Quinapril Mylan

Hypertension

For the treatment of all grades of essential hypertension. Quinapril Mylan Tablets are effective as monotherapy or concomitantly with diuretics in patients with hypertension.

Congestive Heart Failure

For the treatment of congestive heart failure when given concomitantly with a diuretic and/or cardiac glycoside. Treatment of congestive heart failure with Quinapril Mylan Tablets should always be initiated under close medical supervision.

For oral use.

Adults

Hypertension

Monotherapy: The recommended initial dosage is 10 mg once daily in uncomplicated hypertension. Depending upon clinical response, patient's dosage may be titrated (by doubling the dose allowing adequate time for dosage adjustment) to a maintenance dosage of 20 to 40 mg/day given as a single dose or divided into 2 doses. Long-term control is maintained in most patients with a single daily dosage regimen. Patients have been treated with dosages up to 80 mg/day.

Concomitant Diuretics: In order to determine if excess hypotension will occur, an initial dosage of 2.5 mg of Quinapril Mylan Tablets is recommended in patients who are being treated with a diuretic. After this the dosage of Quinapril Mylan Tablets should be titrated (as described above) to the optimal response.

Congestive Heart Failure

In order to closely monitor patients for symptomatic hypotension, a single 2.5 mg initial dosage is recommended. After this, patients should be titrated to an effective dose: (up to 40 mg/day) given in 1 or 2 doses with concomitant diuretic and/or cardiac glycoside therapy. Patients are usually maintained effectively on doses of 10-20 mg/day given with concomitant therapy. Take either with or without food. The dose should always be taken at about the same time of day to help increase compliance.

Severe Heart Failure

In the treatment of severe or unstable congestive heart failure, Quinapril Mylan Tablets should always be initiated in hospital under close medical supervision.

Other patients who may also be considered to be at higher risk and should have treatment initiated in hospital include: patients who are on high dose loop diuretics (e.g.> 80 mg frusemide) or on multiple diuretic therapy, have hypovolaemia, hyponatraemia (serum sodium < 130 mmol/l) or systolic blood pressure < 90 mm Hg, are on high dose vasodilator therapy, have a serum creatinine > 150 µmol/l or are aged 70 years or over.

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

Elderly/Renal Impairment (over 65 years of age)

In elderly patients and in patients with a creatinine clearance of less than 40 ml/min, an initial dosage in essential hypertension of 2.5 mg is recommended followed by titration to the optimal response.

Paediatric population

- Second and third trimesters of pregnancy.

- History of angioedema related to previous treatment with ACE inhibitors.

- Hereditary or idiopathic angioneurotic oedema.

- Quinapril Mylan should not be used in patients with dynamic left ventricular outflow obstruction.

- The concomitant use of Quinapril Mylan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

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 increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Quinapril Mylan Tablets should be used with caution in selected patients with aortic stenosis or outflow obstruction.

Sensitivity reactions:

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, anaphylactic reactions.

Symptomatic hypotension:

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients but it is a possible consequence of ACE inhibition. In hypertensive patients receiving Quinapril Mylan, hypotension is more likely to occur if the patient has been salt/volume-depleted e.g., by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has 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 Mylan 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 Mylan therapy should be started at the recommended dose under close medical supervision; these patients should be followed closely for the first two weeks of treatment and whenever the dosage of Quinapril Mylan 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.

Impaired Renal Function

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.

The half-life of Quinapril Mylanat is prolonged as creatinine clearance falls. Patients with a creatinine clearance of <40 ml/min require a lower initial dosage of Quinapril Mylan. 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 Mylan produces further deterioration in renal function.

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 Mylan, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.

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 vascular disease have developed increases >1.25 times the upper limit of normal) in blood urea and serum creatinine, usually minor and transient, especially when Quinapril Mylan 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 Mylan monotherapy and in 4% and 3%, respectively of hypertensive patients on Quinapril Mylan/HCTZ. These increases are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of a diuretic and/or Quinapril Mylan may be required.

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

Angioedema:

Angioedema has been reported in patients treated with angiotensin-converting enzyme 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.

Intestinal angioedema:

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Ethnic Differences

Black patients receiving ACE inhibitor therapy generally have a higher incidence of angioedema than 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-blacks.

Neutropenia/agranulocytosis:

ACE inhibitors have been rarely associated with agranulocytosis and bone marrow depression in patients with uncomplicated hypertension but more frequently in patients with renal impairment, especially if they also have 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.

Agranulocytosis has been rarely reported during treatment with Quinapril Mylan. Monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered.

Desensitization:

Patients receiving ACE inhibitors during desensitising treatment with hymenoptera venom have sustained life threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld, but they have reappeared upon inadvertent re-challenge.

Haemodialysis and LDL Apheresis:

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 apheresis with dextran-sulphate. This method should therefore not be used in patients treated with ACE inhibitors.

Impaired Hepatic Function:

Quinapril Mylan 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 Mylan to Quinapril Mylanat is normally dependent upon hepatic esterase. Quinapril Mylanat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of Quinapril Mylan.

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 Mylan and receive appropriate medical follow-up.

Cough:

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.

Surgery/Anaesthesia:

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Quinapril Mylan may block angiotensin II formation secondary to compensatory renin release.).

Diabetic patients:

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 particularly during the first month of treatment with an ACE inhibitor.

Pregnancy

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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.

There are no studies on the effect of this medicine on the ability to drive. The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating Quinapril Mylan therapy.

The following undesirable effects have been observed during treatment with Quinapril Mylan and other ACE inhibitors 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 reported 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%).

* 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 Mylan. These observed increases will often reverse on continued therapy.

Rare cases of agranulocytosis have been reported, and also a syndrome including fever, serositis, vasculitis, myalgia, arthralgia/arthritis, positive ANA-titre, SR-elevation, eosinophilia, and leukocytosis.

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

Laboratory values: Transient increases in serum creatinine and urea values have been reported, especially in association with concomitant therapy with diuretics. Slight decreases in haemoglobin and haematocrit values have been reported for other ACE-inhibitors. It cannot be excluded that these observations are group specific.

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.

The oral LD50 of Quinapril Mylan in mice and rats ranges from 1440 to 4280 mg/kg.

No specific information is available on the treatment of overdosage with Quinapril Mylan. 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 Mylan and Quinapril Mylanat.

Treatment is symptomatic and supportive consistent with established medical care.

ATC code: C09AA06

Pharmacotherapeutic group: Angiotensin-converting enzyme (ACE) inhibitor.

Quinapril Mylan is rapidly de-esterified to Quinapril Mylanat (Quinapril Mylan diacid, the principal metabolite), which is a potent angiotensin-converting enzyme (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 Mylan 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 Mylan outlasts its inhibitory effect on circulating ACE, whereas, tissue ACE inhibition more closely correlates with the duration of antihypertensive effects. Administration of 10-40 mg of Quinapril Mylan 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 one hour with peak effects usually achieved by two to four hours after dosing. Achievement of maximum blood pressure lowering effects may require two weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained in most patients throughout the 24 hour dosing interval and continue during long term therapy.

In a randomised clinical trial using target doses of 2.5, 5, 10 and 20 mg of Quinapril Mylan, 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 Mylan 20 mg QD and placebo treatment groups.

Long term effects of Quinapril Mylan on growth, puberty and general development have not been studied.

Two large randomised, controlled trials (ONTARGET (ONgoing 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.

Peak plasma Quinapril Mylan tablets concentrations are observed within 1 hour of oral administration. The extent of absorption is approximately 60%, and is not influenced by food. Following absorption, Quinapril Mylan is de-esterified to its major active metabolite, Quinapril Mylanat, and to minor inactive metabolites. Quinapril Mylan tablets have an apparent half-life of approximately one hour. Peak plasma Quinapril Mylanat concentrations are observed approximately 2 hours following an oral dose of Quinapril Mylan. Quinapril Mylanat 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 ≤40ml/min, peak and trough Quinapril Mylanat concentrations increase, time to peak concentration increases, apparent half-life increases, and time to steady state may be delayed. The elimination of Quinapril Mylanat is also reduced in elderly patients >65 years) and correlates well with the impaired renal function which frequently occurs in the elderly. Quinapril Mylanat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of Quinapril Mylan tablets. Studies in rats indicate that Quinapril Mylan tablets and its metabolites do not cross the blood-brain barrier.

The pharmacokinetics of Quinapril Mylan has been studied in a single dose study (0.2 mg/kg) in 24 children aged 2.5 months to 6.8 years and a multiple dose study (0.016-0.468 mg/kg) in 38 children aged 5-16 years old, weighing 66-98 kg on average.

As in adults, Quinapril Mylan was rapidly converted to Quinapril Mylanat. Quinapril Mylanat concentrations generally peaked 1 to 2 hours post dose and declined with a mean half-life of 2.3 hours. In infants and young children the exposure following a single 0.2-mg/kg dose is comparable to that observed in adults after a single 10-mg dose. In a multiple dose study in school age and adolescents, the AUC and Cmax values of Quinapril Mylanat were observed to increase linearly with increasing dose of Quinapril Mylan on a mg/kg basis.”

Lactation:

After a single oral dose of 20mg of Quinapril Mylan in six breast-feeding women M/P (milk to plasma ratio) for Quinapril Mylan was 0.12. Quinapril Mylan was not detected in milk after 4 hours after the dose. Quinalaprilat milk levels were undetectable (<5µg/L) at all time points. It is estimated that a breastfed infant would receive about 1.6% of the material weight-adjusted dosage of Quinapril Mylan.

The results of the preclinical tests do not add anything of further significance to the prescriber.

No special requirements.

Any unused or waste material should be disposed of in accordance with local requirements.