SAMSCA 30mg tablets medication leaflet

Samsca 7.5 mg tablets

Samsca 15 mg tablets

Samsca 30 mg tablets

Samsca 7.5 mg tablets

Each tablet contains 7.5 mg tolvaptan.

Excipient with known effect51 mg lactose (as monohydrate) per tablet

Samsca 15 mg tablets

Each tablet contains 15 mg tolvaptan.

Excipient with known effect35 mg lactose (as monohydrate) per tablet

Samsca 30 mg tablets

Each tablet contains 30 mg tolvaptan.

Excipient with known effect70 mg lactose (as monohydrate) per tablet

For the full list of excipients, see section 6.1.

Tablet

Samsca 7.5 mg tablets

Blue, rectangular, shallow-convex tablets with dimensions of 7.7 × 4.35 × 2.5 mm, debossed with“OTSUKA” and “7.5” on one side.

Samsca 15 mg tablets

Blue, triangular, shallow-convex tablets with dimensions of 6.58 × 6.2 × 2.7 mm, debossed with“OTSUKA” and “15” on one side.

Samsca 30 mg tablets

Blue, round, shallow-convex tablets with dimensions of Ø8 × 3.0 mm, debossed with “OTSUKA” and“30” on one side.

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

Due to the need for a dose titration phase with close monitoring of serum sodium and volume status(see section 4.4), treatment with Samsca has to be initiated in hospital.

Tolvaptan has to be initiated at a dose of 15 mg once daily. The dose may be increased to a maximumof 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, verylow baseline serum sodium, taking diuretics, or taking sodium supplementation a dose of 7.5 mgshould be considered (see section 4.4).

During titration, patients must be monitored for serum sodium and volume status (see section 4.4). Incase of inadequate improvement in serum sodium levels, other treatment options have to beconsidered, either in place of or in addition to tolvaptan. Use of tolvaptan in combination with otheroptions 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 sodiumlevels must be monitored at regular intervals to evaluate further need of tolvaptan treatment. In thesetting of hyponatremia, the treatment duration is determined by the underlying disease and itstreatment. Tolvaptan treatment is expected to last until the underlying disease is adequately treated oruntil such time that hyponatremia is no longer a clinical issue.

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

Tolvaptan is contraindicated in anuric patients (see section 4.3). Tolvaptan has not been studied inpatients with severe renal failure. The efficacy and safety in this population is not well established.

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

No information is available in patients with severe hepatic impairment (Child-Pugh class C). In thesepatients dosing has to be managed cautiously and electrolytes and volume status must be monitored(see section 4.4). No dose adjustment is needed in patients with mild or moderate hepatic impairment(Child-Pugh classes A and B).

No dose adjustment is needed in elderly patients.

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

Oral use.

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

* Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or tobenzazepine 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)

Urgent need to raise serum sodium acutely

Tolvaptan has not been studied in a setting of urgent need to raise serum sodium acutely. For suchpatients, 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 amountsof water. If fluid restricted patients are treated with tolvaptan, extra caution has to be exercised toensure that patients do not become overly dehydrated.

Volume status must be monitored in patients taking tolvaptan because treatment with tolvaptan mayresult in severe dehydration, which constitutes a risk factor for renal dysfunction. If dehydrationbecomes evident, take appropriate action which may include the need to interrupt or reduce the dose oftolvaptan and increase fluid intake.

Urinary outflow obstruction

Urinary output must be secured. Patients with partial obstruction of urinary outflow, for examplepatients with prostatic hypertrophy or impairment of micturition, have an increased risk of developingacute retention.

Fluid and electrolyte balance

Fluid and electrolyte status has to be monitored in all patients and particularly in those with renal andhepatic 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 patientsmust start no later than 4 to 6 hours after treatment initiation. During the first 1 to 2 days and until thetolvaptan 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 rapidcorrection of serum sodium.

Too rapid correction of hyponatremia (increase ≥ 12 mmol/L/24 hours) can cause osmoticdemyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spasticquadriparesis, seizures, coma or death. Therefore, after initiation of treatment, patients have to beclosely 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 sodiumshould 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 phase.

If sodium correction exceeds 6 mmol/L during the first 6 hours of administration or 8 mmol/L duringthe first 6 to 12 hours, respectively, the possibility that serum sodium correction may be overly rapidshould be considered. These patients should be monitored more frequently regarding their serumsodium and administration of hypotonic fluid is recommended. In case serum sodiumincreases ≥ 12 mmol/L within 24 hours or ≥ 18 mmol/L within 48 hours, tolvaptan treatment is to beinterrupted or discontinued followed by administration of hypotonic fluid.

In patients at higher risk of demyelination syndromes, for example those with hypoxia, alcoholism ormalnutrition, the appropriate rate of sodium correction may be lower than that in patients without riskfactors; these patients should be very carefully managed.

Patients who received other treatment for hyponatremia or medicinal products which increase serumsodium concentration (see section 4.5) prior to initiation of treatment with Samsca must be managedvery cautiously. These patients may be at higher risk for developing rapid correction of serum sodiumduring the first 1 to 2 days of treatment due to potential additive effects.

Co-administration of Samsca with other treatments for hyponatremia, and medicinal products thatincrease serum sodium concentration, is not recommended during initial treatment or for other patientswith 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 presentwith pseudo-hyponatremia. This condition should be excluded prior and during treatment withtolvaptan. Tolvaptan may cause hyperglycemia (see section 4.8). Therefore, diabetic patients treatedwith tolvaptan should be managed cautiously. In particular this applies to patients with inadequatelycontrolled type II diabetes.

Idiosyncratic hepatic toxicity

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 higherdoses than for the approved indication (see section 4.8).

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

In these clinical trials, clinically significant increases (greater than 3 × Upper Limit of Normal [ULN])in serum alanine aminotransferase (ALT), along with clinically significant increases (greater than 2 ×

ULN) in serum total bilirubin were observed in 3 patients treated with tolvaptan. In addition, anincreased 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) ofserum aspartate aminotransferase (AST) was observed in 3.1 % (30/958) of patients on tolvaptan and0.8 % (4/484) patients on placebo. Most of the liver enzyme abnormalities were observed during thefirst 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 fatalliver injury.

In a post-authorisation safety study of tolvaptan in hyponatremia secondary to SIADH, several casesof hepatic disorders and elevated transaminases were observed (see section 4.8).

Liver function tests must be promptly performed in patients taking tolvaptan who report symptomsthat may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, darkurine or jaundice. If liver injury is suspected, tolvaptan must be promptly discontinued, appropriatetreatment has to be instituted, and investigations have to be performed to determine the probablecause. Tolvaptan must not be re-initiated in patients unless the cause for the observed liver injury isdefinitively established to be unrelated to treatment with tolvaptan.

Anaphylaxis

In post-marketing experience, anaphylaxis (including anaphylactic shock and generalised rash) hasbeen reported very rarely following administration of tolvaptan. Patients have to be carefullymonitored during treatment. Patients with known hypersensitivity reactions to benzazepine orbenzazepine derivatives (e.g., benazepril, conivaptan, fenoldopam mesylate or mirtazapine) may be atrisk for hypersensitivity reaction to tolvaptan (see section 4.3 Contraindications).

If an anaphylactic reaction or other serious allergic reactions occur, administration of tolvaptan mustbe discontinued immediately and appropriate therapy initiated. Since hypersensitivity is acontraindication (see section 4.3) treatment must never be restarted after an anaphylactic reaction orother serious allergic reactions.

Samsca contains lactose as an excipient. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

Co-administration with other treatments for hyponatremia and medicinal products that increase serumsodium concentration

There is no experience from controlled clinical trials with concomitant use of Samsca and othertreatments for hyponatremia such as hypertonic sodium chloride solution, oral sodium formulations,and medicinal products that increase serum sodium concentration. Medicinal products with highsodium content such as effervescent analgesic preparations and certain sodium containing treatmentsfor dyspepsia may also increase serum sodium concentration. Concomitant use of Samsca with othertreatments for hyponatremia or other medicinal products that increase serum sodium concentrationmay result in a higher risk for developing rapid correction of serum sodium (see section 4.4) and istherefore not recommended during initial treatment or for other patients with very low baseline serumsodium concentrations where rapid correction may represent a risk for osmotic demyelination (seesection 4.4).

Effect of other medicinal products on the pharmacokinetics of tolvaptan

Tolvaptan plasma concentrations have been increased by up to 5.4-fold area under time-concentrationcurve (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 totolvaptan. Patients taking tolvaptan should avoid ingesting grapefruit juice.

Tolvaptan plasma concentrations have been decreased by up to 87 % (AUC) after the administrationof CYP3A4 inducers. Caution has to be exercised in co-administering CYP3A4 inducers (e.g.,rifampicin, barbiturates) with tolvaptan.

Effect of tolvaptan on the pharmacokinetics of other products

In healthy subjects, tolvaptan, a CYP3A4 substrate, had no effect on the plasma concentrations ofsome other CYP3A4 substrates (e.g., warfarin or amiodarone). Tolvaptan increased plasma levels oflovastatin by 1.3-fold to 1.5-fold. Even though this increase has no clinical relevance, it indicatestolvaptan can potentially increase exposure to CYP3A4 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 plasmaconcentration [Cmax] and 1.2-fold in area under the plasma concentration-time curve over the dosinginterval [AUCτ]) when co-administered with multiple once daily 60 mg doses of tolvaptan. Patientsreceiving digoxin or other narrow therapeutic index P-gp substrates (e.g., dabigatran etexilate) musttherefore be managed cautiously and evaluated for excessive effects when treated with tolvaptan.

BCRP and OCT1

Co-administration of tolvaptan (90 mg) with rosuvastatin (5 mg), a BCRP substrate, increasedrosuvastatin 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 excessiveeffects of these medicinal products.

If OCT1 substrates (e.g., metformin) are co-administered with tolvaptan, patients must be managedcautiously and evaluated for excessive effects of these medicinal products.

While there does not appear to be a synergistic or additive effect of concomitant use of tolvaptan withloop and thiazide diuretics, each class of agent has the potential to lead to severe dehydration, whichconstitutes 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/ordiuretics, increase fluid intake, evaluate and address other potential causes of renal dysfunction ordehydration.

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 endothelialcells. Therefore, the effect of vasopressin analogues such as desmopressin may be attenuated inpatients 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 inanimals 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 haveto use effective contraception during tolvaptan treatment.

It is unknown whether tolvaptan is excreted in human milk. Available pharmacodynamic/toxicologicaldata in animals have shown excretion of tolvaptan in breast milk (for details see 5.3). The potentialrisk 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 isunknown.

Samsca has no or negligible influence on the ability to drive or use machines. However, when drivingor using machines it should be taken into account that occasionally dizziness, asthenia or syncope mayoccur.

The adverse reaction profile of tolvaptan in SIADH is based on a clinical trials database of3,294 tolvaptan-treated patients and is consistent with the pharmacology of the active substance. Thepharmaco-dynamically predictable and most commonly reported adverse reactions are thirst, drymouth 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), veryrare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

The frequency of adverse reactions reported during post-marketing use cannot be determined as theyare derived from spontaneous reports. Consequently, the frequency of these adverse reactions isqualified as 'not known'.

System Organ Frequency

Class

Very common Common Uncommon Not known

Immune system Anaphylacticdisorders shock,

Generalised rash

Metabolism and Polydipsia,nutrition disorders Dehydration,

Hyperkalemia,

Hyperglycemia,

Hypoglycemia1,

Hypernatremia1,

Hyperuricemia1,

Decreasedappetite

Nervous system Syncope1, Dysgeusiadisorders Headache1,

Dizziness1

Vascular Orthostaticdisorders hypotension

Gastrointestinal Nausea Constipation,disorders Diarrhoea1,

Dry mouth

Skin and Ecchymosis, Pruritic rash1subcutaneous Pruritustissue disorders

Renal and urinary Pollakiuria, Renal impairmentdisorders Polyuria

General disorders Thirst Asthenia,and Pyrexia,administration site Malaise1conditions

Hepatobiliary Hepatic disorders2disorders Acute hepaticfailure3

System Organ Frequency

Class

Very common Common Uncommon Not known

Investigations Blood urine Bilirubin Elevatedpresent1, increased (see transaminases2

Alanine section 4.4)1aminotransferaseincreased (seesection 4.4)1,

Aspartateaminotransferaseincreased (seesection 4.4)1,

Blood creatinineincreased

Surgical and Rapid correctionmedical of hyponatremia,procedures sometimesleading toneurologicalsymptoms1 observed in clinical trials investigating other indications2 from post-authorisation safety study in hyponatremia secondary to SIADH3 observed in post-marketing with tolvaptan in ADPKD. Liver transplantation was necessary.

Rapid correction of hyponatremia

In a post-authorisation safety study of tolvaptan in hyponatremia secondary to SIADH, including ahigh proportion of patients with tumours (especially Small Cell Lung Cancer), patients with lowbaseline serum sodium as well as patients with concomitant use of diuretics and/or sodium chloridesolution the incidence of rapid correction of hyponatremia was found to be higher than in clinicaltrials.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses up to 480 mg and multiple doses up to 300 mg per day for 5 days have been welltolerated 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 excessivepharmacologic effect: a rise in serum sodium concentration, polyuria, thirst anddehydration/hypovolemia (profuse and prolonged aquaresis).

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 mustcontinue until aquaresis abates. Dialysis may not be effective in removing tolvaptan because of itshigh binding affinity for human plasma protein (> 98 %).

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

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

In healthy adult subjects, oral administration of 7.5 mg to 120 mg doses of tolvaptan produced anincrease in urine excretion rate within 2 hours of dosing. Following single oral doses of 7.5 mg to60 mg, 24-hour urine volume increased dose dependently with daily volumes ranging from 3 to9 litres. For all doses, urine excretion rates returned to baseline levels after 24 hours. For single doses60 mg to 480 mg, a mean of about 7 litres was excreted during 0 to 12 hours, independent of dose.

Markedly higher doses of tolvaptan produce more sustained responses without affecting the magnitudeof excretion, as active concentrations of tolvaptan are present for longer periods of time.

Hyponatremia

In 2 pivotal, double-blind, placebo-controlled, clinical trials, a total of 424 patients with euvolemic orhypervolemic hyponatremia (serum sodium < 135 mEq/L) due to a variety of underlying causes (heartfailure [HF], liver cirrhosis, SIADH and others) were treated for 30 days with tolvaptan (n = 216) orplacebo (n = 208) at an initial dose of 15 mg/day. The dose could be increased to 30 mg/day and60 mg/day depending on response using a 3-day titration scheme. The mean serum sodiumconcentration at trial entry was 129 mEq/L (range 114 mEq/L to 136 mEq/L).

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

Following 3 days of treatment, the pooled analysis of the two trials revealed 5-fold more tolvaptanthan placebo patients achieved normalisation of serum sodium concentrations (49 % vs. 11 %). Thiseffect continued as on Day 30, when more tolvaptan than placebo patients still had normalconcentrations (60 % vs. 27 %). These responses were seen in patients independent of the underlyingdisease. The results of self-assessed health status using the SF-12 Health Survey for the mental scoresshowed statistically significant and clinically relevant improvements for tolvaptan treatment comparedto placebo.

Data on the long-term safety and efficacy of tolvaptan were assessed for up to 106 weeks in a clinicaltrial in patients (any aetiology) 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 theirprevious randomisation. Improvements in serum sodium levels were observed as early as the first dayafter dosing and continued for on-treatment assessments up to Week 106. When treatment wasdiscontinued, serum sodium concentrations decreased to approximately baseline values, despite thereinstatement of standard care therapy.

In a pilot, randomised (1:1:1), double-blind trial in 30 patients with hyponatremia secondary to

SIADH, the pharmacodynamics of tolvaptan following single doses of 3.75 mg, 7.5 mg and 15 mgwere assessed. Results were highly variable with large overlap between dose groups; changes were notsignificantly correlated with tolvaptan exposure. Mean maximal changes in serum sodium werehighest following the 15 mg dose (7.9 mmol/L) but median maximal changes were highest for the7.5 mg dose (6.0 mmol/L). Individual maximal increases in serum sodium were negatively correlatedwith fluid balance; mean change in fluid balance showed a dose dependent decrease. Mean changefrom baseline in cumulative urine volume and urine excretion rates was 2-fold higher for the 15 mgdose compared to the 7.5 mg and 3.75 mg doses, which showed similar responses.

EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan)was a long-term outcome, double-blind, controlled clinical trial in patients hospitalised with worsening

HF and signs and symptoms of volume overload. In the long-term outcome trial, a total of2,072 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 hospitalisation for HF. Tolvaptan treatment had no statistically significant favourable orunfavourable effects on overall survival or the combined endpoint of CV mortality or HFhospitalisation, 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

Samsca in one or more subsets of the paediatric population in treatment of dilutional hyponatremia(see section 4.2 for information on paediatric use).

After oral administration, tolvaptan is rapidly absorbed with peak plasma concentrations occurringabout 2 hours after dosing. The absolute bioavailability of tolvaptan is about 56 %. Co-administrationof a 60 mg dose with a high-fat meal increases peak concentrations 1.4-fold with no change in AUCand no change in urine output. Following single oral doses of ≥ 300 mg, peak plasma concentrationsappear to plateau, possibly due to saturation of absorption.

Tolvaptan binds reversibly (98 %) to plasma proteins.

Tolvaptan is extensively metabolised by the liver. Less than 1 % of intact active substance is excretedunchanged in the urine.

In-vitro studies indicate that tolvaptan or its oxobutyric metabolite may have the potential to inhibit

OATP1B1, OAT3, BCRP and OCT1 transporters. Administration of rosuvastatin (OATP1B1substrate) or furosemide (OAT3 substrate) to healthy subjects with elevated oxobutyric acidmetabolite (inhibitor of OATP1B1 and OAT3) plasma concentrations did not meaningfully alter thepharmacokinetics of rosuvastatin or furosemide. See also section 4.5.

The terminal elimination half-life is about 8 hours and steady-state concentrations of tolvaptan areobtained after the first dose.

Radio-labelled tolvaptan experiments showed that 40 % of the radioactivity was recovered in the urineand 59 % was recovered in the faeces where unchanged tolvaptan accounted for 32 % of radioactivity.

Tolvaptan is only a minor component in plasma (3 %).

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

Clearance of tolvaptan is not significantly affected by age.

The effect of mildly or moderately impaired hepatic function (Child-Pugh classes A and B) on thepharmacokinetics of tolvaptan was investigated in 87 patients with liver disease of various origins. Noclinically significant changes have been seen in clearance for doses ranging from 5 mg to 60 mg. Verylimited information is available in patients with severe hepatic impairment (Child-Pugh class C).

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

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

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

Teratogenicity was noted in rabbits given 1,000 mg/kg/day (3.9-times the exposure in humans at the60 mg dose, based on AUC). No teratogenic effects were seen in rabbits at 300 mg/kg/day (up to 1.9-times the exposure in humans at the 60 mg dose, based on AUC). 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 consumptionand body weight gain, salivation), but tolvaptan did not affect reproductive performance in males andthere 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 6.7-times the exposure in humans at the 60 mg dose, based on AUC.

Maize starch

Hydroxypropylcellulose

Lactose monohydrate

Magnesium stearate

Microcrystalline cellulose

Indigo carmine aluminium lake (E 132)

Not applicable

Samsca 7.5 mg tablets5 years

Samsca 15 mg tablets and Samsca 30 mg tablets4 years

Store in the original package in order to protect from light and moisture.

Samsca 7.5 mg tablets10 tablets in PP/Alu blisters30 tablets in PP/Alu blisters10 × 1 tablet in PVC/Alu perforated unit dose blisters30 × 1 tablet in PVC/Alu perforated unit dose blisters

Samsca 15 mg and Samsca 30 mg tablets10 × 1 tablet in PVC/Alu perforated unit dose blisters30 × 1 tablet in PVC/Alu perforated unit dose blisters

Not all pack sizes may be marketed.

No special requirements.

Otsuka Pharmaceutical Netherlands B.V.

Herikerbergweg 2921101 CT, Amsterdam

Netherlands

Samsca 7.5 mg tablets

EU/1/09/539/005 (10 tablets)

EU/1/09/539/006 (30 tablets)

EU/1/09/539/007 (10 × 1 tablet)

EU/1/09/539/008 (30 × 1 tablet)

Samsca 15 mg tablets

EU/1/09/539/001 (10 × 1 tablet)

EU/1/09/539/002 (30 × 1 tablet)

Samsca 30 mg tablets

EU/1/09/539/003 (10 × 1 tablet)

EU/1/09/539/004 (30 × 1 tablet)

Date of first authorisation: 03 August 2009

Date of latest renewal: 19 June 2014

{MM/YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.