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SUMMARY OF THE PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Kinoprilam 5 mg film-coated tablet

Kinoprilam 10 mg film-coated tablet

Kinoprilam 20 mg film-coated tablet

Kinoprilam 40 mg film-coated tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Kinoprilam 5 mg tablet contains quinapril hydrochloride corresponding to 5 mg quinapril.

Kinoprilam 10 mg tablet contains quinapril hydrochloride corresponding to 10 mg quinapril.

Kinoprilam 20 mg tablet contains quinapril hydrochloride corresponding to 20 mg quinapril.

Kinoprilam 40 mg tablet contains quinapril hydrochloride corresponding to 40 mg quinapril.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Kinoprilam 5 mg:

Film-coated tablet.

Oval, biconvex, red-brown film-coated tablet, scored on both sides and imprinted with "I" on one side. Size 4.5 x 8.7 mm.

The tablet can be divided into equal doses.

Kinoprilam 10 mg:

Film-coated tablet.

Oval, biconvex, red-brown film-coated tablet, scored on both sides and imprinted with "L" on one side. Size 5.8 x 11.3 mm.

The tablet can be divided into equal doses.

Kinoprilam 20 mg:

Film-coated tablet.

Round, biconvex, red-brown film-coated tablet, scored on both sides and imprinted with "I" on one side. Diameter 7 mm.

The tablet can be divided into equal doses.

Kinoprilam 40 mg:

Film-coated tablet.

Oval, biconvex, red-brown film-coated tablet, scored on both sides and imprinted with "I" on one side. Size 6.5 x 12.7 mm.

The tablet can be divided 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.

Hypertension

Monotherapy: The recommended initial dose is 10 mg once daily. The dose may be subsequently adjusted, depending on the clinical response. In general if the desired therapeutic effect cannot be achieved in a period of 3 to 4 weeks on a certain dose level, the dose can be further increased. The accepted maintenance dose is 20-40 mg /day.

Quinapril should be given as a single dose or in two divided doses. Most patients can be managed with one daily dose.

Diuretic-treated patients

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 recommended therefore, since these patients may be volume and/or salt depleted. If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with quinapril. In hypertensive patients in whom the diuretic cannot be discontinued, therapy with quinapril should be initiated with a 2.5 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of quinapril should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed (see section 4.4 and section4.5).

Heart failure

Kinoprilam should be given as supplement to, or in combination with a diuretic and/or digitalis, when appropriate. Treatment may be initiated in outpatient care. However, in patients with severe or unstable heart failure, reduced renal function, hypovolaemia, hyponatraemia, or systolic blood pressure <90 mmHg treatment should be initiated in hospital. This is also applicable for concomitant treatment with other vasodilating agents and high dose loop diuretics (> 80 mg furosemide), and for patients aged 70 years or over. The patient should be carefully monitored during the first two weeks and always when the dose of quinapril or diuretic is changed.

Initially a dose of 2.5 mg is administered, after which the patient is closely monitored for symptomatic hypotension. The Kinoprilam dose may gradually be titrated up to 40 mg/day divided in 2 doses. Patients are usually maintained effectively on doses of 10-20 mg/day given twice daily. Patients with mild to moderate heart failure, who have been haemodynamically stable on a daily dose of 20 mg divided in 2 doses for at least a month, may also be given the dose once daily.

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)	Recommended initial daily dose (mg)
> 60	10
30-60	5
10-30	2.5

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

Dialysis has no appreciable effect on the elimination of quinaprilat.

If a satisfactory response has not been achieved within 3 months, a change of therapy should be considered.

Older people

As renal function tends to be reduced with age, this should also be taken into consideration in older people and therefore treatment should start with 5 mg once daily.

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.

• History of angioedema related to previous treatment with ACE inhibitors

• Hereditary or idiopathic angioedema.

• Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

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

• The concomitant use of Kinoprilam 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

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, quinapril should be given with caution to patients with mitral valve stenosis or hypertrophic cardiomyopathy. 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).

If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses; however, lower doses of quinapril or any concomitant diuretic therapy should be considered if this event occurs.

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 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 azotaemia, 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.

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.

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.

Angioedema

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

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.

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.

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.

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 de-esterification of quinapril.

Rarely, ACE inhibitors have been associated with a syndrome beginning as a cholestatic jaundice and progresses 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.

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 hypokalaemia 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 anti-hypertensive 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).

Lithium

The combination of lithium and quinapril is generally not recommended (see 4.5).

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

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).

Tetracycline and other drugs that interact with magnesium

Because of the presence of magnesium carbonate in the formulation, quinapril has been shown in healthy volunteers to reduce the absorption of tetracycline in concomitant administration by 28-37%. 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 minimised 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 continued, medical supervision should be provided for up to two hours after the initial dose of quinapril (see sections 4.2 and 4.4).

Furosemide

Studies in patients with chronic heart failure shows that captopril (and most likely other ACE inhibitors) reduces the diuretic and natriuretic effect of furosemide.

Agents increasing serum potassium

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

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 ACE inhibitors have been shown to block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion (see section 4.4).

Other antihypertensive drugs

There may be an additive effect or potentiation when quinapril is combined with other antihypertensive drugs or nitroglycerine and other nitrates, or other vasodilators.

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 (see section 4.4).

Tricyclic antidepressants/Antipsychotics

Concomitant use of tricycles antidepressants and antipsychotic with ACE inhibitors may result in further reduction of blood pressure.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

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.

Acetylsalicylic acid

High doses of acetylsalicylic acid (> 325 mg) may alter the haemodynamic effects of ACE inhibitors when used to treat heart failure. Where concomitant administration is indicated, a low antithrombotic dose (50-100 mg/ day) of acetylsalicylic acid may be used, depending on the individual clinical situation of the patient.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

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 and narcotics

Potentiation of orthostatic hypotension may occur.

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.

Antidiabetic drugs (oral hypoglycaemic agents and insulin)

In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in patients treated with oral antidiabetic agents or insulin. Glycaemic control should be closely monitored particularly during the first month of treatment with an ACE inhibitor (see section 4.4).

Trimethoprim

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

Antacids

Antacids may decrease the bioavailability of quinapril.

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 contra-indicated during the second and third 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 anti-hypertensive 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 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

The ability to engage in activities such as operating machinery or operating 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. In this section frequencies of undesirable effects are defined as follows: 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 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%).

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:

Common: Uncommon:	Insomnia. Confusional state, depression, nervousness

Nervous system disorders:

Common:	Dizziness, headache, paraesthesia.
Uncommon:	Transient ischaemic attack, syncope, somnolence.
Rare: Not known:	Neuropathy, balance disorder. Cerebrovascular accident.

Eye disorders:

Uncommon: Rare:

Amblyopia. Vision blurred.

Ear and labyrinth disorders:

Uncommon:

Vertigo, tinnitus,.

Cardiac disorders:

Uncommon

Myocardial infarction, angina pectoris, tachycardia, palpitations.

Vascular disorders:

Common: Uncommon: Not known:	Hypotension. Vasodilatation. Orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

Common: Uncommon:	Dyspnoea, cough. Dry throat.
Rare: Not known:	Worsening of asthma, eosinophilic pneumonia. Bronchospasm. In individual cases, upper airways obstruction by angioedema (that may be fatal).

Gastrointestinal disorders:

Common:	Vomiting, diarrhoea, dyspepsia, abdominal pain, nausea.
Uncommon:	Flatulence, dry mouth.
Rare: Very rare: Not known:	Glossitis, constipation, dysgeusia. Ileus, small bowel angioedema. Pancreatitis*.

Hepato-biliary disorders:

Rare:	Hepatic function disturbances.
Not known:	Hepatitis, jaundice cholestatic.

Skin and subcutaneous tissue disorders:

Uncommon:

Angioedema, rash, exanthema, pruritus, urticaria, hyperhidrosis.

Rare: Not known:

Erythema multiforme, pemphigus, 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, connective tissue and bone disorders:

Common: Rare:

Back pain, myalgia. Arthralgia.

Renal and urinary disorders:

Uncommon:

Renal impairment, proteinuria,

Reproductive system and breast disorders:

Uncommon:

Erectile dysfunction.

General disorders:

Common:	Fatigue, asthenia, chest pain.
Uncommon:	Generalised oedema, pyrexia, oedema peripheral.

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.

Vasculitis and gynaecomastia have been reported with other ACE-inhibitors and it cannot be excluded that these unwanted effects 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 national reporting system listed in Appendix V.

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

No specific information is available on the treatment of overdosage 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

Kinoprilam contains 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 reduces the peripheral vascular resistance, blood pressure, pulmonary capillary pressure and increases the cardiac output in patients with heart failure.

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.

Kinoprilam could be administered as supplement to non-potassium-sparing diuretics and/or digitalis, where appropriate, in patients with heart failure.

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 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

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 drug 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 .

Lactation

After a single oral dose of 20 mg quinapril in six breastfeeding women the M/P (milk to plasma ratio) for quinapril was 0.12. Quinapril was not detected in milk after 4 hours after the dose. Quinalaprilat milk levels were undetectable (<5 µg/L) at all time points. It is estimated that a breastfed infant would receive about 1.6% of the maternal weight-adjusted dosage of quinapril.

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.

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

Heavy magnesium carbonate

Calcium hydrogen phosphate, anhydrous

Pregelatinised starch (maize)

Croscarmellose sodium

Magnesium stearate

Film coating

Hypromellose

Hydroxypropylcellulose

Titanium dioxide (E171)

Macrogol 400

Red iron oxide (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 30 °C.

6.5 Nature and contents of container

Blister (A1/A1) 10, 14, 28, 30, 50, 56, 98, 100 and 5 x 100 tablets

Tablet container (polypropylene) with desiccant 250 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG

Stadastrasse 2-18

D-61118 Bad Vilbel

Germany

8. MARKETING AUTHORISATION NUMBER(S)

5 mg: 19705

10 mg: 19706

20 mg: 19707

40 mg: 19708

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24 Oct 2003/24 Oct 2008

10. DATE OF REVISION OF THE TEXT

13 Nov 2014