Accupro™ Tablets 5 mg

Accupro™ Tablets 10 mg

Accupro™ Tablets 20 mg

Accupro™ Tablets 40 mg

Each 5mg tablet contains quinapril hydrochloride 5.416 mg (equivalent to 5 mg quinapril base)

Each 10mg tablet contains quinapril hydrochloride 10.832 mg (equivalent to 10 mg quinapril base)

Each 20mg tablet contains quinapril hydrochloride 21.664 mg (equivalent to 20 mg quinapril base)

Each 40mg tablet contains quinapril hydrochloride 43.328 mg (equivalent to 40 mg quinapril base)

Reddish brown oval tablets scored on both sides and “5” embossed on both sides.

Reddish brown triangular tablets scored on both sides and “10” embossed on one side.

Reddish brown round tablets scored on both sides and “20” embossed on one side.

40mg tablet: Reddish-brown, oval, biconvex film-coated tablet with debossing '40' on one side and 'PD 535' on the other side.

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.

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 10-20 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 µmol/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.

.

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.

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.

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 vascular 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 a diuretic and/or quinapril may be required.

Angioedema: Angioedema has been reported in patients treated with angiotensin-converting 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.

Black patients receiving ACE inhibitor therapy generally have a higher incidence of angioedema than non-black patients.

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 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.

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).

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 drugs: In some patients, the administration of a non-steroidal anti-inflammatory agent may reduce the antihypertensive effect of ACE inhibitors. 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.

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 drugs (oral hypoglycaemic agents and insulin): Dosage adjustments of the antidiabetic drug may be required.

Pregnancy:

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.

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 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.

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.

The most frequent clinical adverse reactions in hypertension and congestive heart failure are headache, dizziness, rhinitis, coughing, upper respiratory tract infection, fatigue, nausea and vomiting. Other less frequent side effects are dyspepsia, myalgia, chest pain, abdominal pain, diarrhoea, back pain, sinusitis, insomnia, paraesthesia, nervousness, asthenia, pharyngitis, hypotension, palpitations, flatulence, depression, pruritus, rash, impotence, oedema, arthralgia, amblyopia.

Renal dysfunction, angioedema, hypotension, hyperkalaemia, neutropenia, agranulocytosis - see warnings and precautions.

The following side effects have been observed associated with ACE inhibitor therapy:

Cardiac Disorders: Tachycardia, myocardial infarction

Nervous System Disorders: Cerebral haemorrage, disorders of balance, syncope, taste disturbances, transient ischaemic attacks

Respiratory, Thoracic and Mediastinal Disorders: Bronchitis, bronchospasm, dyspnoea

In individual cases angioneurotic oedema involving the upper airways has caused fatal airway obstruction.

Gastrointestinal Disorders: Constipation, dry mouth, glossitis, ileus, intestinal angioedema. Pancreatitis has been reported rarely in patients treated with ACE inhibitors; in some cases this has proved fatal.

Hepatobiliary Disorders: Cholestatic icterus, hepatitis

Skin and Subcutaneous Tissue Disorders: Alopecia, erythema multiforme, epidermic necrolysis, psoriasis-like efflorescences, Steven Johnson syndrome, urticaria. May be accompanied by fever, eosinophilia and/or increased ANA-titers.

Psychiatric Disorders: Confusion

Eye Disorders: Blurred vision

Ear and Labyrinth Disorders: Tinnitus

Investigations: Increases in blood urea and plasma creatinine may occur. Decreases in haematocrit, platelets and white cell count as well as elevation of liver enzymes and serum bilirubin. In patients with a congential deficiency concerning G-6-PDH individual cases of haemolytic anaemia have been reported.

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.

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.

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 <40ml/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 de-esterification 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 µg/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 half-life 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.”

The results of the preclinical tests do not add anything of further significance to the prescriber.

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)

None known

3 years

Do not store above 25°C

Tampertainer with dessicant containing 56 or 100 tablets

Polyamide/aluminium/PVC blister strip. Supplied in packs of 7, 28, 56 or 100 tablets

No special instructions needed

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

PL 00057/0514

PL 00057/0515

PL 00057/0516

PL 00057/0517

1 August 2003

August 2011

POM

Ref: AC 10_0 UK