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SAMSCA - SAMSCA - CT 7798 - English version

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Introduction SAMSCA 15 mg, tablet B/10 (CIP code: 399 352-7) B/30 (CIP code: 399 353-3) SAMSCA 30 mg, tablet B/10 (CIP code: 399 355-6) B/30 (CIP code: 399 356-2) Posted on Jul 05 2010 Active substance (DCI) tolvaptan Cardiologie - Nouveau médicament Pas d’avantage clinique démontré dans l’hyponatrémie secondaire à une sécrétion inappropriée d’hormone antidiurétique SAMSCA est un antagoniste sélectif des récepteurs V2 de la vasopressine, indiqué dans le traitement des adultes ayant une hyponatrémie secondaire à un syndrome de sécrétion inappropriée d’hormone antidiurétique (SIADH).Chez ces patients, son efficacité en termes d’augmentation de la natrémie par rapport au placebo n’a été démontrée que dans une analyse en sous-groupe.Son intérêt en termes de morbi-mortalité chez les patients hospitalisés pour aggravation de leur insuffisance cardiaque n’a pas été démontré.Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous ATC Code C03XA01 Laboratory / Manufacturer OTSUKA PHARMACEUTICAL FRANCE SAS SAMSCA 15 mg, tablet B/10 (CIP code: 399 352-7) B/30 (CIP code: 399 353-3) SAMSCA 30 mg, tablet B/10 (CIP code: 399 355-6) B/30 (CIP code: 399 356-2) Posted on Jul 05 2010
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The legally binding text is the original French version
TRANSPARENCY COMMITTEE  OPINION  16 June 2010  SAMSCA 15 mg, tablet B/10 (CIP code: 399 352-7) B/30 (CIP code: 399 353-3)   SAMSCA 30 mg, tablet B/10 (CIP code: 399 355-6) B/30 (CIP code: 399 356-2)   Applicant: OTSUKA PHARMACEUTICAL FRANCE SAS  Tolvaptan ATC code: C03XA01 List I  Date of Marketing Authorisation: 3 August 2009 Medicine requiring annual hospital prescription initially and requiring special monitoring during treatment.  Reason for request: Inclusion on the list of medicines reimbursed by National Health Insurance and approved for hospital use.                      Medical, Economic and Public Health Assessment Division
 
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 CHARACTERISTICS OF THE MEDICINAL PRODUCT
1.1. Active ingredient Tolvaptan
1.2. Background SAMSCA (tolvaptan) is a selective antagonist of vasopressin V2-receptors and thus inhibits the antidiuretic action of vasopressin. It is the first member of a new therapeutic category, the vaptans. 
1.3. Indication “Treatment of adult patients with hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH).”
1.4. Dosage “Due to the need for a dose titration phase with close monitoring of serum sodium and volume status, treatment with SAMSCA should be initiated in hospital.  Dosage: a dose of 15 mg once daily. TheTreatment with tolvaptan should be initiated at dose may be increased to a maximum of 60 mg once daily as tolerated to achieve the desired level of serum sodium. During titration, patients should be monitored for serum sodium and volume status (see section 4.4 of the SPC).  In case of inadequate improvement in serum sodium levels, other treatment options should be considered, either in place of or in addition to tolvaptan. For patients with an appropriate increase in serum sodium, the underlying disease and serum sodium levels should be monitored at regular intervals to evaluate further need of tolvaptan treatment. In the setting of hyponatraemia, 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 hyponatraemia is no longer a clinical issue.  Patients with renal impairment: Tolvaptan is contraindicated in anuric patients (see section 4.3 of the SPC). Tolvaptan has not been studied in patients 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 renal impairment.  Patients with hepatic impairment: dose adjustment is needed in patients with mild orNo moderate hepatic impairment (Child-Pugh classes A and B). No information is available in patients with severe hepatic impairment (Child-Pugh class C). In these patients dosing should be managed cautiously and electrolytes and volume status should be monitored (see section 4.4 of the SPC).  Elderly population: No dose adjustment is needed in elderly patients.  Paediatric population: There is no clinical experience in children and adolescents under the age of 18 years. SAMSCA is not recommended in the paediatric age group.  Method of administration:use. Administration preferably in the morning, withoutFor oral regard to meals. Tablets should be swallowed without chewing with a glass of water. SAMSCA should not be taken with grapefruit juice (see section 4.5 of the SPC)” .
 
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 SIMILAR MEDICINAL PRODUCTS
2.1. ATC Classification (2009) C : Cardiovascular system C03 : Diuretics C03X : Other diuretics C03XA : Vasopressin antagonists C03XA01 : Tolvaptan  2.2. Medicines in the same therapeutic category SAMSCA is the first member of the vaptan category.
2.3. Medicines with a similar therapeutic aim ALKONATREM (demeclocycline) indicated in the “Treatment of syndrome of inappropriate of antidiuretic hormone secretion (SIADH), particularly of paraneoplastic origin, with: - hyponatraemia < 125 mEq/l associated with inappropriate natriuresis, chronic  and/or clinical signs connected with hyponatraemia,  -- resistance to fluid restriction”. and  
3 ANALYSIS OF AVAILABLE DATA
 The efficacy and safety of SAMSCA were assessed in 5 studies:  Four studies examined laboratory parameters: - studies (SALT 1 and SALT 2) which aimed to2 randomised double-blind phase III compare the efficacy of SAMSCA 15 mg/day and placebo, used in addition to fluid restriction, for increasing and maintaining serum sodium levels (n = 184 and 232). - 1 long-term open follow-up study (SALTWATER) of the patients from the two ap rreceding studies; its main1aim was to assess safety. - aimed to compare the efficacy of SAMSCA versus which open study andomised fluid restriction in regard to the normalisation of serum sodium in 23 hospitalised hyponatraemic patients.  A study of morbidity/mortality (EVEREST study2), the aim of which was to assess the efficacy of SAMSCA in comparison with placebo in terms of morbidity/mortality. This study, which was part of the MA dossier, was not submitted by the company in its file for the application for inclusion, but will be summarized in this opinion.  3.1. Studies versus placebo which looked at laboratory parameters
3.1.1. SALT 1 and SALT 2 studies Method: randomised double-blind studies comparing SAMSCA 15 mg/day with placebo, used in addition to fluid restriction, which were carried out in 184 (SALT 1) and 232 (SALT 2) patients with hyponatraemia of various causes who were followed up for 30 days.  Inclusion criteria: patients over 18 years of age with euvolaemic or hypervolaemic hyponatraemia defined as a serum sodium level < 135 mEq/l. 
                                            1Gheorgiade et al. « Vasopressin V2 receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia » Am J Cardiol 2006;1064-7. 2 » JAMA 2007; et al. « Effects of oral tolvaptan in patients hospitalized for worsening heart failure Konstam 297:1319-31. 
 
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ascites. Hypervolaemia was defined as an excess of extracellular fluid manifested by oedema or  Euvolaemia was defined as an absence of oedema and ascites.  Treatments: SALT-1 study: - 15 mg/day, n = 95 SAMSCA - n = 89 Placebo,  SALT-2 study: - SAMSCA 15 mg/day, n = 118 - Placebo, n = 114 Note: doses were increased to 30 or 60 mg/day if the increases in serum sodium over 24 h were less than 5 mEq/l, serum sodium remainingmEq/l. Decreases in dose were left to the discretion of  135 the investigators.  Primary endpoints: Change in the mean daily area under the curve (AUC) for serum sodium (mEq/l) between inclusion and 4 days of treatment and between inclusion and 30 days of treatment . The AUCs were referred to the number of days of each of the observation periods.  RESULTS: restricted intention-to-treat analysis3(see Table 1) On inclusion, the patients’ characteristics were comparable. The distribution of the patients according to the cause of the hyponatraemia was as follows: - SIADH: 25.4% in the SALT-1 study and 23.9% in the SALT-2 study, - heart failure: 36.1% and 30.4%, - cirrhosis of the liver: 22.4% and 30.4%, - other causes: 22.4% and 20.6%.  Table 1: Change in the mean daily AUC for serum sodium (mEq/l) after 4 days and 30 days SAMSCAP  g/day obecalct oEffeeatmf trne t p 15 m  [95% CI]  SALT 1 study n = 95 = 89 n AMfteearn4( SdaDy) s 0.0001 < [2.75 - 4.07] 3.41 (2.08) 0.113.52 (2.68) After 30 days 1.436.00 (4.10) 4.57 (3.59) < [3.64 - 5.50] 0.0001 Mean (SD) SALT 2 study n =118 n =114 AMfteearn4( SdaDy)s 4.04 [3.36 - 4.73] < 0.00014.39 (2.87) (2.56) 0.35  After 30 days Mean (SD)  0.0001 < [3.60 - 5.47] 4.54 (3.83) 1.726.26 (3.92)  In the SALT 1 study, after 4 and 30 days of treatment, a significant increase in the daily mean AUC for serum sodium was observed with SAMSCA 15 mg/day in comparison with placebo: difference of 3.41 mEq/l [2.75 - 4.07] after 4 days and 4.57 mEq/l [3.64 - 5.50] after 30 days, p < 0.0001. In the SALT 2 study, after 4 and 30 days of treatment, a significant increase in the daily mean AUC for serum sodium was observed with SAMSCA 15 mg/day in comparison with placebo: difference of 4.04 mEq/l [3.36 - 4.73] after 4 days and 4.54 mEq/l [3.60 - 5.47] after 30 days, p < 0.0001. 
                                            3treated subjects for whom a serum sodium value was restricted ITT included all randomised,  the available on inclusion and on at least one occasion after inclusion.
 
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3.1.2. Open follow-up study: the SALTWALTE R study  111 patients were included in this study (38 from the SALT 1 study and 73 from the SALT 2 study). Seventy-three patients were followed up for 58 weeks and 21 for 106 weeks. The serum sodium levels observed in SALT 1 and 2 were maintained in this follow-up.  3.1.3. Study by Gheorghiade et al. 20061 Method: open randomised comparative study of SAMSCA versus fluid restriction + placebo carried out in 28 hospitalised patients with hyponatraemia who were followed up for 65 days.  Inclusion criteria: patients over 18 years of age with normovolaemic hyponatraemia defined as a serum sodium level < 135 mEq/l.  Treatments: - SAMSCA, n = 17 - restriction + placebo, n = 11 Fluid SAMSCA was administered at an initial dose of 10 mg/day; thereafter, doses could be increased to up to 60 mg/day depending on the response to the treatment.  Primary endpoint: number of patients with serum-sodium normalisation defined as a concentration 135 mEq/l or an increase10% relative to inclusion.  RESULTS: On inclusion, the patients’ characteristics were comparable. The distribution of the patients according to the cause of the hyponatraemia was as follows: - SIADH: n = 10, - heart failure: n = 14, - cirrhosis of the liver: n = 4.  Two patients in the SAMSCA group and 3 patients in the fluid restriction + placebo group were lost to follow-up in the run-in phase and were not included in the analysis. Results are available for 23 patients (15 versus 8).  The number of patients with normalisation of serum sodium was significantly higher in the SAMSCA group than in the fluid restriction + placebo group: 11 patients in the SAMSCA group versus 3 in the fluid restriction + placebo group, p = 0.049. In view of the small number of patients included and the number lost to follow-up, the results of this study must be interpreted with caution.  3.2. Study of morbidity/mortality: the EVEREST study2 Method and aims: Randomised double-blind comparative study of SAMSCA 30 mg/day (n = 2072) versus placebo (n = 2061) carried out in 4133 patients hospitalised because of a worsening of their heart failure (HF), 8% of whom were hyponatraemic.  Inclusion criteria: adult patients over 18 years of age with NYHA class III or IV HF with an LVEF reduced to40% who are hospitalised because of a worsening of their HF within a period of 48 h prior to inclusion. On inclusion, the patients were receiving standard therapy based on ACE inhibitors (84%), diuretics (97%), and beta blockers (70%).  Primary endpoints: - endpoint combining hospitalisation for HF or cardiovascular mortality, composite  all-cause mortality. - Results: Intention-to-treat analysis After one year of treatment, there was no statistical difference between the two groups in terms of the percentage of patients with a cardiovascular event (hospitalisation for HF or cardiovascular mortality): 42% (871/2072 patients) in the SAMSCA 30 mg/day group versus 40.2% (829/2061 patients) in the placebo group , HR 1.04 [0.95 – 1.14], NS. 
 
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(537/2072 patients) in the SAMSCA 30 mg/da y group versus 26.3% (543/2061 patients) in Similarly, no significant difference was observable in regard to all-cause mortality: 25.9% the placebo group, HR 0.98 [0.87 – 1.11], NS.  3.3. Adverse effects In the SALT 1 study, adverse events were observed in 88/100 patients (88%) in the SAMSCA 15 mg/day group and in 83/101 patients (82.2%) in the placebo group. The most frequent adverse events (> 10%) were: - constipation: 14% versus 4% - dry mouth: 16% versus 5% - nausea: 10% versus 7.9% - feeling of thirst: 21% versus 5% - dizziness: 11% versus 5.9%  In the SALT 2 study, adverse events were observed in 91/123 patients (74%) in the SAMSCA 15 mg/day group and in 85/119 patients (71.4%) in the placebo group.The most frequent adverse events (> 5%) were: -ascites: 6.5% versus 9.2%  - dry mouth: 9.8% versus 3.4% -nausea: 6.5% versus 4.2%  - peripheral oedema: 8.1% versus 6.7% - feeling of thirst: 8.9% versus 4.2% - hyperglycaemia: 5.7% versus 0 - pollakiuria: 5.7% versus 1.7% - hypotension: 6.5% versus 5%  In the SALTWATER study, adverse events were observed in 52/56 patients (92.9%) in the SAMSCA 15 mg/day group and in 53/55 patients (96.4%) in the placebo group. The most frequent adverse events (> 10%) were: - anaemia: 10.7% versus 16.4%, - diarrhoea: 16.1% versus 14.5%, - ascites: 10.7% versus 9.1% - peripheral oedema: 16.1% versus 16.4%, - fatigue: 10.7% versus 14.5%, - urinary tract infection: 10.7% versus 16.4%, - pneumonia: 17.9% versus 3.6%, - hyponatraemia: 12.5% versus 12.7%, - headache: 10.7% versus 5.5%, - hypotension: 10.7% versus 10.9%.  In the EVEREST study, adverse events were observed in 89% of the patients in the SAMSCA 30 mg/day group and in 86.1% of the placebo group. The most frequent adverse events (> 10%) were: - feeling of thirst: 16% versus 2.1%. - hypotension: 11.3% versus 11%, - nausea: 11.9% versus 12.1%. 
3.4. Conclusion The efficacy and safety of SAMSCA were assessed in 4 studies based on laboratory parameters (SALT 1 and SALT 2, SALTWATER, and Gheorghiade et al. 2006) and a study of morbidity/mortality (EVEREST study).   
 
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mean AUC for serum sodium was observed w ith SAMSCA 15 mg/day in comparison with In the SALT 1 study, after 4 and 30 days of treatment, a significant increase in the daily placebo: difference of 3.41 mEq/l [2.75 - 4.07] after 4 days and 4.57 mEq/l [3.64 - 5.50] after 30 days, p < 0.0001.   In the SALT 2 study, after 4 and 30 days of treatment, a significant increase in the daily mean AUC for serum sodium was observed with SAMSCA 15 mg/day in comparison with placebo: difference of 4.04 mEq/l [3.36 - 4.73] after 4 days and 4.54 mEq/l [3.60 - 5.47] after 30 days, p < 0.0001.  The serum sodium levels observed in SALT 1 and 2 were maintained in the open follow-up study (SALTWATER).  In the study by Gheorgiade et al., the number of patients with normalisation of serum sodium was significantly higher in the SAMSCA group than in the fluid restriction + placebo group: 11 patients in the SAMSCA group versus 3 in the fluid restriction + placebo group, p = 0.049. In view of the small number of patients included and the number lost to follow-up, the results of this study must be interpreted with caution.  In the EVEREST study, after one year of treatment, there was no statistical difference between the two groups in terms of the percentage of patients with an observed cardiovascular event (hospitalisation for HF or cardiovascular mortality): 42% (871/2072 patients) in the SAMSCA 30 mg/day group versus 40.2% (829/2061 patients) in the placebo group, HR 1.04 [0.95 – 1.14], NS. Similarly, no significant difference was observable in regard to all-cause mortality: 25.9% (537/2072 patients) in the SAMSCA 30 mg/day group versus 26.3% (543/2061 patients) in the placebo group, HR 0.98 [0.87 – 1.11], NS.   In the studies submitted in the dossier, patients with SIADH accounted for about 25% of the patients included. The efficacy of SAMSCA was thus only demonstrated in a subgroup of patients, who had hyponatraemia associated with SIADH. Furthermore, the chosen endpoints (efficacy endpoints based on laboratory parameters) are questionable and their results were not confirmed by clinical data (absence of efficacy in terms of morbidity/mortality). In addition, there are uncertainties over the safety of SAMSCA, in particular over the risk of ischaemic CVA and the neurological risks associated with excessively rapid correction of serum sodium levels in the most severe cases (serum sodium < 120 mEq/l), which were excluded from the studies. Finally, no study versus an active comparator, in particular demeclocycline, is available at present.  In view of these various points, interpretation of the results observed in the studies and SAMSCA’s place in the therapeutic strategy are tricky.  The most frequently observed adverse events (>10%) with SAMSCA were: constipation, dry mouth, nausea, feeling of thirst, dizziness, anaemia, diarrhoea, ascites, peripheral oedema, fatigue, urinary tract infection, pneumonia, headache, and hypotension. 
4 TRANSPARENCY COMMITTEE CONCLUSIONS
4.1. Actual benefit SIADH with chronic hyponatraemia < 135 mEq/l and resistance to fluid restriction can, in severe cases, be life-threatening.  SAMSCA is a medicine whose place in the therapeutic strategy should be clarified.   There are treatment alternatives, notably demeclocycline (ALKONATREM).  
 
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The severity of SIADH varies. As the n umber of patients with SIADH with chronic Public health benefit:  hyponatremia and resistance to fluid restriction is very limited, the public-health burden of this disease is small. In patients who are symptomatic and resistant to fluid restriction there is an unmet therapeutic need, which is partially met by SAMSCA. This need is not, for all that, a public-health need. On the basis of the available data tolvaptan is expected to lead to normalisation of serum sodium levels, which is assumed to be accompanied by the disappearance of the associated clinical signs. In terms of the population, in the absence of evidence in respect of clinical signs, the expected impact of SAMSCA on morbidity is hard to quantify.  Consequently, it is not expected that SAMSCA will benefit public health.   The efficacy/adverse effects ratio of SAMSCA is high.  The actual benefit of SAMSCA in this indication is substantial. 
4.2. Improvement in actual benefit (IAB) In the light of the absence of comparative data versus an active product, the methodological deficiencies of the studies provided (choice of endpoints questionable, results for a subgroup of patients), and the uncertainties over safety, SAMSCA does not provide an improvement in actual benefit (IAB V) in the therapeutic strategy for the management of patients with hyponatraemia secondary to SIADH in whom fluid restriction is ineffective or impossible. SAMSCA nevertheless represents a useful additional therapeutic tool in the management of these patients. 
4.3. Therapeutic use4,5 SIADH is the result of an excess of ADH of neurohypophyseal or ectopic origin. Its causes are tumoral, neurological, bronchopulmonary, and pharmacological.  This syndrome causes hypotonic hyponatraemia with a normal or increased extracellular volume, associated with increased natriuresis; the hyponatraemia can be acute or chronic. The most serious complications include death, neurological disturbances (convulsions, disturbances of consciousness).  Management depends on the severity of the hyponatraemia and on its duration.  Treating SIADH has two components: identifying and treating the cause; hyponatraemia itself; correction must be gradual.correcting the   For SIADH, fluid restriction remains the standard treatment. If fluid restriction is not enough to restore serum sodium levels, demeclocycline, which inhibits the tubular effects of AVP, can be offered, but it takes several weeks to become effective. A similar result can be obtained with lithium, but at the cost of more severe side effects. Urea can likewise be used.  
                                            4Heng et al. « Syndrome de sécrétion inappropriée d’hormone antidiurétique : diagnostic et prise en charge » Réanimation 15 (2006) 490–496 5 The American » et al. « Verbalis Treatment guidelines 2007: Expert Panel Recommendations Hyponatremia Journal of Medicine (2007) Vol 120 (11A), S1–S21 
 
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treatments currently available, particularly in cas es of chronic hyponatraemia. SAMSCA, a vasopressin V2-receptor antagonist, represents an alternative to the medical
4.4. Target population The target population of SAMSCA is patients with hyponatraemia (serum concentration < 135 mEq/l) secondary to SIADH in whom fluid restriction is ineffective or impossible.  It is not possible to estimate the target population of this proprietary product on the basis of the existing epidemiological data. According to expert opinion, the target population of patients who have serum sodium < 135 mEq/l and who are resistant to fluid restriction or cannot undergo fluid restriction is between 1000 and 2000 patients per year.  
4.5. Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines reimbursed by National Health Insurance and on the list of medicines approved for use by hospitals and various public services in the indications and at the dosages in the Marketing Authorisation.  Packaging: appropriate for the prescription conditions  Reimbursement rate: 65%  
 
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