SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Quinhexal 20 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20mg quinapril (as quinapril hydrochloride)

For 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 Quinhexal 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 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 2-3 weeks 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.

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

4.3 Contraindications

Hypersensitivity to quinapril, to any of the excipients or to any other ACE inhibitor 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/idiopathic angioneurotic oedema.

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 not be used in patients with aortic stenosis or outflow obstruction.

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 section 4.5 and 4.8).

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.

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.

Impaired Renal Function 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 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 l therapy.

Some patients with hypertension or heart failure with no apparent pre-existing renal disease have developed increases (>1.25 times the upper limit of normal) in blood urea and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic and has been observed in 4% and 3% respectively of patients on monotherapy.. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or quinapril may be required

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

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.

Angioedema

Angioedema has been reported in patients treated with angiotensin-converting enzyme inhibitors. Symptoms may appear long after initiation of treatment, at any time during therapy. 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 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.

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.

Neutropenia/Agranulocytosis

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

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.

Desensitisation

Patients receiving ACE inhibitors during desensitizing 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-chanllenge.

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

Impaired Hepatic Function

Quinapril when combined with a diuretic should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. The metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.

Hepatic failure

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.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, quinapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion (see section 4.5).

Hyperkalaemia and Potassium-sparing Diuretics

Patients on quinapril alone may have increased serum potassium levels. When administered concomitantly, quinapril may reduce the hypokalemia induced by thiazide diuretics. Because of the risk of further potentiating increases in serum potassium it is advised that combination therapy with potassium-sparing diuretics be

initiated with caution and the patient’s serum potassium levels be closely monitored (see Hypotension above and Section 4.5 Interaction with other medicinal products and other forms of interaction).

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.

Diabetic patients

In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in patients treated with oral antidiabetic agents or insulin. Glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5).

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.

Lactose

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

4.5 Interaction with other medicinal products and other forms of interaction

Tetracycline and other medicinal products that interact with magnesium salts 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%. 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 minimized by discontinuing the diuretic a few days prior to initiation of therapy. If it is not possible to discontinue the diuretic, the starting dose of quinapril should be reduced. In patients in whom a diuretic is discontinued,medical supervision should be provided for up to two hours after the initial dose of quinapril (see section 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.

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 NSAID’s 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 (e.g. sodium aurothiomalate) and concomitant ACE inhibitor therapy.

Allopurinol, cytostatic and immunosuppressive agents, systemic corticosteroids or procainamide Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia (see section 4.4).

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ACE-inhibitors, angiotensin II receptor blockers or aliskiren

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).

Other anti-hypertensive agents

There may be an additive effect or potentiation. Sympathomimetics Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors

Other agents

Coadministration 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 medicinal products (oral hypoglycaemic agents and insulin)

In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in patients treated with oral antidiabetic agents and insulin. Glycaemic control should be closely monitored.

4.6 Pregnancy and lactation

Pregnancy:

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and 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).

Lactation:

Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of Quinhexal 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

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

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 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data

The most frequently adverse reactions found in clinical trial were headache (7.2%), dizziness (5.5%), cough (3.9%), fatigue (3.5%), rhinitis (3.2%), nausea and/or vomiting (2.8%) and myalgia (2.2%).

System Organ Class	Undesirable effect
Blood and the lymphatic system disorders Not known	Neutropenia, agranulocytosis. haemolytic anaemia, thrombocytopenia
Immune system disorders Not known	Anaphylactic reaction
Metabolism and nutrition disorders Common	Hyperkalaemia
Psychiatric disorders Common	Insomnia
Uncommon	Nervousness, depression, confusion
Nervous system disorders Common	Dizziness, headache, paraesthesia
Uncommon	Somnolence, transient ischaemic attacks
Rare Not known	Balance disorder, syncope, neuropathy Cerebrovascular accident
Eye disorders Uncommon Very rare	Amblyopia Blurred vision

Ear and labyrinth disorders Uncommon Cardiac disorders	Tinnitus, vertigo
Uncommon	Palpitations, angina pectoris, tachycardia, myocardial infarction
Vascular disorders Common Uncommon Rare Not known	Hypotension Vasodilation Syncope Postural hypotension
Respiratory, thoracic and mediastinal disorders Common Uncommon Rare Not known	Cough, pharyngitis, dyspnoea, rhinitis Sinusitis, upper respiratory tract infection, bronchitis Eosinophilic pneumonitis, , worsening of asthma Bronchospasm
	In individual cases, angioneurotic oedema involving upper airways has caused fatal airway obstruction
Gastrointestinal disorders Common Uncommon Rare Very rare Not known	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain Dry mouth or throat, flatulence, Altered taste, constipation, glossitis, Ileus, intestinal angioedema Pancreatitis*
Hepato-biliary disorders Not known	Cholestatic icterus, hepatitis
Skin and subcutaneous tissue disorders Uncommon Rare Very rare Not known	Pruritus, rash, increased perspiration angioedema Urticaria, erythema multiforme, pemphigus Psoriasis-like efflorescence Stevens Johnson syndrome, exfoliative dermatitis, alopecia, epidermal necrolysis, photosensitivity. Skin changes may be associated with fever, muscle and joint pain (myalgias, arthralgias, arthritis), vascular inflammation (vasculitis), inflammations of serous tissues and certain changes in laboratory values (eosinophilia, leucocytosis and/or elevated ANA titers, elevated ESR)
Musculoskeletal, connective tissue and bone disorders Common	Back pain, myalgia
Renal and urinary disorders Uncommon	Renal dysfunction, urinary tract infection, proteinuria
Very rare	Kidney failure
Reproductive system and breast disorders Uncommon	Impotence
General disorders and administration site conditions Common Uncommon	Chest pain, fatigue, asthenia Fever, generalised oedema, peripheral oedema

Investigations
Common	Increased serum creatinine, increased blood urea nitrogen**
Unknown	Haemoglobin decreased, haematocrit decreased Decreases in haemocrit and WCXC as well as elevation in liver enzymes and serum bilirubin. In patients with a congenital G-6-PDH deficiency, individual cases of haemolytic anaemia have been reported

* Pancreatitis has been reported in patients treated with ACE inhibitors; in some cases this has proved fatal.

** Such increases are more likely to occur in patients receiving concomitant diuretic therapy than those on monotherapy with quinapril. These observed increases will often reverse on continued therapy.

Vasculitis and gynaecomastia have been reported with other ACE inhibitors and it cannot be excluded that these unwanted effects are group specific.

4.9 Overdose

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

No specific information is available on the treatment of over dosage with quinapril. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by intravenous volume expansion.

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

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.

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 active substance 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.

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 quinaprilat 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 Microcrystalline cellulose 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

3 years.

6.4. Special Precautions for Storage

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

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. Instructions for Use and Handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Hexal AG Industriestrabe 25 83607 Holzkirchen Germany

8.    MARKETING AUTHORISATION NUMBER

PL 10880/0068

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

17/12/2008

10 DATE OF REVISION OF THE TEXT

14/07/2016