ACE inhibitors / thiazide diuretics (thiazides).

Quinapril, hydrochlorothiazide

Pink scored elliptical f-c tablets.

Tablets, quinapril 10mg, hydrochlorothiazide 12.5mg.

Treatment of all grades of essential hypertension in patients who have been stabilised on the individual components given in the same proportions. given in the same proportions.

For patients currently not receiving a diuretic, whether or not they have been receiving quinapril monotherapy, the recommended initial dosage of quinapril/HCTZ is 10/12.5mg. Following initial therapy, the dose may be increased to 20/25mg. Effective blood pressure control is usually achieved with a dosage of 10/12.5mg. Effective blood pressure control is usually achieved with a dosage of 10/12.5mg.

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

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. Accuretic 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.

Renal Impairment:

Accuretic is not recommended for use in patients with creatinine clearance of less than 40 ml/min.

Not recommended. Safety and efficacy in children has not been established.

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

• Accuretic is contra-indicated throughout pregnancy.
• Accuretic is contra-indicated in nursing mothers.
• Accuretic is contra-indicated in patients with hypersensitivity to any of the ingredients.
• Accuretic is contra-indicated in patients with anuria or hypersensitivity to quinapril, thiazides or any sulphonamide derived drug.
• Accuretic is contra-indicated in patients with aortic stenosis or outflow obstruction.
• Accuretic is contra-indicated in patients with a history of angioedema related to previous treatment with ACE inhibitors.
• Accuretic is contra-indicated in patients with hereditary/idiopathic angioneurotic oedema

Hypotension:

Accuretic can cause symptomatic hypotension, usually not more frequently than either drug as monotherapy. Symptomatic hypotension was rarely seen in uncomplicated hypertensive patients treated with quinapril but is a possible consequence of ACE inhibition therapy in salt/volume depleted patients such as those previously treated with diuretics, who have a dietary salt restriction, or who are on dialysis. The thiazide component of Accuretic may potentiate the action of other antihypertensive drugs. 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 the drug should be considered if this event occurs.

Sensitivity reactions:

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma, e.g. purpura, photosensitivity, urticaria, necrotising angitis, respiratory distress including pneumonitis and pulmonary oedema, anaphylactic reactions.

 Renal Disease:

Accuretic 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.

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.

The half-life of quinaprilat (the main active metabolite of quinipril) is prolonged as creatinine clearance falls. Patients with a creatinine clearance of <40 ml/min require a lower initial dosage of quinapril. 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 hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or quinapril may be required.

Anaphylactoid reactions:

Desensitisation: Patients receiving ACE inhibitors during desensitising 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 inadvertant rechallenge.

LDL apheresis: Patients undergoing low-density lipoprotein apheresis with dextran-sulfate absorption when treated concomitantly with an ACE inhibitor, have reported anaphylactoid reactions.

Haemodialysis:

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.

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 with Accuretic should be discontinued immediately; the patient should be treated in accordance with accepted medical care and carefully observed until the swelling disappears. In instances where the 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, emergency therapy including, but not limited to, subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 ml) should be promptly administered.

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.

Black patients receiving ACE inhibitor therapy have been reported to have a higher incidence of angioedema compared to non-black patients.

Liver Disease:

Accuretic should be used cautiously in patients with impaired hepatic function or progressive liver disease because of the known risks associated with alterations in fluid and electrolyte imbalance resulting from thiazide treatment. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril.

Patients receiving Accuretic should be observed for clinical signs of thiazide induced fluid or electrolyte imbalance. In such patients periodic determination of serum electrolytes should be performed. Because quinapril reduces the production of aldosterone, its combination with hydrochlorothiazide may minimise diuretic induced hypokalaemia. However, some patients may still require potassium supplements.

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

Hypoglycaemia and Diabetes:

ACE inhibitors have been associated with hypoglycaemia in diabetic patients on insulin or oral hypoglycaemic agents. Closer monitoring of diabetic patients may be required.

Cough:

Cough has been reported with the use of ACE inhibitors including quinapril. 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.

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

Tetracycline and other drugs that interact with magnesium :

Because of the presence of magnesium carbonate in the formulation it is recommended that concomitant administration of Accuretic with tetracycline be avoided.

Agents increasing serum potassium:

Accuretic 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:

Accuretic 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.

Surgery/anaesthesia:

Although no data are available to indicate that there is an interaction between Accuretic and anaesthetic agents that produce 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 resin release. This may lead to hypotension which can be corrected by volume expansion.

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:

Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy or lithium and thiazide therapy. Lithium should not generally be given with Accuretic since the risk of lithium toxicity may be increased.

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 Accuretic and non-steroidal anti-inflammatory agents are used concomitantly the patients should be observed closely to determine if the desired effect of Accuretic 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.

Other antihypertensive drugs:

There may be an additive effect or potentiation.

Antacids:

May decrease the bioavailability of Accuretic.

Antidiabetic drugs (oral hypoglycaemic agents and insulin):

Dosage adjustments of the antidiabetic drug may be required.

The following adverse reactions have been reported in patients taking Accuretic. The adversereactions are classified according to frequencies determined from clinical trials data.

Very common 1/10 (10%)

Common 1/100 and <1/10 (1% and <10%)

Uncommon 1/1000 and <1/100 (0.1% and <1%)

Rare 1/10,000 and <1/1000 (0.01% and 0.1%)

Very rare < 1/10,000 (<0.1%)

*If a listed adverse reaction term was not reported in clinical trials it was assumed to be rare, based on reporting rates versus estimated product use worldwide.

ADVERSE REACTIONS REPORTED IN PATIENTS TAKING QUINAPRIL

Infections and infestations

Uncommon Urinary tract infection

Blood and Lymphatic System disorders

Rare Agranulocytosis*, haemolytic anaemia*, neutropenia*, thrombocytopenia*

Immune System Disorders

Rare Anaphylactoid reaction*

Endocrine disorders

Uncommon Insulin requirements in diabetic patients may be altered by thiazides and latent diabetes mellitus may occur.

 Metabolism and Nutrition Disorders

Common Hyperkalemia

Psychiatric Disorders

Common Insomnia

Uncommon Confusion, depression, nervousness

Nervous System Disorders Common Dizziness, headache, paresthesia

UncommonSomnolence, taste disturbances, transient ischaemic attacks

Rare Syncope*

Very rare Cerebral haemorrhage*

Eye Disorders

Uncommon Amblyopia

Very rare Blurred vision

Ear and Labyrinth Disorders

Uncommon Tinnitus, vertigo

Cardiac Disorders

Uncommon Angina pectoris, myocardial infarction, palpitations, tachycardia

Vascular Disorders

Common Hypotension, Postural hypotension*

Uncommon Vasodilatation

Respiratory, Thoracic and Mediastinal Disorders

Common Coughing, dyspnea, pharyngitis, rhinitis

Rare Bronchospasm*, eosinophilic pneumonitis

In individual cases angioneurotic oedema involving the upper airways has caused fatal airway instruction.

Gastrointestinal Disorders

Common Abdominal pains, diarrhoea, dyspepsia, nausea, vomiting

Uncommon Dry mouth or throat, flatulence, pancreatitis

Very rare Ileus

Hepato-biliary Disorders

Rare Hepatitis*, cholestatic icterus*

Skin and Subcutaneous Tissue Disorders

Uncommon Angioedema, increased perspiration, pruritus, rash

Rare Alopecia*, epidermic necrolysis*, eosinophilia* and/or increased ANA-titers*, exfoliative dermatitis*, pemphigus*, photosensitivity reaction*, urticaria

Very rare Psoriasis-like efflorescences

Musculoskeletal and Connective Tissue Disorders

Common Back pain, myalgia

Uncommon Arthralgia, hyperuricaemia may occur or frank gout be precipitated by thiazides in certain patients.

Renal and Urinary Disorders

Uncommon Renal dysfunction

Reproductive System and Breast Disorders

Uncommon Impotence 

General Disorders and Administration Site Conditions

Common Chest pain, fatigue

Uncommon Fever, generalized oedema, peripheral oedema 

Investigations

Common Increased serum creatinine, increased blood urea nitrogen.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Decreases in hematocrit and white cell count as well as elevation of liver enzymes and serum bilirubin. In patients with a congenital deficiency concerning G-6-PDH, individual cases of hemolytic anaemia have been reported. 

ADVERSE REACTIONS REPORTED IN PATIENTS TAKING QUINAPRIL/HYDROCHLOROTHIAZIDE

Infections and Infestations

Uncommon Urinary tract infection

Common Upper respiratory infection, viral infection 

Blood and Lymphatic System Disorders

Rare Haemolytic anaemia*, thrombocytopenia*

Immune System Disorders

Rare Anaphylactoid reaction*

Endocrine disorders

Uncommon Insulin requirements in diabetic patients may be altered by thiazides and latent diabetes mellitus may occur.

Psychiatric Disorders

Common Insomnia

Uncommon Confusion, depression, nervousness

Nervous System Disorders

Common Dizziness, headache, somnolence

Uncommon Paresthesia, syncope, taste disturbances, transient ischaemic attacks

Rare Cerebral haemorrhage*

Eye Disorders Uncommon Amblyopia Very rare blurred vision

Ear and Labyrinth Disorders

Uncommon Tinnitus, vertigo

Cardiac Disorders

Common Myocardial infarction

Uncommon Palpitations, tachycardia 

Vascular Disorders

Common Vasodilatation, Postural hypotension*

Uncommon Hypotension

Respiratory, Thoracic and Mediastinal Disorders

Common Bronchitis, coughing, pharyngitis, rhinitis,

Uncommon Dyspnea, sinusitis

Rare Bronchospasm*

In individual cases angioneurotic oedema involving the upper airways has caused fatal airway obstruction.

Gastrointestinal Disorders

Common Abdominal pains, diarrhoea, dyspepsia, nausea, vomiting

Uncommon Flatulence, dry mouth or throat

Rare Pancreatitis*

Very rare Ileus

Hepato-biliary Disorders

Rare Hepatitis*, Cholestatic icterus*

Skin and Subcutaneous Tissue Disorders

Uncommon Alopecia, photosensitivity reaction, pruritus, rash

Rare Epidermic necrolysis*, erythema multiforme*, exfoliative dermatitis*, pemphigus*, Stevens Johnson syndrome*, eosinophilia* and/or increased ANA-titers*, psoriasis-like efflorescences

Very rare Urticaria

Musculoskeletal and Connective Tissue Disorders

Common Back pain, myalgia, hyperuricaemia may occur or frank gout be precipitated by thiazides in certain patients

Uncommon Arthralgia

Renal and Urinary Disorders

Uncommon Renal dysfunction

Reproductive System and Breast Disorders

Uncommon Impotence

General Disorders and Administration Site Conditions

Common Asthenia, chest pain, fatigue

Uncommon Fever, peripheral oedema

Investigations

Uncommon Increased serum creatinine, increased blood urea nitrogen.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Decreases in hematocrit and white cell count as well as elevation of liver enzymes and serum bilirubin. In patients with a congenital deficiency concerning G-6-PDH, individual cases of haemolytic anaemia have been reported.

Parke-Davis

(POM)