1. Name Of The Medicinal Product
Fosinopril Sodium 20mg Tablets
2. Qualitative And Quantitative Composition
Each tablet contains 20mg of Fosinopril sodium
For excipients, see 6.1
3. Pharmaceutical Form
Tablet.
White to off-white, circular, flat, uncoated 8mm tablets marked 'FL 20'.
4. Clinical Particulars
4.1 Therapeutic Indications
Hypertension:
Fosinopril Sodium 20mg Tablets are indicated in the treatment of hypertension. Fosinopril Sodium 20mg Tablets may be used alone as initial therapy or in combination with other antihypertensive agents. The antihypertensive effects of Fosinopril Sodium 20mg Tablets and diuretics used concomitantly are approximately additive.
Heart Failure:
Fosinopril Sodium 20mg Tablets are indicated for the treatment of heart failure in combination with a non-potassium sparing diuretic and where appropriate, digitalis. In these patients, Fosinopril Sodium 20mg Tablets improve symptoms and exercise tolerance, reduce severity of heart failure and decrease the frequency of hospitalisation for heart failure.
4.2 Posology And Method Of Administration
Method of administration:
Oral
Posology
Hypertensive patients not being treated with diuretics:
The dose range is 10 to 40mg per day administered in a single dose and without regard to meals. The normal starting dose for patients is 10mg once a day. Dosage may need to be adjusted after approximately 4 weeks according to blood pressure response. No additional blood pressure lowering is achieved with doses greater than 40mg daily. If blood pressure is not adequately controlled with Fosinopril Sodium 20mg Tablets alone, a diuretic can be added.
Hypertensive patients being treated with concomitant diuretic therapy:
The diuretic should preferably be discontinued for several days prior to beginning therapy with Fosinopril Sodium 20mg Tablets to reduce the risk of an excessive hypotensive response. If blood pressure is inadequately controlled after an observation period of approximately 4 weeks, diuretic therapy may be resumed. Alternatively, if diuretic therapy cannot be discontinued, an initial dose of 10 mg should be used with careful medical supervision for several hours, until blood pressure has stabilised. In diuretic treated hypertensive patients, mean cerebral blood flow is maintained between 4 and 24 hours after fosinopril, despite significant reduction in blood pressure.
Heart Failure:
The recommended initial dose is 10mg once daily, initiated under close medical supervision. If the initial dose is well tolerated patients should then be titrated to a dose of up to 40mg once daily. The appearance of hypotension after the initial dose should not preclude careful dose titration of Fosinopril Sodium 20mg Tablets, following effective management of the hypotension. Fosinopril Sodium 20mg Tablets should be used in addition to diuretics and digitalis where appropriate.
Heart Failure - High Risk Patients:
It is recommended that treatment is initiated in hospital for patients with severe cardiac failure (NYHA IV) and those at particular risk of first dose hypotension, i.e. patients on multiple or high dose diuretics (e.g.> 80mg furosemide), patients with hypovolaemia, hyponatraemia (serum sodium < 130 meq/l), pre-existing hypotension (systolic blood pressure <90 mmHg), patients with unstable cardiac failure and those on high-dose vasodilator therapy.
Children and adolescents
Use in this age group is not recommended. There is limited clinical trial experience of the use of fosinopril in hypertensive children aged 6 years and above (see section 5.1, 5.2 and 4.8). The optimum dosage has not been determined in children of any age. An appropriate dose strength is not available for children weighing less than 50kg.
ELDERLY
No dosage reduction is necessary in patients with clinically normal renal and hepatic function as no significant differences in the pharmacokinetic parameters or antihypertensive effect of fosinoprilat have been found compared with younger subjects.
IMPAIRED HEPATIC FUNCTION
Treatment should be initiated at a dose of 10mg. Although the rate of hydrolysis may be slowed, the extent of hydrolysis is not appreciably reduced in patients with hepatic impairment. In this group of patients, there is evidence of reduced hepatic clearance of fosinoprilat with compensatory increase in renal excretion.
RENAL IMPAIRMENT
Treatment should be initiated at a dose of 10mg. Depending on the response, the dose should then be titrated to achieve the desired therapeutic effect.
Absorption, bioavailability, protein binding, biotransformation and metabolism are not appreciably altered by reduced renal function. In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than that in patients with normal renal function. However, since hepatobiliary elimination compensates at least partially for diminished renal elimination, the body clearance of fosinoprilat is not appreciably different over a wide range of renal insufficiency (creatinine clearances ranging from <10 to 80 ml/min/1.73m2, i.e. including end-stage renal failure).
Neither haemodialysis nor peritoneal dialysis is effective in clearing fosinoprilat. Peritoneal clearance is insignificant, ranging from 0.07 to 0.23ml per minute. Similarly haemodialysis for four hours clears only approximately 1.5% of the administered dose. This corresponds to 7% and 2% respectively, of urea clearance. Hence no dose adjustment is necessary to correct for drug loss during these procedures.
NB Fosinopril is NOT licensed for use in acute myocardial infarction.
4.3 Contraindications
• A history of hypersensitivity to fosinopril or any of the tablet excipients.
• History of angioneurotic oedema
• Renal artery stenosis (bilateral or unilateral in single kidney), and
• Cardiogenic shock.
• Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
4.4 Special Warnings And Precautions For Use
WARNING
Hypotension: As with all ACE inhibitors, a hypotensive response may be observed. If this occurs it is usually associated with the first dose and in most instances, symptoms are relieved simply by the patient lying down. A transient, hypotensive episode is not a contraindication to continuing therapy once the patient's blood pressure has been stabilised.
As with other ACE inhibitors, patients at risk of an excessive hypotensive response, sometimes associated with renal dysfunction, include those with: congestive heart failure, renovascular hypertension, renal dialysis, or volume and/or salt depletion of any aetiology. In patients with any one of these risk factors, it may be prudent to discontinue or reduce the dose of diuretic therapy or take other measures to ensure adequate hydration prior to initiating fosinopril treatment. Treatment of these high risk patients should be initiated under careful medical supervision and they should be followed closely, particularly if it becomes necessary to resume or increase the dose of diuretic or Fosinopril Sodium 20mg Tablets.
Impaired Renal Function: When treated with ACE inhibitors, patients with pre- existing congestive heart failure, renovascular hypertension (especially renal artery stenosis), and salt or volume depletion of any aetiology are at increased risk of developing findings indicative of renal dysfunction, including: increases in BUN and serum creatinine and potassium; proteinuria; changes in urine volume (including oliguria/anuria); and an abnormal urinalysis. Dosage reduction and/or discontinuation of diuretic and/or fosinopril may be required.
Anaphylactoid-like Reactions: Recent clinical observations have shown a high incidence of anaphylactoid-like reactions during haemodialysis with high-flux dialysis membranes (e.g AN69) in patients receiving ACE inhibitors. Therefore, this combination should be avoided. Similar reactions during LDL aphoresis with dextran sulphate absorption have been observed. Rare instances of anaphylactoid reactions during desensitisation treatment (hymenoptera venom) have been recorded with other ACE inhibitors.
Idiosyncratic: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors. If such symptoms occur during treatment with Fosinopril Sodium 20mg Tablets, therapy should be discontinued.
Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx, are likely to experience airway obstruction, especially those with a history of airway surgery. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline (epinephrine) and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
Hepatic failure:
Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving Fosinopril sodium Tablets who develop jaundice or marked elevations of hepatic enzymes should discontinue Fosinopril sodium Tablets and receive appropriate medical follow-up.
Hyperkalaemia: When treated with ACE inhibitors, patients at risk of developing hyperkalaemia include those with renal insufficiency, diabetes mellitus, and those using concomitant potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes.
Neutropenia: ACE inhibitors have been reported rarely to cause reversible agranulocytosis and bone marrow depression; these occur more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Monitoring of white blood cell counts should be considered in such patients.
Surgery/Anaesthesia: ACE inhibitors may augment the hypotensive effects of anaesthetics and analgesics. If hypotension occurs in patients undergoing surgery/anaesthesia and concomitantly receiving ACE inhibitors, it can usually be corrected by intravenous administration of fluid.
PRECAUTIONS
Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent re-administration of the medicinal product.
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 diagnosis of cough.
Diabetic patients
In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5)
Pre-treatment assessment of renal function: Evaluation of the hypertensive patient should include assessment of renal function prior to initiation of therapy and during treatment where appropriate.
Dialysis: See section 4.2 regarding use of fosinopril in patients receiving haemodialysis or peritoneal dialysis.
Aortic Stenosis, Mitral Stenosis and Hypertrophic Cardiomyopathy: In severe cases of these conditions where patients have fixed cardiac output, fosinopril may cause a large fall in blood pressure as such patients cannot compensate for the reduction in peripheral resistance with an increase in cardiac output.
Ethnic Factors: ACE inhibitors cause a higher rate of angioedema in black than in non-black patients. When fosinopril is given as a single agent in hypertension, Afro-Caribbean patients may show a reduced therapeutic response.
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).
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Potentially hazardous interactions:
Antacids: Antacids may impair absorption of fosinopril. Administration of Fosinopril Sodium 20mg Tablets and antacids should be separated by at least 2 hours.
NSAIDs: Non-steroidal anti-inflammatory drugs and more than 3g/day aspirin may interfere with the antihypertensive effect. However, the concomitant use of fosinopril and NSAIDs (including aspirin) is not associated with an increase in clinically significant adverse reactions. As with any ACE inhibitor, in some patients with compromised renal function the co-administration of fosinopril and NSAIDs may result in a further deterioration of renal function.
Lithium: Concomitant therapy with lithium may reversibly increase the serum lithium concentration.
Other Anti-Hypertensive Agents: Combination with other anti-hypertensive agents such as beta blockers, methyldopa, calcium antagonists, and diuretics may increase the anti-hypertensive effect.
Immunosuppressants: Concomitant use of fosinopril with immunosuppressants (e.g. azathioprine) may increase the risk of leucopenia developing.
Combinations not recommended:
Potassium supplements and potassium-sparing diuretics: Fosinopril can attenuate potassium loss caused by a thiazide diuretic. Potassium-sparing diuretics (e.g. spironolactone, amiloride or triamterene) or potassium supplements can increase the risk of hyperkalaemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently.
Other Drugs:
Antidiabetics
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (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.
In pharmacokinetic studies with nifedipine, propranolol, cimetidine, metoclopramide and propantheline the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs.
Fosinopril has been used concomitantly with paracetamol, antihistamines, lipid-lowering agents or oestrogen without evidence of clinically important adverse events.
Laboratory tests: Fosinopril Sodium 20mg Tablets may cause a false low measurement of serum digoxin levels with assays using the charcoal absorption method for digoxin. Other kits which use the antibody coated-tube method may be used.
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 contraindicated 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 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:
Because no information is available regarding the use of fosinopril during breastfeeding, fosinopril 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
Whilst fosinopril is not expected to directly affect performance, it can cause adverse effects such as dizziness, vertigo or hypotension. Patients should make sure they are not affected before driving or operating machinery.
4.8 Undesirable Effects
In the patients treated with Fosinopril sodium Tablets, the adverse effects were in general mild and transient.
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Blood and lymphatic system disorders
Rare: Eosinophilia, leucopenia, lymphadenopathy, neutropenia, thrombocytopenia
Very rare: Agranulocytosis
Metabolism and nutrition disorders
Uncommon: Decreased appetite, gout, hyperkalaemia
Psychiatric disorders
Uncommon: Depression, confusion
Nervous system disorders
Common: Dizziness
Uncommon: Cerebral infarction, paraesthesia, somnolence, stroke, syncope, taste disturbances, tremor
Rare: Dysphasia, memory disturbances
Eye disorders
Uncommon: Visual disturbances
Ear and labyrinth disorders
Uncommon: Ear ache, tinnitus, vertigo
Cardiac disorders
Common: Tachycardia
Uncommon: Angina pectoris, myocardial infarction, palpitations, cardiac arrest, rhythm disturbances, conduction disturbances
Vascular disorders
Common: Hypotension, orthostatic hypotension
Uncommon: Hypertension, shock, transitory ischaemia
Rare: Flush, haemorrhage, peripheral vascular disease
Respiratory, thoracic and mediastinal disorders
Common: Cough
Uncommon: Dyspnoea, rhinitis, sinusitis, tracheobronchitis
Rare: Bronchospasm, epistaxis, laryngitis/ hoarseness, pneumonia, pulmonary congestion
Gastrointestinal disorders
Common: Nausea, vomiting, diarrhoea
Uncommon: Constipation, dry mouth, flatulence
Rare: Oral lesions, pancreatitis, swollen tongue, abdominal distension, dysphagia
Hepatobiliary disorders
Rare: Hepatitis
Skin and subcutaneous tissue disorders
Common: Rash, angioedema, dermatitis
Uncommon: Hyperhidrosis, pruritus, urticaria
Rare: Ecchymosis
Musculoskeletal and connective tissue disorders
Uncommon: Myalgia
Rare: Arthritis
Renal and urinary disorders
Uncommon: Renal failure
Rare: Prostatic disorders
Reproductive and breast disorders
Uncommon: Sexual dysfunction
General disorders and administration site conditions
Common: Chest pain (non-cardiac), weakness
Uncommon: Fever, peripheral oedema, sudden death, thoracic pain
Rare: Weakness in one extremity
Investigations
Common: Increase in alkaline phosphatase, increase in bilirubin, increase in LDH, increase in transaminases
Uncommon: Weight increase
Rare: Slight increase in haemoglobin
In the clinical studies performed with fosinopril, the incidence of adverse effects did not differ between elderly (more than 65 years of age) and younger patients.
Safety data in the paediatric population receiving fosinopril is still limited, only a short-term exposure has been evaluated. In a randomized clinical trial of 253 children and adolescents aged 6 to 16 years, the following adverse events occurred in the 4 week double blind phase: headache (13.9%), hypotension (4.8%), cough (3.6%) and hyperkalaemia (3.6%), elevated serum creatinine levels (9.2%) and elevated serum creatinine kinase levels (2.9%). Different from the adults are this elevated CK reported in this trial (even transient and with no clinical symptoms). The long-term effects of fosinopril on growth, puberty, and general development have not been studied.
4.9 Overdose
The symptoms of overdosage may include severe hypotension, electrolyte disturbance and renal failure. After ingestion of an overdose the patient should be kept under very close supervision. Therapeutic measures depend on the nature and severity of the symptoms. Measures to prevent absorption and methods to speed elimination should be employed. If severe hypotension occurs the patient should be placed in the shock position and an intravenous infusion of normal saline given rapidly. Treatment with angiotensin II (if available) may be considered. The use of high-flux polyacrylonitrile dialysis membrane should be avoided. Serum electrolytes and creatinine should be monitored frequently.
Treatment overview:
• A. ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
• B. HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid, place in Trendelenburg position. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or noradrenaline (norepinephrine) (0.1 to 0.2 mcg/kg/min), titrate to desired response.
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• C. ANGIOEDEMA - Administer antihistamines and corticosteroids. Monitor airway carefully and administer oxygen.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC Code: CO9A A09 Pharmacotherapeutic group: ACE Inhibitors, plain.
Mechanism of action: Fosinopril is the pro-drug (ester) of the long acting active ACE inhibitor fosinoprilat. After oral administration fosinopril is quickly and fully metabolised to the active fosinoprilat. Fosinopril contains a phosphinic group capable of a specific binding to the active site of the angiotensin converting enzyme, preventing the conversion of angiotensin I in angiotensin II. The reduction in angiotensin II leads to a vasoconstriction reduction and a decrease in aldosterone secretion, which might induce a slight increase in serum potassium and a loss of sodium and fluid.
ACE inhibition also interferes with bradykinin degradation, a potent vasodepressant, contributing to the antihypertensive effect; fosinopril presents a therapeutic action in hypertensive patients with renin low levels.
In patients with cardiac failure, it is assumed that Fosinopril beneficial effects are mainly resultant of a suppression of the renin-angiotensin-aldosterone system; ACE inhibition produces a reduction in pre-load and post-load.
The onset of the anti-hypertensive effect is one hour after taking a single dose. The maximum effect is seen after 3-6 hours. With the usual daily dosage the anti-hypertensive effect lasts for 24 hours.
The blood pressure is reduced standing and in decubitus. The orthostatic effects and tachycardia are rare but might occur in patients with salt depletion or in hypovolemia. The blood pressure reduction might be progressive and several can be required to obtain the therapeutic effect.
Fosinopril and thiazide diuretics have additive effects.
In cardiac failure, fosinopril improves the symptoms and the exercise tolerance, reduces the severity of the cardiac failure and the frequency of the hospitalization due to cardiac failure.
Reduction of blood pressure with low (0.1mg/kg), medium (0.3mg/kg) and high (0.6mg/kg) target doses of once-daily fosinopril was evaluated in a randomised double-blind study of 252 children and adolescents aged 6 to 16 years of age with hypertension or high-normal blood pressure. At the end of the four weeks of treatment, the mean reduction from baseline in trough systolic blood pressure was similar for children treated with low, medium and high dose fosinopril. No dosage response relationship was demonstrated between the three doses. The optimum dosage has not been determined in children of any age. An appropriate dose strength is not available for children weighting less then 50kg.
5.2 Pharmacokinetic Properties
Absorption
After oral administration, the extension of the absorption of fosinopril averages 30% to 40%. The absorption of fosinopril is not affected by the presence of food in gastrointestinal tract, however the speed of the absorption might be reduced. The time to reach the maximum plasma concentration is approximately three hours and is independent of administered dose. After multiple or single doses, the pharmacokinetic parameters (Cmax, AUC) are directly proportional to the fosinopril dose that has been taken.
Distribution
Fosinoprilat is protein bound (> 95%), but has a negligible binding to blood cellular components.
Elimination
After intravenous administration, the elimination of fosinopril is by both hepatic and renal routes. In hypertensive patients that receive repeated doses of fosinopril and have normal renal and hepatic functions, the fosinoprilat elimination half-life is 11.5 hours, being of 14 hours in patients with cardiac failure.
Special patient groups
In patients with renal failure (creatinine clearance < 80 ml/min/1,73 m2), the total fosinoprilat body clearance is approximately half of that observed in patients with normal renal function, while no significant changes are seen in the absorption, the bioavailability and the plasma protein binding. The fosinoprilat clearance does not vary according with the degree of renal failure; the reduction in renal elimination is compensated by the increase in hepato-biliary elimination. A slight increase in AUC values (less than the double of normal values) has been observed in patients with several degrees of renal failure, including terminal renal failure (creatinine clearance < 10 ml/min/1.73 m2).
In patients with hepatic failure (alcoholism or biliary cirrhosis), the fosinopril hydrolysis is not significantly reduced, although the rate of the hydrolysis might be reduced; the total fosinoprilat clearance is almost half of the clearance observed in patients with normal hepatic function.
Limited pharmacokinetic data in children and adolescents were provided by a single-dose pharmacokinetic study in 19 hypertensive patients 6 to 16 years of age who received 0.3mg/kg of a solution of fosinopril.
Whether AUC and Cmax values of fosinoprilat (active form of fosinopril) in children from 6 to 16 years of age were comparable to those seen in adults receiving 20mg of fosinopril as a solution, has to be demonstrated.
The terminal elimination half-life for fosinoprilat was 11-13 hours and similar at all stages studied.
5.3 Preclinical Safety Data
Animal studies indicate a toxicity profile which is an extension of the pharmacological effects of fosinopril. It has shown no evidence of carcinogenicity in rodent studies and no potential for mutagenicity in either in vitro or in vivo tests.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Also contains:
Lactose monohydrate
Pregelatinised starch
Croscarmellose sodium
Microcrystalline cellulose
Glycerol dibehenate.
6.2 Incompatibilities
None known.
6.3 Shelf Life
18 months.
6.4 Special Precautions For Storage
Do not store above 25°C.
6.5 Nature And Contents Of Container
Aluminium-aluminium blisters
Each carton will contain either 7, 10, 14, 20, 21, 28, 30, 50, 56, 60, 84, 90, 98, 100* tablets.
*Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Actavis UK Limited (Trading style: Actavis)
Whiddon Valley
BARNSTAPLE
N Devon EX32 8NS
8. Marketing Authorisation Number(S)
PL 0142/0583
9. Date Of First Authorisation/Renewal Of The Authorisation
17.01.05
10. Date Of Revision Of The Text
12.08.09
11. DOSIMETRY
(IF APPLICABLE)
Not applicable.
12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS
(IF APPLICABLE)
Not applicable.
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