1. Name Of The Medicinal Product
Gopten®
2. Qualitative And Quantitative Composition
Trandolapril, 0.5mg
Trandolapril, 1.0mg
Trandolapril, 2.0mg
Trandolapril, 4.0mg
For excipients see section 6.1
3. Pharmaceutical Form
Capsules, Hard
0.5mg: opaque red/yellow capsules
1.0mg: opaque red/orange capsules
2.0mg: opaque red/red capsules
4.0mg: opaque red/maroon capsules
4. Clinical Particulars
4.1 Therapeutic Indications
Mild or moderate hypertension.
Left ventricular dysfunction after myocardial infarction.
It has been demonstrated that Gopten improves survival following myocardial infarction in patients with left ventricular dysfunction (ejection fraction
Long-term treatment with Gopten significantly reduces the overall cardiovascular mortality. It significantly decreases the risk of sudden death and the occurrence of severe or resistant heart failure.
4.2 Posology And Method Of Administration
Adults
Hypertension
For adults not taking diuretics, without congestive heart failure and without renal or hepatic insufficiency, the recommended initial dosage is 0.5mg as a single daily dose. A 0.5mg dose will only achieve a therapeutic response in a minority of patients. Dosage should be doubled incrementally at intervals of 2 to 4 weeks, based on patient response, up to a maximum of 4mg as a single daily dose.
The usual maintenance dose range is 1 to 2mg as a single daily dose. If the patient response is still unsatisfactory at a dose of 4mg Gopten, combination therapy should be considered.
Left ventricular dysfunction after myocardial infarction
Following a myocardial infarction, therapy may be initiated as early as the third day. Treatment should be initiated at a daily dose of 0.5mg. The dose should be progressively increased to a maximum of 4mg as a single daily dose. Depending upon the tolerability such as symptomatic hypotension, this forced titration can be temporarily suspended.
In the event of hypotension, all concomitant hypotensive therapies such as vasodilators, including nitrates and diuretics must be carefully checked and if possible, their dose reduced.
The dose of Gopten should be lowered only if the previous measures are not effective or not feasible.
Elderly
The dose in elderly patients is the same as in adults. There is no need to reduce the dose in elderly patients with normal renal and hepatic function. Caution is required in elderly patients with concomitant use of diuretics, congestive heart failure or renal or hepatic insufficiency. The dose should be titrated according to the need to control blood pressure.
Prior diuretic treatment
In patients who are at risk from a stimulated renin-angiotensin system (e.g. patients with water and sodium depletion), the diuretic should be discontinued 2-3 days before beginning therapy with 0.5mg trandolapril to reduce the likelihood of symptomatic hypotension. The diuretic may be resumed later if required.
Cardiac failure
In hypertensive patients who also have congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed after treatment with ACE inhibitors. In these patients, therapy should be started at a dose of 0.5mg Gopten once daily under close medical supervision in hospital.
Dosage adjustment in renal impairment
For patients with mild or moderate renal impairment (creatinine clearance of 10-70ml/min), the usual adult and elderly doses are recommended.
For patients with severe renal impairment (creatinine clearance of <10ml/min), the usual adult and elderly starting doses are also recommended but the maximum daily dose should not exceed 2mg. In these patients, therapy should be under close medical supervision.
Dialysis: It is not known for certain if trandolapril or trandolaprilat are removed by dialysis. However, it would be expected that dialysis could remove the active moiety, trandolaprilat, from the circulation, resulting in a possible loss of control of blood pressure. Therefore careful monitoring of the patient's blood pressure during dialysis is required, and the dosage of trandolapril adjusted if needed.
Dosage adjustment in hepatic impairment
In patients with severely impaired liver function, a decrease in the metabolic clearance of the parent compound, trandolapril and the active metabolite, trandolaprilat results in a large increase in plasma trandolapril levels and to a lesser extent, an increase in trandolaprilat levels. Treatment with Gopten should therefore be initiated at a dose of 0.5mg once daily under close medical supervision.
Children
Gopten has not been studied in children and therefore use in this age group is not recommended.
4.3 Contraindications
Known hypersensitivity to trandolapril.
History of angioedema associated with administration of an ACE inhibitor.
Hereditary/idiopathic angioneurotic oedema.
Second and third trimester of pregnancy (see sections 4.4 and 4.6).
Lactation.
Use in children.
4.4 Special Warnings And Precautions For Use
Gopten should not be used in patients with aortic stenosis or outflow obstruction.
Assessment of renal function
Evaluation of the patient should include assessment of renal function prior to initiation of therapy and during treatment. Proteinuria may occur if renal impairment is present prior to therapy or relatively high doses are used.
Impaired renal function
Patients with severe renal insufficiency may require reduced doses of Gopten; their renal function should be closely monitored. In the majority, renal function will not alter. In patients with renal insufficiency, congestive heart failure or unilateral or bilateral renal artery stenosis, in the single kidney as well as after renal transplantation, there is a risk of impairment of renal function. If recognised early, such impairment of renal function is reversible upon discontinuation of therapy.
Some hypertensive patients with no apparent pre-existing renal disease may develop minor and usually transient increases in blood urea nitrogen and serum creatinine when Gopten is given concomitantly with a diuretic. Dosage reduction of Gopten and/or discontinuation of the diuretic may be required. Additionally, in patients with renal insufficiency, the risk of hyperkalaemia should be considered and the patient's electrolyte status checked regularly.
Impaired liver function
As trandolapril is a prodrug metabolised to its active moiety in the liver, particular caution and close monitoring should be applied to patients with impaired liver function.
Symptomatic hypotension
In patients with uncomplicated hypertension, symptomatic hypotension has been observed rarely after the initial dose of Gopten, as well as after increasing the dose of Gopten. It is more likely to occur in patients who have been volume- and salt-depleted by prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. Therefore, in these patients, diuretic therapy should be discontinued and volume and/or salt depletion should be corrected before initiating therapy with Gopten.
If symptomatic hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of physiological saline. Intravenous atropine may be necessary if there is associated bradycardia. Treatment with Gopten may usually be continued following restoration of effective blood volume and blood pressure.
Surgery/anaesthesia
In patients undergoing surgery or during anaesthesia with agents producing hypotension, Gopten may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by appropriate treatment.
Agranulocytosis and bone marrow depression
In patients on ACE inhibitors, agranulocytosis and bone marrow depression have been seen rarely. They are more frequent in patients with renal impairment, especially if they have a collagen vascular disease. However, regular monitoring of white blood cell counts and protein levels in urine should be considered in patients with collagen vascular disease (e.g. lupus erythematosus and scleroderma), especially associated with impaired renal function and concomitant therapy, particularly with corticosteroids and antimetabolites.
Hyperkalaemia
Elevated serum potassium has been observed very rarely in hypertensive patients. Risk factors for the development of hyperkalaemia include renal insufficiency, potassium-sparing diuretics, the concomitant use of agents to treat hypokalaemia, diabetes mellitus and/or left ventricular dysfunction after myocardial infarction.
Angioedema:
Rarely, ACE inhibitors (such as trandolapril) may cause angioedema that includes swelling of the face, extremities, tongue, glottis, and/or larynx. Patients experiencing angioneurotic oedema must immediately discontinue Gopten therapy and be monitored until oedema resolution.
Angioedema of the face will usually resolve spontaneously. Oedema involving not only the face but also the glottis may be life-threatening because of the risk of airway obstruction.
Angioedema involving the tongue, glottis or larynx requires immediate subcutaneous administration of 0.3-0.5ml of adrenaline solution (1:1000) along with other therapeutic measures as appropriate.
Caution must be exercised in patients with a history of idiopathic angioneurotic oedema, and Gopten is contra-indicated if angioneurotic oedema was an adverse reaction to an ACE inhibitor (section 4.3).
ACE inhibitors have been shown to cause a higher rate of angioedema in black patients than in non-black patients.
Intestinal angioedema has also been reported in patients treated with ACE inhibitors. This should be considered in patients on trandolapril presenting with abdominal pain (with or without nausea or vomiting).
Cough:
During treatment with an ACE inhibitor, a dry and non-productive cough may occur which disappears after discontinuation.
Hereditary disorders:
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor use is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Drug interactions
Combination with diuretics or other antihypertensive agents may potentiate the antihypertensive response to Gopten. Adrenergic-blocking drugs should only be combined with trandolapril under careful supervision.
Potassium-sparing diuretics (spironolactone, amiloride, triamterene) or potassium supplements may increase the risk of hyperkalaemia, particularly in renal failure. Gopten may attenuate the potassium loss caused by thiazide-type diuretics. If concomitant use of these agents is indicated, they should be given with caution and serum potassium should be monitored regularly.
Antidiabetic agents
As with all ACE inhibitors, concomitant use of antidiabetic medicines (insulin or oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycaemia. Therefore, blood glucose should be closely monitored in diabetics treated with a hypoglycaemic agent and Gopten, particularly when starting or increasing the dose of ACE inhibitor, or in patients with impaired renal function.
Combinations necessitating a warning
In some patients already receiving diuretic treatment, particularly if this treatment has been recently instituted, the fall in blood pressure on initiation of treatment with Gopten may be excessive. The risk of symptomatic hypotension may be reduced by stopping the diuretic a few days before starting treatment with Gopten. If it is necessary to continue the diuretic treatment, the patient should be monitored, at least after the initial administration of Gopten. As with all antihypertensives, combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension. Gopten may reduce the elimination of lithium and serum levels of lithium should be monitored.
Anaphylactoid reactions to high-flux polyacrylonitrile membranes used in haemodialysis have been reported in patients treated with ACE inhibitors. As with other antihypertensives of this chemical class, this combination should be avoided when prescribing ACE inhibitors to renal dialysis patients.
The hypotensive effects of certain inhalation anaesthetics may be enhanced by ACE inhibitors .
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide may increase the risk of leucopoenia, if used concomitantly with ACE inhibitors.
As with all antihypertensives, NSAIDs may reduce the antihypertensive effects of trandolapril. Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with trandolapril. An additive effect on serum potassium increase has been described when NSAIDs and ACE inhibitors have been used concomitantly, while renal function may be reduced.
Antacids may cause reduced bioavailability of ACE inhibitors.
The antihypertensive effects of ACE inhibitors may be reduced by sympathomimetics; patients should be carefully monitored.
No clinical interaction has been observed in patients with left ventricular dysfunction after myocardial infarction when Gopten has been concomitantly administered with thrombolytics, aspirin, beta-blockers, calcium channel blockers, nitrates, anticoagulants, diuretics or digoxin.
4.6 Pregnancy And Lactation
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contra-indicated during the second and third trimester 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 the risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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.
ACE inhibitor therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased, renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia). Should exposure to trandolapril have occurred from the second trimester of pregnancy, an ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.
Studies in animals have shown reproductive toxicity (see section 5.3).
Lactation:
Because no information is available regarding the use of Gopten during breastfeeding, Gopten is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects On Ability To Drive And Use Machines
Given the pharmacological properties of Gopten, no particular effect is expected. However, in some individuals, ACE inhibitors may affect the ability to drive or operate machinery, particularly at the start of treatment, when changing over from other medication or during concomitant use of alcohol. Therefore, after the first dose or subsequent increases in dose, it is not advisable to drive or operate machinery for several hours.
4.8 Undesirable Effects
Reactions during Clinical Trials
Hypertension
The following adverse reactions have been reported in hypertension clinical trials with trandolapril. Within each system organ class, the reactions are ranked under headings of frequency, using the following convention: common (
Adverse Reactions Reported In Long Term Hypertension Trials With Trandolapril (n = 1049) That Occurred At A Frequency Greater Than Or Equal To 0.5%
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Post Myocardial Infarction
The following adverse reactions have been reported in the post myocardial infarction clinical trial with trandolapril. Within each system organ class, the reactions are ranked under headings of frequency, using the following convention: common (
Adverse Reactions Reported With Trandolapril In Post Myocardial Infarction Patients In The TRACE Study (n = 876) That Occurred At A Frequency Greater Than Or Equal To 0.5%
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In addition, other significant adverse events seen in clinical trials and postmarketing surveillance seen with trandolapril and those reported with other ACE inhibitors are listed below:
Infections and infestations:
Upper respiratory tract infection has been reported with the use of trandolapril.
Blood and lymphatic system disorders:
Anaemia has been reported with the use of trandolapril.
Metabolism and nutrition disorders:
Hyperuricaemia has been reported with the use of trandolapril.
Psychiatric disorders:
Insomnia, libido decreased, depression and sleep disorder have been reported with the use of trandolapril.
Nervous system disorders:
Transient ischaemic attacks, somnolence, syncope, myoclonus, migraine and dysgeusia have been reported with the use of trandolapril. Confusion has also been reported with the use of ACE inhibitors.
Eye disorders:
Visual disturbance has been reported with the use of trandolapril. Vision blurred has also been reported with the use ACE inhibitors.
Ear and labyrinth disorders:
Vertigo and tinnitus have been reported with the use of trandolapril.
Cardiac disorders:
Tachycardia, arrhythmias, angina pectoris, and myocardial infarction have been reported in association with hypotension during the use of trandolapril. Atrioventricular block and cardiac arrest have also been observed in postmarketing reports with trandolapril.
Vascular disorders:
Cerebral haemorrhage, hot flush and peripheral vascular disorder have been reported with the use of trandolapril.
Respiratory, thoracic and mediastinal disorders:
Upper respiratory tract inflammation, upper respiratory tract congestion, epistaxis, pharyngeal inflammation, bronchospasm, dyspnoea and bronchitis have been reported with the use of trandolapril. Sinusitis, rhinitis, and glossitis have been reported, but rarely in association with ACE inhibitor treatment.
Gastrointestinal disorders:
Vomiting, abdominal pain, diarrhoea, constipation, dry mouth, dyspepsia, ileus and gastrointestinal pain have been reported with the use of trandolapril. Pancreatitis has also been observed in postmarketing reports with trandolapril. Intestinal angioedema has also been reported in patients treated with ACE inhibitors.
Hepatobiliary disorders:
There have been reports of individual incidents of cholestatic jaundice and hepatitis connected with the use of trandolapril.
Skin and subcutaneous tissue disorders:
Allergic hypersensitivity reactions such as pruritus and rash have been reported. Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like efflorescences, and alopecia, which may be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased ANA (anti-nuclear antibody) -titres have been occasionally reported with ACE inhibitor treatment. Alopecia and hyperhidrosis have also been observed in postmarketing reports with trandolapril.
In very rare cases, angioedema has occurred. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with Gopten must be discontinued and appropriate therapy instituted immediately.
Musculoskeletal and connective tissue disorders:
Back pain, muscle spasms and pain in extremity have been reported with the use of trandolapril.
Renal and urinary disorders:
Pollakiuria, deterioration of renal function and acute renal failure have been reported with the use of trandolapril.
Reproductive system and breast disorders:
Erectile dysfunction has been reported with the use of trandolapril.
General disorders and administration site conditions:
Chest pain, oedema peripheral, feeling abnormal and fatigue have been reported with the use of trandolapril.
Investigations:
Reversible (on stopping treatment) increases in blood urea and plasma creatinine may result, particularly if renal insufficiency, severe heart failure or renovascular hypertension are present. Decreased haemoglobin, haematocrit, platelets and white cell count, and increased blood alkaline phosphatase and blood lactate dehydrogenase, have been reported with the use of trandolapril. Individual cases of agranulocytosis or pancytopenia and increased serum bilirubin have also been reported with trandolapril use.
Haemolytic anaemia has been reported in some patients with a congenital deficiency concerning G-6 PDH (glucose-6-phosphate dehydrogenase) during treatment with ACE inhibitors. Leucopoenia and elevated liver enzymes (including SGOT and SGPT) have also been observed in postmarketing reports with trandolapril.
4.9 Overdose
Symptoms expected with ACE inhibitors are severe hypotension, shock, stupor, bradycardia, electrolyte disturbance and renal failure. In the event of overdosage following recent ingestion, consideration should be given to emptying the stomach contents. Blood pressure should be monitored and if hypotension develops, volume expansion should be considered.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC Code: C 09A A10
Gopten capsules contain the prodrug, trandolapril, a non-peptide ACE inhibitor with a carboxyl group but without a sulphydryl group. Trandolapril is rapidly absorbed and then non-specifically hydrolysed to its potent, long-acting active metabolite, trandolaprilat.
Trandolaprilat binds tightly and in a saturable manner to ACE.
The administration of trandolapril causes decreases in the concentrations of angiotensin II, aldosterone and atrial natriuretic factor and increases in plasma renin activity and concentrations of angiotensin I. Gopten thus modulates the renin-angiotensin-aldosterone system which plays a major part in regulating blood volume and blood pressure and consequently has a beneficial antihypertensive effect.
The administration of usual therapeutic doses of Gopten to hypertensive patients produces a marked reduction in both supine and erect blood pressure. The antihypertensive effect is evident after 1 hour, with a peak effect between 8 and 12 hours, persisting for at least 24 hours.
The properties of trandolapril might explain the results obtained in the regression of cardiac hypertrophy with improvement of diastolic function, and improvement of arterial compliance in humans. In addition, a decrease in vascular hypertrophy has been shown in animals.
5.2 Pharmacokinetic Properties
Trandolapril is very rapidly absorbed after oral administration. The amount absorbed is equivalent to 40 to 60% of the administered dose and is not affected by food consumption.
The peak plasma concentration of trandolapril is observed 30 minutes after administration. Trandolapril disappears rapidly from the plasma with a half-life of less than one hour.
Trandolapril is hydrolysed to trandolaprilat, a specific ACE inhibitor. The amount of trandolaprilat formed is not modified by food consumption. The median peak plasma concentration values of trandolaprilat are reached after 3 to 8 hours. The absolute bioavailability of trandolaprilat following trandolapril dose is about 13%.
In the plasma, trandolaprilat is more than 80% protein-bound. It binds saturably, with a high affinity, to ACE. The major proportion of circulating trandolaprilat is also non-saturably bound to albumin.
After repeated administration of Gopten in a single daily dose, steady state of trandolaprilat is reached on average in four days, both in healthy volunteers and in young or elderly hypertensives. The effective half-life of trandolaprilat is between 15 and 23 hours. The terminal half-life of elimination is between 47 hours and 98 hours depending on dose. This terminal phase probably represents binding/dissociation kinetics of the trandolaprilat/ACE complex.
About 9-14% of an administered trandolapril dose is excreted as trandolaprilat in urine. A negligible amount of trandolapril is excreted unchanged in the urine (<0.5%). After oral administration of the labelled product in man, 33% of the radioactivity is found in the urine and 66% in the faeces.
Renal clearance of trandolaprilat varies from 0.15-4 litres per hour, depending on dose.
Special Patient Populations
Pediatric: Trandolapril pharmacokinetics have not been evaluated in patients less than 18 years of age.
Geriatric and Gender: Trandolapril pharmacokinetics have been investigated in the elderly (over 65 years) and in both genders. The plasma concentration of trandolapril is increased in elderly hypertensive patients, but the plasma concentration of trandolaprilat and inhibition of ACE activity are similar in elderly and young hypertensive patients. The pharmacokinetics of trandolapril and trandolaprilat and inhibition of ACE activity are similar in male and female elderly hypertensive patients.
Race: Pharmacokinetic differences have not been evaluated in different races.
Renal Insufficiency: Compared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately two-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 mL/min and in patients on hemodialysis. Dosage adjustment is recommended in renally impaired patients.
Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, nine-fold and twofold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency.
5.3 Preclinical Safety Data
Reproduction toxicity studies showed effects on renal development in the offspring in rats, with an increased incidence of renal pelvic dilation at doses of 10 mg/kg/day and above. In a rabbit developmental toxicity study, maternal toxicity and fetal toxicity was observed at doses of 0.2 mg/kg and above and 0.8 mg/kg, respectively, but no teratogenicity. In monkeys, maternal toxicity [i.e. diarrhoea, vomiting, reduced body weight gain and food intake] was observed at dosages of 5 mg/kg and above, as well as increased abortions at 125 mg/kg and above. The safety margin for the reported adverse effects is unknown, therefore a risk to man cannot be ruled out.
Preclinical data reveal no special hazard for humans with respect to carcinogenic potential and mutagenicity.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Excipients
Maize starch
Lactose monohydrate
Povidone
Sodium stearyl fumarate
Capsule Shell
Gelatin
Titanium dioxide (E171)
Erythrosine (E127)
Black iron oxide (E172) (Gopten 4mg)
Yellow iron oxide (E172)
Sodium laurylsulphate
6.2 Incompatibilities
None
6.3 Shelf Life
Gopten 0.5mg: 24 months
Gopten 1.0mg: 24months
Gopten 2.0mg: 48months
Gopten 4.0mg: 36months
6.4 Special Precautions For Storage
Do not store above 25 °C.
6.5 Nature And Contents Of Container
Gopten 0.5mg: PVC/AL, PVC/PVDC/Al or Aluminium calendar pack containing 14 capsules or 56 capsules. Colourless glass bottle containing 250 capsules.
Gopten 1.0mg: PVC/AL, PVC/PVDC/Al or Aluminium calendar pack containing 28 capsules or 56 capsules. Colourless glass bottle containing 250 capsules.
Gopten 2.0mg: PVC/AL, PVC/PVDC/Al or Aluminium calendar pack containing 28 capsules or 56 capsules. Colourless glass bottle containing 250 capsules.
Gopten 4.0mg: PVC/PVDC/Al containing 28 capsules or 56 capsules.
6.6 Special Precautions For Disposal And Other Handling
None
7. Marketing Authorisation Holder
Abbott Laboratories Limited
Abbott House
Vanwall Road
Vanwall Business Park
Maidenhead
Berkshire
SL6 4XE
United Kingdom
8. Marketing Authorisation Number(S)
PL 00037/0356
PL 00037/0357
PL 00037/0358
PL 00037/0406
9. Date Of First Authorisation/Renewal Of The Authorisation
Gopten 0.5mg, 1.0mg and 2.0mg: 31st December 2001
Gopten 4.0mg: 12th January 2004
10. Date Of Revision Of The Text
7th February 2012
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