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). For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

White, oval film-coated tablets debossed “20” on one side with a score line on the other side. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

-    Treatment of essential hypertension

-    Treatment of congestive heart failure

4.2    Posology and method of administration

Posology

The dose should be individualised.

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 hypertension. Depending upon clinical response, patient's dosage may be titrated (by doubling the dose allowing 3-4 weeks 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 40 mg/day. In clinical trials, some patients were 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 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 2-3 weeks for dosage adjustment) 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 in 1-2 doses with concomitant therapy. The maximum dose of 40 mg/day should not be exceeded.

Patients who are considered to be at higher risk should have treatment initiated in hospital (see section 4.4).

Older people (>65 years)

As renal function tends to be reduced with age, this should also be taken into consideration in older people. 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    Maximum initial dose

(ml/min)_recommended (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

For oral use.

4.3 Contraindications

Hypersensitivity to the active substance, to any other ACE inhibitor or to any of the excipients listed in section 6.1.

Pregnancy:

Quinapril is contraindicated in the second and third trimester 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/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 with 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). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. 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.

If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, should 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.Patients who may 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.

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. In cases of renal impairment (creatinine clearance <60 ml/min), the initial quinapril dosage should be adjusted according to the patient’s creatinine clearance (see section 4.2) and then as a function of the patient’s response to treatment. Renal function should be closely monitored although initial studies do not indicate that quinapril produces further deterioration in renal function. Routine monitoring of potassium and creatinine is part of normal medical practice for these patients.

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 some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea nitrogen and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of quinapril 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 the diuretic and/or quinapril may be required.

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

Haemodialysis Patients

Anaphylactoid reactions have been reported in patients dialysed with high flux polyacrylonitrile (AN69) membranes and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

Rarely, patients receiving ACE inhibitors during low-density lipoprotein (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.

Desensitisation

Some patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have experienced 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-administration of the medicinal product.

Hypersensitivity/Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including quinapril. Symptoms may appear long after initiation of treatment, at any time during therapy. In such cases, quinapril should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patients. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx, are likely to experience airway obstruction, especially those with a history of airway surgery. In such cases emergency therapy should be administered promptly. This may include the administration of subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 ml) and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.

Caution should be exercised in those known to be hypersensitive to other ACE inhibitors, and particularly those with obstructive airways disease. 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).

Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in 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.

Hepatic failure

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 that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Neutropenia/Agranulocytosis

Neutropenia, agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Quinapril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If quinapril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

Ethnic differences

ACE inhibitors cause a higher rate of angioedema in black patients. As with other ACE inhibitors, quinapril may be less effective in lowering blood pressure in black patients than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

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

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including quinapril. When administered concomitantly, quinapril may reduce the hypokalaemia induced by thiazide diuretics. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or those patients taking other medicinal products associated with increases in serum potassium (e.g. heparin). If concomitant use of the above-mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see 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).

Lithium

The combination of lithium and quinapril is generally not recommended (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).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents acting via the renin-angiotensin-system. Therefore, treatment with ACE inhibitors is not recommended in these patients.

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.

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 salts 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 with tetracycline be avoided.

Concomitant diuretic therapy

Patients treated with diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with quinapril. This hypotensive effect may be effectively minimised by either discontinuing the diuretic a few days prior to initiation of therapy or increasing the salt intake prior to the initial dose of Quinapril. If discontinuation of the diuretic is not possible, the starting dose of quinapril should be reduced. In patients in whom a diuretic is continued, 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. ACE inhibitors attenuate diuretic-induced potassium loss. Potassium sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium (see section 4.4), especially in patients with impaired renal function, since by decreasing aldosterone production, quinapril often causes an increase in serum potassium.

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. These medicinal products 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 medicinal products including acetylsalicylic acid > 3 g/day 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.

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 leucopenia (see section 4.4).

Alcohol, barbiturates, narcotics, tricyclic antidepressants or neuroleptics:

Potentiation of orthostatic hypotension may occur

Other antihypertensive medicinal products

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

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.

Antacids

May decrease the bioavailability of quinapril.

Antidiabetic 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. This phenomenon may be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. Glycaemic control should be closely monitored particularly during the first month of treatment with an ACE inhibitor (see section 4.4). Dosage adjustments of the antidiabetic product may be required

Trimethoprim

A severe hyperkalaemia has been reported during concomitant treatment of ACE-inhibitors with trimethoprim.

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 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

Quinapril has no or negligible influence on the ability to drive and use machines. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness 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, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10000, < 1/1000) very rare (<1/10000), including isolated reports.

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%).

Psychiatric disorders Common:    Insomnia

Uncommon: Confusional state, depression, nervousness

Nervous system disorders Common:    Dizziness, headache, paraesthesia

Uncommon: Transient ischaemic attack,, somnolence Rare:    Disturbances of balance, neuropathy, syncope.

Not known: Cerebrovascular accident

Eye disorders Uncommon: Amblyopia Rare:    Blurred vision

Ear and labyrinth disorders Uncommon: Vertigo, tinnitus

Cardiac disorders

Uncommon: Palpitations, asystole, angina pectoris, myocardial infarction, tachycardia Rare:    Syncope, cerebral haemorrhage

Vascular disorders Common:    Hypotension

Uncommon: Vasodilatation, postural hypotension

Blood and lymphatic system disorders Uncommon: Neutropenia Rare:    Agranulocytosis

Not known: Haemolytic anaemia, thrombocytopenia

Immune system disorders

Very rare:    Anaphylactoid reaction

Respiratory, thoracic and mediastinal disorders Common:    Cough, dyspnoea

Uncommon: Dry throat

Bronchospasm, worsening of asthma, eosinophilic pneumonia Allergic alveolitis

Gastrointestinal disorders

Common:    Nausea, vomiting, diarrhoea, abdominal pain, dyspepsia

Uncommon: Dry mouth or throat, flatulence

Rare:    Altered    taste, constipation, pancreatitis*,    glossitis, ileus

Very rare:    Small    bowel angioedema

Hepato-biliary disorders

Rare:    Hepatic    function disturbance

Very rare:    Cholestatic icterus, hepatitis

Skin and subcutaneous tissue disorders

Uncommon: Pruritus, rash, exfoliative dermatitis, increased perspiration, exanthema, urticaria angioedema

Rare:    Erythema multiforme, Stevens Johnson syndrome, epidermic necrolysis,

psoriasis-like efflorescences, alopecia, pemphigus, photosensitivity

Very rare:    Dermatitis psoriasiform

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, connective tissue and bone disorders Common:    Back pain, myalgia

Rare:    Arthralgia

Renal and urinary disorders

Uncommon: Proteinuria (sometimes with concurrent deterioration of kidney function), renal impairment

Very rare:    Kidney failure

Metabolism and nutrition disorders Common:    Hyperkalaemia

Reproductive system and breast disorders Uncommon: Impotence

General disorders and administration site conditions Common:    Fatigue, asthenia, chest pain

Uncommon: Angioedema (swelling of the extremities, swelling of face, lips, tongue, pharynx, glottis and /or larynx) pyrexia, oedema peripheral, generalised oedema

Investigations

Common:    Blood creatinine increased, blood urea increased**

Not known: 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.

Infections and infestations Common:    Pharyngitis, rhinitis

Uncommon Bronchitis, upper respiratory tract infection, urinary tract infection, sinusitis

* Pancreatitis has been reported rarely 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.

Rare cases of agranulocytosis have been reported, and also a syndrome including fever, serositis, vasculitis, myalgia, arthralgia/arthritis, positive ANA-titre, SR-elevation, eosinophilia, and leukocytosis. Gynaecomastia and vasculitis have been reported with other ACE-inhibitors and it cannot be excluded that these unwanted effects are group specific

Laboratory

Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 3% and 4% respectively of the patients on monotherapy. 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.

Slight decreases in haemoglobin and haematocrit values have been reported for other ACE-inhibitors. It cannot be excluded that these observations are group 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. Symptoms

Symptoms of overdosage are severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure.

Treatment

Measures to prevent absorption (e.g. gastric lavage, administration of adsorbents and sodium sulphate within 30 minutes after intake) and hasten elimination should be applied if ingestion is recent. Haemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. If hypotension occurs, the patient should be placed in the shock position and salt and volume supplementation should be given rapidly. Treatment with angiotensin-II should be considered. Bradycardia or extensive vagal reactions should be

treated by administering atropine. The use of a pacemaker may be considered.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors ATC Code: C09AA06

Quinapril contain the hydrochloride salt of quinapril. The substance has three chiral centres and is a pure stereoisomer.

Quinapril is a prodrug, which is hydrolysed to the active metabolite quinaprilat, a potent long-acting inhibitor of angiotensin converting enzyme (ACE) in plasma and tissue. ACE catalyses the conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. Inhibition of ACE results in decreased concentrations of angiotensin-II and reduced aldosterone secretion; bradykinin metabolism is probably also inhibited. In clinical studies quinapril has been found to be lipid neutral and has no negative effect on glucose metabolism. Quinapril reduces the total peripheral and renal arterial resistance.

In general there are no clinically relevant changes in renal blood flow or glomerular filtration rate. Quinaprilat results in a reduction of prone, sitting and standing blood pressure. The peak effect is achieved after 2-4 hours at recommended doses. Achievement of maximum blood pressure lowering effect may require 2-4 weeks of therapy in some patients. A decrease in left ventricular hypertrophy was observed with quinapril in experimental models of hypertension in animals. Morbidity/mortality data is lacking.

Quinapril can, if necessary, be coadministered with other blood pressure reducing agents. Concomitant treatment with thiazide diuretics increases the blood pressure lowering effect of quinapril

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.

Paediatric population

In a randomized 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

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. The absorption of quinapril is not affected by concurrent food intake, but an extremely high fat content in the food may reduce uptake. Approximately 97% of the activesubstance is bound to plasma proteins. With repeat dosing quinaprilat has a half life of 3 hours. Steady state is reached in 2-3 days. Quinaprilat is mainly excreted unchanged by the kidneys. The clearance is 220 ml/min. Dialysis does not noticeably affect the elimination of quinapril. In patients with renal impairment, quinapril has not been detected in the dialysate and for the metabolite quinaprilat approximately 2.5% of the dose has been detected after peritoneal dialysis and 5.4% after haemodialysis.

Prolonged half life and increased concentration of quinaprilat in plasma occurs in patients with renal impairment (see section 4.2 ). In patients with severe hepatic impairment a reduced concentration of quinaprilat is seen due to reduced hydrolysis of quinapril.

Breastfeeding

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.

Paediatric population

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.

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:

Magnesium carbonate, heavy

Calcium hydrogen phosphate, anhydrous

Gelatin

Crospovidone Type A Magnesium stearate

Film coat:

Hypromellose Titanium dioxide (E171)

Macrogol 6000 Macrogol 400

6.2 Incompatibilities

Not applicable

6.3 Shelf life

18 months

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 blisters. Supplied in packs of 14, 28, 28 (calendar), 30, 50, 50 (hospital pack), 56, 100 or 300 (10x30) tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Teva UK Ltd,

Brampton Road,

Hampden Park Eastbourne East Sussex BN22 9AG England

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/0483

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06/04/2009

10    DATE OF REVISION OF THE TEXT

13/02/2015