Public Assessment Report. Scientific discussion. Natriumklorid Abcur (sodium chloride) SE/H/1443/01/MR

Transcription

1 Public Assessment Report Scientific discussion Natriumklorid Abcur (sodium chloride) SE/H/1443/01/MR This module reflects the scientific discussion for the approval of Natriumklorid Abcur. The procedure was finalised at For information on changes after this date please refer to the module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version:

2 I. INTRODUCTION Abcur AB has applied for a marketing authorisation for Natriumklorid Abcur, 500 mg, filmcoated tablet in Sweden. The active substance is sodium chloride, also known as common salt. Maintenance of sodium homeostasis requires a balance between intake and excretion of sodium. The approved indications are: Symptomatic chronic euvolemic hyponatremia when insufficient efficacy of fluid restriction and/or diuretic therapy (e.g. Syndrome of Inappropriate Antidiuretic hormone secretion, SIADH). Hypovolemic hyponatraemia (e.g. ileostomy/jujenostomy). II. II.1 QUALITY ASPECTS Introduction Natriumklorid Abcur is presented in the form of film-coated tablets containing 500 mg of the active substance sodium chloride. The excipients are microcrystalline cellulose, talc, hypromellose and macrogol. The tablets are packaged in white containers made of high density polyethylene. II.2 Drug Substance Sodium chloride is described in the European Pharmacopeia (Ph. Eur.). It is an ionic compound which appears as a crystalline powder, colourless crystals or white pearls. The molecular formula is NaCl and the molar mass is g/mol. Sodium chloride is freely soluble in water. The active substance specification includes relevant tests and the limits have been justified. The analytical methods applied are suitably described and validated. Stability studies under ICH conditions have been conducted and the data provided are sufficient to confirm the retest period. II.3 Medicinal Product The tablets are formulated using well-known excipients described in the current Ph. Eur. None of the raw materials used in the product are of human or animal origin. The pharmaceutical development work has been sufficiently described. The function of each excipient has been explained. The manufacturing process has been sufficiently described and critical steps identified. Results from the process validation studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product specification. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. The analytical methods applied are suitably described and validated. 2/8

3 Stability studies under ICH conditions have been performed and data presented support the shelf-life claimed in the SPC, with no special storage precautions. III. III.1 NON-CLINICAL ASPECTS Introduction The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is considered to be adequate even though available non-clinical data seem to be scarce. The deficiencies in non-clinical data are considered to be superseded by the long clinical experience with the use of sodium chloride. III.2 Ecotoxicity/environmental risk assessment An environmental risk assessment is not required for electrolytes according to Guidelines because they are unlikely to result in significant risk to the environment. Natriumklorid Abcur contains no components that result in additional hazard to the environment. The absence of environmental risk assessment is therefore acceptable. III.3 Discussion on the non-clinical aspects No new animal or in vitro studies have been performed with Natriumklorid Abcur. This is acceptable since the use of sodium chloride is well established in the clinic. IV. IV.1 CLINICAL ASPECTS Introduction Sodium chloride is an electrolyte supplement that regulates blood volume, blood pressure, osmotic equilibrium and ph. It is involved in the control of extracellular fluid volume, regulation of osmotic, acid-base balance and the membrane potential of the cells. IV.2 Pharmacokinetics There are no pharmacokinetic data in this Application for Natriumklorid Abcur tablets which is acceptable considering that the active compound is sodium chloride. Sodium chloride is absorbed in the whole GI-tract following oral administration. Renal excretion of the electrolytes is the main route of elimination but also to less extent via faeces and sweet. Serum electrolyte levels will have to be monitored in cases of renal and metabolic disorders. IV.3 Pharmacodynamics Water constitutes about 55-65% of body weight, varying with age, sex and amount of body fat, and therefore is the largest single constituent of the body. Total body water is distributed between the intracellular (ICF) and extracellular fluid (ECF) compartments. The solute composition of ICF and ECF differ considerably because membrane-bound Na/K pumps maintain sodium in a primarily extracellular location and potassium in a primarily intracellular 3/8

4 location. The osmotic pressure, which is a function of the concentrations of all the solutes in a fluid compartment, must always be equivalent in the ICF and ECF because most biological membranes are semipermeable (ie, freely permeable to water but not to aqueous solutes). Sodium is the principal osmo-regulator of the ECF and thus has a major impact on water distribution between interstitial fluid and ICF. As in the case of water metabolism, it is possible to define regulated and unregulated components of both sodium intake and excretion. Unlike water intake, however, there is no significant role in humans for regulated sodium intake, with the possible exception of some pathological conditions. Under normal circumstances, serum sodium concentration and osmolality are maintained in a narrow range, between 136 to 145 mmol/l and mosm/kg of water, respectively. This regulation is achieved through the secretion of AVP from the posterior pituitary and through the perception of thirst, both of which occur in response to increases in serum osmolality. An increase in serum osmolality of 1-2% stimulates the release of AVP. AVP facilitates the reabsorption of water by the kidneys into the bloodstream, restoring serum osmolality and therefore serum sodium concentration. A pathological imbalance in the distribution of sodium has an impact on fluid volumes of the ECF and ICF which may result in either (i) cellular over-hydration, whose spectrum of signs and symptoms include drowsiness, confusion, coma and death, or (ii) cellular dehydration whose signs and symptoms also include drowsiness, confusion, coma and death, thus the measurement of plasma sodium, either at the bedside (point-of-care testing) or within a central laboratory is of critical clinical importance. The only solute for which any specific appetite has been clearly demonstrated in man is sodium. This is generally expressed as an appetite for sodium chloride. Because of the importance of sodium for ensuring maintenance of the ECF volume, which in turn directly supports blood volume and pressure, its uniqueness insofar as meriting a specific mechanism for regulated intake seems appropriate. IV.4 Clinical efficacy The two approved indications represent specific types of hyponatraemia that can have different underlying causes and by extension of the causative mechanism, have different level of severity of the hyponatraemia. Although NaCl has been used for decades to treat hyponatraemia, guidelines for managing hyponatraemia are based on retrospective studies and expert opinion since no prospective studies exist, presumably as the molecule is a common electrolyte. A number of publications, reviews and guidelines do however provide evidence based information regarding safety, efficacy and posology guidelines. No exact posology exist as each patient is evaluated individually and their medical treatment regime depends on a multitude of factors, including the causative agent and type of the hyponatraemia to the amount of salt loss that the patient is experiencing as well as the general condition of the patient. A number of formulas exist that assist the physician in a clinical setting to estimate sodium loss and replacement therapy requirements. SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion) In SIADH a number of reports exist in the literature where treatment regimens given are supplied. In one study, patients were given 3g or 6g salt daily in addition to 40 mg furosemide daily. The treatment was reported as successful and no adverse events were reported. Recommended treatment actions of hyponatraemia due to ADH secretion after spinal surgery include fluid restriction, hypertonic saline and oral intake of salt. One review recommends for the treatment of SIADH an average dose of 9 g salt daily which can be combined with furosemide to reduce NaCl reabsorption. Another recommendation for chronic treatment of SIADH includes fluid restriction followed by oral salt tablets and, if necessary loop diuretics or vasopressin receptor agonist can be used in addition to achieve the serum sodium goal. 4/8

5 Hypovolemic hyponatraemia (e.g. ileostomy/jujenostomy). Patients with a short bowel should each be managed as an individual; they are all different in diagnosis, remaining bowel length/function, and psychosocial characteristics. Patients with a jejunostomy have a large volume of stomal output, which is greater after eating or drinking. Each litre of jejunostomy fluid contains about 100 mmol/l of sodium. One guideline states that sodium chloride capsules (500 mg each) are effective when taken in large amounts (14/24 h) but can cause some patients to feel sick and even vomit. If an enteral feed is given, sodium chloride needs to be added to make the total sodium concentration of the feed 100 mmol/l while keeping osmolality near to 300 mosmol/kg. A comparison between alternative treatments for jejunostomy patients comparing sodium chloride capsules, glucose electrolyte solution, and glucose polymer electrolyte solution has been performed in one study. The treatment regime tested with the salt capsules was: 14 x 500 mg salt capsules (8.55 mmol each) 4 taken with breakfast, 5 with lunch, and 5 with supper (total 120 mmol sodium) and a litre of tap water. The salt capsules were tolerated well by four patients but caused vomiting in two patients. The two electrolyte solutions were considered palatable by all the patients. All of the patients participating achieved a positive sodium balance with a sodium supplement of 120 mmol daily. Efficiency of absorption was the same for all regimes. Patients with long-established ileostomies should pay great attention to salt and water needs which may be assessed by measuring the sodium content and volume of a 24 hour collection of urine. Patients should be advised to increase their fluid intake if they have a low urine volume and if they experience a reduction in urinary sodium to increase their salt intake. Furthermore the patients need to be aware, should diarrhea or excessive sweating occur, to increase their fluid and salt intake. If illness occurs and is severe or protracted, the patients need to seek medical advice. Summary Based on the review of the literature concerning the two indications of this application and the recommendation of the various guidelines, it is acknowledged that NaCl supplementation is an acceptable and recommended treatment for hyponatraemia in clinical and outpatients. Each patient is an individual case and a number of factors will influence the treatment regime each patient will receive. NaCl tablets are a safe method of delivery and its efficiency in absorption from the GI track is similar to other formulations and regimes. The Applicant has provided a literature review and sufficient references to substantiate the clinical efficacy of sodium chloride in the application. IV.5 Clinical safety Parenteral administration of large doses may give rise to sodium accumulation, oedema, and hyperchloraemic acidosis. Oral administration of recommended doses causes minimal adverse effects. Sodium chloride intake should be restricted in impaired renal and liver function, cardiac failure and hypertension. Sodium chloride is contraindicated in severe renal impairment (with oliguri/anuri), incompensated cardiac failure, decompensated liver cirrhosis, generalized oedema and toxaemia of pregnancy. An overdose of NaCl has potential serious adverse effects: 5/8

6 Ingestion of 0.5 to 1 g/kg is toxic to most patients. Central nervous system signs and symptoms are common above 150 to 160 mmol/l. Signs and symptoms of hypernatraemia due to overdose include: Cardiovascular - tachycardia, hypertension/hypotension, fluid retention with cerebral and peripheral oedema Respiratory - fluid retention may produce pulmonary oedema leading to respiratory arrest Neurologic headache, restlessness, irritability, dizziness, reduced salivation, seizures and coma. Hyperosmolarity of cerebral fluids may lead to irreversible neurologic damage Gastrointestinal - vomiting, diarrhoea, abdominal cramps, swollen tongue, and thirst Management of overdose should be directed at restoring normal osmolality and fluid volume. V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Beneficial effects According to some original studies, review articles and formal guidelines, oral NaCl is possible to use in proposed indications It is acknowledged that NaCl tablets are used in EU since 10 years. Unfavourable effects Small doses of NaCl are unlikely to cause serious short-term adverse effects. Treatment of some specific types of hyponatreamia with NaCl tablets, too rapid correction of hyponatreamia, or an overdose are likely to have serious consequences. Overdose of NaCl may cause tachycardia, hypertension/hypotension, fluid retention with cerebral and peripheral oedema, pulmonary oedema leading to respiratory arrest, headache, restlessness, irritability, dizziness, reduced salivation, seizures and coma. Hyperosmolarity of cerebral fluids may lead to irreversible neurologic damage. Vomiting, diarrhoea, abdominal cramps, swollen tongue, and thirst may occur. Benefit-risk assessment Hyponatreamia is a common condition with numerous possible underlying causes. NaCl tablets are used based on clinical experience in the proposed indications. The dosage required and dose-response is individual in each patient. Hyponatraemia must be monitored closely to prevent excessive correction. The information in the SmPC is acceptable. User consultation The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was Finnish. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. Recommendation The risk/benefit ratio is considered positive and Natriumklorid Abcur, 500 mg, film-coated tablet is recommended for approval. 6/8

7 VI. APPROVAL Natriumklorid Abcur, 500 mg, film-coated tablet was approved in the national procedure on /8

8 Public Assessment Report Update Scope Procedure number Product Information affected Date of start of the procedure Date of end of procedure Approval/ non approval Initial Mutual Recognition Procedure SE/H/1443/01/MR No Approval No Assessment report attached Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version: