Lisinopril + Hct 10/12.5mg Tablets
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1. NAME OF THE MEDICINAL PRODUCT Lisinopril + HCT 10/12.5mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains: Lisinopril dihydrate 10.9 mg equivalent to lisinopril 10 mg and hydrochlorothiazide 12.5 mg.
For excipients see section 6.1
3. PHARMACEUTICAL FORM
Tablet
pink, round, biconvex, one-sided score notch
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of essential hypertension. Lisinopril + HCT 10/12.5mg Tablets fixed dose combination (10 mg lisinopril and 12.5 mg hydrochlorothiazide) is indicated in patients whose blood pressure is not adequately controlled on lisinopril alone (or hydrochlorothiazide alone).
4.2 Posology and method of administration
The selection of a suitable antihypertensive dose of lisinopril and hydrochlorothiazide will depend upon the clinical evaluation of the patient.
Lisinopril + HCT 10/12.5mg Tablets should be taken once daily.
The administration of the fixed combination lisinopril and hydrochlorothiazide is usually recommended after dosage titration with the individual components.
When clinically appropriate a direct change from monotherapy to fixed combination may be considered.
10 mg/12.5 mg tablets may be administered in patients whose blood pressure is not adequately controlled by 10 mg lisinopril alone.
20 mg/12.5 mg tablets may be administered in patients whose blood pressure is not adequately controlled by 20 mg lisinopril alone.
A maximum daily dose of 40 mg lisinopril/25 mg hydrochlorothiazide should not be exceeded.
Previous diuretic treatment:
Symptomatic hypotension may occur following the initial dose; this is more likely in patients who are volume and/or salt depleted because of diuretic therapy.
Diuretics should be discontinued for 2-3 days before starting Lisinopril + HCT 10/12.5mg Tablets. If this is not possible, treatment should be started with lisinopril alone, in a 2.5 mg dose. These patients should be carefully monitored for objective and subjective symptoms of hypotension after the first dose of Lisinopril + HCT 10/12.5mg Tablets (see 4.4 Special warnings and precautions for use, hypotension and electrolyte/fluid imbalance).
Renal impairments:
The combination lisinopril/hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min). In patients with creatinine clearance between 30 and 80 ml/min it may be used only after titration of the individual components.
The recommended initial dose of lisinopril as mono-therapy for these patients is 5-10 mg (see 4.4 Special warnings and precautions for use).
Elderly patients:
Clinical studies on the combination of lisinopril and hydrochlorothiazide have not shown that age is associated with any changes in efficacy or tolerability. See the above section on “Renal impairment^
Children:
The safety and efficacy of Lisinopril + HCT 10/12.5mg Tablets in children has not been established.
4.3 Contraindications
History of hypersensitivity to lisinopril or to any of the excipients or any other ACE inhibitor History of hypersensitivity to hydrochlorothiazide or other sulphonamide-derived medicinal product
Angioneurotic oedema relating to previous treatment with an ACE inhibitor Hereditary/idiopathic angioneurotic oedema Severe renal- and liver insufficiency Stenosis of the renal arteries
Second and third trimester of pregnancy (see 4.6 Pregnancy)
Lactation (see 4.6 Lactation)
4.4 Special warnings and precautions for use
Hypotension and electrolyte/fluid imbalance: Symptomatic hypotension is rare in uncomplicated hypertension, but is more likely in the presence of fluid or electrolyte imbalance, e.g. salt depletion, hyponatraemia, hypochloraemic alkalosis, hypomagnesaemia or hypokalaemia which may occur from prior diuretic therapy, salt restriction, dialysis, vomiting, diarrhoea.
Regular monitoring of serum electrolytes should be performed at appropriate intervals in such patients.
Particular consideration should be given when therapy is administered to patients with ischaemic heart disease or cerebrovascular disease because an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular event.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of physiological saline. A transient hypotensive response is usually not a contraindication to continued therapy. Following restoration of plasma volume and pressure, reinstitution of therapy may be possible; or either of the components may be used alone, as appropriate.
As with other vasodilators, Lisinopril + HCT 10/12.5mg Tablets should be given with caution to patients with aortic stenosis, mitral stenosis or hypertrophic cardiomyopathy.
Renal function impairment: Thiazides are ineffective in patients with creatinine clearance values < 30 ml/min (i.e. moderate or severe renal insufficiency).
Lisinopril + HCT 10/12.5mg Tablets should not be administered to patients with creatinine clearance 30-80 ml/minutes until titration of the individual components has shown the need for the doses present in the combination tablet.
Some patients with no apparent pre-existing renovascular disease have developed usually minor and transient increases in blood urea and serum creatinine when lisinopril has been given concomitantly with a diuretic. If this occurs during therapy with Lisinopril + HCT 10/12.5mg Tablets, the treatment should be discontinued. Reinstitution of therapy at reduced dosage may be possible, or either of the components may be used alone, as appropriate.
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea and serum creatinine usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal failure. In these patients treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, renal function should be monitored during the first few weeks of treatment.
Hepatic disease: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of the syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Surgery/Anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that cause hypotension, lisinopril may block angiotensin formation secondary to compensatory renin release. This can be corrected by plasma volume expansion.
Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance and may increase cholesterol and triglyceride levels. The glycaemic levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor. Dosage adjustment of antidiabetic agents, including insulin, may be required.
Thiazide therapy may decrease urinary calcium excretion and may cause an intermittent and slight elevation of serum calcium. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Thiazide therapy may precipitate hyperuricaemia and/or gout in some patients. However, lisinopril may increase urinary uric acid and thus may attenuate the hyperuricaemic effect of hydrochlorothiazide.
Electrolyte imbalance: As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).
Angioedema: angioedema of the extremities, face, lips, mucous membranes, tongue, glottis or larynx may occur in patients treated with ACE inhibitors particularly during the first weeks of treatment. However, in rare cases, severe angioedema may develop after long-term treatment with an ACE inhibitor. Treatment should be discontinued promptly. Angioedema involving the tongue, glottis or larynx may be fatal. Emergency therapy should be instituted. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Hypersensitivity, anaphylactic reactions: In patients receiving thiazides, hypersensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.
Anaphylactic reactions during desensitization: Sustained life-threatening anaphylactic reactions have been rarely reported for patients undergoing desensitising treatment with hymenoptera venom while receiving an ACE-inhibitor. In the same patients these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with an ACE inhibitors undergoing such desensitization.
Anaphylactic reactions during high-flux dialysis/lipoprotein apheresis membrane exposure: Anaphylactic reactions have been reported in patients haemodialysed with high-flux dialysis membranes or undergoing low-density lipoprotein apheresis with dextran sulphate absorption. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication.
Serum potassium: The potassium losing effect of thiazide diuretics is usually attenuated by the potassium conserving effect of lisinopril. During treatment with ACE inhibitor the following group of patients are at an increased risk of hyperkalaemia: patients with impaired renal function, diabetes mellitus, patients who are using potassium sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Frequent monitoring of serum potassium is recommended (see 4.5 Interaction with other medicinal products and other forms of interaction). The combination of an ACE inhibitor with a thiazide diuretic does not rule out the occurrence of hypokalaemia. Regular monitoring of kalaemia should be performed.
Cough: As ACE-inhibitors can cause a persistent cough they should be given cautiously to patients who are coughing.
Neutropenia/Agranulocytosis: The risk of neutropenia appears to be dose- and type-related and is dependent on the patient’s clinical status. It is rarely seen in uncomplicated patients but may occur in patients with some degree of renal impairment especially when it is associated with collagen vascular disease e.g. systemic lupus erythematosus (SLE), scleroderma and therapy with immunosuppressive agents. It is reversible after discontinuation of the ACE inhibitor.
Proteinurea: Proteinurea may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.
Ethnic differences: ACE inhibitors cause a higher rate of angioedema in black than in nonblack patients. When lisinopril, a component of the fixed dose combination, is given, Afro-Caribbean patients may show a reduced therapeutic response.
Interaction with other medicinal products and other forms of interaction
Potassium-sparing diuretics, potassium supplements and salt substitutes: The potassium losing effect of thiazide diuretics is usually attenuated by the potassium conserving effect of lisinopril. The use of potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes may lead to a significant increase in serum potassium. If concomitant use of Lisinopril + HCT 10/12.5mg Tablets and any of these agents is required, then they should be used cautiously and with frequent monitoring of serum potassium.
Lithium: Lithium generally should not be given with diuretics or with an ACE inhibitor. Diuretic agents and ACE inhibitors reduce the renal clearance of lithium and add a high risk of lithium toxicity. Careful monitoring of serum lithium should be performed if the combination proves necessary.
Anti-diabetics: Concomitant administration of ACE inhibitors and anti-diabetic medicines may cause an increased blood glucose lowering effect with an increased risk of hypoglycaemia. This phenomenon may be more likely to occur during the first weeks of treatment, and in patients with renal impairment.
NSAID (non-steroidal anti-inflammatory drugs): Concomitant administration with NSAID may reduce the antihypertensive and diuretic effect of ACE inhibitors and thiazide diuretics. In patients with renal dysfunction who are treated with NSAIDs, coadministration of lisinopril may result in a further deterioration of renal function.
Allopurinol: Concomitant administration of ACE inhibitors and allopurinol increases the risk of renal failure.
Ciclosporin: Concomitant administration of ACE inhibitors and ciclosporin increases the risk of renal failure and hyperkalaemia.
Lovastatin: Concomitant administration of ACE inhibitors and lovastatin increases the risk of hyperkalaemia.
Probenecid: Concomitant administration may increase thiazide serum concentrations.
Trimethoprim: Concomitant administration of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkalaemia.
Digitalis glycosides: Hypokalaemia induced by thiazide treatment can increase the effect of digitalis glycosides.
Sotalol: Thiazide-induced hypokalaemia can increase the risk of sotalol-induced arrhythmias.
Colestyramin, colestipol: Concomitant administration of colestyramin or colestipol, reduces the elimination of thiazide by 85% and 43% respectively. If concomitant administration of these agents and the combination product is indicated, administration should be separated by several hours.
Tricyclic antidepressants/antipsychotics: May enhance the hypotensive effects of ACE-inhibitors.
Torsades de pointes-inducing drugs: Should not be combined with HCTZ.
Corticosteroids, amphotericin B (parenteral), carbenoxolone, corticotropin (ACTH) or stimulant laxatives: HCTZ may intensify electrolyte imbalance, in particular hypokalaemia.
Other antihypertensive agents: Additive effects may occur.
Sympathomimetics: May reduce the antihypertensive effects of ACE inhibitors, patients should be carefully monitored to confirm that the desired effects are being obtained.
Allopurinol, procainamide, cytostatic or immunosuppressive agents: Concomitant administration with ACE inhibitors may lead to an increased risk of leucopenia.
Calcium salts: Increased serum calcium levels due to decreased excretion may occur when administered concurrently with thiazide diuretics.
Other agents: Thiazides may increase the response to tubocurarine.
Haemodialysis:
Lisinopril + HCT 10/12.5mg Tablets are not indicated in patients requiring dialysis as a high incidence of anaphylactic reactions have been reported in patients dialysed with high flux membranes and treated concomitantly with an ACE inhibitor. This combination should be avoided.
4.6 Pregnancy and lactation
Pregnancy
Lisinopril + HCT 10/12.5mg Tablets are not recommended during the first trimester of pregnancy. When a pregnancy is planned or confirmed, an alternative treatment should be initiated as soon as possible. Controlled studies with ACE inhibitors have not been done in humans, but limited number of cases of first trimester exposure has not shown malformations.
Lisinopril + HCT 10/12.5mg Tablets are contraindicated during the second and third trimesters of pregnancy. Prolonged lisinopril exposure during the second and third trimesters is known to induce toxicity in foetuses (decreased renal function, oligohydramnios, skull ossification retardation) and in neonates (neonatal renal failure, hypotension, hyperkalaemia).
Hydrochlorothiazide in case of prolonged exposure during the third trimester of pregnancy may cause a foeto-placentar ischaemia and risk of growth retardation. Moreover, rare case of hypoglycaemia and thrombocytopenia in neonates has been reported in case of exposure near the term.
Hydrochlorothiazide can reduce plasma volume as well as the uteroplacental blood flow.
Should exposure to Lisinopril + HCT 10/12.5mg Tablets have occurred from the second trimester of pregnancy ultrasound check of renal function and skull is recommended.
Lactation
Lisinopril + HCT 10/12.5mg Tablets are contraindicated in the lactation period. Both lisinopril and hydrochlorothiazide are excreted in human milk. Thiazides during breastfeeding by lactating mothers have been associated with a decrease or even suppression of the milk lactation. Hypersensitivity to sulphonamide-derived drugs, hypokalaemia and jaundice in foetus or neonate might occur. Because of the potential for serious adverse reactions in nursing infants from both drugs, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of this therapy to the mother.
4.7 Effects on ability to drive and use machines
As with other antihypertensives, the ability to drive and use machines may be reduced, e.g. at the start of the treatment or when the dose is modified, and also when used in combination with alcohol, but these effects depend on the individual’s susceptibility. The risk of hypotension, dizziness and fainting should be considered.
4.8 Undesirable effects
In clinical studies, side effects are the same as those reported previously with lisinopril or hydrochlorothiazide administered separately.
Common (>1/100, < 1/10)
General: Dizziness, which generally responded to dosage reduction and seldom required discontinuation of therapy. Headache, fatigue.
Respiratory: Dry and persistent cough that disappears after discontinuation of therapy. Cardiovascular: Hypotension including orthostatic hypotension.
Uncommon (> 1/1000, < 1/100)
Gastro-intestinal: Diarrhoea, nausea, vomiting, indigestion, pancreatitis, dry mouth.
Skin: Rash Metabolic: Gout
Cardiovascular: Palpitation, chest pain, muscle cramps and muscle weakness.
Nervous system: Paraesthesia, asthenia Urogenital: Impotence
Rare (> 1/10,000, <1/1,000)
Hypersensitivity reactions: Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx (see 4.4, Special warnings and precautions for use).
Others: A symptom complex which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, leucocytosis, rash, photosensitivity or other dermatological manifestations.
Laboratory test values: Alterations of laboratory values have rarely been of clinical importance. Occasional hyperglycaemia, hyperuricaemia, hyperkalaemia or hypokalaemia have been noted. Increase in blood cholesterol and triglyceride concentration can be observed with thiazide treatment. Usually minor increases in blood urea and serum creatinine have been seen in patients without evidence of pre-existing renal impairment. If such increases persist, they are usually reversible upon discontinuation of the treatment. Bone marrow depression, manifest as anaemia and/or thrombocytopenia and/or leucopenia has been reported. Agranulocytosis has been rarely reported, but a causal relationship to the combination medicinal product has not been established. Small decreases in haemoglobin and haematocrit have been reported frequently in hypertensive patients but were rarely of clinical importance unless other causes of anaemia co-existed. Rarely, elevations of liver enzymes and/or serum bilirubin have occurred, but a causal relationship to Lisinopril + HCT 10/12.5mg Tablets has not been established. Haemolytic anaemia has rarely been reported.
Undesirable effects reported with the individual components:
Hydrochlorothiazide
Anorexia, gastric irritation, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialoadenitis, vertigo, xanthopsia, leucopenia, agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary oedema, anaphylactic reactions, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance including hyponatraemia, muscle spasm, restlessness, transient blurred vision, renal failure, renal dysfunction, cardiac arrhythmias, cutaneous lupus-erythematosus-like reactions, toxic epidermal necrolysis and interstitial nephritis.
Lisinopril:
Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients, tachycardia, angina pectoris, syncope, flush, anaphylactic reactions, Raynaud syndrome, proteinuria, photosensitivity, abdominal pain and indigestion, mood alterations, mental confusion, vertigo have occurred; as with other angiotensin converting enzyme inhibitors, taste disturbance and sleep disturbance have been reported; bronchospasm, rhinitis, sinusitis, alopecia, urticaria, diaphoresis, pruritus, psoriasis and severe skin disorders, (including pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme), have been reported; hyponatraemia, uraemia, oliguria/anuria, renal dysfunction, acute renal failure, hepatitis (hepatocellular or cholestatic), jaundice and haemolytic anaemia.
4.9 Overdose
No specific information is available regarding overdose with Lisinopril + HCT 10/12.5mg Tablets. Treatment is symptomatic with correction of dehydration, electrolyte disturbance and hypotension. Emptying of stomach and gastric lavage after recently administration. Patients should be kept under close supervision.
Lisinopril:
Symptoms of overdose: Severe hypotension, electrolyte disturbances and renal failure. After overdose, the patients should be kept under close supervision.
Treatment of overdose: The treatment is determined by the symptoms severity and nature. Measures to prevent absorption and methods to speed elimination should be employed. If severe hypotension occurs, the patients should be placed in the shock position and an intravenous infusion of physiological saline should be given rapidly. Treatment with angiotensin II (if available) may be considered. ACE inhibitors may be removed from the general circulation by haemodialysis. The use of high-flux polyacrylonitrile dialysis membranes should be avoided. Serum electrolytes and creatinine should be monitored frequently.
Hydrochlorothiazide:
Symptoms of overdose: Symptoms are caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has also been administered hypokalaemia may accentuate cardiac arrhythmias.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitor (ACE: angiotensin converting enzyme) and thiazide diuretic, ATC-Code: C09B A03.
Mechanism of action: Both components, the ACE inhibitor and diuretic, have complementary modes of action and exert an additive antihypertensive effect. ACE catalyses the conversion of angiotensin I to angiotensin II, which has strong vasoconstrictor effect and stimulates aldosterone secretion. The antihypertensive effect of Lisinopril is mainly due to the suppression of the renin-angiotensin-aldosterone system with reduction of plasma concentration of angiotension II and aldosterone. Lisinopril exerts an antihypertensive effect even in patients with low-renin hypertension. ACE is identical to kinase II, an enzyme that degrades bradykinin. It remains unclear whether increased levels of bradykinin (a potent vasodilator) plays a role in the therapeutic effect of lisinopril.
Hydrochlorothiazide is a thiazide diuretic and an antihypertensive that increases the plasma-renin activity. Hydrochlorothiazide suppresses the renal reabsorption of electrolytes in the renal distal tubule and increases the excretion of sodium, chloride, potassium, magnesium, bicarbonates and water. The excretion of calcium may be reduced. Concomitant administration of lisinopril and hydrochlorothiazide gives a greater reduction in blood pressure than monotherapy. Lisinopril normally attenuates the potassium loss associated with hydrochlorothiazide.
5.2 Pharmacokinetic properties
The combination tablet is bioequivalent with separate administration of each of the active substances.
Absorption: Lisinopril: Approximately 25% with interpatient variability (6-60%) at all doses tested (5-80 mg). The absorption of lisinopril is not influenced by food. Maximal serum concentration is reached after 6-8 hours. Effect on blood pressure is observed after 1-2 hours. The effect is maximal after 6 hours and lasts for at least 24 hours.
Hydrochlorothiazide: Diuretic effect is seen within 2 hours. Maximal effect is reached after 4 hours. Clinically adequate diuretic effect lasts for 6-12 hours.
Distribution'. Protein binding: Lisinopril is not bound to plasma proteins other than ACE. Reduced volume of distribution in elderly can give a higher plasma concentration than in younger patients.
Half-life: Lisinopril: On multiple dosing 12 hours. Hydrochlorothiazide 5.5 - 15 hours.
Metabolism/elimination: Both of the active substances are eliminated unchanged via the kidneys. Approximately 60% of hydrochlorothiazide that is administrated orally is eliminated within 24 hours.
5.3 Preclinical safety data
In animal studies ACE inhibitors gives harmful injury on the foetal development in the last phase of gestation (see 4.6 Pregnancy and lactation).
Available preclinical data indicate no other potential hazards than effects caused by the pharmacological mechanisms of action of the two compounds.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
calcium hydrogenphosphate dihydrate
croscarmellose sodium
mannitol
maize starch
magnesium stearate
ferric oxide red (E 172)
6.2 Incompatibilities
Not applicable
6.3 Shelf-life
3 years
6.4 Special precautions for storage
None
6.5 Nature and contents of container
The tablets are packed in polyvinylchloride /aluminium blisters and inserted into a carton. Package sizes: 14, 28, 30, 50, 56, 98, 100, 400.
Not all pack sizes may be marketed.
6.6 Instructions for use and handling
None
ADMINISTRATIVE DATA
7. MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd 3 Howard Road Eaton Socon St Neots
Cambs PE19 3ET United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 11311/0235
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
07/03/2009
10 DATE OF REVISION OF THE TEXT
07/03/2009