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1. Valni Xl 60mg Prolonged Release Tablets
2. Valni Xl 60mg Prolonged Release Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

VALNI XL 60 mg PROLONGED RELEASE TABLETS

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 60 mg of nifedipine For excipients see 6.1

3 PHARMACEUTICAL FORM

Prolonged release tablet

Each pale red tablet is round and biconvex and embossed with "60" on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The tablets are indicated for:

-    the treatment of all grades of hypertension

-    the prophylaxis of chronic stable angina pectoris, either as monotherapy or in combination with a beta-blocker

4.2 Posology and method of administration

Route of Administration For oral use.

These tablets should be swallowed whole with a glass of water, either with or without food. VALNI XL must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.

VALNI XL should not be taken with grapefruit juice (see Section 4.5).

Dosage Recommendations

It is recommended that each dose should be taken at approximately 24 hours intervals i.e., at the same time each day, preferably in the morning.

Adults: In mild to moderate hypertension the recommended initial dose is one 20 mg tablet once daily. In severe hypertension and the prophylaxis of angina pectoris the recommended initial dose is one 30 mg tablet once daily. The dose may be adjusted to a maximum of 90 mg once daily.

Prophylactic anti-anginal efficacy is maintained when patients are switched from other calcium antagonists e.g. verapamil or diltiazem. When patients are switched, the recommended initial dose is 30 mg nifedipine, once daily. Subsequent titration to a higher dosage should be according to clinical response.

Co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers may result in the recommendation to adapt the nifedipine dose or not to use nifedipine at all (see Section 4.5).

Elderly: Based on pharmacokinetic data for nifedipine. No dose adaption in elderly people above 65 years is necessary

Patients with Renal Impairment: Dosage adjustments should not be required for patients with impaired renal function.

Children and adolescents: The safety and efficacy of nifedipine in children below 18 years of age has not been established. Currently available data for the use of nifedipine in hypertension are described in section 5.1

Treatment with nifedipine may be continued long term.

4.3 Contraindications

VALNI XL 60 mg PROLONGED RELEASE TABLETS are contraindicated:

-    in patients with a known hypersensitivity to nifedipine or other constituents of the tablets

-    in patients with a known hypersensitivity to other dihydropyridines calcium antagonists, because of the theoretical risk of cross-reactivity

-    in patients with clinically significant aortic stenosis, in cardiogenic shock or unstable angina or for the treatment of acute attacks of angina

-    in patients with inflammatory bowel disease, Crohn’s disease or with a history of gastrointestinal obstruction, oesophageal obstruction or with decreased diameter of the gastrointestinal lumen

-    in patients with hepatic impairment

-    for secondary prevention of myocardial infarction or during or within one month of a myocardial infarction

in patients with a Kock pouch (ileostomy after proctocolectomy)

VALNI XL 60 mg PROLONGED RELEASE TABLETS should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see section 4.5).

The safety of nifedipine prolonged release tablets has not been established in patients with malignant hypertension.

4.4 Special warnings and precautions for use

VALNI XL 60 MG PROLONGED RELEASE TABLETS must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.

Nifedipine should be used with caution in patients with hypotension, as there is a risk of blood pressure decreasing further and care must be exercised in patients with very low blood pressure (severe hypotension with systolic blood pressure less than 90 mm Hg).

Caution should be exercised in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

Cardiac ischaemic pain has been reported to occur in a small proportion of patients following the introduction of nifedipine therapy. In such cases, treatment with nifedipine should be discontinued.

Diabetic patients taking VALNI XL 60MG PROLONGED RELEASE TABLETS may require adjustment of their control.

In patients with malignant hypertension and hypovolaemia and who are on dialysis, a significant decrease in blood pressure can occur.

Nifedipine may be used in combined therapy with other antihypertensive agents, including beta-blocker drugs, but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Withdrawal of any previous antihypertensive agents should be gradual, as nifedipine will not prevent any possible rebound effects.

Valni XL should not be used during pregnancy unless the clinical condition of the woman required treatment with nifedipine

Valni XL should be reserved for women with severe hypertension who are unresponsive to standard therapy (see section 4.6).

Caution must be exercised when nifedipine with intravenous magnesium sulfate is given to pregnant women due to the possibility of an excessive fall in blood pressure which has the potential to harm both mother and foetus.

Valni XL is not recommended for use during breastfeeding because nifedipine has been reported to be excreted in human mild and the effects of nifedipine exposure to the infant are not known (see section 4.6)

In patients with impaired liver function careful monitoring and in severe cases a dose reduction may be necessary.

Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may alter the first pass or clearance of nifedipine. Drugs which are known inhibitors of the cytochrome P450 3A4 system and which may therefore lead to increased plasma concentrations of nifedipine include, for example:

-    macrolide antibiotics (e.g. erythromycin)

-    anti-HIV protease inhibitors (e.g. ritonavir)

-    azole antimycotics (e.g. ketoconazole)

-    the antidepressants, nefazodone and fluoxetine

-    quinupristin/dalfopristin

-    valproic acid

-    cimetidine

Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.

A false positive effect may be obtained when carrying out a barium contrast X-ray.

VALNI XL 60 mg PROLONGED RELEASE TABLETS contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption, should be advised not to take these tablets.

4.5 Interaction with other medicinal products and other forms of interaction

Known Interactions

Nifedipine should not be taken with grapefruit juice because bioavailability is increased.

Cimetidine may potentiate the antihypertensive effect of nifedipine tablets if it is administered simultaneously.

It is reported that serum quinidine levels have been reduced when it is used in combination with nifedipine, irrespective of the quinidine dose taken.

The administration of nifedipine and digoxin concurrently may lead to reduced digoxin clearance and therefore, bring about an increase in the plasma digoxin level. Close monitoring of plasma digoxin levels should take place and, if necessary, a reduction in the dosage of digoxin.

Phenytoin induces the cytochrome P450 3A4 system. When nifedipine is coadministered with phenytoin, nifedipine’s bioavailability is reduced and consequently, its efficacy is weakened. In such cases, the clinical response to nifedipine should be monitored following concomitant administration and, if necessary, consideration should be given to increasing the nifedipine dose. If the nifedipine dose is increased during the co-administration of both drugs, consideration should be given to reducing the nifedipine dose when phenytoin therapy is discontinued.

Diltiazem decreases the clearance of nifedipine and hence increases plasma nifedipine levels. Caution should be exercised when both drugs are given simultaneously. A reduction of nifedipine dose may be required when the two are used together.

Nifedipine may falsely increase the spectrophotometric values of urinary vanillylmandelic acid. HPLC measurements are not affected.

Nifedipine should not be administered concomitantly with rifampicin, as effective plasma levels of nifedipine may not be achieved as a result of enzyme induction.

Simultaneous administration of cisapride and nifedipine or quinupristin / dalfopristin and nifedipine may lead to increased plasma concentration of nifedipine. Hence, the blood pressure may need to be monitored and a reduction in the nifedipine dose may be necessary.

Nifedipine enhances the effect of non-polarising muscle relaxants.

Theoretical Interactions

Nifedipine is metabolised via the cytochrome P450 3A4 system. Therefore, there are theoretical interactions with drugs such as erythromycin, ketoconazole, itraconazole, fluconazole, fluoxetine, indinavir, nelfinavir, ritonavir and saquinavir that are known to inhibit this enzyme system. Although no in vivo interaction studies with these drugs have been carried out, their co-administration with nifedipine in vitro, have shown increases in nifedipine plasma concentrations. Therefore, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose should be considered.

Similarly, the potential interaction between nifedipine and nefazodone has not been clinically investigated. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs and therefore, co-administration with nifedipine may increase the plasma concentrations of nifedipine. Again, monitoring of the blood pressure is advised when both drugs are simultaneously administrated with, if necessary, a reduction in the nifedipine dose.

Tacrolimus is metabolised via the cytochrome P450 3A4 system. Upon coadministration with nifedipine, the plasma levels of tacrolimus should be monitored and, if necessary, consideration should be given to reducing the tacrolimus dose.

Carbamazepine, phenobarbital or valproic acid have been shown to alter the plasma levels of a structurally similar calcium channel blocker, however, no interactive studies have been carried out with these drugs and nifedipine. A decrease (with carbamazepine or phenobarbital) or an increase (with valproic acid) in nifedipine plasma concentrations, leading to a change in efficacy, can therefore not be ruled out.

Drugs Shown Not to Interact with Nifedipine

Aspirin, benazepril, candesartan cilexetil, debrisoquine, doxazosin, irbesartan, omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone and triamterene hydrochlorothiazide are drugs known not to affect the pharmacokinetics of nifedipine when they are administered concomitantly with nifedipine.

4.6 Fertility, pregnancy and lactation

Pregnancy

Nifedipine should not be used during pregnancy unless the clinical conditions of the woman requires treatment with nifedipine (see section 4.4).

Safe use of nifedipine during human pregnancy has not been established. Animal studies have shown reproductive toxicity (embryotoxic, foetotoxic and teratogenic effects) at maternally toxic doses.

From clinical evidence available a specific prenatal risk has not been identified, although an increase in perinatal asphyxia, caesarean delivery, prematurity and intrauterine growth retardation have been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment or to a specific drug effect.

Available information is inadequate to rule out adverse drug effects on the unborn and newborn child. Any use in pregnancy requires very careful risk benefit assessment and should only be considered if all other treatment options are not indicated or have failed to be efficacious.

Breastfeeding

Nifedipine passes into breast milk and therefore, VALNI XL 60 mg PROLONGED RELEASE TABLETS are contraindicated for use in nursing mothers as there is no experience of possible effects on infants.

Fertility

In single reports of in vitro fertilisation, calcium antagonists like nifedipine have been associated with reversible biochemical alterations in the head of the spermatozoa that may impair sperm function. Calcium antagonists like nifedipine should be considered as possible causes in those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation and where no other explanation can be found.

4.7 Effects on ability to drive and use machines

Reactions to nifedipine may vary in intensity in patients, especially at the onset of therapy, on changing medication or when combined with alcohol. Therefore, the patient should be warned of the possible effects and advised not to drive or operate machinery, if affected.

4.8 Undesirable effects

Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n = 2,661; placebo n = 1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n = 3,825; placebo n = 3,840) are listed below:

ADRs listed under "common" were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%).

The frequencies of ADRs reported with nifedipine-containing products are summarised in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common (>1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100) and rare (> 1/10,000 to < 1/1,000). The ADRs identified only during the ongoing postmarketing surveillance, and for which a frequency could not be estimated, are listed under “Not known”.

System	Common	Uncommon	Rare
Organ Class	(>1/100 to	£1/1,000 to	£1/10,000 to	Not Known
(MedDRA)	<1/10)	<1/100)	<1/1,000)
Blood and				Agranulocytosis
Lymphatic System Disorders				Leucopenia
		Allergic reaction	Pruritus	Anaphylactic/
Immune System Disorders		Allergic	Urticaria	anaphylactoid reaction.
		oedema/angiooe dema (incl. larynx oedema*)	Rash
Psychiatric		Anxiety	Mood changes

Disorders		reactions
		Sleep disorders
Metabolism and Nutrition Disorders			Anorexia	Hyperglycaemia
Nervous System Disorders	Headache	Vertigo Nervousness Migraine Insomnia Dizziness Tremor	Par- /Dysaesthesia Hyperaesthesia	Hypoaesthesia Somnolence
Eye Disorders		Visual disturbances		Eye pain
Cardiac Disorders		Tachycardia Palpitations	Cardiovascular disease	Chest pain (Angina pectoris)
Vascular Disorders	Oedema (incl peripheral oedema) Vasodilatation	Hypotension Posternal Hypotension Syncope
Respiratory, Thoracic, and Mediastinal Disorders		Nosebleed Nasal congestion		Dyspnoea Oesophagitis
Gastrointesti nal Disorders	Constipation	Gastrointestinal and abdominal pain Nausea Dyspepsia Flatulence Diarrhoea Dry mouth	Gingival hyperplasia Gingivitis Gastro-intestinal disorder Eructation	Bezoar Dysphagia Intestinal obstruction Intestinal ulcer Vomiting Gastroesophage al sphincter insufficiency

				Gum disorder
Hepatobiliary Disorders		Transient increase in liver enzymes		Jaundice
Skin and Subcutaneous Tissue Disorders		Erythema Pruritus	Sweating	Toxic epidermal necrolysis Photosensitivity allergic reaction Exfoliative dermatitis Palpable purpura
Musculoskele tal and Connective Tissue Disorders		Muscle cramps Joint swelling Leg cramps	Joint disorder	Arthralgia Myalgia
Renal and Urinary Disorders		Polyuria Nocturia Dysuria
Reproductive System and Breast Disorders		Erectile dysfunction
General Disorders and Administrati on Site Conditions	Feeling unwell	Unspecified pain Chills Leg pain	Fever Hypersensitivity type jaundice Facial oedema	Weight loss

*may result in life-threatening outcome

In dialysis patients, with malignant hypertension and hypovolaemia, a distinct fall in blood pressure can occur as a result of vasodilation.

There have also been reports of gynaecomastia in older men on long-term therapy, but this usually regresses when treatment is withdrawn.

Myocardial infarction is also known to occur although it is not possible to distinguish it from the natural course of ischaemic heart disease.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

The following symptoms are observed in cases of severe nifedipine intoxication:

Disturbances of consciousness to the point of coma, a drop in blood pressure, tachycardia, bradycardia, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.

Treatment

As far as treatment is concerned, elimination of nifedipine and the restoration of stable cardiovascular conditions have priority. Elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance.

The benefit of gastric decontamination is uncertain.

1.    Consider activated charcoal (50 g for adults, 1 g/kg for children) if the patient presents within 1 hour of ingestion of a potentially toxic amount.

Although it may seem reasonable to assume that late administration of activated charcoal may be beneficial for sustained release (SR, MR) preparations there is no evidence to support this.

2.    Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose.

3.    Consider further doses of activated charcoal every 4 hours if a clinically significant amount of a sustained release preparation has been ingested with a single dose of an osmotic laxative (e.g. sorbitol, lactulose or magnesium sulfate).

4.    Asymptomatic patients should be observed for at least 4 hours after ingestion and for 12 hours if a sustained release preparation has been taken.

Haemodialysis serves no purpose as nifedipine is not dialysable.

Hypotension as a result of cardiogenic shock and arterial vasodilatation can be treated with calcium (10-20 ml of a 10 % calcium gluconate solution administered intravenously over 5-10 minutes). If the effects are inadequate, the treatment can be continued, with ECG monitoring. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these drugs should be determined by the patient's response.

Symptomatic bradycardia may be treated with atropine, beta-sympathomimetics or a temporary cardiac pacemaker as required.

Additional fluids should be administered with caution to avoid cardiac overload.

5.1    Pharmacodynamic properties

Anatomical Therapeutic Chemical (ATC) code:    C08C A05

Selective calcium channel blocker (dihydropyridine derivative), with mainly

vascular effects

Nifedipine is a calcium antagonist of the 1,4-dihydropyridine type and is a specific and potent antagonist of calcium influx through the slow channel of the cell membrane of cardiac and smooth muscle cells, both in coronary and peripheral circulation.

The antihypertensive effects of nifedipine are achieved by causing peripheral vasodilatation resulting in a reduction in peripheral resistance. Nifedipine administered once daily provides twenty-four hours control of elevated blood pressure. Nifedipine reduces blood pressure such that the percentage lowering is proportional to its initial level. In normotensive individuals, nifedipine has little or no effect.

Nifedipine produces its effects in the treatment of angina by reducing peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume and causing a decrease in afterload. Also, nifedipine submaximally dilates clear and atherosclerosis coronary arteries to protect the heart against coronary artery spasm and improve perfusion to the ischaemic myocardium. Nifedipine decreases the frequency of painful attacks and the ischaemic ECG changes regardless of the relative contribution from coronary artery spasm or atheroschlerosis.

Paediatric population:

Limited information on comparison of nifedipine with other antihypertensives is available for both acute hypertension and long-term hypertension with different formulations and dosages. The antihypertensive effects of nifedipine have been demonstrated but dose recommendations, long term safety and effect on cardiovascular outcome remain unestablished, thus paediatric dosing forms are lacking.

5.2    Pharmacokinetic properties

General Characteristics

VALNI XL 60 mg PROLONGED RELEASE TABLETS are formulated as prolonged release products. They are designed to control the release of nifedipine over twenty-four hours so that a clinical effect is achieved when the tablets are swallowed, once a day.

The pharmacokinetic profile is characterised by low peak-trough fluctuation. Over twenty-four hours plasma concentrations versus time profile at steady state are plateau-like, rendering the VALNI XL 60 mg PROLONGED RELEASE TABLETS suitable for once daily administration.

Absorption

Nifedipine is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. However, due to extensive hepatic first pass metabolism in the liver, the resultant bioavailability lies between 45 % and 68 %. The absorption rate is slightly changed when the tablets are taken after ingesting food but the extent of drug availability is not affected.

Distribution

Nifedipine is about 95 % bound to plasma proteins.

Biotransformation

Nifedipine is almost completely metabolised in the gut wall and liver, primarily by oxidative and hydrolytic processes.

Elimination

The elimination half-life is 2 to 5 hours. About 70 % to 80 % of the administered dose of nifedipine is excreted via the kidneys, mostly as its active metabolites. The rest (5% to 15%) is excreted via the bile in the faeces. The non-metabolised drug substance is only found in traces (less than 1.0%) in the urine.

Characteristics in Patients Patients With Renal Impairment

There are no significant differences in the pharmacokinetics of nifedipine in patients with renal impairment and in healthy subjects. Therefore, dosage adjustments should not be required for patients with impaired renal function.

Patients With Hepatic Impairment

Nifedipine is primarily metabolised in the liver. The elimination half-life is markedly prolonged and there is a reduction in total clearance. Therefore, owing to the duration of action, nifedipine should not be administered to patients with reduced hepatic function.

5.3 Preclinical safety data

Preclinical data reveal no special hazards for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.

The LD50 values (in mg per Kg) determined when nifedipine was given orally and intravenously to different animal species, are reported below:

Animal Species    Oral    Intravenous

Rat	1022 ( 950 - 1087)	15.5 ( 13.7 - 17.5)
	*	*
Rabbit	250 - 500	2 - 3
Cat	~ 100	0.5 - 8
Dog	> 250	2 - 3

*    95 % confidence interval

Subacute & Subchronic Toxicity Studies (in Rats and Dogs)

Nifedipine doses of up to 50 mg per Kg in rats and 100 mg per Kg in dogs p.o were tolerated without any damage when administered orally over periods of thirteen and four weeks, respectively.

Nifedipine doses of 2.5 mg per Kg in rats and 0.1 mg per Kg in dogs were tolerated without any damage when administered intravenously over periods of three weeks and six days, respectively.

Chronic Toxicity Studies (in Rats and Dogs)

Nifedipine doses of up to and including 100 mg per Kg in dogs p.o were tolerated without any damage when administered orally up to one year.

In rats, toxic effect occurred at nifedipine concentrations above 100 ppm in the feed (about 5 mg to 7 mg per Kg body weight).

Carcinogenic Studies (in Rats)

Studies in rats over two years produced no evidence of carcinogenic effects caused by nifedipine.

Reproductive Studies (in Rats, Mice, Rabbits & Monkeys)

Studies in rats, mice and rabbits have shown nifedipine to produce teratogenic effects, including digital anomalies, malformation of extremities, cleft palates, cleft sternum and malformation of the ribs. Digital anomalies and malformation of extremities may be due to a reduction in uterine blood flow, but have also been observed in animals treated with nifedipine solely after the end of the organogenesis period.

Administration of nifedipine has been associated with a variety of embryotoxic, placentotoxic and foetotoxic effects. These include stunted foetuses (rats, mice and rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and foetal deaths (rats, mice and rabbits) and prolonged pregnancy/decreased neonatal survival (rats). If sufficiently high systemic exposure is achieves the risk to humans cannot be ruled out, however, all doses associated with teratogenic, embryotoxic or foetotoxic effects were maternally toxic and several times above the recommended human maximum dose.

Mutagenic Studies

In vivo and in vitro studies showed that nifedipine has no mutagenic properties.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

In Tablet Core Povidone K30 Lactose monohydrate Carbomer 974P Silica, colloidal anhydrous

In Tablet Core & Coat Talc

Hypromellose (E. 464)

Magnesium stearate

In Tablet Coat

Dimethylaminoethyl methacrylate-Butyl methacrylate-Methyl methacrylate copolymer

Macrogol 4000

Red iron oxide (E. 172)

Titanium dioxide (E. 171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Shelf Life of the Medicinal Product as Packaged for Sale 36 months

Shelf Life After Dilution or Reconstitution Not applicable

Shelf Life After First Opening the Container Not applicable

6.4 Special precautions for storage

Do not store above 25 °C. Keep blister in the outer carton.

6.5 Nature and contents of container

The tablets are enclosed in blisters composed of 25 pm aluminium foil coated with 20 g m^-2 PVDC film / 250 pm PVC foil coated with 40 g m^-2 PVDC film

The blisters are boxed in cardboard cartons containing 28 tablets and a patient information leaflet.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS

Or

Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 17780/0318

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/02/2008

DATE OF REVISION OF THE TEXT

19/11/2014