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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Quinapril 20 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg quinapril (as quinapril hydrochloride) Excipient with known effect:

Each 20 mg film-coated tablet contains 96.3 mg of lactose monohydrate For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Beige, round, scored on both sides, imprinted "QP/20" on one side and "G" on the other. The 20 mg tablets cannot be broken.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Essential Hypertension

For the treatment of all grades of essential hypertension. Quinapril are 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 Quinapril should always be initiated under close medical supervision.

4.2 Posology and method of administration

For oral use.

For the different dosage regimens, appropriate strengths of Quinapril are available.

Adults

Essential 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. The usual maximum maintenance dose is 40mg/day however, patients have been treated with dosages up to 80 mg/day.

Concomitant diuretics: Symptomatic hypotension may occur following initiation of therapy with quinapril. This is more likely in patients who are being treated currently with diuretics. Caution is therefore recommended, since these patients may be volume and/or salt depleted. If possible, the diuretic should be discontinued 2-3 days before beginning therapy with quinapril. In order to determine if excess hypotension will occur, an initial dosage of 2.5 mg of Quinapril is recommended in patients who are being treated with a diuretic. After this the dosage of Quinapril Tablets should be titrated (allowing adequate time for dosage adjustment) to the optimal response (see section 4.5).

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 (allowing adequate time for dosage adjustment) to an effective dose (up to 40 mg/day) given in 1-2 doses, with concomitant diuretic and/or cardiac glycoside therapy. Patients are usually maintained effectively on doses of 10-20 mg/day given in 1-2 doses with concomitant therapy. The maximum dose of 40mg/day should not be exceeded.

Severe Heart Failure

In the treatment of severe or unstable congestive heart failure, Quinapril 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

As renal function tends to be reduced with age, this should also be taken into consideration in elderly patients. An initial dosage in essential hypertension of 2.5 mg is recommended followed by titration to the optimal response.

Renal impairment

The initial dose of quinapril should be reduced in patients with impaired renal function as the plasma concentration of quinaprilat increases with reduced creatinine clearance. The following initial doses are recommended:

Creatinine clearance (ml/min)	Maximum recommended initial daily dose (mg)
> 60	10
30-60	5
10-30	2.5
< 10	Insufficient experience

Paediatric Population

Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Take either with or without food. The dose should always be taken at about the same time of day to help increase compliance.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (listed in section 6.1).

Pregnancy: Quinapril is contraindicated in the second and third trimesters of pregnancy (see sections

4.4 and 4.6)

Quinapril is contraindicated in patients with a history of angioedema related to previous treatment with ACE inhibitors.

Quinapril is contraindicated in patients with hereditary or idiopathic angioneurotic oedema.

Quinapril should not be used in patients with dynamic left ventricular outflow obstruction.

The concomitant use of Quinapril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

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

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 and pulmonary oedema, anaphylactic reactions.

Symptomatic hypotension

Symptomatic hypotension is seen rarely 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 sections 4.5 and 4.8).

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 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.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Renal Function Impairment including Renal artery stenosis

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.

The half-life of quinaprilat is prolonged as creatinine clearance falls. Patients with a creatinine clearance of <60 ml/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.

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.

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 nitrogen and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. Increases in blood urea nitrogen and serum creatinine have been observed in 2% and 2%, respectively of hypertensive patients on quinapril monotherapy and in 4% and 3%, respectively of hypertensive patients on quinapril/HCTZ. These increases are 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.

There is insufficient experience in patients with severe renal impairment (creatinine clearance <10 ml/min). Treatment is therefore not recommended in these patients.

Kidney Transplantation

There is no experience regarding the administration of quinapril in patients with a recent kidney transplantation. Treatment with quinapril is therefore not recommended.

Anaphalactoid reactions Haemodialysis Patients

Anaphylactoid reactions are highly likely in patients dialysed with high flux polyacrylonitrile (‘AN69’) membranes and treated concomitantly with an ACE inhibitor. This combination should therefore be avoided, either by use of alternative antihypertensive drugs or alternative membranes for haemodialysis.

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis Patients receiving ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis. This method should therefore not be used in patients treated with ACE inhibitors.

Desensitisation

Patients receiving ACE inhibitors during desensitisation 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 re-challenge.

Angioedema

Angioedema has been reported in patients treated with angiotensin converting enzyme inhibitors, including quinapril. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, 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 increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).

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.

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 de-esterification 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 quinapril and receive appropriate medical follow-up.

Neutropenia/ Agranulocytosis

Agranulocytosis and bone marrow depression have been reported rarely in patients with uncomplicated hypertension receiving ACE inhibitors but more frequently in patients with renal impairment, especially if they also have collagen vascular disease.

Agranulocytosis has been rarely reported during treatment with quinapril. Monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered.

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.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, 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).

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 particularly during the first month of treatment with an ACE inhibitor (see section 4.5)

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).

Lactose monohydrate

Quinapril film coated tablets contain lactose monohydrate. 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

Tetracycline and other medicinal products 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%. This interaction should be considered if coprescribing quinapril and tetracycline.

Concomitant diuretic therapy

Patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with quinapril. Hypotensive effects after the first dose of quinapril may be effectively minimised by either discontinuing the diuretic or increasing the salt intake prior to the initial dose of quinapril. 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 sections 4.2 and 4.4).

Agents increasing serum potassium

Quinapril is an angiotensin-converting enzyme inhibitor capable of lowering aldosterone levels, which in turn can result in a mild elevation in serum potassium. Concomitant treatments with potassium sparing diuretics, potassium supplements or potassium salts should only be used with caution and with appropriate monitoring of 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 quinapril 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 (see section 4.4).

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. Quinapril and lithium 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, including possible acute renal failure. These effects are in principle reversible and occur especially in patients with compromised renal function. Monitor renal function periodically in patients receiving quinapril and NSAID therapy.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (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 leukopenia (see section 4.4).

Alcohol, barbiturates and narcotics Potentiation of orthostatic hypotension may occur.

Other antihypertensive agents

There may be an additive effect or potentiation.

B-blockers, methyldopa and diuretics may enhance the hypotensive effects of quinapril, and should only be used under careful supervision. Concomitant propranolol did not affect the pharmacokinetics of quinapril in a single dose study.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors Antacids

May decrease the bioavailability of quinapril.

Antidiabetic medicinal products (oral hypoglycaemic agents and insulin)

Concomitant administration of ACE inhibitors and anti-diabetic medicines (insulin, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with the risk of hypoglycaemia. In diabetic patients ACE inhibitors may enhance insulin sensitivity. Glycaemic control should be closely monitored particularly during the first month of treatment with an ACE inhibitor (see section 4.4).

Other Agents:

Co-administration of multiple 10 mg doses of atorvastatin with 80 mg quinapril resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

4.6 Fertility, pregnancy and lactation

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 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).

Breastfeeding

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 quinapril 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 quinapril in a breastfeeding 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. The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating quinapril therapy.

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or tiredness may occur, especially at the beginning of treatment or in combination with alcohol

4.8 Undesirable effects

The following undesirable effects have been observed during treatment with quinapril and other ACE inhibitors with the following frequencies: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, < 1/1,000), very rare (<1/10000), not known (cannot be estimated from the available data).

The most frequently reported adverse reactions found in controlled clinical trials 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%).

Infections and Infestations

Pharyngitis, rhinitis.

Bronchitis, upper respiratory tract infection, urinary

tract infection, sinusitis.

Blood and lymphatic system disorders

Not known:    Agranulocytosis, haemolytic anaemia, neutropenia,

thrombocytopenia.

Immune system disorders

Not Known    Anaphylactoid reaction.

Metabolism and nutrition disorders

Common    Hyperkalaemia.

Psychiatric disorders

Insomnia.

Confusional state, depression, nervousness.

Dizziness, headache, paraesthesia.

Transient ischaemic attack, somnolence. Balance disorder, syncope.

Cerebrovascular accident/cerebral haemorrhage.

Amblyopia. Blurred vision.

Ear and labyrinth disorders

Respiratory, thoracic and mediastinal disorders

Dyspnoea, cough.

Dry throat.

Eosinophilic pneumonia.

Bronchospasm. In individual cases, upper airways obstruction by

angioedema (that may be fatal).

Hepatobiliary disorders Not known:

Skin and subcutaneous tissue disorders

Angioedema, pruritus, rash, hyperhidrosis.

Erythema multiforme, pemphigus, urticaria.

Dermatitis psoriasiform.

Stevens Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, alopecia, photosensitivity reaction.

Skin disorders may be associated with pyrexia, muscle and joint pain (myalgia, arthralgia, arthritis), vascular inflammation (vasculitis), inflammation of serous tissues and certain changes in laboratory values (eosinophilia, leukocytosis and/or antinuclear antibody increased, red blood sedimentation rate increased).

Musculoskeletal and connective tissue disorders

Common:    Myalgia, back pain.

Renal and urinary disorders

Uncommon:    Proteinuria, renal impairment.

Reproductive system and breast disorders

Uncommon:    Erectile dysfunctionr.

General disorders and administration site conditions

Common:    Fatigue, asthenia, chest pain.

Uncommon:    Generalised oedema, pyrexia, oedema peripheral.

Investigations

Common:    Blood creatinine increased, blood urea increased.*

Uncommon:    Haemoglobin decreased, haematocrit decreased, decreases in

haematocrit and WCXC, hepatic enzyme increased, blood bilirubin increased. In patients with a congenital G-6-PDH deficiency, individual cases of haemolytic anaemia have been reported.

*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.

Gynaecomastia and vasculitis have been reported with other ACE-inhibitors and it cannot be excluded that these unwanted effects are class specific.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov .uk/yellowcard.

4.9 Overdose

The oral LD50 of quinapril in mice and rats ranges from 1440 to 4280 mg/kg.

No data are available on the treatment of overdosage with quinapril in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by intravenous volume expansion.

Treatment

Treatment is symptomatic and supportive, consistent with established medical care.

Haemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors ATC Code: C09AA06

Mechanism of action

Quinapril is a prodrug, which is rapidly hydrolysed to the active metabolite quinaprilat, a potent long-acting inhibitor of angiotensin converting enzyme (ACE) in plasma and tissue of humans and animals. ACE, a peptidyl dipeptidase, catalyses the conversion of angiotensin I to angiotensin II, which is involved in vascular control and function through many different mechanisms, including stimulation of aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin-II, decreasing vasopressor activity and reduced aldosterone secretion.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

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.

Paediatric population

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 quinapril concentrations are observed within 1 hour of oral administration. The extent of absorption of quinapril is 60%, and is not affected by concurrent food intake. Approximately 97% of the active substance is bound to plasma proteins. Quinapril is de-esterified to its major metabolite, quinaprilat, and to minor inactive metabolites. The bioavailability of the active metabolite, quinaprilat, is 30-40% of the given oral dose of quinapril. Peak plasma concentrations are reached after approximately 2 hours following an oral dose of quinapril. With repeat dosing quinaprilat has a halflife of 3 hours. Steady state is reached in 2-3 days. Quinaprilat is mainly excreted unchanged by the kidneys. In patients with renal impairment 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 de-esterification of quinapril. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.

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 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 C_max values of quinaprilat were observed to increase linearly with increasing dose of quinapril on a mg/kg basis.

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.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that quinapril has no negative effects on fertility and reproductive performance in rats and is not teratogenic. ACE inhibitors, as a class, have been shown to be foetotoxic (causing injury and/or death to the foetus) when given in the second or third trimester.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core Lactose monohydrate Cellulose, microcrystalline Magnesium oxide Crospovidone Type A Magnesium stearate

Coat

Hypromellose Macrogol 400 Polysorbate 80

Iron oxide yellow (E172)

Iron oxide black (E172)

Titanium dioxide (E171).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

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

6.5 Nature and contents of container

Polyamide-aluminium-PVC/Aluminium blister containing 10, 14, 28, 30, 50, 60 or 100 tablets. Not all pack sizes maybe marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Generics UK Limited trading as Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/0539

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

September 2009

10 DATE OF REVISION OF THE TEXT

03/07/2015