Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Accupro is contraindicated:
Quinapril should be used in caution in selected patients with aortic stenosis.
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 and anaphylactic reactions.
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 (LDL) apheresis with dextran-sulfate. This method should therefore not be used in patients treated with 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.
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.
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, quinapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion (see section 4.5).
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 (see Hypotension below and section 4.5). When administered concomitantly, quinapril may reduce the hypokalaemia induced by thiazide diuretics.
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.
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 during the first month of treatment with an ACE inhibitor (see section 4.5).
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.
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 (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 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. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or quinapril may be required.
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
There is insufficient experience in patients with severe renal impairment (creatinine clearance <10 mL/min). Treatment is therefore not recommended in these patients.
Angioedema has been reported in patients treated with ACE 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).
The combination of quinapril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section 4.3). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of quinapril therapy. If treatment with sacubitril/valsartan is stopped, quinapril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may also increase the risk of angioedema (see section 4.5). Hence, a careful benefit-risk assessment is needed before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients on quinapril.
Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) or concomitant DPP-IV inhibitor (e.g. vildagliptin) 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.
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-black patients.
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.
Symptomatic hypotension was rarely seen in uncomplicated hypertensive patients treated with Accupro but it is a possible consequence of ACE inhibitor therapy particularly in salt/volume depleted patients such as those previously treated with diuretics, who have a dietary salt reduction, who are on dialysis, have diarrhoea or vomiting or have severe renin-dependent hypertension. If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses; however, lower doses of quinapril or any concomitant diuretic therapy should be considered if this event occurs.
In patients with congestive heart failure, who are at risk of excessive hypotension, quinapril therapy should be started at the recommended dose under close medical supervision; these patients should be followed closely for the first 2 weeks of treatment and whenever the dosage of quinapril is increased.
Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
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.
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).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not use this medicine.
Because of the presence of magnesium carbonate in the formulation, Accupro 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.
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 Accupro. 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 Accupro. If discontinuation of the diuretic is not possible, the starting dose of Accupro should be reduced and medical supervision should be provided for up to two hours following administration of the initial dose (see sections 4.4 and 4.2).
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. When administered concomitantly, quinapril may reduce the hypokalaemia induced by thiazide diuretics. 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.
Although no data are available to indicate there is an interaction between Accupro 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).
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, 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.
Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) or concomitant DPP-IV inhibitor (e.g. vildagliptin) 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 inhibition 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 (see sections 4.3 and 4.4). Concomitant use of other NEP inhibitors (e.g. racecadotril) and quinapril may also increase the risk of angioedema (see section 4.4).
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.
Concomitant administration with ACE inhibitors may lead to an increased risk for leukopenia.
Potentiation of orthostatic hypotension may occur.
There may be an additive effect or potentiation.
Co-administration of multiple 10 mg doses of atorvastatin with 80 mg quinapril resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Antacids may decrease the bioavailability of quinapril.
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 (see section 4.4).
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).
Do not co-administer aliskiren with quinapril in patients with diabetes or in patients with renal impairment (GFR <60 mL/min/1.73m²).
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 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative 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) (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. 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 (see sections 4.3 and 4.4). 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 (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of Accupro 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 Accupro 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%).
Common: Pharyngitis, rhinitis
Uncommon: Bronchitis, upper respiratory tract infection, urinary tract infection, sinusitis
Not Known: Agranulocytosis, haemolytic anaemia, neutropenia, thrombocytopenia
Not Known: Anaphylactoid reaction
Common: Hyperkalaemia
Not Known: Hyponatraemia (see section 4.4)
Common: Insomnia
Uncommon: Confusional state, depression, nervousness
Common: Dizziness, headache, paraesthesia
Uncommon: Transient ischaemic attack, somnolence
Rare: Balance disorder, syncope
Not Known: Cerebrovascular accident/cerebral haemorrhage
Uncommon: Amblyopia
Very Rare: Vision blurred
Uncommon: Vertigo, tinnitus
Uncommon: Myocardial infarction, angina pectoris, tachycardia, palpitations
Common: Hypotension
Uncommon: Vasodilatation
Not Known: Orthostatic hypotension
Common: Dyspnoea, cough
Uncommon: Dry throat
Rare: Eosinophilic pneumonia
Not Known: Bronchospasm. In individual cases, upper airways obstruction by angioedema (that may be fatal).
Common: Vomiting, diarrhoea, dyspepsia, abdominal pain, nausea
Uncommon: Flatulence, dry mouth
Rare: Glossitis, constipation, dysgeusia
Very Rare: Ileus, small bowel angioedema
Not Known: Pancreatitis*
Not Known: Hepatitis, jaundice cholestatic
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).
Common: Back pain, myalgia
Uncommon: Renal impairment, proteinuria
Uncommon: Erectile dysfunction
Common: Fatigue, asthenia, chest pain
Uncommon: Generalised oedema, pyrexia, oedema peripheral
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 (see section 4.4).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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