desired level of serum sodium.

For patients at risk of overly rapid correction of sodium e.g. patients with oncological conditions, very low baseline serum sodium, taking diuretics, or taking sodium supplementation a dose of 7.5 mg should be considered (see section 4.4).

During titration, patients must be monitored for serum sodium and volume status (see section 4.4). In case of inadequate improvement in serum sodium levels, other treatment options have to be considered, either in place of or in addition to tolvaptan. Use of tolvaptan in combination with other options may increase the risk of overly rapid correction of serum sodium (see sections 4.4 and 4.5). For patients with an appropriate increase in serum sodium, the underlying disease and serum sodium levels must be monitored at regular intervals to evaluate further need of tolvaptan treatment. In the setting of hyponatremia, the treatment duration is determined by the underlying disease and its treatment. Tolvaptan treatment is expected to last until the underlying disease is adequately treated or until such time that hyponatremia is no longer a clinical issue.

Vaprena must not be taken with grapefruit juice (see section 4.5).

For autosomal dominant polycystic kidney disease (ADPKD):

Vaprena is to be administered twice daily in split dose regimens of 45 mg + 15 mg, 60 mg + 30 mg or 90 mg + 30 mg. The morning dose is to be taken at least 30 minutes before the morning meal. The second daily dose can be taken with or without food. According to these split dose regimens the total daily doses are 60 mg, 90 mg, or 120 mg.

Dose titration:

The initial dose is 60 mg tolvaptan per day as a split-dose regimen of 45 mg + 15 mg (45 mg taken upon waking and prior the morning meal and 15 mg taken 8 hours later). The initial dose is to be titrated upward to a split-dose regimen of 90 mg tolvaptan (60 mg + 30 mg) per day and then to a target split dose regimen of 120 mg tolvaptan (90 mg + 30 mg) per day, if tolerated, with at least weekly intervals

between titrations. Dose titration has to be performed cautiously to ensure that high doses are not poorly tolerated through overly rapid up-titration. Patients may down-titrate to lower doses based on tolerability. Patients have to be maintained on the highest tolerable tolvaptan dose.

The aim of dose titration is to block activity of vasopressin at the renal V2 receptor as completely and constantly as possible, while maintaining acceptable fluid balance (see section 4.4).

Measurements of urine osmolality are recommended to monitor the adequacy of vasopressin inhibition.

Periodic monitoring of plasma osmolality or serum sodium (to calculate plasma osmolarity) and/or body weight should be considered to monitor the risk of dehydration secondary to the aquaretic effects of tolvaptan in case of patient’s insufficient water intake.

The safety and efficacy of Vaprena in CKD stage 5 have not been explored and therefore tolvaptan treatment should be discontinued if renal insufficiency progresses to CKD stage 5 (see section 4.4).

Therapy must be interrupted if the ability to drink or the accessibility to water is limited (see section 4.4).

Patients must be instructed to drink sufficient amounts of water or other aqueous fluids (see section 4.4).

In patients taking strong CYP3A inhibitors (see section 4.5), tolvaptan doses have to be reduced as follows:

Dose adjustment for patients taking moderate CYP3A inhibitors

In patients taking moderate CYP3A inhibitors, tolvaptan doses have to be reduced as follows:

Further reductions have to be considered if patients cannot tolerate the reduced tolvaptan doses.

Special populations

Elderly population

Increasing age has no effect on tolvaptan plasma concentrations. Limited data on the safety and effectiveness of tolvaptan in ADPKD patients aged over 55 are available (see section 5.1).

No dose adjustment is needed in elderly patients.

Renal impairment

Tolvaptan is contraindicated in anuric patients (see section 4.3).

Based on the data available, no dose adjustment is required in those with mild to moderate renal impairment.

No clinical trials in subjects with indices of glomerular filtration rate < 10 mL/min or in patients undergoing dialysis have been conducted. The risk of hepatic damage in patients with severely reduced renal function (i.e. estimated glomerular filtration rate [eGFR] < 20) may be increased; these patients should be carefully monitored for hepatic toxicity. Data for patients in CKD early stage 4 are more limited than for patients in stage 1, 2 or 3 (see section 5.1). Limited data are available for patients with CKD late stage 4 (eGFR < 25 mL/min/1.73 m2). No data are available for patients with CKD stage 5. Tolvaptan treatment should be discontinued if renal insufficiency progresses to CKD stage 5 (see section 4.4).

Hepatic impairment

No dose adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B).

Vaprena is contraindicated in patients with elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan (see sections 4.3 and 4.4).

Paediatric population

The safety and efficacy of tolvaptan in children and adolescents under the age of 18 years have not yet been established. Vaprena is not recommended in the paediatric age group.

Method of administration

Oral use.

For correction of hyponatremia:

Administration preferably in the morning, without regard to meals. Tablets must be swallowed without chewing with a glass of water.

For autosomal dominant polycystic kidney disease (ADPKD):

The morning dose is to be taken at least 30 minutes before the morning meal. The second daily dose can be taken with or without food.

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.

Additionally, patients have to drink 1 to 2 glasses of fluid before bedtime regardless of perceived thirst and replenish fluids overnight with each episode of nocturia.

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. Accurate monitoring of body weight is recommended. A progressive reduction in body weight could be an early sign of progressive dehydration. If dehydration becomes evident, take appropriate action, which may include the need to interrupt or reduce the dose of tolvaptan and increase fluid intake. Special care must be taken in patients having diseases that impair appropriate fluid intake or who are at an increased risk of water loss e.g. in case of vomiting or diarrhoea.

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 4-6 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.

Therefore, serum creatinine, electrolytes and symptoms of electrolyte imbalances (e.g. dizziness, fainting, palpitations, confusion, weakness, gait instability, hyper-reflexia, seizures, coma) have to be assessed prior to and after starting tolvaptan to monitor for dehydration.

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 minimize 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 tolvaptan 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 tolvaptan 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).

Diabetes mellitus

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.

Uric acid increases

Decreased uric acid clearance by the kidney is a known effect of tolvaptan. In a double-blind, placebo controlled trial of patients with ADPKD, potentially clinically significant increased uric acid (greater than 10 mg/dL) was reported at a higher rate in tolvaptan-patients (6.2 %) compared to placebo-treated patients (1.7 %). Adverse reactions of gout were reported more frequently in tolvaptan-treated patients (28/961, 2.9 %) than in patients receiving placebo (7/483, 1.4 %). In addition, increased use of allopurinol and other medicinal products used to manage gout were observed in the double-blind, placebo-controlled trial. Effects on serum uric acid are attributable to the reversible renal hemodynamic changes that occur in response to tolvaptan effects on urine osmolality and may be clinically relevant.

However, events of increased uric acid and/or gout were not serious and did not cause discontinuation of therapy in the double-blind, placebo-controlled trial. Uric acid concentrations are to be evaluated prior to initiation of Vaprena therapy, and as indicated during treatment based on symptoms.

Effect of tolvaptan on glomerular filtration rate (GFR)

A reversible reduction in GFR has been observed in ADPKD trials at the initiation of tolvaptan treatment.

Idiosyncratic hepatic toxicity

Tolvaptan has been associated with idiosyncratic elevations of blood alanine and aspartate aminotransferases (ALT and AST) with infrequent cases of concomitant elevations in bilirubin-total (BT).

In post-marketing experience with tolvaptan in ADPKD, acute liver failure requiring liver transplantation has been reported (see section 4.8).

In a double-blind, placebo-controlled trial in patients with ADPKD, the period of onset of hepatocellular injury (by ALT elevations > 3 × ULN) was within 3 to 14 months after initiating treatment and these increases were reversible, with ALT returning to < 3 × ULN within 1 to 4 months. While these concomitant elevations were reversible with prompt discontinuation of tolvaptan, they represent a potential for significant liver injury. Similar changes with other medicinal products have been associated with the potential to cause irreversible and potentially life-threatening liver injury (see section 4.8).

Prescribing physicians must comply fully with the safety measures required below.

To mitigate the risk of significant and/or irreversible liver injury, blood testing for hepatic transaminases and bilirubin is required prior to initiation of Vaprena, continuing monthly for 18 months and at regular 3-monthly intervals thereafter. Concurrent monitoring for symptoms that may indicate liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, dark urine or jaundice) is recommended.

If a patient shows abnormal ALT, AST or BT levels prior to initiation of treatment which fulfil the criteria for permanent discontinuation (see below), the use of tolvaptan is contraindicated (see section 4.3). In case of abnormal baseline levels below the limits for permanent discontinuation treatment can only be initiated if the potential benefits of treatment outweigh the potential risks and liver function testing must continue at increased time frequency. The advice of a hepatologist is recommended.

During the first 18 months of treatment, Vaprena can only be supplied to patients whose physician has determined that liver function supports continued therapy.

At the onset of symptoms or signs consistent with hepatic injury or if clinically significant abnormal ALT or AST increases are detected during treatment, Vaprena administration must be immediately interrupted and repeat tests including ALT, AST, BT and alkaline phosphatase (AP) must be obtained as soon as possible (ideally within 48 hours to 72 hours). Testing must continue at increased time frequency until symptoms/signs/laboratory abnormalities stabilise or resolve, at which point Vaprena may be re-initiated.

Current clinical practice suggests that Vaprena therapy is to be interrupted upon confirmation of sustained or increasing transaminase levels and permanently discontinued if significant increases and/or clinical symptoms of hepatic injury persist.

Recommended guidelines for permanent discontinuation include:

• ALT or AST > 8-times ULN

• ALT or AST > 5-times ULN for more than 2 weeks

• ALT or AST > 3-times ULN and (BT > 2-times ULN or International Normalised Ratio [INR] > 1.5)

• ALT or AST > 3-times ULN with persistent symptoms of hepatic injury noted above.

If ALT and AST levels remain below 3-times the ULN, Vaprena therapy may be cautiously re-started, with frequent monitoring at the same or lower doses, as transaminase levels appear to stabilize during continued therapy in some patients.

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-authorization 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.

Anaphylaxis

In post-marketing experience, anaphylaxis (including anaphylactic shock and generalized rash) has been reported very rarely following administration of tolvaptan. This type of reaction occurred after the first 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.

Lactose intolerance

Vaprena 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.

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 Vaprena 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 Vaprena 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).

CYP3A4 inhibitors

Concomitant use of medicinal products that are moderate CYP3A inhibitors (e.g. amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) or strong CYP3A inhibitors (e.g. itraconazole, ketoconazole, ritonavir, clarithromycin) increase tolvaptan exposure.

Co-administration of tolvaptan and ketoconazole resulted in a 440 % increase in area under time-concentration curve (AUC) and 248 % increase in maximum observed plasma concentration (Cmax) for tolvaptan.

Co-administration of tolvaptan and fluconazole, a moderate CYP3A inhibitor, produced a 200 % and 80 % increase in tolvaptan AUC and Cmax, respectively.

Co-administration of tolvaptan with grapefruit juice, a moderate to strong CYP3A inhibitor, produced a doubling of peak tolvaptan concentrations (Cmax).

Dose reduction of tolvaptan is recommended for patients while taking moderate or strong CYP3A inhibitors (see section 4.2). Patients taking moderate or strong CYP3A inhibitors must be managed cautiously, in particular if the inhibitors are taken more frequently than once a day.

CYP3A4 inducers

Concomitant use of medicinal products that are potent CYP3A inducers (e.g. rifampicin) will decrease tolvaptan exposure and efficacy. Co-administration of tolvaptan with rifampicin reduces Cmax and AUC for tolvaptan by about 85 %. Therefore, concomitant administration of tolvaptan with potent CYP3A inducers (e.g. rifampicin, rifabutin, rifapentine, phenytoin, carbamazepine, and St. John’s Wort) is to be avoided.

Co-administration with medicinal products that increase serum sodium concentration

There is no experience from controlled clinical trials with concomitant use of tolvaptan and 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 medicinal products that increase serum sodium concentration may result in a higher risk for developing hypernatraemia and is therefore not recommended.

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 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.

Transporter substrates

P-glycoprotein substrates: In-vitro studies indicate that tolvaptan is a substrate and competitive inhibitor of P-glycoprotein (P-gp). Steady state digoxin concentrations were increased (1.3-fold in maximum observed plasma concentration [Cmax] and 1.2-fold 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 or other narrow therapeutic P-gp substrates (e.g. dabigatran) must therefore be managed cautiously and evaluated for excessive effects when treated with tolvaptan.

OATP1B1/OAT3/BCRP and OCT1: In-vitro studies indicate that tolvaptan or its oxobutyric metabolite may have the potential to inhibit OATP1B1, OAT3, BCRP and OCT1 transporters. Co-administration of tolvaptan (90 mg) with rosuvastatin (5 mg), a BCRP substrate, increased rosuvastatin Cmax and AUCt of 54 % and 69 %, respectively. If BCRP substrates (e.g. sulfasalazine) are co-administered with tolvaptan, patients must be managed cautiously and evaluated for excessive effects of these medicinal products.

Administration of rosuvastatin (OATP1B1 substrate) or furosemide (OAT3 substrate) to healthy subjects with elevated oxobutyric acid metabolite (inhibitor of OATP1B1 and OAT3) plasma concentrations did not meaningfully alter the pharmacokinetics of rosuvastatin or furosemide. 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 OCT1 substrates (e.g. metformin) are co-administered with tolvaptan, patients must be managed cautiously and evaluated for excessive effects of these medicinal products.

Diuretics or non-diuretic anti-hypertensive medicinal product(s)

Standing blood pressure was not routinely measured in ADPKD trials. Therefore, a risk of orthostatic/postural hypotension due to a pharmacodynamic interaction with tolvaptan cannot be excluded

Diuretics

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.

Digoxin

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 ]) 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.

Co-administration with vasopressin analogues

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. It is not recommended to administer Vaprena with vasopressin analogues.

Smoking and alcohol

Data related to smoking or alcohol history in ADPKD trials are too limited to determine possible interactions of smoking or alcohol with efficacy and safety of ADPKD treatment with tolvaptan.

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).

Fertility

Studies in animals showed effects on fertility (see section 5.3). The potential risk for humans is unknown.

Vaprena 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 pharmacodynamically predictable and most commonly reported adverse reactions are thirst, polyuria, nocturia, and pollakiuria occurring in approximately 55 %, 38 %, 29 % and 23 % of patients, respectively. Furthermore, tolvaptan has been associated with idiosyncratic elevations of blood alanine aminotransferase (ALT; 4.4 %) and aspartate aminotransferases (AST; 3.1 %) with infrequent cases of concomitant elevations in bilirubin-total (BT; 0.2 %).

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".

¹ observed in clinical trials investigating other indications

² from post-authorization 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

Laboratory results

Elevation (> 3 × upper limit of normal [ULN]) of ALT was observed in 4.4 % (42/958) of patients on tolvaptan and 1.0 % (5/484) of patients on placebo, while elevation (> 3 × ULN) of AST was observed in 3.1 % (30/958) of patients on tolvaptan and 0.8 % (4/484) patients on placebo in a double-blind, placebo-controlled trial in patients with ADPKD. Two (2/957, 0.2 %) of these tolvaptan treated-patients, as well as a third patient from an extension open label trial, exhibited increases in hepatic enzymes (> 3 × ULN) with concomitant elevations in BT (> 2 × ULN).

Rapid correction of hyponatremia

In a post-authorization 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 of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Please report adverse drug events to:

For Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

For UAE

Pharmacovigilance & Medical Device section

P.O.Box: 1853 

Tel: 80011111

Email: pv@moh.gov.ae

Drug Department Ministry of Health & Prevention, Dubai, UAE.

For Oman

Department of Pharmacovigilance & Drug Information

Directorate General of Pharmaceutical Affairs & Drug Control

Ministry of Health, Sultanate of Oman

Phone Nos. 22357687 / 22357686

Fax: 22358489

Email: dg-padc@moh.gov.om

Website: www.moh.gov.om

Single doses up to 480 mg and multiple doses up to 300 mg per day for 5 days have been well tolerated in clinical trials in healthy volunteers. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst and dehydration/hypovolemia (profuse and prolonged aquaresis).

No mortality was observed in rats or dogs following single oral doses of 2,000 mg/kg (maximum feasible dose). A single oral dose of 2,000 mg/kg was lethal in mice and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia.

In patients with suspected tolvaptan overdose, assessment of vital signs, electrolyte concentrations, ECG and fluid status is recommended. Appropriate replacement of water and/or electrolytes must continue until aquaresis abates. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (> 98 %).

Pharmacotherapeutic group: Diuretics, vasopressin antagonists, ATC code: C03XA01

Mechanism of action

Tolvaptan is a selective vasopressin V2-receptor antagonist that specifically blocks the binding of arginine vasopressin (AVP) at the V2-receptor of the distal portions of the nephron. Tolvaptan affinity for the human V2-receptor is 1.8 times that of native AVP.

Pharmacodynamic effects

The pharmacodynamic effects of tolvaptan have been determined in healthy subjects and subjects with ADPKD across CKD stages 1 to 4. Effects on free water clearance and urine volume are evident across all CKD stages with smaller absolute effects observed at later stages, consistent with the declining number of fully functioning nephrons. Acute reductions in mean total kidney volume were also observed following 3 weeks of therapy in all CKD stages, ranging from −4.6 % for CKD stage 1 to −1.9 % for CKD stage 4.

In healthy adult subjects, oral administration of 7.5 to 120 mg doses of tolvaptan produced an increase in urine excretion rate within 2 hours of dosing. Following single oral doses of 7.5 to 60 mg, 24-hour urine volume increased dose dependently with daily volumes ranging from 3 to 9 liters. For all doses, urine excretion rates returned to baseline levels after 24 hours. For single doses 60 mg to 480 mg, a mean of about 7 liters was excreted during 0 to 12 hours, independent of dose. Markedly higher doses of tolvaptan produce more sustained responses without affecting the magnitude of excretion, as active concentrations of tolvaptan are present for longer periods of time.

Clinical efficacy and safety

Hyponatremia

In 2 pivotal, double-blind, placebo-controlled, clinical trials, a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium < 135 mEq/L) due to a variety of underlying causes (heart failure [HF], liver cirrhosis, SIADH and others) were treated for 30 days with tolvaptan (n = 216) or placebo (n = 208) at an initial dose of 15 mg/day. The dose could be increased to 30 and 60 mg/day depending on response using a 3-day titration scheme. The mean serum sodium concentration at trial entry was 129 mEq/L (range 114-136).

The primary endpoint for these trials was the average daily AUC for change in serum sodium from baseline to Day 4 and baseline to Day 30. Tolvaptan was superior to placebo (p < 0.0001) for both periods in both studies. This effect was seen in all patients, the severe (serum sodium: < 130 mEq/L) and mild (serum sodium: 130 -< 135 mEq/L) subsets and for all disease aetiology subsets (e.g. HF, cirrhosis, SIADH/other). At 7 days after discontinuing treatment, sodium values decreased to levels of placebo treated patients.

Following 3 days of treatment, the pooled analysis of the two trials revealed five-fold more tolvaptan than placebo patients achieved normalization of serum sodium concentrations (49 % vs. 11 %). This effect continued as on Day 30, when more tolvaptan than placebo patients still had normal concentrations (60 % vs. 27 %). These responses were seen in patients independent of the underlying disease. The results of self-assessed health status using the SF-12 Health Survey for the mental scores showed statistically significant and clinically relevant improvements for tolvaptan treatment compared to placebo.

Data on the long-term safety and efficacy of tolvaptan were assessed for up to 106 weeks in a clinical trial in patients (any etiology) who had previously completed one of the pivotal hyponatremia trials. A total of 111 patients started tolvaptan treatment in an open-label, extension trial, regardless of their previous randomization. Improvements in serum sodium levels were observed as early as the first day after dosing and continued for on-treatment assessments up to Week 106. When treatment was discontinued, serum sodium concentrations decreased to approximately baseline values, despite the reinstatement of standard care therapy.

In a pilot, randomized (1:1:1), double-blind trial in 30 patients with hyponatremia secondary to SIADH, the pharmacodynamics of tolvaptan following single doses of 3.75, 7.5 and 15 mg were assessed. Results were highly variable with large overlap between dose groups; changes were not significantly correlated with tolvaptan exposure. Mean maximal changes in serum sodium were highest following the 15 mg dose (7.9 mmol/L) but median maximal changes were highest for the 7.5 mg dose (6.0 mmol/L). Individual maximal increases in serum sodium were negatively correlated with fluid balance; mean change in fluid balance showed a dose dependent decrease. Mean change from baseline in cumulative urine volume and urine excretion rates was 2-fold higher for the 15 mg dose compared to the 7.5 and 3.75 mg doses, which showed similar responses.

Heart failure

EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) was a long-term outcome, double-blind, controlled clinical trial in patients hospitalized with worsening HF and signs and symptoms of volume overload. In the long-term outcome trial, a total of 2,072 patients received 30 mg tolvaptan with standard of care (SC) and 2,061 received placebo with SC. The primary objective of the study was to compare the effects of tolvaptan + SC with placebo + SC on the time to all-cause mortality and on the time to first occurrence of cardiovascular (CV) mortality or hospitalization for HF. Tolvaptan treatment had no statistically significant favorable or unfavorable effects on overall survival or the combined endpoint of CV mortality or HF hospitalization, and did not provide convincing evidence for clinically relevant benefit.

The European Medicines Agency has deferred the obligation to submit the results of studies with Name in one or more subsets of the pediatric population in treatment of dilutional hyponatremia (see section 4.2 for information on pediatric use).

Polycystic kidney disease

The primary focus of the clinical program for development of tolvaptan tablets for the treatment of ADPKD is a single pivotal, multi-national, phase 3, randomised, placebo-controlled trial in which the long-term safety and efficacy of oral split dose tolvaptan regimens (titrated between 60 mg/day and 120 mg/day) were compared with placebo in 1,445 adult subjects with ADPKD.

In total, 14 clinical trials involving tolvaptan have been completed worldwide in support of the ADPKD indication, including 8 trials in the US, 1 in the Netherlands, 3 in Japan, 1 in Korea, and the multinational phase 3 pivotal trial.

The phase 3 pivotal trial (TEMPO 3:4, 156-04-251) included subjects from 129 centres in the Americas, Japan, Europe and other countries. The primary objective of this trial was to evaluate the long-term efficacy of tolvaptan in ADPKD through rate of total kidney volume (TKV) change (normalised as percentage; %) for tolvaptan-treated compared with placebo-treated subjects. In this trial a total of 1,445 adult patients (age 18 years to 50 years) with evidence of rapidly-progressing, early ADPKD (meeting modified Ravine criteria, TKV ≥ 750 mL, estimated creatinine clearance ≥ 60 mL/min) were randomised 2:1 to treatment with tolvaptan or placebo. Patients were treated for up to 3 years.

Tolvaptan (n = 961) and placebo (n = 484) groups were well matched in terms of gender with an average age of 39 years. The inclusion criteria identified patients who at baseline had evidence of early disease progression. At baseline, patients had average estimated glomerular filtration rate (eGFR) of 82 mL/min/1.73 m2 (Chronic Kidney Disease-Epidemiology Collaboration; CKD-EPI) with 79 % having hypertension and a mean TKV of 1,692 mL (height adjusted 972 mL/m). Approximately 35 % of subjects were CKD stage 1, 48 % CKD stage 2, and 17 % CKD stage 3 (eGFRCKD-EPI). While these criteria were useful in enriching the study population with patients who were rapidly progressing, subgroup analyses based on stratification criteria (age, TKV, GFR, Albuminuria, Hypertension) indicated the presence of such risk factors at younger ages predicts more rapid disease progression.

The results of the primary endpoint, the rate of change in TKV for subjects randomized to tolvaptan (normalized as percentage, %) to the rate of change for subjects on placebo, were highly statistically significant. The rate of TKV increase over 3 years was significantly less for tolvaptan-treated subjects than for subjects receiving placebo: 2.80 % per year versus 5.51 % per year, respectively (ratio of

geometric mean 0.974; 95 % CI 0.969 to 0.980; p < 0.0001).

Pre-specified secondary endpoints were tested sequentially. The key secondary composite endpoint (ADPKD progression) was time to multiple clinical progression events of:

1) Worsening kidney function (defined as a persistent [reproduced over at least 2 weeks] 25 % reduction in reciprocal serum creatinine during treatment [from end of titration to last on medicinal product visit])

2) Medically significant kidney pain (defined as requiring prescribed leave, last-resort analgesics, narcotic and anti-nociceptive, radiologic or surgical interventions)

3) Worsening hypertension

4) Worsening albuminuria

The relative rate of ADPKD-related events was decreased by 13.5 % in tolvaptan-treated patients, (hazard ratio, 0.87; 95 % CI, 0.78 to 0.97; p = 0.0095).

The result of the key secondary composite endpoint is primarily attributed to effects on worsening kidney function and medically significant kidney pain. The renal function events were 61.4 % less likely for tolvaptan compared with placebo (hazard ratio, 0.39; 95 % CI, 0.26 to 0.57; nominal p < 0.0001), while renal pain events were 35.8 % less likely in tolvaptan-treated patients (hazard ratio, 0.64; 95 % CI, 0.47 to 0.89; nominal p = 0.007). In contrast, there was no effect of tolvaptan on either progression of hypertension or albuminuria.

TEMPO 4:4 is an open-label extension study that included 871 subjects that completed TEMPO 3:4 from 106 centres across 13 countries. This trial evaluated the effects of tolvaptan on safety, TKV and eGFR in subjects receiving active treatment for 5 years (early-treated), compared with subjects treated with placebo for 3 years, then switched to active treatment for 2 years (delayed-treated).

The primary end point for TKV did not distinguish a difference in change (−1.7 %) over the 5-year treatment between early- and delayed-treated subjects at the pre-specified threshold of statistical significance (p = 0.3580). Both groups’ TKV growth trajectory was slowed, relative to placebo in the first 3 years, suggesting both early- and delayed- tolvaptan treated subjects benefitted to a similar degree.

A secondary endpoint testing the persistence of positive effects on renal function indicated that the preservation of eGFR observed by the end of the TEMPO 3:4 pivotal trial (3.01 to 3.34 mL/min/1.73 m² at follow-up visits 1 and 2) could be preserved during open-label treatment. This difference was maintained in the pre-specified mixed effect model repeat measurement (MMRM) analysis (3.15 mL/min/1.73 m2, 95 %CI 1.462 to 4.836, p = 0.0003) and with sensitivity analyses where baseline eGFR data were carried forward (2.64 mL/min/1.73 m2, 95 % CI 0.672 to 4.603, p = 0.0086). These data suggest that tolvaptan can slow the rate of renal function decline, and that these benefits persist over the duration of therapy.

Longer term data are not currently available to show whether long-term therapy with tolvaptan continues to slow the rate of renal function decline and affect clinical outcomes of ADPKD, including delay in the onset of end-stage renal disease.

Genotyping for PKD1 and PKD2 genes was conducted in a majority of patients entering the open-label extension study (TEMPO 4:4) but the results are not yet known.

Following an additional 2 years of tolvaptan treatment, resulting in a total of 5 years on tolvaptan therapy no new safety signals were identified.

The phase 3, multi-center, international, randomized-withdrawal, placebo-controlled, double-blind trial 156-13-210 compared the efficacy and safety of tolvaptan (45 mg/day to 120 mg/day) to placebo in patients able to tolerate tolvaptan during a five-week titration and run-in period on tolvaptan. The trial utilized a randomized withdrawal design, to enrich for patients that were able to tolerate tolvaptan for a

5-week, single-blind pre-randomization period consisting of a 2-week titration period and 3-week run-in period. The design was used to minimise the impact of early discontinuation and missing data on trial endpoints.

A total of 1,370 patients (age 18 years to 65 years) with CKD with an eGFR between 25 and 65 mL/min/1.73 m2 if younger than age 56 years; or eGFR between 25 and 44 mL/min/1.73 m2, plus eGFR decline >2.0 mL/min/1.73 m2/year if between age 56 years to 65 years were randomized to either tolvaptan (n = 683) or placebo (n = 687) and were treated for a period of 12 months.

For subjects randomized, the baseline, average eGFR was 41 mL/min/1.73 m2 (CKD-EPI) and historical TKV, available in 318 (23 %) of subjects, averaged 2,026 mL. Approximately 5 %, 75 % and 20 % had an eGFR 60 mL/min/1.73 m2 or greater (CKD stage 2), or less than 60 and greater than 30 mL/min/1.73 m2 (CKD stage 3) or less than 30 but greater than 15 mL/min/1.73 m2 (CKD stage 4), respectively. The CKD stage 3 can be subdivided further to stage 3a 30 %, (eGFR 45 mL/min/1.73 m2

to less than 60 mL/min/1.73 m2) and stage 3b 45 %, (eGFR between 30 and 45 mL/min/1.73 m2).

The primary endpoint of the trial was the change in eGFR from pre-treatment baseline levels to posttreatment assessment. In patients treated with tolvaptan the reduction in eGFR was significantly less than in patients treated with placebo (p < 0.0001). The treatment difference in eGFR change observed in this trial is 1.27 mL/min/1.73 m2, representing a 35 % reduction in the LS means of change in eGFR of −2.34 mL/min/1.73 m2 in tolvaptan group relative to a −3.61 mL/min/1.73 m2 in placebo group observed over the course of one year. The key secondary endpoint was a comparison of the efficacy of tolvaptan treatment versus placebo in reducing the decline of annualized eGFR slope across all measured time points in the trial. These data also showed significant benefit from tolvaptan versus placebo (p < 0.0001).

Subgroup analysis of the primary and secondary endpoints by CKD stage found similar, consistent treatment effects relative to placebo for subjects in stages 2, 3a, 3b and early stage 4 (eGFR 25 to 29 mL/min/1.73 m2) at baseline.

A pre-specified subgroup analysis suggested that tolvaptan had less of an effect in patients older than 55 years of age, a small subgroup with a notably slower rate of eGFR decline.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with tolvaptan in one or more subsets of the paediatric population in polycystic kidney disease (see section 4.2 for information on paediatric use).

Absorption

After oral administration, tolvaptan is rapidly absorbed with peak plasma concentrations occurring about 2 hours after dosing. The absolute bioavailability of tolvaptan is about 56 %. Co-administration of tolvaptan with a high-fat meal increased peak concentrations of tolvaptan up to 2-fold but left AUC unchanged. Even though the clinical relevance of this finding is not known, the morning dose should be taken under fasted conditions to minimize the unnecessary risk of increasing the maximal exposure (see section 4.2).

Distribution

Following single oral doses of ≥ 300 mg, peak plasma concentrations appear to plateau, possibly due to saturation of absorption. Tolvaptan binds reversibly (98 %) to plasma proteins.

Biotransformation

Tolvaptan is extensively metabolized in the liver almost exclusively by CYP3A. Tolvaptan is a weak CYP3A4 substrate and does not appear to have any inhibitory activity. In vitro studies indicated that tolvaptan has no inhibitory activity for CYP3A. Fourteen metabolites have been identified in plasma, urine and faeces; all but one were also metabolised by CYP3A. Only the oxobutyric acid metabolite is present at greater than 10 % of total plasma radioactivity; all others are present at lower concentrations than tolvaptan. Tolvaptan metabolites have little to no contribution to the pharmacological effect of tolvaptan; all metabolites have no or weak antagonist activity for human V2 receptors when compared with tolvaptan. The terminal elimination half-life is about 8 hours and steady-state concentrations of tolvaptan are obtained after the first dose.

Elimination

Less than 1 % of intact active substance is excreted unchanged in the urine. The terminal elimination half-life is about 8 hours and steady-state concentrations of tolvaptan are obtained after the first dose.

Radio labelled tolvaptan experiments showed that 40 % of the radioactivity was recovered in the urine and 59 % was recovered in the faeces where unchanged tolvaptan accounted for 32 % of radioactivity. Tolvaptan is only a minor component in plasma (3 %).

Linearity

Tolvaptan has linear pharmacokinetics for doses of 7.5 to 60 mg.

Following single oral doses, Cmax values show less than dose proportional increases from 30 mg to 240 mg and then a plateau at doses from 240 mg to 480 mg. AUC increases linearly.

Following multiple once daily dosing of 300 mg, tolvaptan exposure was only increased 6.4-fold when compared to a 30 mg dose. For split-dose regimens of 30 mg/day, 60 mg/day and 120 mg/day in ADPKD patients, tolvaptan exposure (AUC) increases linearly.

Pharmacokinetics in special patient groups

Age

Clearance of tolvaptan is not significantly affected by age.

Hepatic impairment

The effect of mildly or moderately impaired hepatic function (Child-Pugh classes A and B) on the pharmacokinetics of tolvaptan was investigated in 87 patients with liver disease of various origins. No clinically significant changes have been seen in clearance for doses ranging from 5 to 60 mg. Very limited information is available in patients with severe hepatic impairment (Child-Pugh class C).

In a population pharmacokinetic analysis in patients with hepatic edema, AUC of tolvaptan in severely (Child-Pugh class C) and mildly or moderately (Child-Pugh classes A and B) hepatic impaired patients were 3.1 and 2.3 times higher than that in healthy subjects.

Renal impairment

In an analysis on population pharmacokinetics for patients with heart failure, tolvaptan concentrations of patients with mildly (creatinine clearance [C_cr] 50 to 80 mL/min) or moderately (C_cr 20 to 50 mL/min) impaired renal function were not significantly different to tolvaptan concentrations in patients with normal renal function (C_cr 80 to 150 mL/min). The efficacy and safety of tolvaptan in those with a creatinine clearance < 10 mL/min has not been evaluated and is therefore unknown.

In a population pharmacokinetic analysis for patients with ADPKD, tolvaptan concentrations were increased, compared to healthy subjects, as renal function decreased below eGFR of 60 mL/min/1.73 m². An eGFR _CKD-EPI decrease from 72.2 to 9.79 (mL/min/1.73 m2) was associated with a 32 % reduction in total body clearance.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Teratogenicity was noted in rabbits given 1,000 mg/kg/day. No teratogenic effects were seen in rabbits at 300 mg/kg/day.

In a peri-and post-natal study in rats, delayed ossification and reduced pup bodyweight were seen at the high dose of 1,000 mg/kg/day.

Two fertility studies in rats showed effects on the parental generation (decreased food consumption and body weight gain, salivation), but tolvaptan did not affect reproductive performance in males and there were no effects on the foetuses. In females, abnormal oestrus cycles were seen in both studies.

The no observed adverse effects level (NOAEL) for effects on reproduction in females (100 mg/kg/day) was about 8-times the total daily dose of 60 mg/day on a mg/m² basis.

Crospovidone,

Povidone,

Butylated Hydroxytoluene,

Microcrystalline Cellulose,

Lactose Monohydrate,

Pregelatinized Starch,

Croscarmellose Sodium,

Colloidal Silicon Dioxide,

Magnesium Stearate.

Not applicable

Do not store above 30º C.

Vaprena 15 mg and Vaprena 30 mg tablets:

PVC/PVDC/Al/paper blister; 10 tablets per blister strip for both of 15 mg & 30 mg.

No special requirements.