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Drugs List
Therapeutic Indications
Dosage
Administration
Contraindications
Precautions and Warnings
Pregnancy and Lactation
Side Effects
Monograph

Precautions and Warnings

In patients with uncomplicated hypertension, symptomatic hypotension has been observed rarely after the initial dose of quinapril as well as after increasing the dose of quinapril. It is more likely to occur in patients who have been volume and salt-depleted by prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea, vomiting or patients with severe renin dependent hypertension. Therefore, in these patients, diuretic therapy should be discontinued and volume and/or salt depletion should be corrected before initiating therapy with quinapril.

If symptomatic hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of physiological saline. Treatment with quinapril may usually be continued at lower doses following restoration of effective blood volume and blood pressure.

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, azotaemia and in rare cases, with acute renal failure and death. Therapy should be started under close medical supervision. Patients should be closely monitored for the first two weeks of treatment and whenever the dosage is increased.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients. 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 azotaemia and rarely acute renal failure and/or death.

Renal impairment - see Dosage - Patients with Renal Impairment .

Renal function should be assessed prior to initiation of therapy and during treatment in all patients. There is a risk of impairment of renal function particularly in patients with existing renal impairment and congestive heart failure. If recognised early, such impairment of renal function is reversible upon discontinuation of therapy. A specialist should be involved if renal function is significantly reduced as a result of treatment with an ACE inhibitor. Patients with renal impairment may be at risk of hyperkalaemia.

Patients with bilateral renal artery stenosis and unilateral renal artery stenosis in the single kidney may experience increases in blood urea nitrogen and serum creatinine. These usually return to normal after discontinuation of therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease (plus patients with unilateral or bilateral renal artery stenosis), may develop minor and usually transient increases in blood urea nitrogen and serum creatinine when quinapril is given, in particular concomitantly with a diuretic. Dosage reduction of quinapril and/or discontinuation of the diuretic may be required.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

Use with caution in peripheral vascular disease or severe generalised atherosclerosis due to the risk of clinically silent renovascular disease.

Quinapril should be used with caution in patients with aortic stenosis and hypertrophic obstructive cardiomyopathy.

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 dialysis. Similar reactions have been observed during low-density lipoprotein apheresis with dextran sulfate. This method should, therefore, not be used in patients treated with ACE inhibitors.

Temporarily withhold ACE inhibitor therapy prior to desensitisation to hymenoptera venom.

Steven-Johnson syndrome and exacerbations/activation of systemic lupus erythematosus have been reported with thiazide use.

Angioneurotic oedema has occurred in very rare cases. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with quinapril and hydrochlorothiazide must be discontinued and appropriate therapy instituted immediately. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.

Intestinal angioedema has been reported in association with ACE inhibitor use. This has been diagnosed with procedures including abdominal CT scan or ultrasound or during surgery These patients experienced abdominal pain (without nausea or vomiting). In some cases there was no history of facial angioedema and C-1 esterase levels were normal. Symptoms were resolved after discontinuation of the ACE inhibitor.

Black patients on ACE inhibitor therapy generally have a higher incidence of angioedema than non-black patients. Afro-Caribbean patients may also show a reduced response to blood pressure lowering.

Caution in patients with hepatic impairment or progressive hepatic disease - see Dosage Patients with Hepatic Impairment . Rarely ACE inhibitors have been associated with a syndrome beginning as cholestatic jaundice and progressing to a fulminant hepatic necrosis, in some cases fatal. Patients who develop jaundice or elevated hepatic enzymes should discontinue treatment and receive appropriate medical follow up.

Observe for signs of thiazide induced fluid or electrolyte imbalance. Periodic determination of serum electrolytes should be performed. Although the quinapril component may reduce diuretic induced hypokalaemia, some patients may still require potassium supplements. Potassium sparing diuretics, potassium supplements or drugs that may increase serum potassium levels should only be co-administered cautiously. Patients should be advised to avoid the use of potassium containing salt substitutes or a high intake of potassium rich foods as these may lead to significant increases in serum potassium.

Agranulocytosis and bone marrow depression have been seen rarely in patients on ACE inhibitors. These are more frequent in patients with renal impairment, especially if they have a connective tissue 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, as this could be a sign of neutropenia. 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.

In patients undergoing surgery or during anaesthesia with agents producing 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 appropriate treatment.

Use with caution in the elderly, patients with nephrotic syndrome, hyperaldosteronism and malnutrition.
May precipitate gout in susceptible patients.

May aggravate or precipitate diabetes mellitus.
Diabetic control may need adjustment as therapy may cause diminished glucose tolerance. Close monitoring of these patients is required.

Hydrochlorothiazide may rarely cause acute transient myopia and acute angle-closure glaucoma within hours to weeks of drug initiation. Symptoms include acute onset or decreased visual acuity or ocular pain. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Alcohol may potentiate orthostatic hypotension.

Antacids may decrease the bioavailability of quinapril with hydrochlorothiazide.

ACE inhibitors are associated with a non-productive/persistent cough. This should resolve on discontinuation.

NSAIDS may reduce antihypertensive effect and increase risk of renal impairment. Patients should be advised not to purchase these unless on medical advice.

This treatment may affect the ability to drive and operate machinery as dizziness and fatigue are side effects.

Contains lactose, use with caution in patients with glucose - galactose malabsorption syndrome or lactose intolerance.

Women of child-bearing age should take adequate contraceptive precautions whilst on this medication.

Breastfeeding (see Lactation section)

Dose dependent increased risk of non-melanoma skin cancer with exposure to increasing cumulative doses of hydrochlorothiazide.

Use with caution in patients who have had previous skin cancer.

Advise patient to monitor for and report any skin changes.

Advise patient to minimise exposure to sunlight and avoid sunlamps during therapy.

Pregnancy and Lactation

Pregnancy

The use of quinapril and hydrochlorothiazide during pregnancy is contraindicated.

Quinapril appears to be a human teratogen. The drug produces foetal hypocalvaria and renal defects which is probably related to foetal hypotension and decreased renal blood flow. Two reviews have indicated that both renal perfusion and glomerular plasma flow are low during gestation. In order for the foetus to maintain glomerular filtration at low pressures high levels of angiotensin ll may be necessary. Quinapril prevents conversion of angiotensin l to angiotensin ll which may lead to in utero renal failure. The main method of removal of this drug is via the kidneys and impairment of this system will prevent elimination of the drug.

ACE inhibitors are contraindicated during the second and third trimesters of pregnancy as exposure during these trimesters is known to induce human foetal toxicity (renal dysfunction, oligohydramnios, pulmonary hypoplasia, patent ductus arteriosus, delay in skull ossification, neonatal toxicity and even death). Severe and sometimes fatal anuria in the foetus and in the newborn have been observed and is thought to be caused by the compromise of the foetal renal system. Foetal renal failure resulting from in utero exposure to ACE inhibitors has been reported where dialysis has been required shortly after birth. Evidence of a risk of teratogenicity in the first trimester exposure is conflicting, however, the MHRA advises that a risk cannot be excluded. Recent data published does associate first trimester ACE inhibitor exposure with congenital CNS and cardiovascular defects. Unless treatment with an ACE inhibitor is considered absolutely essential, women who are planning to become pregnant should be switched to an alternative drug with an established safety record. If exposure has occurred in the first trimester a detailed ultrasound diagnosis is advisable. Exposure to an ACE inhibitor during pregnancy is not an indication for either invasive diagnostic procedures or termination of pregnancy. In cases involving long term prenatal therapy in the second and/ or third trimesters, the foetus should be monitored for the potential development of oligohydramnios, and foetal growth should be assessed with detailed ultrasound scans (Schaefer, 2007).

Hydrochlorothiazide is contraindicated during pregnancy for hypertension. Hydrochlorothiazide is known to cross the placenta. Risks to the foetus or newborn include bone marrow depression, hypoglycaemia, thrombocytopenia, hyponatraemia, hypokalaemia, jaundice and death from maternal complications. Prolonged labour has also been described as the result of inhibition of smooth muscle action caused by hydrochlorothiazide.

Diuretics are no longer used as part of the standard therapy for hypertension and oedema during pregnancy, due to the maternal, hypovolaemic character of the disease. Many sources contraindicate the use of diuretics during pregnancy, except for patients with heart disease, mainly because they do not prevent or alter the course of toxaemia and they may decrease placental perfusion. If long term treatment is necessary the mother's electrolytes and haematocrit should be measured and the foetus should be monitored for the development of oligohydramnios. The newborn should also be monitored for hyperglycaemia and thrombocytopenia.

Adequate contraceptive measures should be used whilst on this medication. If pregnancy occurs this drug should be discontinued immediately.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Licensed in pregnancy? - No, contraindicated

Recommended for use in pregnancy? - No

Known human teratogen? - Yes

Crosses placenta? - Hydrochlorothiazide - yes, quinapril - unknown

Effects on foetus - ACE inhibitors can cause renal dysfunction, oligohydramnios, pulmonary hypoplasia, patent ductus arteriosus, death, anuria, renal failure. Hydrochlorothiazide will exacerbate the hypovolaemia characteristic to hypertension in pregnancy and could therefore reduce placental perfusion, adversely affecting the foetus.

Lactation

Quinapril and hydrochlorothiazide may be considered during breastfeeding of older infants.

Quinapril is excreted into breast milk. The authors of one study, where a 20mg oral dose of quinapril was given to 6 healthy mothers who had been breastfeeding for 2 weeks, have estimated the infant dose as 1.6% of the mother's weight adjusted dose.

The MHRA has stated that although ACE inhibitors are not generally recommended for use by breastfeeding mothers they are not absolutely contraindicated and may be prescribed if treatment is considered essential. The MHRA states that ACE inhibitors should not be used by breastfeeding mothers in the first few weeks after delivery because of possible profound neonatal hypotension particularly in preterm infants. If ACE inhibitor therapy is considered essential for the mother the use of captopril, enalapril or quinapril may be considered when the infant is older. The infant should be carefully followed up for signs of hypotension should ACE inhibitor treatment be deemed necessary.

The UK Drugs in Lactation Advisory Service states that there is insufficient information available to allow for classification as safe. LactMed states that the low levels found in breast milk would not be expected to cause any adverse effects in the newborn and Briggs (2011) suggests that quinapril is probably compatible with breast feeding.

Hydrochlorothiazide is excreted in small quantities into breast milk. There have been reports of thrombocytopenia in the nursing infants of mothers receiving a thiazide diuretic, however, the risk is considered low by Hale (2010) and Briggs (2011). Thiazide diuretics have been used in large quantities to suppress lactation. Overall, hydrochlorothiazide is considered safe while breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Drug excreted in breast milk? - Yes, both quinapril and hydrochlorothiazide are excreted in small amounts.

Considered suitable or recommended by manufacturer? - No.

MHRA/ UK Drugs in Lactation Advisory Service Classification for quinapril - Maybe suitable for use during breastfeeding of older infants.

UK Drugs in Lactation Advisory Service Classification for hydrochlorothiazide - safe except in large quantities.

Drug substance licensed in infants? - No.

Drug known to affect lactation? - Thiazide diuretics have been used in large quantities to suppress lactation.

Presentation

Tablets containing 10mg quinapril (as quinapril hydrochloride) and 12.5mg hydrochlorothiazide.

Drugs List

ACCURETIC 12.5mg+10mg tablets

hydrochlorothiazide 12.5mg and quinapril 10mg tablets

Therapeutic Indications

Uses

Essential hypertension in patients already stabilised on the individual components.

Dosage

Adults

One (10mg+12.5mg) tablet daily is usually effective. Dose may be increased up to two tablets (20mg+25mg) daily as indicated by blood pressure response.

Elderly

Dose should be kept as low as possible.

Children

Not recommended in children as safety and efficacy have not been established.

Patients with Renal Impairment

Creatinine clearance below 40ml/minute:
Not recommended, but if necessary patient can be started on a lower dose of quinapril, using single ingredient products. Dose can then be titrated upwards as appropriate based on therapeutic response. Renal function should be closely monitored.

Thiazides are considered ineffective at a creatinine clearance below 30ml/minute.

Patients with Hepatic Impairment

Contraindicated in severe hepatic impairment.

Use with caution in patients with mild or moderate hepatic impairment or progressive liver disease since minor alterations of fluid and electrolyte balance may result from thiazide treatment and may precipitate hepatic coma.

The metabolism of quinapril is normally dependant on hepatic esterase. Concentrations of the active metabolite quinaprilat are reduced in patients with alcoholic cirrhosis.

Administration

For oral administration, with or without food at approximately the same time each day.

Contraindications

Anuria
Hypersensitivity to sulfonamide derivatives
Ventricular outflow tract obstruction
History of angioedema with previous ACE inhibitor therapy
Hereditary/idiopathic angioneurotic oedema
Refractory hypokalaemia
Hyponatraemia
Hypercalcaemia
Symptomatic hyperuricaemia
Addison's disease
Severe hepatic impairment
Renal impairment (creatinine clearance below 40ml/minute) - see Dosage - Patients with Renal Impairment.
Severe bilateral renal artery stenosis
Severe unilateral renal artery stenosis of a solitary functioning kidney
Pregnancy (see Pregnancy section)
Children under 18 years
Withdraw ACE-inhibitor before desensitisation or apheresis
Haemodialysis using high-flux polyacrylonitrile membranes
Galactosaemia