This information is intended for use by health professionals

1. Name of the medicinal product

Quinapril 5 mg Tablets

2. Qualitative and quantitative composition

Each 5 mg tablet contains quinapril hydrochloride 5.416 mg equivalent to 5 mg Quinapril

For a full list of excipients, see section 6.1

3. Pharmaceutical form

Film-coated Tablet

Quinapril Tablets 5mg are Yellow coloured, Oval shaped, film-coated tablets debossed with '5' on one side and score line on the other side.

The tablet can be divided into equal halves.

4. Clinical particulars
4.1 Therapeutic indications

Hypertension

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

4.2 Posology and method of administration

Posology

For oral use.

Adults

Hypertension

Monotherapy: The recommended initial dosage is 10 mg once daily in uncomplicated hypertension. Depending upon clinical response, patient's dosage may be titrated (by doubling the dose allowing adequate time for dosage adjustment) to a maintenance dosage of 20 to 40 mg/day given as a single dose or divided into 2 doses. Long-term control is maintained in most patients with a single daily dosage regimen. Patients have been treated with dosages up to 80 mg/day.

Concomitant Diuretics: In order to determine if excess hypotension will occur, an initial dosage of 2.5 mg of Quinapril Tablets is recommended in patients who are being treated with a diuretic. After this the dosage of Quinapril Tablets should be titrated (as described above) to the optimal response.

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

Severe Heart Failure

In the treatment of severe or unstable congestive heart failure, Quinapril Tablets should always be initiated in hospital under close medical supervision.

Other patients who may also be considered to be at higher risk and should have treatment initiated in hospital include: patients who are on high dose loop diuretics (e.g.> 80 mg frusemide) or on multiple diuretic therapy, have hypovolaemia, hyponatraemia (serum sodium < 130 mmol/l) or systolic blood pressure < 90 mm Hg, are on high dose vasodilator therapy, have a serum creatinine > 150 µmol/l or are aged 70 years or over.

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

Elderly/Renal Impairment (over 65 years of age)

In elderly patients and in patients with a creatinine clearance of less than 40 ml/min, an initial dosage in essential hypertension of 2.5 mg is recommended followed by titration to the optimal response.

Paediatric population

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

4.3 Contraindications

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

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

• History of angioedema related to previous treatment with ACE inhibitors.

• Hereditary or idiopathic angioneurotic oedema.

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

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

4.4 Special warnings and precautions for use

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.

Quinapril Tablets should be used with caution in selected patients with aortic stenosis or outflow obstruction.

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 but it is a possible consequence of ACE inhibition. In hypertensive patients receiving quinapril, hypotension is more likely to occur if the patient has been salt/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 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 <40 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 ACE inhibitors including quinapril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.

In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases >1.25 times the upper limit of normal) in blood urea and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. 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.

Angioedema:

Angioedema has been reported in patients treated with angiotensin-converting enzyme inhibitors. If laryngeal stridor or angioedema of the face, tongue, or glottis occur, treatment should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Angioedema associated with laryngeal involvement may be fatal. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, appropriate therapy e.g., subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 ml) should be promptly administered.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at 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 generally have a higher incidence of angioedema than 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. As with other ACE inhibitors, monitoring of white blood cell counts in patients with collagen vascular disease and/or renal diseases should be considered.

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.

Desensitization:

Patients receiving ACE inhibitors during desensitising treatment with hymenoptera venom have sustainedlife threatening anaphylactoid reactions. In the same patients, these reactions have beenavoided whenACE 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 progressing to a fulminant hepatic necrosis (in some cases fatal). Patients who during ACE inhibitor therapy experience jaundice or clearly elevated hepatic enzymes should discontinue quinapril and receive appropriate medical follow-up.

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).

Hyperkalemia 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).

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).

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 Tablets 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 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. or increasing the salt intake prior to the initial dose of Quinapril Tablets. 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).

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, potassium supplements or potassium salts should be used with caution and with appropriate monitoring of serum potassium. As with other ACE inhibitors, patients on quinapril alone may have increased serum potassium levels.

When administered concomitantly, quinapril may reduce the hypokalaemia induced by thiazide diuretics.

Surgery/anaesthesia:

Although no data are available to indicate there is an interaction between Quinapril Tablets and anaesthetic agents that produces hypotension, caution should be exercised when patients undergo major surgery or anaesthesia since angiotensin converting enzyme inhibitors have been shown to block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension, which can be corrected by volume expansion. (See Section 4.4).

Lithium:

Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy due to the sodium-losing effect of these agents. Quinapril and lithium should be co-administered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity.

Non-steroidal anti-inflammatory drugs:

In some patients, the administration of a non-steroidal anti-inflammatory agent may reduce the antihypertensive effect of ACE inhibitors. Furthermore, it has been described that NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium, whereas renal function may decrease. 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 or narcotics:

Potentiation of orthostatic hypotension may occur.

Other hypertensive drugs:

There may be an additive effect or potentiation.

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 Tablets.

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).

4.6 Fertility, 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 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 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 inhibitors 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 concentration 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 case of an older infant the use of quinapril in the breastfeeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

4.7 Effects on ability to drive and use machines

There are no studies on the effect of this medicine on the ability to drive. The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating quinapril therapy.

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 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%).

System Organ Class

Frequency

Undesirable effects

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

Insomnia

Uncommon

Confusional state, depression, nervousness, sleep disorders

Nervous system disorders

Common

Dizziness, headache, paraesthesia

Uncommon

Transient ischaemic attack, somnolence

Rare

Balance disorder, syncope, Neuropathy

Not known

Cerebrovascular accident

Eye disorders

Uncommon

Amblyopia

Very Rare

Vision blurred

Ear and labyrinth disorders

Uncommon

Vertigo, tinnitus

Cardiac disorders

Uncommon

Myocardial infarction, angina pectoris, tachycardia, asystole, palpitations

Rare

Cerebral haemorrhage

Vascular disorders

Common

Hypotension

Uncommon

Vasodilatation

Not known

Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea, cough

Uncommon

Dry throat,

Rare

Eosinophilic pneumonia, worsening of asthma

Very Rare

Allergic alveolitis, anaphylactoid reaction

Not known

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

Glossitis, constipation, dysgeusia, Ileus

Very Rare

Small bowel angioedema

Not Known

Pancreatitis*

Hepato-biliary disorders

Rare

Hepatic function disturbances

Not Known

Hepatitis, jaundice cholestatic

Skin and subcutaneous tissue disorders

Uncommon

Angioedema, rash, pruritus, hyperhidrosis, Exanthema, increased perspiration

Rare

Erythema multiforme, pemphigus, urticaria, psoriasis-like efflorescences

Very Rare

Dermatitis psoriasiform

Not Known

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

Back pain, myalgia

Renal and urinary disorders

Uncommon

Renal impairment, proteinuria

Very Rare

Kidney failure

Reproductive system and breast disorders

Uncommon

Erectile dysfunction

General disorders and administration site conditions

Common

Fatigue, asthenia, chest pain,

Uncommon

Generalised oedema, pyrexia, oedema peripheral, Angioedema (with swelling of face, lips, tongue, pharynx)

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 class specific.

Laboratory values: Transient increases in serum creatinine and urea values have been reported, especially in association with concomitant therapy with diuretics. 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.

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.

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

Treatment is symptomatic and supportive consistent with established medical care.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC code: C09AA06

Pharmacotherapeutic group: Angiotensin-converting enzyme (ACE) inhibitor.

Quinapril is rapidly de-esterified to quinaprilat (quinapril diacid, the principal metabolite), which is a potent angiotensin-converting enzyme (ACE) inhibitor.

ACE is a peptidyl dipeptidase that catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II which is involved in vascular control and function through many different mechanisms, including stimulation of aldosterone secretion by the adrenal cortex. The mode of action of quinapril in humans and animals is to inhibit circulating and tissue ACE activity, thereby decreasing vasopressor activity and aldosterone secretion.

In animal studies, the antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE, whereas, tissue ACE inhibition more closely correlates with the duration of antihypertensive effects. Administration of 10-40 mg of quinapril to patients with mild to severe hypertension results in a reduction of both sitting and standing blood pressure with minimal effect on heart rate. Antihypertensive activity commences within one hour with peak effects usually achieved by two to four hours after dosing. Achievement of maximum blood pressure lowering effects may require two weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained in most patients throughout the 24hour dosing interval and continue during long term therapy.

In a randomised clinical trial using target doses of 2.5, 5, 10 and 20 mg of quinapril, 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.

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.

5.2 Pharmacokinetic properties

Peak plasma quinapril tablets concentrations are observed within 1 hour of oral administration. The extent of absorption is approximately 60%, and is not influenced by food. Following absorption, quinapril is de-esterified to its major active metabolite, quinaprilat, and to minor inactive metabolites. Quinapril tablets have an apparent half-life of approximately one hour. Peak plasma quinaprilat concentrations are observed approximately 2 hours following an oral dose of quinapril. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of 3 hours. In patients with renal insufficiency and creatinine clearance of <40ml/min, peak and trough quinaprilat concentrations increase, time to peak concentration increases, apparent half-life increases, and time to steady state may be delayed. The elimination of quinaprilat is also reduced in elderly patients >65 years) and correlates well with the impaired renal function which frequently occurs in the elderly. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril tablets. Studies in rats indicate that quinapril tablets and its metabolites do not cross the blood-brain barrier.

The pharmacokinetics of quinapril has been studied in a single dose study (0.2 mg/kg) in 24 children aged 2.5 months to 6.8 years and a multiple dose study (0.016-0.468 mg/kg) in 38 children aged 5-16 years old, weighing 66-98 kg on average.

As in adults, quinapril was rapidly converted to quinaprilat. Quinaprilat concentrations generally peaked 1 to 2 hours post dose and declined with 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.”

Lactation:

After a single oral dose of 20mg of quinapril in six breast-feeding women 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 (<5µg/L) at all time points. It is estimated that a breastfed infant would receive about 1.6% of the material weight-adjusted dosage of quinapril.

5.3 Preclinical safety data

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

6. Pharmaceutical particulars
6.1 List of excipients

Core

Magnesium carbonate, Heavy

Calcium Sulfate dihydrate

Silica, Colloidal Anhydrous

Crospovidone

Povidone

Magnesium Stearate

Coating

Polyvinyl alcohol

Titanium dioxide (E171)

Talc

Lecithin

Iron Oxide Yellow (E172)

Xanthan gum

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Quinapril tablets are supplied in blister packs using aluminium as forming (base) material and aluminium foil as the lidding, which are further packed in cartons.

Packs of 1, 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100, 112, 250, 300 and 500 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Lupin Healthcare (UK) Limited

The Urban Building, 2nd floor

3-9 Albert Street, Slough, Berkshire

SL1 2BE, United Kingdom

8. Marketing authorisation number(s)

PL 35507/0050

9. Date of first authorisation/renewal of the authorisation

01/07/2010

10. Date of revision of the text

14/08/2018