Four.1 Therapeutic warning signs
(1) For the treatment of all grades of critical hypertension. Accupro is effective as monotherapy or concomitantly with diuretics in sufferers with high blood pressure (see sections four.3, 4.Four, 4.5 and five.1).
(2) For the remedy of congestive coronary heart failure when given concomitantly with a diuretic and/or cardiac glycoside. Treatment of congestive coronary heart failure with Accupro ought to constantly be initiated underneath near medical supervision.
4.2 Posology and technique of administration
Posology
Adults
Hypertension
- Monotherapy:
The encouraged preliminary dosage is 10 mg once each day in uncomplicated high blood pressure. Depending upon clinical response, patient's dosage can be titrated (via doubling the dose allowing adequate time for dosage adjustment) to a protection dosage of 20 mg/day to 40 mg/day given as a unmarried dose or divided into 2 doses. Long-term control is maintained in maximum patients with a unmarried daily dosage routine. Patients have been handled with dosages up to eighty mg/day. Take either with or without meals. The dose ought to continually be taken at approximately the identical time of day to help increase compliance.
- Concomitant Diuretics:
In order to decide if excess hypotension will arise, an preliminary dosage of two.5 mg of Accupro is usually recommended in patients who are being dealt with with a diuretic. After this the dosage of Accupro should be titrated (as defined above) to the highest quality response (see sections 4.Three, four.Four, 4.Five and 5.1).
Congestive Heart Failure
In order to carefully monitor sufferers for symptomatic hypotension, a single 2.5 mg preliminary dosage is recommended. After this, patients have to be titrated to an effective dose: (up to forty mg/day) given in 1 or 2 doses with concomitant diuretic and/or cardiac glycoside remedy. Patients are typically maintained correctly on doses of 10 mg/day to 20 mg/day given with concomitant remedy. Take both with or without food. The dose ought to always be taken at about the same time of day to assist growth compliance.
In the remedy of severe or risky congestive heart failure, Accupro must continually be initiated in health center beneath near clinical supervision.
Other sufferers who can also be taken into consideration to be at better danger and must have remedy initiated in hospital include: sufferers who are on high dose loop diuretics (e.G. > 80 mg furosemide) or on more than one diuretic therapy, have hypovolemia, hyponatremia (serum sodium < one hundred thirty mgEq/l) or systolic blood stress < 90 mm Hg, are on high dose vasodilator therapy, have a serum creatinine > one hundred fifty µmol/l or are elderly 70 years or over.
Elderly/Renal Impairment
In aged sufferers and in patients with a creatinine clearance of less than forty mL/min, an preliminary dosage in essential hypertension of 2.5 mg is recommended followed by using titration to the best reaction (see phase four.Four).
Paediatric populace
Currently to be had facts are described in sections five.1 and five.2 however no recommendation on a posology may be made.
Method of management
For oral use. The drugs must no longer be chewed, crushed or divided.
Four.Three Contraindications
Accupro is contraindicated:
• In patients with allergy to the lively substance or to any of the excipients listed in segment 6.1.
• In the second and third trimesters of pregnancy (see sections four.Four and four.6).
• In patients with a records of angioedema related to previous treatment with angiotensin converting enzyme (ACE) inhibitors.
• In patients with hereditary or idiopathic angioneurotic oedema.
• In sufferers with dynamic left ventricular outflow obstruction.
• With management of aliskiren-containing merchandise in patients with diabetes mellitus or in sufferers with renal impairment (glomerular filtration fee [GFR] < 60 ml/min/1.Seventy three m2) (see sections 4.5 and 5.1).
• In combination with sacubitril/valsartan because of the accelerated threat of angioedema.
4.4 Special warnings and precautions for use
Aortic Stenosis
Quinapril have to be used in warning in selected sufferers with aortic stenosis.
Sensitivity Reactions
Sensitivity reactions may additionally occur in sufferers with or without a history of allergy or bronchial bronchial asthma, e.G. Purpura, photosensitivity, urticaria, necrotising angiitis, respiration distress which include pneumonitis and pulmonary oedema and anaphylactic reactions.
Patients haemodialysed the usage of excessive-flux polyacrylonitrile ('AN69') membranes are enormously likely to enjoy anaphylactoid reactions if they're treated with ACE inhibitors. This mixture ought to consequently be avoided, either with the aid of use of alternative antihypertensive capsules or alternative membranes for haemodialysis. Similar reactions were located at some stage in low density lipoprotein (LDL) apheresis with dextran-sulfate. This approach must consequently now not be used in patients handled with ACE inhibitors.
Impaired Hepatic Function
Quinapril when mixed with a diuretic must be used with caution in patients with impaired hepatic characteristic or modern liver disorder, on account that minor changes of fluid and electrolyte balance may precipitate hepatic coma. The metabolism of quinapril to quinaprilat is commonly based upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril.
Rarely, ACE inhibitors were related to a syndrome starting as a cholestatic jaundice and progressing to a fulminant hepatic necrosis (in some cases fatal). Patients who, during ACE inhibitor therapy, enjoy jaundice or in reality elevated hepatic enzymes should stop quinapril and obtain suitable clinical comply with-up.
Cough
Cough has been stated with the usage of ACE inhibitors. Characteristically, the cough is non-effective, chronic and resolves after discontinuation of remedy. ACE inhibitor-caused cough must be taken into consideration as part of the differential analysis of cough.
Surgery/Anaesthesia
In patients present process fundamental surgical procedure or at some stage in anaesthesia with agents that produce hypotension, quinapril may block angiotensin II formation secondary to compensatory renin launch. If hypotension happens and is taken into consideration to be because of this mechanism, it can be corrected by means of quantity enlargement (see segment four.5).
Hyperkalaemia
Patients on quinapril alone might also have accelerated serum potassium tiers. Because of the hazard of further potentiating increases in serum potassium it is recommended that combination therapy with potassium-sparing diuretics or other capsules recognised to elevate serum potassium degrees, be initiated with caution and the patient's serum potassium degrees be closely monitored (see Hypotension below and segment 4.5). When administered concomitantly, quinapril may additionally reduce the hypokalaemia induced by means of thiazide diuretics.
Hyponatraemia and Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH)
Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH) and next hyponatraemia has been determined in a few patients dealt with with different ACE inhibitors. It is recommended that serum sodium levels be monitored regularly in the aged and in different sufferers prone to hyponatraemia.
Diabetic Patients
In diabetic patients ACE inhibitors may additionally enhance insulin sensitivity and have been associated with hypoglycaemia in sufferers handled with oral antidiabetic agents or insulin. Glycaemic manipulate need to be carefully monitored during the first month of treatment with an ACE inhibitor (see segment four.5).
Anaphylactoid Reactions
Patients receiving ACE inhibitors for the duration of desensitising remedy with hymenoptera venom have experienced lifestyles-threatening anaphylactoid reactions. These reactions were averted by means of temporarily withholding ACE inhibitor remedy prior to every desensitisation, however they have reappeared upon inadvertent re-project.
Impaired Renal Function
In sufferers with renal insufficiency, monitoring of renal function during remedy must be completed as deemed appropriate, despite the fact that in the general public renal characteristic will no longer modify or may additionally enhance.
As a consequence of inhibiting the renin-angiotensin-aldosterone machine, adjustments in renal function can be anticipated in prone individuals. In sufferers with excessive heart failure whose renal characteristic may also depend on the activity of the renin-angiotensin-aldosterone gadget, treatment with ACE inhibitors which include quinapril, can be associated with oliguria and/or innovative azotaemia and seldom acute renal failure and/or demise.
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 instances the top restrict of ordinary) in blood urea nitrogen and serum creatinine, typically minor and brief, mainly whilst 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 three%, respectively of hypertensive patients on quinapril/HCTZ. This is more likely to arise in patients with pre-present renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or quinapril may be required.
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 will increase the risk of hypotension, hyperkalaemia and decreased renal function (inclusive of acute renal failure). Dual blockade of RAAS via the mixed use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore now not encouraged (see sections 4.5 and five.1).
If twin blockade therapy is taken into consideration surely important, this need to only occur underneath professional supervision and problem to frequent near tracking of renal characteristic, electrolytes and blood stress.
ACE-inhibitors and angiotensin II receptor blockers have to no longer be used concomitantly in patients with diabetic nephropathy.
There is insufficient experience in patients with excessive renal impairment (creatinine clearance <10 mL/min). Treatment is therefore now not endorsed in those patients.
Angioedema
Angioedema has been stated in patients dealt with with ACE inhibitors. If laryngeal stridor or angioedema of the face, tongue, or glottis arise, remedy ought to be discontinued without delay, the affected person treated as it should be in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is restricted to the face and lips, the situation typically resolves without treatment; antihistamines may be beneficial in relieving signs and symptoms. Angioedema related to laryngeal involvement may be fatal. Where there is involvement of the tongue, glottis, or larynx probable to motive airway obstruction, appropriate remedy e.G., subcutaneous adrenaline answer 1:a thousand (0.3 to 0.Five mL) ought to be right away administered.
Patients with a records of angioedema unrelated to ACE inhibitor therapy can be at increased hazard of angioedema whilst receiving an ACE inhibitor (see section four.Three).
The combination of quinapril with sacubitril/valsartan is contraindicated due to the increased threat of angioedema (see segment four.3). Sacubitril/valsartan should not be initiated until 36 hours after taking the last dose of quinapril therapy. If remedy with sacubitril/valsartan is stopped, quinapril remedy need to no longer be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and four.5). Concomitant use of other NEP inhibitors (e.G. Racecadotril) and ACE inhibitors might also growth the danger of angioedema (see segment 4.Five). Hence, a cautious gain-hazard assessment is needed before initiating treatment with NEP inhibitors (e.G. Racecadotril) in sufferers on quinapril.
Patients taking concomitant mTOR inhibitor (e.G. Temsirolimus) or concomitant DPP-IV inhibitor (e.G. Vildagliptin) therapy may be at improved risk for angioedema. Caution ought to be used while starting an mTOR inhibitor or a DPP-IV inhibitor in a affected person already taking an ACE inhibitor.
Ethnic Differences
Black sufferers receiving ACE inhibitor therapy were mentioned to have a higher prevalence of angioedema compared to non-black sufferers. It need to additionally be cited that in managed scientific trials, ACE inhibitors have an effect on blood stress that is less in black patients than in non-black sufferers.
Intestinal Angioedema
Intestinal angioedema has been suggested in sufferers handled with ACE inhibitors. These patients presented with belly pain (without or with nausea or vomiting); in a few cases there was no earlier history of facial angioedema and C-1 esterase tiers were regular. The angioedema changed into identified by means of strategies along with belly CT scan or ultrasound, or at surgery, and signs and symptoms resolved after preventing the ACE inhibitor. Intestinal angioedema need to be covered in the differential prognosis of patients on ACE inhibitors offering with belly pain.
Hypotension
Symptomatic hypotension became hardly ever visible in simple hypertensive sufferers dealt with with Accupro however it's far a possible result of ACE inhibitor therapy particularly in salt/extent depleted patients which include those formerly handled with diuretics, who have a dietary salt discount, who are on dialysis, have diarrhoea or vomiting or have intense renin-based hypertension. If symptomatic hypotension occurs, the patient should be positioned inside the supine position and, if vital, acquire an intravenous infusion of normal saline. A brief hypotensive reaction is not a contraindication to in addition doses; however, lower doses of quinapril or any concomitant diuretic therapy have to be considered if this event occurs.
In sufferers with congestive heart failure, who're at risk of immoderate hypotension, quinapril therapy ought to be began at the encouraged dose below close medical supervision; these sufferers need to be accompanied intently for the primary 2 weeks of remedy and on every occasion the dosage of quinapril is elevated.
Similar concerns follow to sufferers with ischaemic heart or cerebrovascular disorder in whom an immoderate fall in blood stress ought to result in a myocardial infarction or cerebrovascular coincidence.
Neutropenia/Agranulocytosis
ACE inhibitors had been not often associated with agranulocytosis and bone marrow melancholy in sufferers with straight forward hypertension however more often in patients with renal impairment, mainly if they also have collagen vascular ailment. As with other ACE inhibitors, tracking of white blood mobile counts in sufferers with collagen vascular ailment and/or renal illnesses must be considered.
Pregnancy
ACE inhibitors need to not be initiated during pregnancy. Unless persisted ACE inhibitor remedy is considered crucial, sufferers planning being pregnant need to be changed to alternative antihypertensive treatments which have an established protection profile to be used in pregnancy. When being pregnant is diagnosed, remedy with ACE inhibitors must be stopped straight away, and, if appropriate, opportunity remedy ought to be commenced (see sections 4.3 and four.6).
Lactose
Patients with uncommon hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption need to no longer use this medicine.
Four.5 Interaction with different medicinal products and different styles of interaction
Tetracycline and Other Drugs That Interact with Magnesium
Because of the presence of magnesium carbonate in the formulation, Accupro has been proven in healthful volunteers to reduce the absorption of tetracycline in concomitant administration with the aid of 28-37%. This interplay need to be taken into consideration if co-prescribing quinapril and tetracycline. It is usually recommended that concomitant administration with tetracycline be avoided.
Concomitant Diuretic Therapy
Patients dealt with with diuretics, specifically the ones on recently instituted diuretic therapy, might also now and again revel in an excessive discount of blood stress after initiation of remedy with Accupro. This hypotensive impact may be correctly minimised by either discontinuing the diuretic some days previous to initiation of remedy, or increasing the salt intake prior to the preliminary dose of Accupro. If discontinuation of the diuretic isn't always possible, the starting dose of Accupro need to be reduced and medical supervision should be provided for up to 2 hours following administration of the preliminary dose (see sections 4.4 and 4.2).
Agents Increasing Serum Potassium
Quinapril is an ACE inhibitor capable of reducing aldosterone stages, which in flip can bring about elevation in serum potassium. Concomitant treatments with potassium sparing diuretics, potassium supplements, potassium salts or other capsules regarded to raise serum potassium degrees should be used with caution and with appropriate tracking of serum potassium. As with other ACE inhibitors, sufferers on quinapril on my own may additionally have accelerated serum potassium degrees. When administered concomitantly, quinapril may additionally lessen the hypokalaemia prompted by using thiazide diuretics. In sufferers who're aged or have compromised renal characteristic, co-management of an ACE inhibitor with sulfamethoxazole/trimethoprim has been related to excessive hyperkalaemia, that's concept to be due to trimethoprim. Quinapril and trimethoprim-containing products need to therefore be co-administered with warning and with suitable monitoring of serum potassium.
Surgery/Anaesthesia
Although no records are to be had to suggest there is an interaction among Accupro and anaesthetic marketers that produces hypotension, caution should be exercised when sufferers undergo foremost surgical treatment or anaesthesia considering ACE inhibitors have been proven to block angiotensin II formation secondary to compensatory renin launch. This may also result in hypotension which can be corrected by means of volume growth (see phase four.4).
Lithium
Increased serum lithium levels and signs of lithium toxicity have been suggested in sufferers receiving concomitant lithium and ACE inhibitor remedy because of the sodium-dropping effect of these retailers. These tablets have to be co-administered with warning and common monitoring of serum lithium degrees is recommended. If a diuretic is likewise used, it is able to growth the danger of lithium toxicity.
Non-Steroidal Anti-Inflammatory Agents consisting of Selective Cyclooxygenase-2 Inhibitors (COX-2 inhibitors)
In sufferers who are elderly, volume-depleted (inclusive of the ones on diuretic remedy), or with compromised renal feature, co-management of non-steroidal anti inflammatory tablets (NSAIDs), including selective COX-2 inhibitors, with ACE inhibitors, inclusive of quinapril, can also result in deterioration of renal characteristic, including feasible acute renal failure. These consequences are usually reversible. Monitor renal function periodically in sufferers receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, consisting of quinapril may be attenuated by using NSAIDs.
Other tablets regarded to cause Angioedema
Patients taking concomitant mTOR inhibitor (e.G. Temsirolimus) or concomitant DPP-IV inhibitor (e.G. Vildagliptin) therapy can be at extended hazard for angioedema. Caution ought to be used when beginning an mTOR inhibitor or a DPP-IV inhibitor in a patient already taking an ACE inhibitor.
NEP Inhibitors
The concomitant use of quinapril with sacubitril/valsartan is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE may also growth the chance of angioedema. Sacubitril/valsartan should no longer be started out till 36 hours after taking the final dose of quinapril remedy. Quinapril therapy must no longer be began till 36 hours after the final dose of sacubitril/valsartan (see sections four.3 and 4.Four). Concomitant use of other NEP inhibitors (e.G. Racecadotril) and quinapril may additionally growth the risk of angioedema (see phase 4.Four).
Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) were pronounced rarely in patients on remedy with injectable gold (e.G. Sodium aurothiomalate) and concomitant ACE inhibitor remedy.
Allopurinol, Cytostatic and Immunosuppressive Agents, Systemic Corticosteroids or Procainamide
Concomitant administration with ACE inhibitors can also lead to an improved hazard for leukopenia.
Alcohol, Barbiturates or Narcotics
Potentiation of orthostatic hypotension might also arise.
Other Hypertensive Drugs
There can be an additive effect or potentiation.
Other Agents
Co-management of a couple of 10 mg doses of atorvastatin with eighty mg quinapril ended in no big exchange in the consistent-kingdom pharmacokinetic parameters of atorvastatin.
Antacids
Antacids might also decrease the bioavailability of quinapril.
Antidiabetic Agents (Oral Hypoglycaemic Agents and Insulin)
In diabetic patients ACE inhibitors may beautify insulin sensitivity and were related to hypoglycaemia in patients treated with oral antidiabetic agents and insulin. Glycaemic manipulate should be intently monitored in particular for the duration of the first month of remedy with an ACE inhibitor (see section four.4).
Dual Blockade of the Renin-Angiotensin-Aldosterone-System (RAAS)
Clinical trial records has proven that twin blockade of the renin-angiotensin-aldosterone-system (RAAS) thru the mixed use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is related to a better frequency of adverse events which includes hypotension, hyperkalaemia and reduced renal feature (along with acute renal failure) as compared to using a single RAAS-performing agent (see sections four.3, four.4 and 5.1).
Aliskiren
Do no longer co-administer aliskiren with quinapril in sufferers with diabetes or in patients with renal impairment (GFR <60 mL/min/1.73m2).
4.6 Fertility, being pregnant and lactation
Pregnancy
The use of ACE inhibitors isn't always encouraged in the course of the primary trimester of pregnancy (see segment four.4). The use of ACE inhibitors is contraindicated for the duration of the 2d and 3rd trimester of pregnancy (see sections four.Three and 4.Four).
Epidemiological evidence regarding the hazard of teratogenicity following exposure to ACE inhibitors throughout the primary trimester of pregnancy has no longer been conclusive; however a small boom in risk can not be excluded. Unless endured ACE inhibitor therapy is taken into consideration vital, patients planning pregnancy should be modified to opportunity antihypertensive remedies that have a longtime protection profile for use in pregnancy. When being pregnant is recognized, remedy with ACE inhibitors have to be stopped without delay, and, if appropriate, alternative remedy have to be began.
Exposure to ACE inhibitor remedy at some stage in the second one and 1/3 trimesters is understood to induce human foetotoxicity (reduced renal function, oligohydramnios, skull ossification retardation and/or dying in the new child) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see segment 5.3). Should exposure to ACE inhibitor have occurred from the second trimester of being pregnant, ultrasound take a look at of renal feature and skull is suggested. Limb contractures, craniofacial deformities, hypoplastic lung improvement and intrauterine boom retardation were said in association with oligohydramnios.
Infants whose mothers have taken ACE inhibitors need to be intently observed for hypotension, oliguria and hyperkalaemia (see sections four.3 and 4.4). If oliguria takes place, interest must be directed in the direction of help of blood strain and renal perfusion.
Breast-feeding
Limited pharmacokinetic facts show very low concentrations in breast milk (see segment 5.2). Although those concentrations appear to be clinically inappropriate, the use of Accupro in breastfeeding isn't always encouraged for preterm babies and for the primary few weeks after shipping, due to the hypothetical threat of cardiovascular and renal outcomes and because there isn't sufficient medical enjoy.
In the case of an older little one, using Accupro in a breast-feeding mom may be taken into consideration if this remedy is essential for the mom and the kid is determined for any destructive impact.
Four.7 Effects on capacity to drive and use machines
There are no research at the impact of this medicinal drug on the capacity to pressure. When driving cars or working machines it should be taken into account that from time to time dizziness or weariness may additionally arise.
Four.Eight Undesirable results
The following unwanted consequences were found and mentioned throughout treatment with quinapril with the subsequent frequencies: very not unusual (≥1/10); commonplace (≥1/100 to <1/10); unusual (≥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%).
System Organ Class
Frequency
Undesirable effects
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 (see section 4.4)
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 (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 the Yellow Card Scheme at www.Mhra.Gov.Uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
The oral LD50 of quinapril in mice and rats ranges from 1440 to 4280 mg/kg.
No data are available with respect to overdosage in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by intravenous volume expansion.
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: Angiotensin-converting enzyme (ACE) inhibitor, plain
ATC code: CO9A AO6
Quinapril is rapidly de-esterified to quinaprilat (quinapril diacid, the principal metabolite) which is a potent ACE inhibitor.
ACE is a peptidyl dipeptidase that catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II which is involved in vascular control and function through many different mechanisms, including stimulation of aldosterone secretion by the adrenal cortex. The mode of action of quinapril in humans and animals is to inhibit circulating and tissue ACE activity, thereby decreasing vasopressor activity and aldosterone secretion.
In animal studies, the antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE, whereas, tissue ACE inhibition more closely correlates with the duration of antihypertensive effects. Administration of 10 mg to 40 mg of quinapril to patients with mild to severe hypertension results in a reduction of both sitting and standing blood pressure with minimal effect on heart rate. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. Achievement of maximum blood pressure lowering effects may require 2 weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained in most patients throughout the 24 hour dosing interval and continued during long term therapy.
In a randomised clinical trial using target doses of 2.5 mg, 5 mg, 10 mg and 20 mg of quinapril, in 112 children and adolescents with hypertension or high normal blood pressure over 8 weeks (2 weeks double blind and 6 weeks extension) failed to reach its primary objective of reduction of diastolic blood pressure after 2 weeks. For systolic blood pressure (secondary objective of efficacy) at Week 2 only there was a statistically significant linear dose response across treatments with a significant difference between the quinapril 20 mg QD and placebo treatment groups.
Long term effects of quinapril on growth, puberty and general development have not been studied.
Two large randomised, controlled trials (ONTARGET (On-going Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the 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. Cardiovascular 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
Peak plasma Accupro concentrations are observed within 1 hour of oral administration. The extent of absorption is approximately 60%, and is not influenced by food. Following absorption, Accupro is de-esterified to its major active metabolite, quinaprilat, and to minor inactive metabolites. Accupro has an apparent half-life of approximately 1 hour. Peak plasma quinaprilat concentrations are observed approximately 2 hours following an oral dose of quinapril. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of 3 hours. In patients with renal insufficiency and creatinine clearance of ≤40 mL/min, peak and trough quinaprilat concentrations increase, time to peak concentration increases, apparent half-life increases, and time to steady state may be delayed. The elimination of quinaprilat is also reduced in elderly patients (>sixty five years) and correlates well with the impaired renal feature which regularly happens in the elderly. Quinaprilat concentrations are decreased in patients with alcoholic cirrhosis because of impaired de-esterification of Accupro. Studies in rats suggest that Accupro and its metabolites do no longer move the blood-mind barrier.
Lactation
After a unmarried oral dose of 20 mg of quinapril in six breast-feeding girls, the M/P (milk to plasma ratio) for quinapril was 0.12. Quinapril became not detected in milk after four hours after the dose. Quinalaprilat milk tiers had been undetectable (<five µg/L) at all time factors. It is anticipated that a breastfed toddler could receive approximately 1.6% of the maternal weight-adjusted dosage of quinapril.
The pharmacokinetics of quinapril has been studied in a unmarried dose take a look at (zero.2 mg/kg) in 24 children aged 2.5 months to 6.8 years and a more than one dose have a look at (0.016-zero.468 mg/kg) in 38 youngsters elderly 5-16 years old, weighing 66-98 kg on average.
As in adults, quinapril become hastily converted to quinaprilat. Quinaprilat concentrations commonly peaked 1 to 2 hours publish dose and declined with a median half of-lifestyles of 2.3 hours. In infants and young youngsters the exposure following a single zero.2 mg/kg dose is similar to that observed in adults after a single 10 mg dose. In a a couple of dose observe in school age and teens, the AUC and Cmax values of quinaprilat were discovered to increase linearly with growing dose of quinapril on a mg/kg basis.
(1) For the treatment of all grades of critical hypertension. Accupro is effective as monotherapy or concomitantly with diuretics in sufferers with high blood pressure (see sections four.3, 4.Four, 4.5 and five.1).
(2) For the remedy of congestive coronary heart failure when given concomitantly with a diuretic and/or cardiac glycoside. Treatment of congestive coronary heart failure with Accupro ought to constantly be initiated underneath near medical supervision.
4.2 Posology and technique of administration
Posology
Adults
Hypertension
- Monotherapy:
The encouraged preliminary dosage is 10 mg once each day in uncomplicated high blood pressure. Depending upon clinical response, patient's dosage can be titrated (via doubling the dose allowing adequate time for dosage adjustment) to a protection dosage of 20 mg/day to 40 mg/day given as a unmarried dose or divided into 2 doses. Long-term control is maintained in maximum patients with a unmarried daily dosage routine. Patients have been handled with dosages up to eighty mg/day. Take either with or without meals. The dose ought to continually be taken at approximately the identical time of day to help increase compliance.
- Concomitant Diuretics:
In order to decide if excess hypotension will arise, an preliminary dosage of two.5 mg of Accupro is usually recommended in patients who are being dealt with with a diuretic. After this the dosage of Accupro should be titrated (as defined above) to the highest quality response (see sections 4.Three, four.Four, 4.Five and 5.1).
Congestive Heart Failure
In order to carefully monitor sufferers for symptomatic hypotension, a single 2.5 mg preliminary dosage is recommended. After this, patients have to be titrated to an effective dose: (up to forty mg/day) given in 1 or 2 doses with concomitant diuretic and/or cardiac glycoside remedy. Patients are typically maintained correctly on doses of 10 mg/day to 20 mg/day given with concomitant remedy. Take both with or without food. The dose ought to always be taken at about the same time of day to assist growth compliance.
In the remedy of severe or risky congestive heart failure, Accupro must continually be initiated in health center beneath near clinical supervision.
Other sufferers who can also be taken into consideration to be at better danger and must have remedy initiated in hospital include: sufferers who are on high dose loop diuretics (e.G. > 80 mg furosemide) or on more than one diuretic therapy, have hypovolemia, hyponatremia (serum sodium < one hundred thirty mgEq/l) or systolic blood stress < 90 mm Hg, are on high dose vasodilator therapy, have a serum creatinine > one hundred fifty µmol/l or are elderly 70 years or over.
Elderly/Renal Impairment
In aged sufferers and in patients with a creatinine clearance of less than forty mL/min, an preliminary dosage in essential hypertension of 2.5 mg is recommended followed by using titration to the best reaction (see phase four.Four).
Paediatric populace
Currently to be had facts are described in sections five.1 and five.2 however no recommendation on a posology may be made.
Method of management
For oral use. The drugs must no longer be chewed, crushed or divided.
Four.Three Contraindications
Accupro is contraindicated:
• In patients with allergy to the lively substance or to any of the excipients listed in segment 6.1.
• In the second and third trimesters of pregnancy (see sections four.Four and four.6).
• In patients with a records of angioedema related to previous treatment with angiotensin converting enzyme (ACE) inhibitors.
• In patients with hereditary or idiopathic angioneurotic oedema.
• In sufferers with dynamic left ventricular outflow obstruction.
• With management of aliskiren-containing merchandise in patients with diabetes mellitus or in sufferers with renal impairment (glomerular filtration fee [GFR] < 60 ml/min/1.Seventy three m2) (see sections 4.5 and 5.1).
• In combination with sacubitril/valsartan because of the accelerated threat of angioedema.
4.4 Special warnings and precautions for use
Aortic Stenosis
Quinapril have to be used in warning in selected sufferers with aortic stenosis.
Sensitivity Reactions
Sensitivity reactions may additionally occur in sufferers with or without a history of allergy or bronchial bronchial asthma, e.G. Purpura, photosensitivity, urticaria, necrotising angiitis, respiration distress which include pneumonitis and pulmonary oedema and anaphylactic reactions.
Patients haemodialysed the usage of excessive-flux polyacrylonitrile ('AN69') membranes are enormously likely to enjoy anaphylactoid reactions if they're treated with ACE inhibitors. This mixture ought to consequently be avoided, either with the aid of use of alternative antihypertensive capsules or alternative membranes for haemodialysis. Similar reactions were located at some stage in low density lipoprotein (LDL) apheresis with dextran-sulfate. This approach must consequently now not be used in patients handled with ACE inhibitors.
Impaired Hepatic Function
Quinapril when mixed with a diuretic must be used with caution in patients with impaired hepatic characteristic or modern liver disorder, on account that minor changes of fluid and electrolyte balance may precipitate hepatic coma. The metabolism of quinapril to quinaprilat is commonly based upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril.
Rarely, ACE inhibitors were related to a syndrome starting as a cholestatic jaundice and progressing to a fulminant hepatic necrosis (in some cases fatal). Patients who, during ACE inhibitor therapy, enjoy jaundice or in reality elevated hepatic enzymes should stop quinapril and obtain suitable clinical comply with-up.
Cough
Cough has been stated with the usage of ACE inhibitors. Characteristically, the cough is non-effective, chronic and resolves after discontinuation of remedy. ACE inhibitor-caused cough must be taken into consideration as part of the differential analysis of cough.
Surgery/Anaesthesia
In patients present process fundamental surgical procedure or at some stage in anaesthesia with agents that produce hypotension, quinapril may block angiotensin II formation secondary to compensatory renin launch. If hypotension happens and is taken into consideration to be because of this mechanism, it can be corrected by means of quantity enlargement (see segment four.5).
Hyperkalaemia
Patients on quinapril alone might also have accelerated serum potassium tiers. Because of the hazard of further potentiating increases in serum potassium it is recommended that combination therapy with potassium-sparing diuretics or other capsules recognised to elevate serum potassium degrees, be initiated with caution and the patient's serum potassium degrees be closely monitored (see Hypotension below and segment 4.5). When administered concomitantly, quinapril may additionally reduce the hypokalaemia induced by means of thiazide diuretics.
Hyponatraemia and Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH)
Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH) and next hyponatraemia has been determined in a few patients dealt with with different ACE inhibitors. It is recommended that serum sodium levels be monitored regularly in the aged and in different sufferers prone to hyponatraemia.
Diabetic Patients
In diabetic patients ACE inhibitors may additionally enhance insulin sensitivity and have been associated with hypoglycaemia in sufferers handled with oral antidiabetic agents or insulin. Glycaemic manipulate need to be carefully monitored during the first month of treatment with an ACE inhibitor (see segment four.5).
Anaphylactoid Reactions
Patients receiving ACE inhibitors for the duration of desensitising remedy with hymenoptera venom have experienced lifestyles-threatening anaphylactoid reactions. These reactions were averted by means of temporarily withholding ACE inhibitor remedy prior to every desensitisation, however they have reappeared upon inadvertent re-project.
Impaired Renal Function
In sufferers with renal insufficiency, monitoring of renal function during remedy must be completed as deemed appropriate, despite the fact that in the general public renal characteristic will no longer modify or may additionally enhance.
As a consequence of inhibiting the renin-angiotensin-aldosterone machine, adjustments in renal function can be anticipated in prone individuals. In sufferers with excessive heart failure whose renal characteristic may also depend on the activity of the renin-angiotensin-aldosterone gadget, treatment with ACE inhibitors which include quinapril, can be associated with oliguria and/or innovative azotaemia and seldom acute renal failure and/or demise.
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 instances the top restrict of ordinary) in blood urea nitrogen and serum creatinine, typically minor and brief, mainly whilst 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 three%, respectively of hypertensive patients on quinapril/HCTZ. This is more likely to arise in patients with pre-present renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or quinapril may be required.
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 will increase the risk of hypotension, hyperkalaemia and decreased renal function (inclusive of acute renal failure). Dual blockade of RAAS via the mixed use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore now not encouraged (see sections 4.5 and five.1).
If twin blockade therapy is taken into consideration surely important, this need to only occur underneath professional supervision and problem to frequent near tracking of renal characteristic, electrolytes and blood stress.
ACE-inhibitors and angiotensin II receptor blockers have to no longer be used concomitantly in patients with diabetic nephropathy.
There is insufficient experience in patients with excessive renal impairment (creatinine clearance <10 mL/min). Treatment is therefore now not endorsed in those patients.
Angioedema
Angioedema has been stated in patients dealt with with ACE inhibitors. If laryngeal stridor or angioedema of the face, tongue, or glottis arise, remedy ought to be discontinued without delay, the affected person treated as it should be in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is restricted to the face and lips, the situation typically resolves without treatment; antihistamines may be beneficial in relieving signs and symptoms. Angioedema related to laryngeal involvement may be fatal. Where there is involvement of the tongue, glottis, or larynx probable to motive airway obstruction, appropriate remedy e.G., subcutaneous adrenaline answer 1:a thousand (0.3 to 0.Five mL) ought to be right away administered.
Patients with a records of angioedema unrelated to ACE inhibitor therapy can be at increased hazard of angioedema whilst receiving an ACE inhibitor (see section four.Three).
The combination of quinapril with sacubitril/valsartan is contraindicated due to the increased threat of angioedema (see segment four.3). Sacubitril/valsartan should not be initiated until 36 hours after taking the last dose of quinapril therapy. If remedy with sacubitril/valsartan is stopped, quinapril remedy need to no longer be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and four.5). Concomitant use of other NEP inhibitors (e.G. Racecadotril) and ACE inhibitors might also growth the danger of angioedema (see segment 4.Five). Hence, a cautious gain-hazard assessment is needed before initiating treatment with NEP inhibitors (e.G. Racecadotril) in sufferers on quinapril.
Patients taking concomitant mTOR inhibitor (e.G. Temsirolimus) or concomitant DPP-IV inhibitor (e.G. Vildagliptin) therapy may be at improved risk for angioedema. Caution ought to be used while starting an mTOR inhibitor or a DPP-IV inhibitor in a affected person already taking an ACE inhibitor.
Ethnic Differences
Black sufferers receiving ACE inhibitor therapy were mentioned to have a higher prevalence of angioedema compared to non-black sufferers. It need to additionally be cited that in managed scientific trials, ACE inhibitors have an effect on blood stress that is less in black patients than in non-black sufferers.
Intestinal Angioedema
Intestinal angioedema has been suggested in sufferers handled with ACE inhibitors. These patients presented with belly pain (without or with nausea or vomiting); in a few cases there was no earlier history of facial angioedema and C-1 esterase tiers were regular. The angioedema changed into identified by means of strategies along with belly CT scan or ultrasound, or at surgery, and signs and symptoms resolved after preventing the ACE inhibitor. Intestinal angioedema need to be covered in the differential prognosis of patients on ACE inhibitors offering with belly pain.
Hypotension
Symptomatic hypotension became hardly ever visible in simple hypertensive sufferers dealt with with Accupro however it's far a possible result of ACE inhibitor therapy particularly in salt/extent depleted patients which include those formerly handled with diuretics, who have a dietary salt discount, who are on dialysis, have diarrhoea or vomiting or have intense renin-based hypertension. If symptomatic hypotension occurs, the patient should be positioned inside the supine position and, if vital, acquire an intravenous infusion of normal saline. A brief hypotensive reaction is not a contraindication to in addition doses; however, lower doses of quinapril or any concomitant diuretic therapy have to be considered if this event occurs.
In sufferers with congestive heart failure, who're at risk of immoderate hypotension, quinapril therapy ought to be began at the encouraged dose below close medical supervision; these sufferers need to be accompanied intently for the primary 2 weeks of remedy and on every occasion the dosage of quinapril is elevated.
Similar concerns follow to sufferers with ischaemic heart or cerebrovascular disorder in whom an immoderate fall in blood stress ought to result in a myocardial infarction or cerebrovascular coincidence.
Neutropenia/Agranulocytosis
ACE inhibitors had been not often associated with agranulocytosis and bone marrow melancholy in sufferers with straight forward hypertension however more often in patients with renal impairment, mainly if they also have collagen vascular ailment. As with other ACE inhibitors, tracking of white blood mobile counts in sufferers with collagen vascular ailment and/or renal illnesses must be considered.
Pregnancy
ACE inhibitors need to not be initiated during pregnancy. Unless persisted ACE inhibitor remedy is considered crucial, sufferers planning being pregnant need to be changed to alternative antihypertensive treatments which have an established protection profile to be used in pregnancy. When being pregnant is diagnosed, remedy with ACE inhibitors must be stopped straight away, and, if appropriate, opportunity remedy ought to be commenced (see sections 4.3 and four.6).
Lactose
Patients with uncommon hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption need to no longer use this medicine.
Four.5 Interaction with different medicinal products and different styles of interaction
Tetracycline and Other Drugs That Interact with Magnesium
Because of the presence of magnesium carbonate in the formulation, Accupro has been proven in healthful volunteers to reduce the absorption of tetracycline in concomitant administration with the aid of 28-37%. This interplay need to be taken into consideration if co-prescribing quinapril and tetracycline. It is usually recommended that concomitant administration with tetracycline be avoided.
Concomitant Diuretic Therapy
Patients dealt with with diuretics, specifically the ones on recently instituted diuretic therapy, might also now and again revel in an excessive discount of blood stress after initiation of remedy with Accupro. This hypotensive impact may be correctly minimised by either discontinuing the diuretic some days previous to initiation of remedy, or increasing the salt intake prior to the preliminary dose of Accupro. If discontinuation of the diuretic isn't always possible, the starting dose of Accupro need to be reduced and medical supervision should be provided for up to 2 hours following administration of the preliminary dose (see sections 4.4 and 4.2).
Agents Increasing Serum Potassium
Quinapril is an ACE inhibitor capable of reducing aldosterone stages, which in flip can bring about elevation in serum potassium. Concomitant treatments with potassium sparing diuretics, potassium supplements, potassium salts or other capsules regarded to raise serum potassium degrees should be used with caution and with appropriate tracking of serum potassium. As with other ACE inhibitors, sufferers on quinapril on my own may additionally have accelerated serum potassium degrees. When administered concomitantly, quinapril may additionally lessen the hypokalaemia prompted by using thiazide diuretics. In sufferers who're aged or have compromised renal characteristic, co-management of an ACE inhibitor with sulfamethoxazole/trimethoprim has been related to excessive hyperkalaemia, that's concept to be due to trimethoprim. Quinapril and trimethoprim-containing products need to therefore be co-administered with warning and with suitable monitoring of serum potassium.
Surgery/Anaesthesia
Although no records are to be had to suggest there is an interaction among Accupro and anaesthetic marketers that produces hypotension, caution should be exercised when sufferers undergo foremost surgical treatment or anaesthesia considering ACE inhibitors have been proven to block angiotensin II formation secondary to compensatory renin launch. This may also result in hypotension which can be corrected by means of volume growth (see phase four.4).
Lithium
Increased serum lithium levels and signs of lithium toxicity have been suggested in sufferers receiving concomitant lithium and ACE inhibitor remedy because of the sodium-dropping effect of these retailers. These tablets have to be co-administered with warning and common monitoring of serum lithium degrees is recommended. If a diuretic is likewise used, it is able to growth the danger of lithium toxicity.
Non-Steroidal Anti-Inflammatory Agents consisting of Selective Cyclooxygenase-2 Inhibitors (COX-2 inhibitors)
In sufferers who are elderly, volume-depleted (inclusive of the ones on diuretic remedy), or with compromised renal feature, co-management of non-steroidal anti inflammatory tablets (NSAIDs), including selective COX-2 inhibitors, with ACE inhibitors, inclusive of quinapril, can also result in deterioration of renal characteristic, including feasible acute renal failure. These consequences are usually reversible. Monitor renal function periodically in sufferers receiving quinapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, consisting of quinapril may be attenuated by using NSAIDs.
Other tablets regarded to cause Angioedema
Patients taking concomitant mTOR inhibitor (e.G. Temsirolimus) or concomitant DPP-IV inhibitor (e.G. Vildagliptin) therapy can be at extended hazard for angioedema. Caution ought to be used when beginning an mTOR inhibitor or a DPP-IV inhibitor in a patient already taking an ACE inhibitor.
NEP Inhibitors
The concomitant use of quinapril with sacubitril/valsartan is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE may also growth the chance of angioedema. Sacubitril/valsartan should no longer be started out till 36 hours after taking the final dose of quinapril remedy. Quinapril therapy must no longer be began till 36 hours after the final dose of sacubitril/valsartan (see sections four.3 and 4.Four). Concomitant use of other NEP inhibitors (e.G. Racecadotril) and quinapril may additionally growth the risk of angioedema (see phase 4.Four).
Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) were pronounced rarely in patients on remedy with injectable gold (e.G. Sodium aurothiomalate) and concomitant ACE inhibitor remedy.
Allopurinol, Cytostatic and Immunosuppressive Agents, Systemic Corticosteroids or Procainamide
Concomitant administration with ACE inhibitors can also lead to an improved hazard for leukopenia.
Alcohol, Barbiturates or Narcotics
Potentiation of orthostatic hypotension might also arise.
Other Hypertensive Drugs
There can be an additive effect or potentiation.
Other Agents
Co-management of a couple of 10 mg doses of atorvastatin with eighty mg quinapril ended in no big exchange in the consistent-kingdom pharmacokinetic parameters of atorvastatin.
Antacids
Antacids might also decrease the bioavailability of quinapril.
Antidiabetic Agents (Oral Hypoglycaemic Agents and Insulin)
In diabetic patients ACE inhibitors may beautify insulin sensitivity and were related to hypoglycaemia in patients treated with oral antidiabetic agents and insulin. Glycaemic manipulate should be intently monitored in particular for the duration of the first month of remedy with an ACE inhibitor (see section four.4).
Dual Blockade of the Renin-Angiotensin-Aldosterone-System (RAAS)
Clinical trial records has proven that twin blockade of the renin-angiotensin-aldosterone-system (RAAS) thru the mixed use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is related to a better frequency of adverse events which includes hypotension, hyperkalaemia and reduced renal feature (along with acute renal failure) as compared to using a single RAAS-performing agent (see sections four.3, four.4 and 5.1).
Aliskiren
Do no longer co-administer aliskiren with quinapril in sufferers with diabetes or in patients with renal impairment (GFR <60 mL/min/1.73m2).
4.6 Fertility, being pregnant and lactation
Pregnancy
The use of ACE inhibitors isn't always encouraged in the course of the primary trimester of pregnancy (see segment four.4). The use of ACE inhibitors is contraindicated for the duration of the 2d and 3rd trimester of pregnancy (see sections four.Three and 4.Four).
Epidemiological evidence regarding the hazard of teratogenicity following exposure to ACE inhibitors throughout the primary trimester of pregnancy has no longer been conclusive; however a small boom in risk can not be excluded. Unless endured ACE inhibitor therapy is taken into consideration vital, patients planning pregnancy should be modified to opportunity antihypertensive remedies that have a longtime protection profile for use in pregnancy. When being pregnant is recognized, remedy with ACE inhibitors have to be stopped without delay, and, if appropriate, alternative remedy have to be began.
Exposure to ACE inhibitor remedy at some stage in the second one and 1/3 trimesters is understood to induce human foetotoxicity (reduced renal function, oligohydramnios, skull ossification retardation and/or dying in the new child) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see segment 5.3). Should exposure to ACE inhibitor have occurred from the second trimester of being pregnant, ultrasound take a look at of renal feature and skull is suggested. Limb contractures, craniofacial deformities, hypoplastic lung improvement and intrauterine boom retardation were said in association with oligohydramnios.
Infants whose mothers have taken ACE inhibitors need to be intently observed for hypotension, oliguria and hyperkalaemia (see sections four.3 and 4.4). If oliguria takes place, interest must be directed in the direction of help of blood strain and renal perfusion.
Breast-feeding
Limited pharmacokinetic facts show very low concentrations in breast milk (see segment 5.2). Although those concentrations appear to be clinically inappropriate, the use of Accupro in breastfeeding isn't always encouraged for preterm babies and for the primary few weeks after shipping, due to the hypothetical threat of cardiovascular and renal outcomes and because there isn't sufficient medical enjoy.
In the case of an older little one, using Accupro in a breast-feeding mom may be taken into consideration if this remedy is essential for the mom and the kid is determined for any destructive impact.
Four.7 Effects on capacity to drive and use machines
There are no research at the impact of this medicinal drug on the capacity to pressure. When driving cars or working machines it should be taken into account that from time to time dizziness or weariness may additionally arise.
Four.Eight Undesirable results
The following unwanted consequences were found and mentioned throughout treatment with quinapril with the subsequent frequencies: very not unusual (≥1/10); commonplace (≥1/100 to <1/10); unusual (≥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%).
System Organ Class
Frequency
Undesirable effects
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 (see section 4.4)
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 (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 the Yellow Card Scheme at www.Mhra.Gov.Uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
The oral LD50 of quinapril in mice and rats ranges from 1440 to 4280 mg/kg.
No data are available with respect to overdosage in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by intravenous volume expansion.
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: Angiotensin-converting enzyme (ACE) inhibitor, plain
ATC code: CO9A AO6
Quinapril is rapidly de-esterified to quinaprilat (quinapril diacid, the principal metabolite) which is a potent ACE inhibitor.
ACE is a peptidyl dipeptidase that catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II which is involved in vascular control and function through many different mechanisms, including stimulation of aldosterone secretion by the adrenal cortex. The mode of action of quinapril in humans and animals is to inhibit circulating and tissue ACE activity, thereby decreasing vasopressor activity and aldosterone secretion.
In animal studies, the antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE, whereas, tissue ACE inhibition more closely correlates with the duration of antihypertensive effects. Administration of 10 mg to 40 mg of quinapril to patients with mild to severe hypertension results in a reduction of both sitting and standing blood pressure with minimal effect on heart rate. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. Achievement of maximum blood pressure lowering effects may require 2 weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained in most patients throughout the 24 hour dosing interval and continued during long term therapy.
In a randomised clinical trial using target doses of 2.5 mg, 5 mg, 10 mg and 20 mg of quinapril, in 112 children and adolescents with hypertension or high normal blood pressure over 8 weeks (2 weeks double blind and 6 weeks extension) failed to reach its primary objective of reduction of diastolic blood pressure after 2 weeks. For systolic blood pressure (secondary objective of efficacy) at Week 2 only there was a statistically significant linear dose response across treatments with a significant difference between the quinapril 20 mg QD and placebo treatment groups.
Long term effects of quinapril on growth, puberty and general development have not been studied.
Two large randomised, controlled trials (ONTARGET (On-going Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the 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. Cardiovascular 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
Peak plasma Accupro concentrations are observed within 1 hour of oral administration. The extent of absorption is approximately 60%, and is not influenced by food. Following absorption, Accupro is de-esterified to its major active metabolite, quinaprilat, and to minor inactive metabolites. Accupro has an apparent half-life of approximately 1 hour. Peak plasma quinaprilat concentrations are observed approximately 2 hours following an oral dose of quinapril. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of 3 hours. In patients with renal insufficiency and creatinine clearance of ≤40 mL/min, peak and trough quinaprilat concentrations increase, time to peak concentration increases, apparent half-life increases, and time to steady state may be delayed. The elimination of quinaprilat is also reduced in elderly patients (>sixty five years) and correlates well with the impaired renal feature which regularly happens in the elderly. Quinaprilat concentrations are decreased in patients with alcoholic cirrhosis because of impaired de-esterification of Accupro. Studies in rats suggest that Accupro and its metabolites do no longer move the blood-mind barrier.
Lactation
After a unmarried oral dose of 20 mg of quinapril in six breast-feeding girls, the M/P (milk to plasma ratio) for quinapril was 0.12. Quinapril became not detected in milk after four hours after the dose. Quinalaprilat milk tiers had been undetectable (<five µg/L) at all time factors. It is anticipated that a breastfed toddler could receive approximately 1.6% of the maternal weight-adjusted dosage of quinapril.
The pharmacokinetics of quinapril has been studied in a unmarried dose take a look at (zero.2 mg/kg) in 24 children aged 2.5 months to 6.8 years and a more than one dose have a look at (0.016-zero.468 mg/kg) in 38 youngsters elderly 5-16 years old, weighing 66-98 kg on average.
As in adults, quinapril become hastily converted to quinaprilat. Quinaprilat concentrations commonly peaked 1 to 2 hours publish dose and declined with a median half of-lifestyles of 2.3 hours. In infants and young youngsters the exposure following a single zero.2 mg/kg dose is similar to that observed in adults after a single 10 mg dose. In a a couple of dose observe in school age and teens, the AUC and Cmax values of quinaprilat were discovered to increase linearly with growing dose of quinapril on a mg/kg basis.
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