Enalapril Maleate 10mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Enalapril Maleate 10mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 10mg of the active substance enalapril maleate.
For excipients, see section 6.1
3 PHARMACEUTICAL FORM
Circular peach tablets with a score on one side and marked ‘E 10’ on the reverse. Diameter = 7mm.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension: Treatment of all grades of essential hypertension, also renovascular hypertension.
Congestive heart failure: Enalapril tablets should be used as an adjunctive therapy with digitalis and/or non potassium-sparing diuretics as appropriate. Enalapril has been shown to improve symptoms, retard the progression of the disease, and reduce mortality and hospitalisation (See Sections 4.3, 4.4, 4.5 and 5.1).
Prevention of symptomatic heart failure: When used in asymptomatic patients with left ventricular dysfunction, enalapril retards the development of symptomatic heart failure, and reduces hospitalisation for heart failure.
Prevention of coronary ischaemic events in patients with left ventricular dysfunction: Enalapril reduces the incidence of myocardial infarction and reduces hospitalisation for unstable angina pectoris.
4.2 Posology and method of administration
For oral use.
The maximum daily dose is 40mg. Absorption is not affected by food. Essential and renovascular hypertension:
A starting dose of 5 mg once a day is recommended. Where concomitant therapy is a diuretic, the recommended initial dose of enalapril is 2.5 mg (see 'with concomitant diuretic therapy' section). The dose should be titrated to give optimum control of blood pressure. The usual maintenance dose is 10-20 mg given once daily. In severe hypertension the dosage may be increased incrementally to a maximum of 40 mg once daily (See Sections 4.3, 4.4, 4.5 and 5.1).
The dosage of other antihypertensive agents being used together with enalapril may need to be adjusted. Where enalapril replaces a beta-blocking drug in the therapeutic regime, the beta-blocking agent should not be discontinued abruptly; the dosage should be titrated down after commencing therapy with enalapril (see Manufacturer's recommendations) (See Sections 4.3, 4.4, 4.5 and 5.1).
With concomitant diuretic therapy: The recommended initial dose of enalapril is 2.5 mg. Symptomatic hypotension can occur following the initial dose of enalapril; this is more likely when enalapril is added to previous diuretic therapy. Caution is recommended, therefore, since these patients may be volume or salt-depleted. If possible, the diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with enalapril. Enalapril minimises the development of thiazide-induced hypokalaemia and hyperuricaemia (See Sections 4.3, 4.4, 4.5 and 5.1).
Use in the elderly (over 65 years):
A reduced starting dose of 2.5 mg is recommended in the elderly. Enalapril has been shown to be effective in the treatment of hypertension in the elderly, and some elderly patients may be more responsive to enalapril than younger patients.
The dose should be titrated according to need for the control of blood pressure.
Heart failure/asymptomatic left ventricular dysfunction:
The recommended starting dose in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction is 2.5 mg once daily initiated under close medical supervision. For patients with severe heart failure, therapy should be initiated in hospital. Evidence of systolic left ventricular dysfunction should be obtained by relevant techniques (e.g. radionuclide ventriculography or echocardiography or equivalent), prior to initiation of preventative treatment; however, a repeated measurement may not be necessary in patients with one or more myocardial infarctions and documented reduction in cardiac function.
In patients with symptomatic heart failure, this dosage schedule has been shown to improve survival.
The dose should be titrated gradually over a two to four week period, or more rapidly if indicated by the residual signs and symptoms of heart failure, to the usual maintenance dose of 20 mg given as a single dose or two divided doses, according to the tolerability of the patient.
Blood pressure and renal function should be monitored closely both before and during treatment with enalapril. Serum potassium should also be monitored.
In order to decrease the possibility of symptomatic hypotension, patients on previous high dose diuretics should have the diuretic dose reduced before introducing enalapril. The appearance of hypotension after the initial dose of enalapril does not preclude subsequent careful dose titration with the drug, following effective treatment of the hypotension.
Some patients are considered to be at higher risk when started on an ACE inhibitor and are recommended for initiation of therapy in hospital. Research data have shown such patients to be: those with severe heart failure; those on multiple or high-dose diuretics (e.g. > 80 mg frusemide); patients with hypovolaemia; hyponatraemia (serum sodium < 130 mmol/L); pre-existing hypotension (systolic blood pressure < 90 mm Hg); patients with unstable cardiac failure; renal impairment (serum creatinine > 150 Dml/L); those on high-dose vasodilator therapy; patients aged 70 years or over (see 'Precautions').
Use in impaired renal function:
Excretion is primarily by the renal route. Enalapril should therefore be used with caution in patients with renal impairment. The recommended starting dose is 2.5 mg. The dose should be titrated against the response, and should be kept as low as possible to maintain adequate control of blood pressure or heart failure.
Enalapril is dialysable. Dialysis patients may be given the usual dose of enalapril on dialysis days. A high incidence of anaphylactoid reactions has been reported in patients dialysed with high-flux membranes and treated concomitantly with an ACE inhibitor. This combination should therefore be avoided. On the days when patients are not on dialysis the dosage should be tailored to the blood pressure response.
Children:
Not recommended. The paediatric use of enalapril has not been studied.
4.3 Contraindications
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Hypersensitivity to the product or any of its components, and in patients with a history of angioneurotic oedema relating to previous treatment with an ACE inhibitor.
The concomitant use of Enalapril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see Sections 4.5 and 5.1).
4.4 Special warnings and precautions for use
Pretreatment assessment of renal function: Evaluation of the patient should include assessment of renal function prior to initiation of therapy, and during treatment where appropriate.
Symptomatic hypotension has been seen only rarely in uncomplicated hypertensive patients. In hypertensive patients receiving enalapril, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. (see Dosage and administration for management of these patients.)
Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension develops, the patient should be placed in a supine position. Volume repletion with oral fluids or intravenous normal saline may be required. Intravenous atropine may be necessary if there is associated bradycardia. A transient hypotensive response is not a contra-indication to further doses, which can usually be given without difficulty once the blood pressure has increased after volume expansion.
In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with enalapril. This effect is anticipated, and usually is not a reason to discontinue treatment. If such hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or enalapril may become necessary.
The appearance of hypotension after the initial dose of enalapril does not preclude subsequent careful dose titration with the drug after effective management of the hypotension.
Impaired renal function: Enalapril should be used with caution in patients with renal insufficiency as they may require reduced or less frequent doses.
Close monitoring of renal function before and during therapy should be performed as deemed appropriate in those with renal insufficiency. In the majority, renal function will not alter, or may improve.
Renal failure has been reported in association with enalapril and has been mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognised promptly and treated appropriately, renal failure when associated with therapy with enalapril is usually reversible.
Some hypertensive patients, with no apparent pre-existing renal disease have developed increases in blood urea and creatinine when enalapril has been given concurrently with a diuretic. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required. This situation should raise the possibility of underlying renal artery stenosis (see 'Renovascular hypertension').
Renovascular hypertension: Enalapril can be used when surgery is not indicated, or prior to surgery. In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases of blood urea and creatinine, reversible upon discontinuation of therapy, have been seen. This is especially likely in patients treated with diuretics and/or those with renal insufficiency.
Angioneurotic oedema has been reported with angiotensin-converting enzyme inhibitors, including enalapril. This may occur at any time during treatment.
In such cases, enalapril should be discontinued immediately and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Where swelling is confined to the face, lips and mouth, the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airways obstruction, appropriate therapy such as subcutaneous adrenaline (0.5 mL 1:1000) should be administered promptly.
Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also 'Contra-indications').
Other hypersensitivity reactions, including urticaria, have been reported.
Anaphylactic reactions during hymenoptera desensitisation: Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom (e.g. Bee or Wasp venom) have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each desensitisation.
Haemodialysis patients: A high incidence of anaphylactoid reactions have been reported in patients dialysed with high-flux membranes and treated concomitantly with an ACE inhibitor. This combination should therefore be avoided.
Anaphylactoid reactions during LDL apheresis: Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.
Cough: Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnoses of cough.
Surgery/anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril blocks angiotensin-II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.
General: Where enalapril has been used as a single agent in hypertension, Afro-Caribbean patients may show a reduced therapeutic response.
Enalapril should not be used in patients with aortic stenosis or outflow obstruction.
Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Section 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
4.5 Interaction with other medicinal products and other forms of interaction
Combination with other antihypertensive agents such as beta-blockers, methyldopa, calcium antagonists, and diuretics may increase the antihypertensive efficacy of enalapril. Adrenergic-blocking drugs should only be combined with enalapril under careful supervision. Concomitant propranolol may reduce the bioavailability of enalapril, but this does not appear to be of any clinical significance.
Concomitant therapy with lithium may increase the serum lithium concentration.
Plasma potassium usually remains within normal limits, although cases of hyperkalaemia have been reported. If enalapril is given with a potassiumlosing diuretic, the likelihood of diuretic-induced hypokalaemia may be lessened. Enalapril may elevate plasma potassium levels in patients with renal failure. Potassium supplements, potassium-sparing diuretics and potassium-containing salt substitutes are not recommended, particularly in patients with impaired renal function, since they may lead to significant increases in plasma potassium. However, if the concomitant use of these agents is deemed appropriate, they should be used with caution and with frequent monitoring of plasma potassium.
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. Long-term controlled clinical trials with enalapril have not confirmed these findings and do not preclude the use in diabetic patients. It is advised, however, that these patients be monitored.
Narcotic drugs/antipsychotics: postural hypotension may occur with ACE inhibitors.
Allopurinol, cytostatic or immunosuppresive agents, systemic corticosteriods and procainamide: concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.
Non-steroid anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory agent may reduce the antihypertensive effect of an ACE inhibitor. However, in a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril and there was no evidence of a blunting of the antihypertensive action of enalapril. Furthermore, it has been described that NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium, whereas renal function may decrease. These effects are in principle reversible, and occur especially in patients with compromised renal function.
Antacids: induce decreased bioavaliability of ACE inhibitors.
Sympathomimetics: may reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored, to confirm that the desired effect is being obtained.
Alcohol', enhances the hypotensive effect with ACE inhibitors.
Cyclosporin: increases the risk of hyperkalaemia with ACE inhibitors.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Sections 4.3, 4.4 and 5.1).
4.6 Fertility, Pregnancy and lactation
Pregnancy:_
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3.) Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).
Lactation: Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of enalapril in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of enalapril in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.
4.7 Effects on ability to drive and use machines
There is no data to suggest that enalapril affects the ability to drive and use machines.
4.8 Undesirable effects
Severe hypotension and renal failure have occurred in association with therapy with enalapril. These appear to occur in certain specific sub-groups.
Other adverse reactions: Dizziness and headaches are the most commonly reported side effects. Less frequently, fatigue, asthenia, hypotension, orthostatic hypotension, syncope, nausea, diarrhoea, muscle cramps, rash, and cough have been reported. Even less frequently, renal dysfunction, renal failure, and oliguria have been reported.
Rarely reported side-effects include:
Cardiovascular: Myocardial infarction or cerebrovascular accident, possibly secondary to severe hypotension in high-risk patients (see 'Precautions'), chest pain, palpitations, rhythm disturbances, angina pectoris.
Gastro-intestinal: Ileus, pancreatitis, hepatic failure, hepatitis-either hepatocellular or cholestatic, jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis.
Nervous system/Psychiatric: Depression, confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo.
Respiratory: Pulmonary infiltrates, bronchospasm, asthma, dyspnoea, rhinorrhoea, sore throat and hoarseness.
Skin: Diaphoresis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, pruritus, urticaria, alopecia.
Other: Impotence, flushing, taste alteration, tinnitus, glossitis, blurred vision.
A complex of symptoms has been reported which may include fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.
Hypersensitivity/Angioneurotic oedema: Angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported rarely (see 'Precautions').
Laboratory test findings: Increases in blood urea and plasma creatinine, reversible on discontinuation of enalapril, are most likely in the presence of severe heart failure or bilateral renal artery stenosis, especially in patients with renal insufficiency (see 'Precautions'). However, increases in blood urea and plasma creatinine may occur without evidence of pre-existing renal impairment, especially in patients taking diuretics. In this event undiagnosed renal artery stenosis should be suspected. Dosage reduction of enalapril and/or discontinuation of the diuretic should be considered.
Hyperkalaemia and hyponatraemia have also been reported in a few cases. Decreases in haemoglobin and haematocrit as well as elevation of liver enzymes and/or serum bilirubin have been reported in a few patients, and are usually reversible upon discontinuation of enalapril.
Decreases in platelets and white cell count, and rare cases of neutropenia, thrombocytopenia, bone marrow depression, and agranulocytosis have been reported, but a causal relationship to enalapril has not been established.
4.9 Overdose
Limited data are available for overdosage in humans. The most prominent features of overdosage reported to date are marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor. Serum enalaprilat levels 100 times and 200 times higher than usually seen after therapeutic doses have been reported after ingestion of 300mg and 440mg of enalapril, respectively
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Following oral administration, enalapril is rapidly absorbed and hydrolysed to enalaprilat, a highly specific, long-acting, non-sulphydryl angiotensinconverting enzyme inhibitor. Enalaprilat modulates a specific physiological mechanism, the renin-angiotensin-aldosterone system, which plays a major role in the regulation of blood pressure. Onset of action begins smoothly and gradually within one hour and the effects continue usually for 24 hours after a single daily dose.
Data indicate no loss of effect during long term therapy. Rebound hypertension does not occur following abrupt cessation of therapy.
Congestive heart failure patients benefit particularly from reduction in preload and after-load of the heart, with an increase in cardiac output, without reflex tachycardia.
Two large randomised, controlled trials (ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of combination of ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanies by evidence or end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed.
Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. CV death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
The concomitant use of aliskiren with an ACE-inhibitor or an angiotensin II receptor blocker is contraindicated in patients with type 2 diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2).
5.2 Pharmacokinetic properties
Following oral administration, peak serum concentrations occur within one hour. Based on urinary recovery, the extent of absorption is approximately 60%. The absorption of enalapril is not affected by food. Peak serum concentrations occur three to four hours after an oral dose. Excretion is primary renal. Approximately 94% of the dose is recovered in the urine and faeces as enalaprilat or enalapril. Enalaprilat is 50% to 60% bound to plasma proteins, its elimination is multiphasic with a half life of 11 hours after multiple doses to patients with normal renal function.
Lactation: After a single 20mg oral dose in five postpartum women, the average peak enalapril milk level was 1.7pg/L (range 0.54 to 5.9pg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7pg/L (range
1.2 to 2.3pg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dosage. A woman who had been taking oral enalapril 10mg daily for 11 months had peak enalapril milk levels of 2pg/L 4 hours after a dose and peak enalaprilat levels of 0.75pg/L about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44pg/L and 0.63 pg/L of milk respectively. Enalaprilat milk levels were undetectable (<0.2pg/L) 4 hours after a single dose of enalapril 5mg in one mother and 10mg in two mothers; enalapril levels were not determined.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that enalapril does not have serious adverse effects on fertility and reproductive performance in rats, and it is not teratogenic. It crosses the placenta and has been shown to be foetotoxic in rabbits during middle and late pregnancy.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablets contain:
Croscarmellose sodium Lactose monohydrate Magnesium stearate Maize starch, pregelatinised Sodium hydrogen carbonate Iron oxides (E172)
6.2 Incompatibilities
None known
6.3 Shelf life
30 months
6.4 Special precautions for storage
Do not store above 25°C
6.5 Nature and contents of container
Al/Al blisters in cardboard outer container Pack sizes: 28 tablets (blister)
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
MEDLEY PHARMA LIMITED
2A OLYMPIC WAY, SEFTON BUSINESS PARK
BOOTLE
L30 1RD
UNITED KINGDOM
8 MARKETING AUTHORISATION NUMBER(S)
PL 43870/0033
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/06/2010
10 DATE OF REVISION OF THE TEXT
17/12/2014