SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Quinapril/Hydrochlorothiazide 10/12.5 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

10/12.5 mg:

Each film-coated tablet contains 10 mg of quinapril equivalent to 10.83 mg of quinapril hydrochloride and 12.5 mg hydrochlorothiazide.

Excipient with known effect: Each film-coated tablet contains 18.45 mg of lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

10mg/12.5mg:

Pink coloured, scored, oval shaped, biconvex, film-coated tablets debossed with ‘D’ on scored side and ‘18’ on other side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

CLINICAL PARTICULARS

Quinapril/Hydrochlorothiazide is indicated as substitution therapy only in adult patients with essential hypertension already adequately controlled with quinapril and hydrochlorothiazide given concurrently.

4.2 Posology and method of administration Posology

Patients receiving quinapril and hydrochlorothiazide from separate tablets may be switched to combination tablets of Quinapril/Hydrochlorothiazide containing the same component doses.

Adults:

The recommended dose of Quinapril/Hydrochlorothiazide is one tablet per day.

Renal impairment

Due to hydrochlorothiazide component, Quinapril/Hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.3, 4.4 and 5.2).

Elderly patients (>65 years old)

The dose should be kept as low as possible commensurate with achievement of adequate blood pressure control.

Children and adolescents (less than 18 years of age)

Quinapril/Hydrochlorothiazide is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

Method of administration For oral use.

To be taken with or without food. The dose should always time of day to help increase compliance.

•    Quinapril/HCTZ is contraindicated in Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

•    Quinapril/HCTZ is contraindicated in patients with hypersensitivity to any of the ingredients including patients with a history of angioedema related to previous treatment with ACE inhibitors or to any of the excipients listed in section 6.1.

•    Quinapril/HCTZ is contraindicated in patients with hereditary/idiopathic angioneurotic oedema.

•    Quinapril/HCTZ contraindicated in patients with dynamic left ventricular outflow obstruction.

•    Quinapril/HCTZ is contraindicated in patients with anuria or with severe renal dysfunction.

•    Quinapril/HCTZ is contraindicated in patients with hypersensitivity to other sulphonamide-derived drugs.

•    The concomitant use of Quinapril/HCTZ 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/HCTZ 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.

Hypotension:

Quinapril/HCTZ can cause symptomatic hypotension, usually not more frequently than either drug as monotherapy. 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).

Quinapril/HCTZ should be used cautiously in patients receiving concomitant therapy with other antihypertensive agents. The thiazide component of quinapril/HCTZ may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in postsympathectomized patients.

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 of any concomitant diuretic therapy should be considered if this event occurs.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy for hypertension may cause an excessive drop in blood pressure, which may be associated with oliguria, azotemia, and in rare instances, with acute renal failure and death in such patients. Quinapril/HCTZ therapy should be started under close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dosage is increased.

Heart Failure/Heart Disease:

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 rennin-angiotensin- aldosterone system, treatment with quinapril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.

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.

Renal Disease:

Quinapril/HCTZ should be used with caution in patients with renal disease. In severe renal disease thiazides may precipitate azotemia and in moderate renal impairment (creatinine clearance 10-20ml/min) thiazides are generally ineffective in such patients, and the effects of repeated dosing may be cumulative.

There is insufficient experience in patients with severe renal impairment (creatinine clearance <10 ml/min). Before ACE inhibitor treatment, renal artery stenosis should be excluded in renal transplant patients.

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.

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 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 preexisting renal impairment. Dosage reduction and/or discontinuation of a diuretic and/or quinapril may be required.

Impaired Hepatic Function:

Quinapril/HCTZ should be used with caution in patients with impaired hepatic function or progressive liver disease since minor alterations of fluid and electrolyte balance may result from thiazide treatment and may precipitate hepatic coma. Quinapril is rapidly deesterified to quinaprilat, (quinapril diacid, the principal metabolite), which, in human and animal studies, is a potent angiotensin-converting enzyme inhibitor. The metabolism of quinapril is normally dependent upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification 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/HCTZ and receive appropriate medical follow-up.

Immune-mediated drug reactions/ Anaphylactoid reactions:

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 rechallenge.

Stevens-Johnson syndrome and exacerbations or activation of systemic lupus erythematosus have been reported with thiazides.

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 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.

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.

Derangements of Serum Electrolytes:

Patients receiving quinapril/HCTZ should be observed for clinical signs of thiazide induced fluid or electrolyte imbalance. In such patients periodic determination of serum electrolytes (sodium and potassium in particular) should be performed. Because quinapril reduces the production of aldosterone, its combination with hydrochlorothiazide may minimise diuretic induced hypokalaemia.

The opposite effects of quinapril and hydrochlorothiazide on serum potassium will approximately balance each other in many patients so that no net effect upon serum potassium will be seen. In other patients, one or the other effect may be dominant and some patients may still require potassium supplements. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Calcium excretion is decreased by thiazides. In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid gland have been observed, with hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone resorption, and peptic ulceration) have not been seen.

Thiazides should be discontinued before performing tests for parathyroid function.

Thiazides increase the urinary excretion of magnesium, and hypomagnesemia may result. See section 4.5).

Other Metabolic Disturbances: Thiazide diuretics tend to reduce glucose tolerance and raise serum levels of cholesterol, triglycerides, and uric acid. These effects are usually minor, but frank gout or overt diabetes may be precipitated in susceptible patients.

Hypokalemia:

Conversely, treatment with thiazide diuretics has been associated with hypokalaemia, hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of the following: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, confusion, seizures and vomiting. Hypokalaemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or adrenocorticotrophic hormone (ACTH) (see Section 4.5).

Hyperkalaemia:

Concomitant medications that could raise serum potassium levels should be carefully considered. Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see Section 4.5).

Hypoglycaemia and Diabetes:

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).

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 a connective disease with the concomitant use of immunosuppressive or other agents which may be associated with neutropenia/agranulocytosis. Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) as this could be a sign of neutropenia (see Section 4.5).

Agranulocytosis has been rarely reported during treatment with quinapril. As with other ACE inhibitors, monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered.

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.

Acute Myopia and Secondary Angle-Closure Glaucoma:

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy

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).

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 Section 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.

Lactose:

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

Lithium:

Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Tetracycline and other drugs that interact with magnesium:

Because of the presence of magnesium carbonate in the formulation, quinapril has been shown in healthy volunteers to reduce the absorption of tetracycline in concomitant administration by 28-37%. It is recommended that concomitant administration with tetracycline be avoided. This interaction should be considered if coprescribing quinapril and tetracycline.

Agents increasing serum potassium:

Quinapril/HCTZ contains a thiazide diuretic, which tends to increase the urinary excretion of potassium but it also contains an ACE inhibitor, which tends to conserve potassium by lowering aldosterone levels. It is not advisable to routinely add potassium sparing diuretics or potassium supplements as this may result in elevated serum potassium.

Other diuretics:

Quinapril/HCTZ contains a diuretic. Concomitant use of another diuretic may have an additive effect. Also, patients on diuretics, especially those who are volume and/or salt depleted, may experience an excessive reduction of blood pressure on initiation of therapy, or with increased dosage of an ACE inhibitor.

Other antihypertensive drugs:

There may be an additive effect or potentiation when quinapril/HCTZ is combined with other antihypertensive drugs such as nitrates or vasodilators.

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).

Thiazides may decrease the arterial response to noradrenaline. In emergency surgery pre-anaesthetic and anaesthetic agents should be administered in reduced doses. Thiazides may increase the response to tubocurarine.

Lithium:

Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. 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. With quinapril/HCTZ, the risk of lithium toxicity may be increased. Quinapril/HCTZ should be administered with caution and frequent monitoring of serum lithium levels is recommended.

Corticosteroids, ACTH:

Intensified electrolyte depletion, particularly hypokalaemia has been observed.

Non-steroidal anti-inflammatory drugs:

In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing, and thiazide diuretics and may reduce the antihypertensive effect of ACE inhibitors. Therefore, when quinapril/HCTZ and nonsteroidal anti-inflammatory agents are used concomitantly the patients should be observed closely to determine if the desired effect of quinapril/HCTZ is obtained. 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.

Allopurinol, cytostatic and immunosuppressive agents, systemic corticosteroids or

procainamide:

Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.

Alcohol, barbiturates or narcotics:

Potentiation of orthostatic hypotension may occur.

Drugs associated with torsades de pointes:

Due to the potential risk of hypokalemia, caution should be used when hydrochlorothiazide is co administered with medicines such as digitalis glycosides or agents associated with torsades de pointes.

Antacids:

Antacids may decrease the bioavailability of quinapril/HCTZ .

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).

Pressor amines (e.g., norepinephrine):

Possible decreased response to pressor amines, but not sufficient to preclude their

use.

Anion exchange resins:

Absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins, such as cholestyramine and colestipol. Single doses of the resins bind the hydrochlorothiazide and reduce

its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Other Agents: No clinically important pharmacokinetic interactions occurred when quinapril was used concomitantly with propranolol, hydrochlorothiazide, digoxin or cimetidine.

The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice daily.

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).

4.6 Fertility,pregnancy and lactation

Pregnancy:

ACE-inhibitors:

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 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 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).

Hydrochlorothiazide:

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Breastfeeding /Quinapril:

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/Hydrochlorothiazide 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/Hydrochlorothiazide 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.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Quinapril/Hydrochlorothiazide during breast feeding is not recommended. If Quinapril/Hydrochlorothiazide is used during breast feeding, doses should be kept as low as possible.

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.

4.8 Undesirable effects

The following undesirable effects have been observed and reported during treatment with quinapril/HCTZ 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 form the available data).

System Organ Class	Frequency	Undesirable effects
Blood and the lymphatic system disorders	Not known	Agranulocytosis##, haemolytic anemia#^, neutropenia##, thrombocytopenia# eosinophilia#
Immune system disorders	Not known	Anaphylactoid reaction#
Metabolism and nutrition disorders	Common	Hyperkalaemia## gout#, hyperuricaemia#
	Uncommon	Glucose tolerance impaired
Psychiatric disorders	Common	Insomnia#
	Uncommon	Confusion#, depression#, nervousness#
Nervous system disorders	Common	Dizziness#, headache#, somnolence#
	Uncommon	Paraesthesia#, Transient ischaemic attacks# Syncope#, Dysgeusia#
	Rare	Balance disorder
	Not known	Cerebrovascular accident
Eye disorders	Uncommon	Amblyopia#
	Very Rare	Blurred vision#
Ear and labyrinth disorders	Uncommon	Tinnitus#, vertigo#
Cardiac disorders	Common	Angina pectoris##, tachycardia#, palpitations#
	Uncommon	Myocardial infarction#
	Not known	Arrhythmia
Vascular disorders	Common	Vasodilation#
	Uncommon	Hypotension#
	Not known	Orthostatic hypotension#
Respiratory, thoracic and	Common	Cough#,
mediastinal disorders	Uncommon	Dyspnoea#, dry throat
	Rare	Eosinophilic pneumonia##, upper airways obstruction by angioedema (that may be fatal)#
	Not known	Bronchospasm#

Gastrointestinal disorders	Common	Abdominal pain#, diarrhoea#, dyspepsia#, nausea#, vomiting#
	Uncommon	Flatulence#, dry mouth
	Rare	Constipation, glossitis
	Very Rare	Ileus#, small bowel angioedema
	Not known	Pancreatitis#
Hepato-biliary disorders	Not known	Hepatitis#, jaundice cholestatic #
Skin and subcutaneous tissue disorders	Uncommon	Alopecia#, photosensitivity reactions # pruritus#, rash#, angioedema##, hyperhidrosis ##
	Rare	Skin disorders may be associated with fever, muscle and joint pain (myalgias, arthralgias, arthritis), vascular inflammation (vasculitis), dermatitis psoriasiforms #
	Very Rare	Urticaria#
	Not known	Toxic epidermal necrolysis#, erythema multiforme#, exfoliative dermatitis#, pemphigus#, purpura, Stevens-Johnson syndrome#,
Musculoskeletal, connective tissue and bone disorders	Common	Back pain#, myalgia#,
	Uncommon	Arthralgia#
	Not known	Systemic lupus erythematosus
Renal and urinary disorders	Uncommon	Renal dysfunction#, proteinuria,
	Not known	Tubulointerstitial nephritis
Reproductive system and breast disorders	Uncommon	Erectile dysfunction #
General disorders and administration site conditions	Common	Asthenia#, Chest pain#, fatigue#
	Uncommon	Pyrexia #, generalised oedema#,#, peripheral oedema#
	Not known	Serositis
Investigations	Common	Blood creatinine increased#, blood urea increased#*
	Not known	Blood cholesterol increased#, blood triglycerides increased#, haematocrit decreased#, hepatic

		enzyme increased, blood bilirubin increased, antinuclear antibody increased#, red blood cell sedimentation rate increased.
Infections and infestations	Common	Bronchitis, upper respiratory tract infection, pharyngitis#, rhinitis#
	Uncommon	Viral infection, urinary tract infection, sinusitis
Endocrine disorders	Uncommon	Insulin requirements in diabetic patients may be altered by thiazides and latent diabetes mellitus may occur#

* 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.

Adverse reactions associated with quinapril component, frequencies observed when taking quinapril/HCTZ.

Adverse reactions associated with quinapril component, frequencies observed in quinapril, adverse reactions not associated with quinapril/HCTZ component.

<x> In patients with a congenital G-6-PDH deficiency, individual cases of haemolytic anaemia# have been reported.

Clinical Laboratory Test Findings:

Serum Electrolytes: (See section 4.4).

Serum Uric Acid, Glucose, Magnesium, PBI, Parathyroid Function tests and Calcium: (See section 4.4).

Haematology test: (See section 4.4).

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

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

No data are available for quinapril/HCTZ with respect to overdosage in humans.

The most likely clinical manifestation would be symptoms attributable to quinapril monotherapy overdosage such as severe hypotension, which would usually be treated by infusion of intravenous normal saline.

The most common signs and symptoms observed for HCTZ monotherapy overdosage are those caused by electrolyte depletion (hypokalaemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrythmias.

No specific information is available on the treatment of overdosage with quinapril/HCTZ.

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

Pharmacotherapeutic group: Quinapril and diuretics, ATC code: C09BA06

Quinapril/Hydrochlorothiazide is a fixed combination of the ACE inhibitor, quinapril, and a diuretic, hydrochlorothiazide. Concomitant administration of these agents reduces blood pressure to a greater degree than either component alone, given as monotherapy. Quinapril may, like other ACE inhibitors, counteract the loss of potassium that is inherent with hydrochlorothiazide.

Quinapril is a prodrug, which is hydrolysed to the active metabolite quinaprilat, a potent longacting 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 filtrationrate. 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.

Hydrochlorothiazide is a thiazide diuretic and an antihypertensive agent that increases renin activity in plasma. Hydrochlorothiazide decreases the renal reabsorption of electrolytes in distal tubuli and increases the excretion of sodium, chloride, potassium, magnesium, bicarbonate and water. The excretion of calcium may be reduced. Concomitant administration of quinapril and hydrochlorothiazide produces a stronger hypotensive effect than that of either of the agents, given alone as monotherapy.

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

Quinapril

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.

In patients with renal dysfunction the half-life of quinaprilat is prolonged and the plasma quinaprilat concentrations are elevated. In patients with severely impaired hepatic function the concentrations of quinaprilat are reduced due to inhibited hydrolysis of quinapril.

After a single oral dose of 20 mg of quinapril in six breast-feeding women, Milk/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.

Hydrochlorothiazide

The bioavailability is 60-80%. The diuretic effect is evident within 2 hours of administration, with a maximum effect after ca 4 hours. The effect is maintained for 6-12 hours. Hydrochlorothiazide is excreted unchanged through the kidneys. The mean plasma half-life is in the range of 5-15 hours.

The half-life of Hydrochlorothiazide is prolonged in patients with impaired renal function.

5.3 Preclinical safety data

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

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate Magnesium carbonate heavy Crospovidone (Type A) Povidone (K30)

Magnesium stearate

Tablet coat: (Opadry pink) Hypromellose Titanium dioxide (E171) Hydroxypropyl cellulose Macrogol 400 Iron oxide red (E172)

Iron oxide yellow (E172)

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Blister packs Polyamide/Al/PV/Al blister: 7, 10, 14, 20, 28, 30, 42, 50, 56, 60, 84, 90, 98, 100, 156, 250 and 500 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Milpharm Limited

Ares, Odyssey Business Park

West End Road, South Ruislip HA4 6QD

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16363/0256

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15/06/2010

10 DATE OF REVISION OF THE TEXT

25/11/2014