Accupro Tablets 5mg
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Accupro Tablets 5 mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5 mg tablet contains:
Quinapril hydrochloride 5.416 mg (Equivalent to 5 mg quinapril base)
3 PHARMACEUTICAL FORM
Reddish brown oval tablets scored on both sides and “5” embossed on both sides
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension
For the treatment of all grades of essential hypertension. Accupro is effective as monotherapy or concomitantly with diuretics in patients with hypertension.
Congestive Heart Failure
For the treatment of congestive heart failure when given concomitantly with a diuretic and/or cardiac glycoside. Treatment of congestive heart failure with Accupro should always be initiated under close medical supervision.
4.2 Posology and method of administration
For oral use
Adults
Hypertension
Monotherapy: The recommended initial dosage is 10 mg once daily in uncomplicated hypertension. Depending upon clinical response, patient's dosage may be titrated (by doubling the dose allowing adequate time for dosage adjustment) to a maintenance dosage of 20 to 40 mg/day given as a single dose or divided into 2 doses. Long-term control is maintained in most patients with a single daily dosage regimen. Patients have been treated with dosages up to 80 mg/day. Take either with or without food. The dose should always be taken at about the same time of day to help increase compliance.
Concomitant Diuretics: In order to determine if excess hypotension will occur, an initial dosage of 2.5 mg of Accupro is recommended in patients who are being treated with a diuretic. After this the dosage of Accupro should be titrated (as described above) to the optimal response (see section 4.5 Interaction with other medicaments and other forms of interaction).
Congestive Heart Failure
In order to closely monitor patients for symptomatic hypotension, a single 2.5 mg initial dosage is recommended. After this, patients should be titrated to an effective dose: (up to 40 mg/day) given in 1 or 2 doses with concomitant diuretic and/or cardiac glycoside therapy. Patients are usually maintained effectively on doses of 1020 mg/day given with concomitant therapy. Take either with or without food. The dose should always be taken at about the same time of day to help increase compliance.
Severe Heart Failure
In the treatment of severe or unstable congestive heart failure, Accupro should always be initiated in hospital under close medical supervision.
Other patients who may also be considered to be at higher risk and should have treatment initiated in hospital include: patients who are on high dose loop diuretics (e.g. > 80 mg furosemide) or on multiple diuretic therapy, have hypovolaemia, hyponatraemia (serum sodium < 130 mgEq/l) or systolic blood pressure < 90 mm Hg, are on high dose vasodilator therapy, have a serum creatinine > 150 pmol/l or are aged 70 years or over.
Elderly/Renal Impairment
In elderly patients and in patients with a creatinine clearance of less than 40 ml/min, an initial dosage in essential hypertension of 2.5 mg is recommended followed by titration to the optimal response (see section 4.4 Special Warnings and Precautions for Use).
Paediatric population
Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.
4.3 Contraindications
Accupro is contraindicated in patients with hypersensitivity to any of the ingredients.
Accupro is contraindicated during the second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Accupro is contraindicated in patients with a history of angioedema related to previous treatment with ACE inhibitors.
Accupro is contraindicated in patients with hereditary/idiopathic angioneurotic oedema.
4.4 Special warnings and precautions for use
Accupro should not be used in patients with aortic stenosis or outflow obstruction.
Patients haemodialysed using high-flux polyacrylonitrile ('AN69') membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. This combination should therefore be avoided, either by use of alternative antihypertensive drugs or alternative membranes for haemodialysis. Similar reactions have been observed during low density lipoprotein apheresis with dextran-sulphate. This method should therefore not be used in patients treated with ACE inhibitors.
Impaired Hepatic Function
Quinapril when combined with a diuretic should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. The metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase.
Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.
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.
Surgery/Anaesthesia
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, quinapril 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 volume expansion (see section 4.5).
Hyperkalaemia and Potassium-sparing Diuretics
Patients on quinapril alone may have increased serum potassium levels. When administered concomitantly, quinapril may reduce the hypokalemia induced by thiazide diuretics. Because of the risk of further potentiating increases in serum potassium it is advised that combination therapy with potassium-sparing diuretics be initiated with caution and the patient’s serum potassium levels be closely monitored (see Hypotension above and Section 4.5 Interaction with other medicinal products and other forms of interaction).
Diabetic patients
In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in 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).
Anaphylactoid reactions: Patients receiving ACE inhibitors during desensitising treatment with hymenoptera venom have experienced life threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.
In patients with renal insufficiency, monitoring of renal function during therapy should be performed as deemed appropriate, although in the majority renal function will not alter or may improve.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors including quinapril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
The half-life of quinaprilat is prolonged as creatinine clearance falls. Patients with a creatinine clearance of <40 ml/min require a lower initial dosage of quinapril (see section 4.2 Posology and Method of Administration). These patients' dosage should be titrated upwards based upon therapeutic response, and renal function should be closely monitored although initial studies do not indicate that quinapril produces further deterioration in renal function.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal disease have developed increases (>1.25 times the upper limit of normal) in blood urea and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic and has been observed in 4% and 3% respectively of patients on monotherapy.. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or quinapril may be required
There is insufficient experience in patients with severe renal impairment (creatinine clearance <10 ml/min). Treatment is therefore not recommended in these patients.
Angioedema: Angioedema has been reported in patients treated with angiotensinconverting enzyme inhibitors. If laryngeal stridor or angioedema of the face, tongue, or glottis occur, treatment should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Angioedema associated with laryngeal involvement may be fatal. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, appropriate therapy e.g., subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 ml) should be promptly administered.
Ethnic differences
Black patients receiving ACE inhibitor therapy have been reported to have a higher incidence of angioedema compared to non-black patients. It should also be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.
Intestinal angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Hypotension: Symptomatic hypotension was rarely seen in uncomplicated hypertensive patients treated with Accupro but it is a possible consequence of ACE inhibition therapy particularly in salt/volume depleted patients such as those previously treated with diuretics, who have a dietary salt reduction, or who are on dialysis. If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses; however, lower doses of quinapril or any concomitant diuretic therapy should be considered if this event occurs.
In patients with congestive heart failure, who are at risk of excessive hypotension, quinapril therapy should be started at the recommended dose under close medical supervision; these patients should be followed closely for the first two weeks of treatment and whenever the dosage of quinapril is increased
Similar considerations 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.
Neutropenia/agranulocytosis: ACE inhibitors have been rarely associated with agranulocytosis and bone marrow depression in patients with uncomplicated hypertension but more frequently in patients with renal impairment, especially if they also have collagen vascular disease. As with other ACE inhibitors, monitoring of white blood cell counts in patients with collagen vascular disease and/or renal diseases should be considered.
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).
4.5 Interaction with other medicinal products and other forms of interaction
Tetracycline and other drugs that interact with magnesium: Because of the presence of magnesium carbonate in the formulation, Accupro has been shown in healthy volunteers to reduce the absorption of tetracycline in concomitant administration by 28-37%. It is recommended that concomitant administration with tetracycline be avoided.
Concomitant diuretic therapy: Patients treated with diuretics may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Accupro. This hypotensive effect may be effectively minimised by either discontinuing the diuretic or increasing the salt intake prior to the initial dose of Accupro. If discontinuation of the diuretic is not possible, medical supervision should be provided for up to two hours following administration of the initial dose (see section 4.4 Special Warnings and Precautions for Use and section 4.2 Posology and Method of Administration).
Agents increasing serum potassium: Quinapril is an angiotensin-converting enzyme inhibitor capable of lowering aldosterone levels, which in turn can result in elevation in serum potassium. Concomitant treatments with potassium sparing diuretics, potassium supplements or potassium salts should be used with caution and with appropriate monitoring of serum potassium. As with other ACE inhibitors, patients on quinapril alone may have increased serum potassium levels. When administered concomitantly, quinapril may reduce the hypokalaemia induced by thiazide diuretics.
Surgery/anaesthesia: Although no data are available to indicate there is an interaction between Accupro and anaesthetic agents that produces hypotension, caution should be exercised when patients undergo major surgery or anaesthesia since angiotensin converting enzyme inhibitors have been shown to block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy due to the sodium-losing effect of these agents. These drugs should be co-administered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity.
Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by NSAIDs.
Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (e.g. sodium aurothiomalate) and concomitant ACE inhibitor therapy
Allopurinol, cytostatic and immunosuppressive agents, systemic corticosteroids or procainamide: Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.
Alcohol, barbiturates or narcotics: Potentiation of orthostatic hypotension may occur. Other hypertensive drugs: There may be an additive effect or potentiation.
Antacids: May decrease the bioavailability of Accupro.
Antidiabetic agents (oral hypoglycaemic agents and insulin)
In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in patients treated with oral antidiabetic agents and insulin. Glycaemic control should be closely monitored.
4.6 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 2nd and 3rd 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/or death in the newborn) 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. Limb contractures, craniofacial deformities, hypoplastic lung development and intrauterine growth retardation have been reported in association with oligohydramnios.
Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see sections 4.3 and 4.4). If oliguria occurs, attention should be directed towards support of blood pressure and renal perfusion.
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 Accupro 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 Accupro 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 are no studies on the effect of this medicine on the ability to drive. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.
4.8 Undesirable effects
Very common (>1/10)
Common (>1/100 to <1/10)
Uncommon (>1/1,000 to <1/100)
Rare (>1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
“The most frequently adverse reactions found in clinical trial were headache (7.2%), dizziness (5.5%), cough (3.9%), fatigue (3.5%), rhinitis (3.2%), nausea and/or vomiting (2.8%) and myalgia (2.2%).
System Organ Class Undesirable effect
Blood and the lymphatic system disorders
Not known
Immune system disorders Not known
Metabolism and nutrition disorders Common
Psychiatric disorders
Common
Uncommon
Neutropenia, agranulocytose. haemolytic anemia, thrombocytopenia
Anaphylactoid reaction
Hyperkalaemia
Insomnia
Nervousness, depression, confusion
Nervous system disorders
Common
Uncommon
Rare
Not known
Eye disorders Uncommon Very rare
Ear and labyrinth disorders Uncommon Cardiac disorders Uncommon
Vascular disorders Common Uncommon Rare
Not known
Respiratory, thoracic and mediastinal
Common
Uncommon
Rare
Not known
Dizziness, headache, paraestesia Somnolence,transient ischaemic attacks
Balance disorder
Syncope, cerebrovascular accident /cerebral haemorrage
Amblyopia Blurred vision
Tinnitus, vertigo
Palpitations, angina pectoris, tachycardia, myocardial infarction
Hypotension
Vasodilation
Syncope
Postural hypotension disorders
Cough, pharyngitis, dyspnoea, rhinitis Sinusitis, upper respiratory tract infection, bronchitis
Eosinophilic pneumonitis Bronchospasm
In individual cases, angioneurotic oedema involving upper airways has caused fatal airway obstruction
Gastrointestinal disorders Common
Uncommon
Rare
Very rare Not known
Hepato-biliary disorders Not known
Skin and subcutaneous tissue disorders Uncommon
Rare
Very rare Not known
Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain Dry mouth or throat, flatulence, Altered taste, constipation, glossitis, Ileus, intestinal angioedema Pancreatitis*
Cholestatic icterus, hepatitis
Pruritus, rash, increased perspiration, , angioedema
Urticaria, erythema multiforme, pemphigus
Psoriasis-like efflorescence Stevens Johnson syndrome, exfoliative dermatitis, alopecia, epidermal necrolysis, photosensitivity.
Skin changes may be associated with fever, muscle and joint pain (myalgias, arthralgias, arthritis), vascular inflammation (vasculitis), inflammations of serous tissues and certain changes in laboratory values (eosinophilia, leucocytosis and/or elevated ANA titers, elevated ESR)
Musculoskeletal, connective tissue and bone disorders
Common Back pain, myalgia
Renal and urinary disorders
Uncommon Renal dysfunction, urinary tract
infection, proteinuria,
Reproductive system and breast disorders
Uncommon Impotence
General disorders and administration site conditions
Common
Uncommon
Chest pain, fatigue, asthenia
Fever, generalised oedema, peripheral
oedema
Investigations
Common Increased serum creatinine, increased
blood urea nitrogen**
Unknown Haemoglobin decreased, haematocrit
decreased
Decreases in hemocrit and WCXC as well as elevation in liver enzymes and serum bilirubin. In patients with a congenital G-6-PDH deficiency, individual cases og haemolytic anemia have been reported
* Pacreatitis has been reported in patients treated with ACE inhibitors; in some cases this has proved fatal.
** Such increases are more likely to occur in patients receiving concomitant diuretic therapy than those on monotherapy with quinapril. These observed increases will often reverse on continued therapy.
Vasculitis and gyncomastia have been reported with other ACE inhibitors and it cannot be excluded that these unwanted effects are group specific.
4.9 Overdose
No data are available with respect to overdosage in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by intravenous volume expansion.
Haemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.
Treatment is symptomatic and supportive consistent with established medical care.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Quinapril is rapidly de-esterified to quinaprilat (quinapril diacid, the principal metabolite) which is a potent angiotensin-converting enzyme (ACE) inhibitor.
ACE is a peptidyl dipeptidase that catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II which is involved in vascular control and function through many different mechanisms, including stimulation of aldosterone secretion by the adrenal cortex. The mode of action of quinapril in humans and animals is to inhibit circulating and tissue ACE activity, thereby decreasing vasopressor activity and aldosterone secretion.
In animal studies the antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE, whereas, tissue ACE inhibition more closely correlates with the duration of antihypertensive effects. Administration of 10-40 mg of quinapril to patients with mild to severe hypertension results in a reduction of both sitting and standing blood pressure with minimal effect on heart rate. Antihypertensive activity commences within one hour with peak effects usually achieved by two to four hours after dosing. Achievement of maximum blood pressure lowering effects may require two weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained in most patients throughout the 24-hour dosing interval and continue during long term therapy.
In a randomised clinical trial using target doses of 2.5, 5, 10 and 20 mg of quinapril, in 112 children and adolescents with hypertension or high normal blood pressure over 8 weeks (2 weeks double blind and 6 weeks extension) failed to reach its primary objective of reduction of diastolic blood pressure after 2 weeks. For systolic blood pressure (secondary objective of efficacy) at Week 2 only there was a statistically significant linear dose response across treatments with a significant difference between the quinapril 20 mg QD and placebo treatment groups.
Long term effects of quinapril on growth, puberty and general development have not been studied.
5.2 Pharmacokinetic properties
Peak plasma Accupro concentrations are observed within 1 hour of oral administration. The extent of absorption is approximately 60%, and is not influenced by food. Following absorption, Accupro is de-esterified to its major active metabolite, quinaprilat, and to minor inactive metabolites. Accupro has an apparent half-life of approximately one hour. Peak plasma quinaprilat concentrations are observed approximately 2 hours following an oral dose of quinapril. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of 3 hours. In patients with renal insufficiency and creatinine clearance of < 40 ml/min, peak and trough quinaprilat concentrations increase, time to peak concentration increases, apparent half-life increases, and time to steady state may be delayed. The elimination of quinaprilat is also reduced in elderly patients (> 65 years) and correlates well with the impaired renal function which frequently occurs in the elderly. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of Accupro. Studies in rats indicate that Accupro and its metabolites do not cross the blood-brain barrier.
Lactation:
After a single oral dose of 20 mg of quinapril in six breast-feeding women, the M/P (milk to plasma ratio) for quinapril was 0.12. Quinapril was not detected in milk after 4 hours after the dose. Quinalaprilat milk levels were undetectable (<5 pg/L) at all time points. It is estimated that a breastfed infant would receive about 1.6% of the maternal weight-adjusted dosage of quinapril.
The pharmacokinetics of quinapril has been studied in a single dose study (0.2 mg/kg) in 24 children aged 2.5 months to 6.8 years and a multiple dose study (0.016-0.468 mg/kg) in 38 children aged 5-16 years old, weighing 66-98 kg on average.
As in adults, quinapril was rapidly converted to quinaprilat. Quinaprilat concentrations generally peaked 1 to 2 hours post dose and declined with a mean halflife of 2.3 hours. In infants and young children the exposure following a single 0.2-mg/kg dose is comparable to that observed in adults after a single 10-mg dose. In a multiple dose study in school age and adolescents, the AUC and Cmax values of quinaprilat were observed to increase linearly with increasing dose of quinapril on a mg/kg basis.
5.3 Preclinical safety data
The results of the preclinical tests do not add anything of further significance to the prescriber.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Accupro Tablets 5 mg contain the following excipients:
Magnesium carbonate Hydrous lactose Gelatin
Crospovidone Magnesium stearate Candelilla wax
Colourings (Opadry Y-5-9020):
Hydroxypropylmethylcellulose Hydroxypropylcellulose Macrogol 400 Red iron oxide (E172) Titanium dioxide (E171)
6.2 Incompatibilities
None known.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
Tampertainer with desiccant containing 56 or 100 tablets.
Polyamide/aluminium/PVC blister strip. Supplied in packs of 7, 28, 56 or 100 tablets.
6.6 Special precautions for disposal
No special instructions needed.
MARKETING AUTHORISATION HOLDER
7
Pfizer Limited
Sandwich
Kent
CT13 9NJ United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00057/0514
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
1 August 2003
10 DATE OF REVISION OF THE TEXT
21/08/2012