Summary Basis of Decision for Samsca ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
SamscaTM
Tolvaptan, 15 mg, 30 mg, 60 mg, Tablet, Oral
Otsuka Pharmaceutical Company, Ltd.
Submission control no: 139413
Date issued: 2011-12-08
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02370468 - 15 mg/tablet
- 02370476 - 30 mg/tablet
- 02370484 - 60 mg/tablet
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control Number 139413
Date of Submission:
Date of authorization:
2 Notice of decision
On July 25, 2011, Health Canada issued a Notice of Compliance to Otsuka Pharmaceuticals Company, Ltd. for the drug product Samsca.
Samsca contains the medicinal ingredient, tolvaptan, which is a selective vasopressin V2-receptor antagonist. Arginine vasopressin (AVP) is a hormone which causes vasoconstriction via V1a-receptors and promotes water reabsorption in the kidneys via V2-receptors. The V2-receptors are primarily responsible for the anti-diuretic effects of AVP, also known as anti-diuretic hormone (ADH). Blockade of this receptor may thus be expected to result in aquaresis, that is (i.e.), excretion of free water, low in sodium or potassium.
Samsca is indicated for the treatment of clinically important, non-hypovolemic hyponatraemia for example (e.g.) serum sodium <130 mEq/L or symptomatic hyponatraemia. Samsca helps raise salt levels in the blood by removing extra body water through increased urination.
The market authorization was based on quality, non-clinical, and clinical information submitted. Two 30-day, double-blind, placebo-controlled, multicentre studies evaluated the efficacy and safety of Samsca in patients with euvolemic or hypervolemic hyponatraemia, due to a variety of underlying causes, i.e., heart failure, liver cirrhosis, syndrome of inappropriate anti-diuretic hormone (SIADH), and others. The study design was similar in both studies whereby a total of 424 patients were stratified by hyponatraemia status, and then received either Samsca at an initial dose of 15 mg/day [number (n) = 223], or a placebo (n = 220). The dose of Samsca could then be increased to 30 mg/day, and subsequently to 60 mg/day, until either the maximum dose or normonatremia (serum sodium >135 mEq/L) was reached. Following completion of the study, all patients resumed previous therapies for hyponatraemia and were re-evaluated on Day 37 for follow-up. In both studies, results showed that Samsca treatment was superior to placebo, with serum sodium concentrations increasing as early as 8 hours following first dose administration, and being maintained for up to 30 days. This effect was also seen in all patients, in both severe (<130 mEq/L) and mild (<135 mEq/L) hyponatraemic patients, and regardless of underlying causes, for example (e.g.), heart failure, liver cirrhosis, and SIADH.
Samsca (15 mg, 30 mg, and 60mg) is presented in a tablet form. The recommended starting dose of Samsca is a 15 mg tablet once daily. After 24 hours, the dose may be increased to 30 mg once daily, and then to a maximum of 60 mg once daily, as needed, to achieve the desired level of serum sodium. Samsca should be administered only by physicians experienced in the management of clinically important hyponatraemia. During initiation and titration, serum electrolytes and volume should be monitored frequently for any changes. During the first 24 hours of therapy, fluid restriction should be avoided and patients should be advised to continue drinking fluids in response to thirst. Following discontinuation of Samsca, patients whose cause of hyponatraemia has not been determined should be evaluated for maintenance of acceptable serum sodium levels and appropriate therapy instituted, if needed. Further dosing guidelines are available in the Product Monograph.
Samsca is contraindicated in the following conditions:
- hypovolemic hyponatraemia;
- urgent need to raise serum sodium acutely;
- inability of the patients to sense or appropriately respond to thirst;
- concomitant use of strong cytochrome P450 (CYP) 3A inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, saquinivir, and nefazadone);
- anuric patients;
- in patients who are hypersensitive to Samsca or to any ingredient in the formulation. For a complete listing, see Dosage Forms, Composition and Packaging in the Product Monograph.
Samsca should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Samsca are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Samsca is favourable for the indication stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Tolvaptan, the medicinal ingredient of Samsca, is a selective vasopressin V2-receptor antagonist. The V2-receptor is primarily responsible for the anti-diuretic effects of arginine vasopressin (AVP). Blocking the V2-receptor results in the excretion of free water, low in sodium or potassium (aquaresis). This activity helps to increase sodium levels in the blood by removing extra body water as urine.
Manufacturing Process and Process Controls
Tolvaptan is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits.
Characterization
The structure of tolvaptan has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within International Conference on Harmonisation (ICH) established limits.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of tolvaptan.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Samsca (tolvaptan) tablets are available in the following strengths and packages:
- Samsca 15 mg tablets are non-scored, bevelled-edge, blue, triangular, shallow-convex, debossed with "OTSUKA" and "15" on one side, and are packaged in blister packs of 10 tablets or in 10, 30, 90 or 500 count bottles.
- Samsca 30 mg tablets are non-scored, bevelled-edge, blue, round, shallow-convex, debossed with "OTSUKA" and "30" on one side, and are packaged in blister packs of 10 tablets or in 10, 30, 90 or 500 count bottles.
- Samsca 60 mg tablets are non-scored, bevelled-edge, blue, modified rectangular, shallow-convex, beveled-edge tablet, debossed with "OTSUKA" and "60" on one side, and packaged in blister packs of 10 tablets or in 10, 30, 90 or 500 count bottles.
All of the tablets contain the following inactive ingredients: corn starch; hydroxypropyl cellulose; lactose monohydrate; low-substituted hydroxypropyl cellulose; magnesium stearate; microcrystalline cellulose; purified water; and FD&C Blue Number 2 Aluminum Lake as colourant.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of tolvaptan with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Samsca is tested to verify that its identity, appearance, content uniformity, assay, dissolution, and levels of degradation products, drug-related impurities, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
The validation process is considered to be complete. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH-established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 48-month shelf-life at 15-30°C for Samsca tablets in the proposed packaging is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through the stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Samsca are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Except for lactose monohydrate, no other ingredients used in the manufacture of Samsca tablets are derived from human or animal origin. The lactose is sourced from New Zealand and this country is not regarded as a source of BSE risk. In addition, the lactose monohydrate is derived from milk for human consumption, and is unlikely to present any risk or contamination.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Samsca has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The results of the pharmacology studies indicate that tolvaptan is a competitive AVP antagonist with a much higher affinity for V2-receptors than V1a-receptors. AVP causes vasoconstriction via V1a-receptors, and promotes water reabsorption in the kidneys via V2-receptors. The V2-receptors are primarily responsible for the antidiuretic effects of AVP.
Tolvaptan did not stimulate cyclic adenosine monophosphate (cAMP) production, thus demonstrating no agonistic activity. The results of in vivo studies in different models of at least four animal species clearly demonstrated that tolvaptan has aquaretic properties with very little or no saluretic effect. These findings were also confirmed without exception in experimental animal models of heart failure, hyponatraemia and polycystic kidney disease. The combination of tolvaptan and furosemide increased urine volume more than each drug alone. The effects of these two drugs were found to be independent and additive, supporting the feasibility of combining tolvaptan treatment with that of other diuretic agents.
3.2.2 Pharmacokinetics
Absorption
After a single oral dose of radiolabelled tolvaptan 30 mg/kg to male and female rats and male dogs, the serum concentration of radioactivity peaked at 2 to 4 hours post-dose with maximum plasma concentration (Cmax) values of 4.441 and 7.739 µg eq/mL, respectively, in male and female rats and 6.193 µg eq/mL in male dogs. The values for the elimination half-life were 4.4 and 6.4 hours, respectively, for male and female rats and 4.8 hours for male dogs. In a 14-day repeated oral dose study of radiolabelled tolvaptan at 30 mg/kg/day to male rats, the blood concentration of radioactivity gradually increased, reaching a plateau on the 12th dosing day. The concentration decreased gradually after the final dosing.
Distribution
Following a single intravenous dose of 1 to 30 mg/kg tolvaptan, the volume of distribution in male rats ranged from 3,400 to 5,002 mL/kg suggesting extensive extravascular distribution of the unchanged compound in rats. The volume of distribution value in dogs (3,526 mL/kg) was also high.
After a single oral dose of radiolabelled 30 mg/kg tolvaptan to male and female rats, the radioactivity was high in the liver, stomach, small intestine, adrenals, large intestine, and kidneys in both male and female rats. In female rats it was also high in the pituitary gland, Harder's gland, mandibular gland, heart, lung, and pancreas. In pregnant female rats, the concentration of radioactivity was low in the foetus and amniotic fluid on Day 18 of gestation.
Tolvaptan binds extensively (>97.2%) to plasma proteins in vitro in mouse, rat, dog, and human plasma. The extent of binding was independent of drug concentration. The metabolites of tolvaptan were also extensively bound (>98.3%) to plasma proteins in human plasma. The binding of tolvaptan and its metabolites to human plasma proteins remained high (>98.3%) in the presence of concomitant drugs, furosemide, spironolactone, propranolol, dispyramide, lidocaine, and warfarin. These data suggest that a potential for drug-drug interactions via competitive displacement from protein binding sites is low. Furthermore, there was no effect on the protein binding of propranolol, lidocaine, or spironolactone in human plasma.
Metabolism
In mice, rats, rabbits, dogs, and humans, tolvaptan was metabolized primarily by three major biotransformation pathways: dehydrogenation; hydroxylation; and deamidation. These pathways generate a number of metabolites. Based on in vitro studies with recombinant human cytochrome P450 (CYP) isoforms, CYP3A4 has been identified to be responsible for the primary metabolic reactions.
Excretion
Tolvaptan was mainly eliminated via metabolic clearance in both animals and humans as determined by the excretion of the metabolites as well as the unchanged compound. The primary route of excretion was the faeces.
3.2.3 Toxicology
Single-Dose Toxicity
The acute toxicity of tolvaptan was low in rats and dogs with no mortality or clinical signs indicative of toxicity observed after single gavage doses up to 2,000 mg/kg.
In mice, single oral tolvaptan doses of 300 mg/kg were tolerated, but 1,000 mg/kg was lethal.
Repeat-Dose Toxicity
In the pivotal chronic toxicity study conducted in rats, oral administration of spray-dried tolvaptan at 30, 100, and 1,000 mg/kg/day for 26 weeks resulted in clinical deterioration of several high-dose females that necessitated them being replaced during the first week of the study. Thereafter tolvaptan was clinically well-tolerated, but was associated with minor decreases in body weight gain and food consumption at the mid- and high-dose levels. Dose-dependent increases in water consumption and corresponding increased urine volume and reduced urine specific gravity and osmolarity were reported at all dose levels, as well as a number of mild clinical pathology findings. These clinical findings included decreases in red blood cell (RBC) levels mainly with the high dose; mildly (up to 30%) prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) in high-dose males, increased total bilirubin levels in mid- and high-dose males and/or females, lower potassium levels at all dose levels in males and high-dose females, and increased levels of inorganic phosphate in high-dose males and mid- and high-dose females. Increases in liver, kidney, adrenal, pituitary, and uterus weight and decreased thymus weight in male and/or female high-dose animals were without microscopic correlates, with the potential exception of a 1-fold increased incidence of hydronephrosis in both sexes at the high dose compared to controls.
The 100 mg/kg dose was considered the no-observed-adverse-effect-level (NOAEL) in rats based on the poor initial clinical tolerance in females at 1,000 mg/kg; the severity of diuretic effects in both sexes; increased kidney weight and incidence of hydronephrosis in both sexes; and increased coagulation time in males at the 1,000 mg/kg dose level. The drug exposure in rats at 100 mg/kg compared to the drug exposure at the maximum recommended human dose (MRHD) of 60 mg/day was 2.4-fold in male rats and 6.4-fold for female rats.
In a chronic toxicity study of tolvaptan in dogs, dose levels of 30, 100, and 1,000 mg/kg/day administered for 52 weeks were well-tolerated at 30 and 100 mg/kg and caused mortality and transient decreases in body weight and food consumption at the high dose. Dose-dependent increases in water consumption and urine volume at all dose levels; increased adrenal gland weight, decreased adrenal cortical vacuolation, and increased adrenal cortical width at the mid- and high-dose levels; as well as increased adrenal cortical width at the low dose were reported and were likely a response to the pharmacologic action of the drug. Increases in serum alkaline phosphatase, gamma-glutamyl transpeptidase, bilirubin, and cholesterol at 1,000 mg/kg in both sexes at one or more time intervals are consistent with a hepatobiliary effect; however there were no increases in serum transaminase activities or urine bilirubin and no treatment-related microscopic changes in the liver. Other mild clinical pathology changes were seen mainly at the high-dose level and not considered toxicologically significant and included decreases in RBC parameters, increased triglycerides and phospholipids (also seen to a lesser extent in mid-dose females), decreases in total protein and albumin/globulin ratio due to lower albumin; and slight decreases in sodium and chloride. The changes were considered reversible.
The 100 mg/kg dose was the NOAEL in dogs. The drug exposure in dogs at 100 mg/kg compared to the MRHD of 60 mg/day was 9.8-fold in male dogs and 13.2-fold for female dogs. It was assumed that the adrenal microscopic findings of cortical vacuolation and increased cortical width that correlated with increased adrenal gland weight at 100 and 1,000 mg/kg as well as increased cortical width at 30 mg/kg were likely due to the pharmacologic activity of tolvaptan.
Genotoxicity
Tolvaptan exhibited no genotoxic potential in the bacterial reverse-mutation test, in the forward gene mutation test in mouse lymphoma cells, in the chromosomal aberration test, and in the rat micronucleus test.
Carcinogenicity
In the 104-week oral carcinogenicity studies, tolvaptan was not associated with a decrease in survival or an increase in the incidence of neoplastic or non-neoplastic drug-related findings in rats and mice. Exposures at the high doses in mice were comparable to that at the MRHD (60 mg). The highest dose tested in rats resulted in exposures that were approximately 4-times the MRHD in male rats and 10-times the MHRD in female rats.
Reproductive and Developmental Toxicity
Tolvaptan did not impair reproductive performance at doses up to 1,000 mg/kg/day in males and 100 mg/kg/day in females (approximately 162- and 16-times the MRHD, respectively). Fertility was not affected at 1,000 mg/kg/day in males and females. The 10 mg/kg dose was the NOAEL with respect to maternal toxicity and 100 mg/kg was the no-observed-effect-level (NOEL) with respect to embryo-foetal toxicity at which the exposure was approximately 9-times the exposure at the MRHD.
In rabbits, maternal reproductive performance, as assessed by the ability to maintain pregnancy, was altered at dose levels of 300 mg/kg and higher where a dose-dependent incidence of abortion was observed. There was also evidence of developmental toxicity in rabbits at the maternally toxic dose of 1,000 mg/kg (324-times the exposure at the MRHD). This developmental toxicity consisted of increased incidences of embryo-fetal death, microphthalmia, open eyelids, cleft palate, brachymelia (zygopodium malformations) and fused phalanx. The NOAEL for maternal toxicity in rabbits was 10 mg/kg, based on dose-dependent decreases in body weight and food consumption at 30-1,000 mg/kg, and abortions at 300 and 1,000 mg/kg. Exposure in rabbits at 100 mg/kg was comparable to that at the MRHD. Due to the teratogenicity finding in rabbits and relatively low no-effect exposure margin, as well as maternal toxicity, it is recommended that tolvaptan not be taken by women who might become pregnant.
In a pre- and post-natal development study in rats, the 1,000 mg/kg high dose caused slightly increased pup mortality and reduced pup body weight during the lactation and post-weaning phases of the study. However there were no treatment-related effects on the physical and sexual development, reflexes and learning ability, or reproductive performance of the pups. The 100 mg/kg maternal dose level was considered a NOEL for offspring development.
3.2.4 Summary and Conclusion
The scope of the non-clinical studies provides sufficient pre-clinical information in regard to the pharmacodynamics, pharmacokinetics and toxicology of tolvaptan. Based on the results of in vitro and in vivo non-clinical pharmacology studies presented, tolvaptan appears to provide adequate and appropriate pharmacologic effects for its clinical evaluation in patients with clinically relevant hyponatraemia. In the toxicity program, there was no evidence of findings to preclude the proposed therapeutic administration of Samsca (tolvaptan) in patients. Adequate statements are in place in the Samsca Product Monograph to address the identified safety concerns.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
In the clinical pharmacology studies, serum potassium concentrations were unchanged following tolvaptan administration, while serum sodium concentrations were increased following tolvaptan administration. In healthy subjects, increases were seen within 2 hours post-dose. In subjects given single, oral doses of 60 to 480 mg, the increase in mean serum sodium concentrations from 0 to 24 hours post-dose (4 to 6 mEq/L) was the same for all doses, which was consistent with the observation that urine volumes over the 0- to 12-hour interval were similar for all doses. In patients with hyponatraemia secondary to liver disease, there was a dose-dependent increase in serum sodium concentrations for doses ranging from 5 to 60 mg.
At the recommended clinical doses (15 to 60 mg daily), tolvaptan had no known significant pharmacologic action in subjects other than to increase the urinary excretion of free water (aquaresis) entraining an increase in urine excretion rate and volume, a decrease in urine electrolyte concentrations with no clinically significant change in total electrolyte excretion, and a resulting increase in plasma sodium concentration. The blood flow to the kidney was also increased with no detrimental effect on the glomerular filtration rate.
Tolvaptan did not affect the natriuretic actions of furosemide or hydrochlorothiazide. Tolvaptan also did not appear to stimulate the renin-angiotensin-aldosterone system. Co-administration of furosemide or hydrochlorothiazide with tolvaptan did not produce additive effects on maximal urine excretion rate. Such co-administration had no or little effect on 24-hour urine volume, similar to tolvaptan alone.
3.3.2 Pharmacokinetics
Absorption
Following single 30 to 480 mg oral doses to healthy subjects, tolvaptan was rapidly absorbed. The median time-to-peak plasma concentration was approximately 2 hours (range 1 to 12 hours). Values of maximum plasma concentration increased linearly with the dose from 30 to 300 mg and plateaued at doses ≥300 mg.
The absolute oral bioavailability of tolvaptan was reported as 56% following administration of the 30 mg clinical tablet. Food does not impact the bioavailability of tolvaptan.
Distribution
The human plasma protein binding of tolvaptan was 99.0%. The binding was mainly to serum albumin and α1-acid glycoprotein.
Metabolism
Tolvaptan was extensively metabolized by CYP3A4 into many metabolites, with fourteen identified in plasma, urine, and faeces. In vitro studies indicated that many of the metabolites were also metabolized by CYP3A4/5. The metabolites have little or no V2-receptor antagonist activity.
Excretion
Tolvaptan was eliminated primarily via metabolism mediated by CYP3A4. Less than 1% of unchanged tolvaptan was excreted in the urine. Approximately 19% of the administered dose was excreted as unchanged in the faeces.
Drug-Drug Interactions
Tolvaptan is a substrate of CYP3A4. Plasma concentrations may be meaningfully elevated; for example (e.g.), up to 5-fold, when co-administered with a potent CYP3A4 inhibitor. Marked elevations of tolvaptan concentrations produced a sustained, but not greater, magnitude of response because active concentrations of tolvaptan were present for longer periods of time. Conversely, co-administration with potent CYP3A4 inducers may decrease tolvaptan concentrations to the extent that a clinical response would be lost. Tolvaptan did not appear to have any clinically significant inhibitory activity on CYP3A4 but did appear to be a competitive substrate and inhibitor of P-glycoprotein with moderate activity, resulting in digoxin concentrations that were increased approximately 20%.
Special Populations
In subjects with hyponatraemia secondary to liver disease, tolvaptan concentrations appeared to accumulate 1.7- to 1.8-fold after multiple dosing. Clearance following a single dose was approximately half that of healthy subjects, and following multiple dosing it was approximately a third that of healthy subjects.
Bioequivalence
A dose proportionality study comparing four 15 mg tablets, two 30 mg tablets and one 60 mg tablet was submitted for review. The comparative in vitro dissolution profiles demonstrated similar dissolution profiles of the Phase II/III clinical formulations and the commercial formulations for the 30 mg and 60 mg tablets. Also, the comparative in vitro dissolution profiles demonstrated similar dissolution profiles between the 15 mg and 30 mg commercial formulations. The in vitro results support the interchangeability of the three product strengths.
3.3.3 Clinical Efficacy
In two pivotal Phase III 30-day, double-blind, placebo-controlled, multicentre studies, a total of 416 patients with euvolemic or hypervolemic hyponatraemia (serum sodium <135 mEq/L) due to a variety of underlying causes [heart failure, liver cirrhosis, syndrome of inappropriate anti-diuretic hormone (SIADH), and others] were treated for 30 days with Samsca (tolvaptan) or placebo, then followed for an additional 7 days after withdrawal. Patients were stratified by hyponatraemia status (serum sodium 130-134 mEq/L for mild or <130 mEq/L for severe), and received either Samsca [number of patients (N) = 213] at an initial oral dose of 15 mg/day, or placebo (N = 203). The mean serum sodium concentration at trial entry was 129 mEq/L overall (133 mEq/L for mild and 126 mEq/L for severe patients). Fluid restriction was generally not used during the first 24 hours of therapy to avoid overly rapid correction rates (>12 mEq/L/day). Thereafter, all patients could resume or initiate fluid restriction (defined as daily fluid intake of ≤1.0 L/day) as clinically indicated. The dose of Samsca could be increased to 30 mg/day, then 60 mg/day until either the maximum dose or normonatraemia (serum sodium >135 mEq/L) was reached. The primary endpoint for both studies was the change in average 24-hour area under the curve (AUC) in serum sodium from baseline to that obtained on Day 4, and from baseline to that obtained on Day 30.
In both studies, Samsca was superior to placebo for the primary endpoint of average change of 24-hour AUC in serum sodium concentration from the start of treatment, that is (i.e.), at baseline to Day 4, or at baseline to Day 30, irrespective of hyponatraemia severity at baseline or underlying aetiology of hyponatraemia (congestive heart failure, cirrhosis, or SIADH/other). Significant improvements in serum sodium concentrations were observed in the Samsca group compared to placebo within 8 hours after initiating treatment, and persisted throughout the treatment duration. Secondary endpoints also demonstrated highly significant improvements for Samsca over placebo, including percentage of patients with normalized serum sodium at different, relevant time points following treatment initiation. This was true for the overall hyponatraemia population, regardless of severity of hyponatraemia, and remained so even when analyzed by the majority of other subgroups (e.g., by aetiology, age, and gender).
A Phase III open-label extension study assessed the long-term efficacy and safety of Samsca. Patients with non-hypovolemic hyponatraemia arising from a variety of aetiologies were enrolled. Samsca was given as a titrated oral dose of 15, 30, or 60 mg once daily (QD) for up to 214 weeks, followed by a 1-week, post-treatment follow-up assessment. Samsca was generally well-tolerated and significant increases from baseline in serum sodium concentrations were observed at all on-treatment visits up to Week 214 in both the prior Samsca-treated group and the prior placebo-treated group. The results of this study demonstrated that Samsca maintained serum sodium concentrations at normal concentrations in a majority of patients with hyponatraemia of varying aetiologies in a safe and effective manner.
In summary, the placebo-controlled, Phase III hyponatraemia studies that were conducted to evaluate use of Samsca to increase serum sodium concentrations demonstrated reliably both acute (over four days) and sustained efficacy (over 30 days), regardless of hyponatraemia severity or aetiology. Upon discontinuation of tolvaptan treatment, these studies showed a rather consistent and reproducible decline in serum sodium concentrations back to those of the placebo group. These observations were limited to non-hypovolemic patients with hyponatraemia only.
3.3.4 Clinical Safety
In the two pivotal Phase III studies (described in section 3.3.3 Clinical Efficacy), Samsca at a dose of 15 mg QD, titratable to 30 or 60 mg QD, was generally safe and well-tolerated in hyponatremic patients. The most commonly reported treatment-emergent adverse events were dry mouth and thirst, consistent with the mechanism of action of the drug. In both studies combined, 27 deaths were associated with treatment-emergent adverse events. Thirteen of these occurred in the placebo group, compared to 14 in the Samsca group. All but one of the deaths in the Samsca group was considered by the investigator to be unrelated to study medication.
Samsca appeared to produce no clinically significant trends in the overall population of hyponatraemia subjects with respect to vital or electrocardiographic evaluation. Subtle, but significant and expected changes in certain laboratory tests (serum potassium, chloride, uric acid, serum and urine osmolality, and urine specific gravity), beyond that seen with serum sodium, that were related to the mechanism of action of Samsca were observed in the Samsca group.
Hyponatremic patients with hypovolemia have not been studied, nor should Samsca be used in this clinical setting, due to the expected increase in risk of acute renal failure, with or without circulatory collapse, i.e., shock.
A rapid correction of hyponatraemia can cause osmotic demyelination syndrome, which may result in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. Although a few cases of rapid correction of serum sodium have been noted with Samsca use, based on generally recognised norms, no cases of serious neurological sequelae were reported.
Samsca appears to be safe and effective in the treatment of hyponatraemia as labelled. Although symptomatic benefit and improvement in clinical outcomes have not yet been proven with such use, a variety of datasets of patients, with or without hyponatraemia, exposed to Samsca for either the short-term or the long-term, did not show evidence of increased mortality.
Over 4,300 patients to date have received at least a single dose of Samsca in 55 completed or ongoing clinical studies. Over 2,500 patients have been exposed to Samsca for at least 30 days, over 930 for at least 365 days, and over 100 for more than 720 days. The most important adverse events associated with Samsca use are related to its mechanism of action, i.e., raised serum sodium, increased urine volume, and increased thirst.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Samsca acts on the distal collecting ducts of the kidney, where inhibition of vasopressin action leads to electrolyte-free water excretion, thereby increasing serum sodium and osmolality. Regardless of hyponatraemia severity or aetiology, Samsca has been shown to produce controlled and sustained increases in serum sodium that were observed within 8 hours and lasted for several months. The risks of severely low serum sodium have been well-established in the literature.
There are limited alternative therapies for patients with chronic hyponatraemia. Acute or symptomatic hyponatraemia requires treatment with hypertonic saline. Fluid restriction has been shown to be poorly tolerated and of limited effectiveness in outpatient management of hyponatraemia. The management of hyponatraemia with Samsca is facilitated by a titration scheme (15 to 60 mg QD), which may be adapted to individual serum sodium response and symptoms.
Specifically, the benefits of the use of Samsca in the treatment of hyponatraemia include evidence of improvement in:
- predictable rise in serum sodium through titrated (managed) dosing;
- effective maintenance of serum sodium during continued treatment; and
- signs of fluid overload (e.g., body weight).
These therapeutic effects were achieved in the context of a favourable safety profile with no reports of central or peripheral myelinolysis and rare cases of (<2%) hypernatremia. The safety profile includes adverse events that were generally anticipated based on the mechanism of action, and thus apparently should be managed effectively.
Although chronic data were limited for some populations (e.g., SIADH, cirrhosis), there were no substantial differences in the safety profile of Samsca for the subgroups evaluated (e.g., hyponatraemia severity and aetiology, volume status, age, and gender). As seen in the heart failure subpopulation, Samsca did not negatively affect blood pressure, heart rate, or electrocardiogram parameters in either euvolemic or hypervolemic states.
Samsca fulfils an unmet medical need for the treatment of hyponatraemia. These patients are already burdened with a significantly elevated mortality, and tolvaptan does not appear to impact mortality (either positively or negatively).
Given the effective and reproducible action of Samsca in raising serum sodium, with its acceptable safety profile as demonstrated, the benefits of Samsca outweigh its risks in patients with non-hypovolemic hyponatraemia if used as directed by a physician experienced in the management of clinically important hyponatraemia.
Other important conditions and limitations related to patients eligible for this drug product are captured in the Samsca Product Monograph, including the need to initiate, or re-initiate, Samsca only in a hospital where serum sodium can be monitored closely to avoid too rapid correction of hyponatraemia. Too rapid correction of hyponatraemia, e.g., >12 mEq/L over 24 hours, can cause osmotic demyelination which may result in severe neurologic complications, leading to coma or death.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Samsca is favourable in the treatment of clinically important, non-hypovolemic hyponatraemia, e.g., serum sodium <130 mEq/L or symptomatic hyponatraemia. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: SamscaTM
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2010-08-18 |
| Screening | |
| Screening Acceptance Letter issued: | 2010-09-29 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2011-06-02 |
| Quality Evaluation complete: | 2011-07-15 |
| Clinical Evaluation complete: | 2011-07-22 |
| Labelling Review complete: | 2011-07-19 |
| Notice of Compliance issued by Director General: | 2011-07-25 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SAMSCA | 02370476 | OTSUKA PHARMACEUTICAL CO LTD | TOLVAPTAN 30 MG |
| SAMSCA | 02370468 | OTSUKA PHARMACEUTICAL CO LTD | TOLVAPTAN 15 MG |
| SAMSCA | 02370484 | OTSUKA PHARMACEUTICAL CO LTD | TOLVAPTAN 60 MG |