Pfizer Healthcare Ireland

Accuretic 20 mg/12.5 mg Tablets

Each tablet contains quinapril 20mg (as 21.70 mg quinapril hydrochloride) and hydrochlorothiazide 12.5mg.

Excipients: includes lactose monohydrate, 77 mg per tablet.

For a full list of excipients, see section 6.1.

Film coated tablet

Pink, triangular, biconvex, film-coated tablets with a scoreline on one side and plain on the reverse. The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

For the treatment of all grades of essential hypertension in patients who have been stabilised on the individual components given in the same proportions.

For oral use.

Adults

For patients not currently receiving a diuretic, whether or not they have been receiving quinapril monotherapy, the recommended initial dosage of quinapril/HCTZ is 10/12.5mg. Following initial therapy, the dose may be increased to 20/12.5mg. Effective blood pressure control is usually achieved with a dosage of 10/12.5mg to 20/12.5mg.

The rate of quinapril absorption was reduced by 14% when Accuretic tablets were administered with a high fat meal as compared to fasting, while the extent of absorption was not affected. The rate of hydrochlorothiazide absorption was reduced by 12% when Accuretic tablets were administered with a high fat meal, while the extent of absorption was not significantly affected. Therefore, Accuretic may be administered without regard to food. The dose should always be taken at about the same time of day to increase compliance.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy for hypertension may cause an excessive drop in blood pressure.

Accuretic therapy should be started under close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dosage is increased.

Renal Impairment

Accuretic is not recommended for use in patients with creatinine clearance of less than 40 ml/min.

Elderly

The dose should be kept as low as possible commensurate with achievement of adequate blood pressure control.

Children

Not recommended. Safety and efficacy in children has not been established.

Accuretic is contraindicated in patients with hereditary/idiopathic angioneurotic oedema.

Accuretic is contraindicated in patients with hypersensitivity to any of the ingredients including patients with a history of angioedema related to previous treatment with ACE inhibitors.Accuretic is contraindicated in women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraceptive measures (see Sections 4.4 and 4.6).

Accuretic should not be used in patients with ventricular outflow obstruction.

Accuretic is contraindicated in patients with anuria, hyperkalaemia, or severe renal dysfunction.

Accuretic is contraindicated in patients with hypersensitivity to other sulphonamide-derived drugs.

Accuretic should be used with caution in selected patients with aortic stenosis.

Hypotension

Accuretic can cause symptomatic hypotension, usually not more frequently than either drug as monotherapy. Symptomatic hypotension was rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving quinapril, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension (see Section 4.5).

Accuretic should be used cautiously in patients receiving concomitant therapy with other antihypertensive agents. The thiazide component of Accuretic may potentiate the action of other hypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in postsympathectomized patients.

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 of any concomitant diuretic therapy should be considered if this event occurs.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy for hypertension may cause an excessive drop in blood pressure, which may be associated with oliguria, azotemia, and in rare instances, with acute renal failure and death in such patients. Accuretic therapy should be started under close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dosage is increased.

Sensitivity Reactions

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma, e.g. purpura, photosensitivity, urticaria, necrotising angiitis, respiratory distress including pneumonitis, pulmonary oedema and anaphylactic reactions.

Heart Failure/Heart Disease:

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 quinapril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.

Cough:

Cough has been reported with the use of ACE inhibitors, including quinapril. 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.

Renal Disease

Accuretic should be used in caution in patients with severe renal disease. In severe renal disease thiazides may precipitate azotemia and in moderate renal impairment (creatinine clearance 10-20ml/min) thiazides are generally ineffective in such patients, and the effects of repeated dosing may be cumulative.

There is insufficient experience in patients with severe renal impairment (creatinine clearance <10 ml/min).

The half-life of quinaprilat is prolonged as creatinine clearance falls. Patients with a creatinine clearance of <60ml/min require a lower initial dosage of quinapril (see section 4.2). 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 inhibition 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 any diuretic and/or quinapril may be required.

Impaired Hepatic Function

Accuretic should be used with caution in patients with impaired hepatic function or progressive liver disease since minor alterations of fluid and electrolyte balance may result from thiazide treatment and may precipitate hepatic coma. Quinapril is rapidly deesterified to quinaprilat, (quinapril diacid, the principal metabolite), which, in human and animal studies, is a potent angiotensin-converting enzyme inhibitor. The metabolism of quinapril is normally dependent upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.

Rarely, ACE inhibitors have been associated with a syndrome beginning as a cholestatic jaundice and progressing to a fulminant hepatic necrosis (in some cases fatal). Patients who during ACE inhibitor therapy experience jaundice or clearly elevated hepatic enzymes should discontinue Accuretic and receive appropriate medical follow-up.

Immune-mediated drug reactions/ Anaphylactoid reactions

Desensitisation: Patients receiving ACE inhibitors during desensitising treatment with hymenoptera venom have sustained life-threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld, but they have reappeared upon inadvertent challenge.

Stevens-Johnson syndrome and exacerbations or activation of systemic lupus erythematosus have been reported with thiazides

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.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at an increased risk of angioedema while receiving an ACE inhibitor (See also section 4.3).

Other hypersensitivity reactions have been reported.

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.

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.

Haemodialysis and LDL Apheresis

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.

Derangements of Serum Electrolytes

Patients receiving Accuretic should be observed for clinical signs of thiazide induced fluid or electrolyte imbalance. In such patients periodic determination of serum electrolytes (sodium and potassium in particular) should be performed. Because quinapril reduces the production of aldosterone, its combination with hydrochlorothiazide may minimise diuretic induced hypokalaemia.

The opposite effects of quinapril and hydrochlorothiazide on serum potassium will approximately balance each other in many patients so that no net effect upon serum potassium will be seen. In other patients, one or the other effect may be dominant and some patients may still require potassium supplements. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Hypokalemia

Conversely, treatment with thiazide diuretics has been associated with hypokalaemia, hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of the following: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, confusion, seizures and vomiting. Hypokalaemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or adrenocorticotrophic hormone (ACTH) (see Section 4.5).

Hyperkalaemia

Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see Section 4.5).

Hypoglycaemia and Diabetes

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 (see Section 4.5).

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 a connective disease with the concomitant use of immunosuppressive or other agents which may be associated with neutropenia/agranulocytosis. Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) as this could be a sign of neutropenia (see Section 4.5).

Agranulocytosis has been rarely reported during treatment with quinapril. As with other ACE inhibitors, monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered.

The preparation should be used with particular care in elderly patients, or those with potential obstruction of the urinary tract, or with disorders rendering their electrolyte balance precarious or those with impaired hepatic or renal function.

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.

Pregnancy

Accuretic is contraindicated in pregnancy. Accuretic should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus (see Sections 4.3 and 4.6).

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/galactose malabsorption should not use this medicine.

Tetracycline and other drugs that interact with magnesium

Because of the presence of magnesium carbonate in the formulation, quinapril has been shown in healthy volunteers to reduce the absorption of tetracycline in concomitant administration by 28-37%. It is recommended that concomitant administration of Accuretic with tetracycline be avoided. This interaction should be considered if coprescribing quinapril and tetracycline.

Agents increasing serum potassium

Accuretic contains a thiazide diuretic, which tends to increase the urinary excretion of potassium but it also contains an ACE inhibitor, which tends to conserve potassium by lowering aldosterone levels. It is not advisable to routinely add potassium sparing diuretics or potassium supplements as this may result in elevated serum potassium.

Other diuretics

Accuretic contains a diuretic. Concomitant use of another diuretic may have an additive effect. Also, patients on diuretics, especially those who are volume and/or salt depleted, may experience an excessive reduction of blood pressure on initiation of therapy, or with increased dosage of an ACE inhibitor.

Other antihypertensive drugs

There may be an additive effect or potentiation when Accuretic is combined with other antihypertensive drugs such as nitrates or vasodilators.

Surgery/Anaesthesia

Although no data are available to indicate that there is an interaction between Accuretic and anaesthetic agents that produce hypotension, caution should be exercised when patients undergo major surgery or anaesthesia since ACE 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. (see Section 4.4).

Thiazides may decrease the arterial response to noradrenaline. In emergency surgery pre-anaesthetic and anaesthetic agents should be administered in reduced doses.

Thiazides may increase the response to tubocurarine.

Lithium

Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. 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. . With Accuretic, the risk of lithium toxicity may be increased. Accuretic should be administered with caution and frequent monitoring of serum lithium levels is recommended.

Corticosteroids, ACTH

Intensified electrolyte depletion, particularly hypokalaemia has been observed.

Non-steroidal anti-inflammatory drugs

In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing, and thiazide diuretics, and may reduce the antihypertensive effect of ACE inhibitors. Therefore, when Accuretic and non-steroidal anti-inflammatory agents are used concomitantly the patients should be observed closely to determine if the desired effect of Accuretic is obtained. 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.

Drugs associated with torsades de pointes

Due to the potential risk of hypokalemia, caution should be used when hydrochlorothiazide is co-administered with medicines such as digitalis glycosides or agents associated with torsades de pointes.

Antacids

Antacids may decrease the bioavailability of Accuretic.

Antidiabetic drugs (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 or insulin. Glycaemic control should be closely monitored (see Section 4.4). Dosage adjustments of antidiabetic drugs may be required when administered concomitantly with ACE-inhibitors. This is more likely to be required during the first weeks of combined treatment and in patients with renal impairment.

Pregnancy

Accuretic is contraindicated in pregnancy (see Section 4.3). ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, Accuretic should be discontinued.

Infants exposed to ACE inhibitors during pregnancy may be at increased risk for malformations of the cardiovascular system and central nervous system. There have also been reports of prematurity, hypotension, renal system disorders (including renal failure), skull hypoplasia, oligohydramnios, limb contractures, craniofacial deformities, hypoplastic lung development, intrauterine growth retardation, patent ductus arteriosus, fetal death and/or death in the newborn in association with the maternal use of ACE inhibitors.

Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants who may have been exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalaemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion.

Thiazides cross the placental barrier and appear in cord blood. Nonteratogenic effects to the fetus may include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

There are no adequate and well-controlled studies of Accuretic in pregnant women.

Lactation

ACE inhibitors, including quinapril, are secreted in human milk to a limited extent. Thiazides appear in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue Accuretic or discontinue nursing, taking into account the importance of the drug to the mother.

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating Accuretic therapy. Patients should be stabilised on medication before driving.

The following undesirable effects have been observed and reported during treatment with quinapril/HCTZ with the following frequencies: 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 form the available data).

* 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.

# Adverse reactions associated with quinapril component, frequencies observed when taking quinapril/HCTZ.

## Adverse reactions associated with quinapril component, frequencies observed in quinapril, adverse reactions not associated with quinapril/HCTZ component.

Clinical Laboratory Test Findings:

Serum Electrolytes: (See section 4.4).

Serum Uric Acid, Glucose, Magnesium, PBI, Parathyroid Function tests and Calcium: (See section 4.4).

Haematology test: (See section 4.4).

No data are available for Accuretic with respect to overdosage in humans. The most likely clinical manifestation would be symptoms attributable to quinapril monotherapy overdosage such as severe hypotension, which would usually be treated by infusion of intravenous normal saline.

The most common signs and symptoms observed for hydrochlorothiazide monotherapy overdosage are those caused by electrolyte depletion (hypokalaemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrythmias.

No specific information is available on the treatment of overdosage with Accuretic.

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.

Quinapril and hydrochlorothiazide lower blood pressure by different, though complementary mechanisms. With diuretic treatment, blood pressure and blood volume fall, resulting in a rise in angiotensin II levels which tend to blunt the hypotensive effect. Quinapril blocks this rise in angiotensin II. The antihypertensive effects of quinapril and hydrochlorothiazide are additive.

Quinapril

Peak plasma quinapril concentrations are observed within 1 hour of oral administration. The extent of absorption is approximately 60%, and is not influenced by food. Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat, and to minor inactive metabolites. Quinapril 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 7 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 (see section 4.2Posology and method of administration). Studies in rats indicate that Accuretic and its metabolites do not cross the blood-brain barrier.

Hydrochlorothiazide

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours. Hydrochlorothiazide is excreted unchanged by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placenta but not the blood-brain barrier.

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

Heavy Magnesium carbonate

Lactose Monohydrate

Povidone

Crospovidone

Magnesium stearate

Candelilla wax

Colourings: Opadry pink OY-S-6937 (contains iron oxide (E172), titanium dioxide (E171), hypromellose, hydroxypropyl cellulose and polyethylene glycol).

Not applicable

3 years

Do not store above 25°C. Store in the original package.

Double sided aluminium foil blister enclosed in printed carton, containing 7, 28, 30, 56 or 100 tablets.

Not all pack sizes may be marketed.

No special requirements

Pfizer Healthcare Ireland

9 Riverwalk

National Digital Park

Citywest Business Campus

Dublin 24

PA 822/8/2

22 August 2003

September 2010

Ref AH 8_1 IE