Quinapril

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) or concomitant DPP-IV inhibitor (e.g. vildagliptin) with quinapril therapy may be at increased risk for angioedema. Caution should be used when starting an mTOR inhibitor or a DPP-IV inhibitor in a patient already taking an ACE inhibitor.

The concomitant use of quinapril with sacubitril/valsartan is contraindicated, as the concomitant administration of inhibitors of neprilysin (NEP) and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be started until 36 hours after taking the last dose of quinapril therapy. Quinapril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan. Concomitant use of other NEP inhibitors (e.g. racecadotril) and quinapril may also increase the risk of angioedema.

Co-administration of quinapril with sympathomimetics may reduce the antihypertensive properties of ACE inhibitors.

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.

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.

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 azotaemia and rarely acute renal failure and/or death.

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. 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.

Potentiation of orthostatic hypotension may occur.

Antacids may decrease the bioavailability of quinapril.

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

Patients treated with diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with quinapril. This hypotensive effect may be effectively minimised by either discontinuing the diuretic a few days prior to initiation of therapy, or increasing the salt intake prior to the initial dose of quinapril. If discontinuation of the diuretic is not possible, the starting dose of quinapril should be reduced and medical supervision should be provided for up to two hours following administration of the initial dose.

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

Quinapril is an ACE inhibitor capable of lowering aldosterone levels, which in turn can result in elevation in serum potassium. Concomitant treatments with potassium sparing diuretics, potassium supplements, potassium salts or other drugs known to raise serum potassium levels 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.

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.

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.

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

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

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by NSAIDs.

Concomitant administration of allopurinol, cytostatic and immunosuppressive agents, systemic corticosteroids or procainamide with ACE inhibitors may lead to an increased risk for leukopenia.

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. These drugs 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.

In patients who are elderly or have compromised renal function, co-administration of an ACE inhibitor with sulfamethoxazole/trimethoprim has been associated with severe hyperkalaemia, which is thought to be due to trimethoprim. Quinapril and trimethoprim-containing products should therefore be co-administered with caution and with appropriate monitoring of serum potassium.

Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH) and subsequent hyponatraemia has been observed in some patients treated with other ACE inhibitors. It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatraemia.

Patients receiving ACE inhibitors during desensitising treatment with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation, but they have reappeared upon inadvertent re-challenge.

Patients on quinapril alone may have increased serum potassium levels. Because of the risk of further potentiating increases in serum potassium it is advised that combination therapy with potassium-sparing diuretics or other drugs known to raise serum potassium levels, be initiated with caution and the patient’s serum potassium levels be closely monitored. When administered concomitantly, quinapril may reduce the hypokalaemia induced by thiazide diuretics.

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.

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.

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.

Quinapril should be used in caution in selected patients with aortic stenosis.

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.

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (e.g. sodium aurothiomalate) and concomitant ACE inhibitor therapy.

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimester of pregnancy.

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/or death in the newborn) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Limb contractures, craniofacial deformities, hypoplastic lung development and intrauterine growth retardation have been reported in association with oligohydramnios.

Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia. If oliguria occurs, attention should be directed towards support of blood pressure and renal perfusion.

Limited pharmacokinetic data demonstrate very low concentrations in breast milk. 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 the case of an older infant, the use of quinapril 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.

There are no studies on the effect of this medicine on the ability to drive. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.

The following undesirable effects have been observed and reported during treatment with quinapril 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 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%).

Infections and infestations

Common: Pharyngitis, rhinitis

Uncommon: Bronchitis, upper respiratory tract infection, urinary tract infection, sinusitis

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

Not Known: Hyponatraemia

Psychiatric disorders

Common: Insomnia

Uncommon: Confusional state, depression, nervousness

Nervous system disorders

Common: Dizziness, headache, paraesthesia

Uncommon: Transient ischaemic attack, somnolence

Rare: Balance disorder, syncope

Not Known: Cerebrovascular accident/cerebral haemorrhage

Eye disorders

Uncommon: Amblyopia

Very Rare: Vision blurred

Ear and labyrinth disorders

Uncommon: Vertigo, tinnitus

Cardiac disorders

Uncommon: Myocardial infarction, angina pectoris, tachycardia, palpitations

Vascular disorders

Common: Hypotension

Uncommon: Vasodilatation

Not Known: Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, cough

Uncommon: Dry throat

Rare: Eosinophilic pneumonia

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

Very Rare: Ileus, small bowel angioedema

Not Known: Pancreatitis*

Hepato-biliary disorders

Not Known: Hepatitis, jaundice cholestatic

Skin and subcutaneous tissue disorders

Uncommon: Angioedema, rash, pruritus, hyperhidrosis

Rare: Erythema multiforme, pemphigus, urticaria

Very Rare: Dermatitis psoriasis forms

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

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

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.

* Pancreatitis has been reported rarely in patients treated with ACE inhibitors; in some cases this has proved fatal.
** Such increases are more likely to occur in patients receiving concomitant diuretic therapy than those on monotherapy with quinapril. These observed increases will often reverse on continued therapy.

Vasculitis and gynecomastia have been reported with other ACE inhibitors and it cannot be excluded that these unwanted effects are class specific.

Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent hyponatraemia has been observed in some patients treated with other ACE inhibitors.