Renedil

Hypertension

Stable angina pectoris

- Essential hypertension

- Stable angina pectoris

Posology

Hypertension

The dose should be adjusted individually. Treatment can be started with 5 mg once daily. Depending on the patient's response, the dosage can, where applicable, be decreased to 2.5 mg or increased to 10 mg daily. If necessary another antihypertensive agent may be added. The standard maintenance dose is 5 mg once daily.

Angina pectoris

The dose should be adjusted individually. Treatment should be initiated with 5 mg once daily and, if needed, increased to 10 mg once daily.

Elderly population

Initial treatment with lowest available dose should be considered.

Renal impairment

Dose adjustment is not needed in patients with impaired renal function.

Hepatic impairment

Patients with impaired hepatic function may have elevated plasma concentrations of felodipine and may respond to lower doses.

Paediatric population

There is limited clinical trial experience of the use of felodipine in hypertensive paediatric patients.

Method of administration

The tablets should be taken in the morning and be swallowed with water. In order to keep the prolonged-release properties, the tablets must not be divided, crushed or chewed. The tablets can be administered without food or following a light meal not rich in fat or carbohydrate.

Posology

Hypertension

The dose should be adjusted individually. Treatment can be started with 5 mg once daily. Depending on the patient's response, the dosage can, where applicable, be decreased to 2.5 mg or increased to 10 mg daily. If necessary another antihypertensive agent may be added. The standard maintenance dose is 5 mg once daily.

Angina Pectoris

The dose should be adjusted individually. Treatment should be initiated with 5 mg once daily and, if needed, increased to 10 mg once daily.

Elderly

Initial treatment with lowest available dose should be considered.

Renal impairment

Dose adjustment is not needed in patients with impaired renal function.

Hepatic impairment

Patients with impaired hepatic function may have elevated plasma concentrations of Renedil and may respond to lower doses.

Paediatric population

There is limited clinical trial experience of the use of Renedil in hypertensive paediatric patients.

Method of administration

The tablets should be taken in the morning and be swallowed with water. In order to keep the prolonged-release properties, the tablets must not be divided, crushed or chewed. The tablets can be administered without food or following a light meal not rich in fat or carbohydrate.

Note: Other medicinal products may be available for the starting dose of 2.5 mg Renedil, as Vascalpha (Renedil) prolonged release tablets is not available in this strength.

- Pregnancy

-

- Decompensated heart failure

- Acute myocardial infarction

- Unstable angina pectoris

- Haemodynamically significant cardiac valvular obstruction

- Dynamic cardiac outflow obstruction

- Decompensated heart failure

- Acute myocardial infarction

- Unstable angina pectoris

- Haemodynamically significant cardiac valvular obstruction

- Dynamic cardiac outflow obstruction

The efficacy and safety of felodipine in the treatment of hypertensive emergencies has not been studied.

Felodipine may cause significant hypotension with subsequent tachycardia. This may lead to myocardial ischaemia in susceptible patients.

Felodipine is cleared by the liver. Consequently higher therapeutic concentrations and response can be expected in patients with clearly reduced liver function.

Concomitant administration of drugs that strongly induce or inhibit CYP3 A4 enzymes result in extensively decreased or increased plasma levels of felodipine, respectively. Therefore, such combinations should be avoided.

Renedil contains lactose. Patients with rare hereditary problems of galactose intolerance, or glucose-galactose malabsorption should not take this medicinal product.

Renedil contains castor oil, which may cause stomach upset and diarrhoea.

Mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful oral hygiene.

The efficacy and safety of Renedil in the treatment of hypertensive emergencies has not been studied.

Renedil may cause significant hypotension with subsequent tachycardia. This may lead to myocardial ischaemia in susceptible patients.

Renedil is cleared by the liver. Consequently higher therapeutic concentrations and response can be expected in patients with clearly reduced liver function.

Concomitant administration of drugs that strongly induce or inhibit CYP3 A4 enzymes result in extensively decreased or increased plasma levels of Renedil, respectively. Therefore such combinations should be avoided.

Vascalpha (Renedil) prolonged release tablets contains lactose. Patients with rare hereditary problems of galactose intolerance or glucose-galactose malabsorption should not take this medicinal product.

Mild gingival enlargement has been reported in patients with pronounced gingivitis/peridontitis. The enlargement can be avoided or reversed by careful oral hygiene.

Felodipine has minor or moderate influence on the ability to drive and use machines. If patients taking felodipine suffer from headache, nausea, dizziness or fatigue and ability to react may be impaired. Caution is recommended especially at the start of treatment.

Vascalpha (Renedil) prolonged release tablets has minor or moderate influence on the ability to drive and use machines. If patients taking Renedil suffer from headache, nausea, dizziness or fatigue and ability to react may be impaired. Caution is recommended especially at the start of treatment.

Summary of the safety profile

Felodipine can cause flushing, headache, palpitations, dizziness and fatigue. Most of these adverse reactions are dose-dependent and appear at the start of treatment or after a dose increase. Should such adverse reactions occur, they are usually transient and diminish with time.

Dose-dependent ankle swelling can occur in patients treated with felodipine. This results from precapillary vasodilatation and is not related to any generalised fluid retention.

Mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful oral hygiene.

Tabulated list of adverse reactions

The adverse reactions listed below have been identified from clinical trials and from post marketing surveillance.

The following definitions of frequencies are used:

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

Table 1: Undesirable effects

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.

Website: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

Renedil can cause flushing, headache, palpitations, dizziness and fatigue. Most of these adverse reactions are dose-dependent and appear at the start of treatment or after a dose increase. Should such adverse reactions occur, they are usually transient and diminish with time.

Dose-dependent ankle swelling can occur in patients treated with Renedil. This results from precapillary vasodilatation and is not related to any generalised fluid retention.

Mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful oral hygiene.

Tabulated list of adverse reactions

The adverse reactions listed below have been identified from clinical trials and from post marketing surveillance.

The following definitions of frequencies are used:

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

Table 1 Undesirable effects

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; website: www.mhra.gov.uk/yellowcard

Symptoms

Overdosage may cause excessive peripheral vasodilatation with marked hypotension and sometimes bradycardia.

Management

If justified: activated charcoal, gastric lavage if performed within one hour after ingestion.

If severe hypotension occurs, symptomatic treatment should be instituted.

The patient should be placed supine with the legs elevated. In case of accompanying bradycardia, atropine 0.5-1 mg should be administered intravenously. If this is not sufficient, plasma volume should be increased by infusion of e.g. glucose, saline, or dextran. Sympathomimetic medicinal products with predominant effect on the α1-adrenoceptor may be given if the above-mentioned measures are insufficient.

Symptoms

Overdose may cause excessive peripheral vasodilatation with marked hypotension and sometimes bradycardia.

Management

If justified: activated charcoal, gastric lavage if performed within one hour after ingestion.

If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed supine with the legs elevated. In case of accompanying bradycardia, atropine 0.5-1 mg should be administered intravenously. If this is not sufficient, plasma volume should be increased by infusion of e.g., glucose, saline, or dextran. Sympathomimetic medicinal products with predominant effect on the α1-adrenoceptor may be given if the above-mentioned measures are insufficient.

Pharmacotherapeutic group: calcium channel blockers, dihydropyridine derivatives;

ATC code: C08CA02

Mechanism of action

Felodipine is a vascular selective calcium antagonist, which lowers arterial blood pressure by decreasing systemic vascular resistance. Due to the high degree of selectivity for smooth muscle in the arterioles, felodipine in therapeutic doses has no direct effect on cardiac contractility or conduction. Because there is no effect on venous smooth muscle or adrenergic vasomotor control, felodipine is not associated with orthostatic hypotension.

Felodipine possesses a mild natriuretic/diuretic effect and fluid retention does not occur.

Pharmacodynamic effects

Felodipine is effective in all grades of hypertension. It can be used as monotherapy or in combination with other antihypertensive medicinal products, e.g. ß-adrenoceptor blockers, diuretics or ACE-inhibitors, in order to achieve an increased antihypertensive effect. Felodipine reduces both systolic and diastolic blood pressure and can be used in isolated systolic hypertension.

Felodipine has anti-anginal and anti-ischaemic effects due to improved myocardial oxygen supply/demand balance. Coronary vascular resistance is decreased and coronary blood flow and myocardial oxygen supply are increased by felodipine due to dilatation of both epicardial arteries and arterioles. The reduction in systemic blood pressure caused by felodipine leads to decreased left ventricular afterload and myocardial oxygen demand.

Felodipine improves exercise tolerance and reduces anginal attacks in patients with stable effort-induced angina pectoris. Felodipine can be used as monotherapy or in combination with β-adrenoceptor blockers in patients with stable angina pectoris.

Haemodynamic effects

The primary haemodynamic effect of felodipine is a reduction of total peripheral vascular resistance, which leads to a decrease in blood pressure. These effects are dose-dependent. Generally, a reduction in blood pressure is evident two hours after the first oral dose and lasts for at least 24 hours and the trough/peak ratio is usually well above 50%.

Plasma concentrations of felodipine are positively correlated to the decrease in total peripheral resistance and blood pressure.

Cardiac effects

Felodipine in therapeutic doses has no effect on cardiac contractility or atrioventricular conduction or refractoriness.

Antihypertensive treatment with felodipine is associated with significant regression of pre-existing left ventricular hypertrophy.

Renal effects

Felodipine has a natriuretic and diuretic effect due to reduced tubular reabsorption of filtered sodium. Felodipine does not affect daily potassium excretion. The renal vascular resistance is decreased by felodipine. Felodipine does not influence urinary albumin excretion.

In cyclosporin-treated renal transplant recipients, felodipine reduces blood pressure and improves both the renal blood flow and the glomerular filtration rate. Felodipine may also improve early renal graft function.

Clinical efficacy

In the HOT (Hypertension Optimal Treatment) study, the effect on major cardiovascular events (i.e. acute myocardial infarction, stroke and cardiovascular death) was studied in relation to diastolic blood pressure targets <90 mmHg, <85 mmHg and <80 mmHg and achieved blood pressure, with felodipine as baseline therapy.

A total of 18,790 hypertensive patients (DBP 100-115 mmHg), aged 50-80 years were followed for a mean period of 3.8 years (range 3.3-4.9). Felodipine was given as monotherapy or in combination with a betablocker, and/or an ACE-inhibitor and/or a diuretic. The study showed benefits of lowering SBP and DBP down to 139 and 83 mmHg, respectively.

According to the STOP-2 (Swedish Trial in Old Patients with Hypertension-2 study), performed in 6614 patients, aged 70-84 years, dihydropyridine calcium antagonists (felodipine and isradipine) have shown the same preventive effect on cardiovascular mortality and morbidity as other commonly used classes of antihypertensive medicinal products - ACE inhibitors, beta-blockers and diuretics.

Paediatric population

There is limited clinical trial experience of the use of felodipine in hypertensive paediatric patients. In a randomised, double-blind, 3-week, parallel group study in children aged 6-16 years with primary hypertension, the antihypertensive effects of once daily felodipine 2.5 mg (n=33), 5 mg (n=33) and 10 mg (n=31) were compared with placebo (n=35). The study failed to demonstrate the efficacy of felodipine in lowering blood pressure in children aged 6-16 years.

The long-term effects of felodipine on growth, puberty and general development have not been studied. The long-term efficacy of antihypertensive therapy as therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.

Pharmacotheraputic group: calcium channel blockers, didydropyridine derivatives;

ATC code: C08C A02

Mechanism of action

Renedil is a vascular selective calcium antagonist, which lowers arterial blood pressure by decreasing systemic vascular resistance. Due to the high degree of selectivity for smooth muscle in the arterioles, Renedil in therapeutic doses has no direct effect on cardiac contractility or conduction. Because there is no effect on venous smooth muscle or adrenergic vasomotor control, Renedil is not associated with orthostatic hypotension.

Renedil possesses a mild natriuretic/diuretic effect and fluid retention does not occur.

Pharmacodynamic effects

Renedil is effective in all grades of hypertension. It can be used as monotherapy or in combination with other antihypertensive medicinal products, e.g., ß-adrenoceptor blockers, diuretics or ACE-inhibitors, in order to achieve an increased antihypertensive effect. Renedil reduces both systolic and diastolic blood pressure and can be used in isolated systolic hypertension.

Renedil has anti-anginal and anti-ischaemic effects due to improved myocardial oxygen supply/demand balance. Coronary vascular resistance is decreased and coronary blood flow and myocardial oxygen supply are increased by Renedil due to dilatation of both epicardial arteries and arterioles. The reduction in systemic blood pressure caused by Renedil leads to decreased left ventricular afterload and myocardial oxygen demand.

Renedil improves exercise tolerance and reduces anginal attacks in patients with stable effort-induced angina pectoris. Renedil can be used as monotherapy or in combination with ß-adrenoceptor blockers in patients with stable angina pectoris.

Haemodynamic effects

The primary haemodynamic effect of Renedil is a reduction of total peripheral vascular resistance, which leads to a decrease in blood pressure. These effects are dose-dependent. Generally, a reduction in blood pressure is evident two hours after the first oral dose and lasts for at least 24 hours and the trough/peak ratio is usually well above 50 %.

Plasma concentrations of Renedil are positively correlated to the decrease in total peripheral resistance and blood pressure.

Cardiac effects

Renedil in therapeutic doses has no effect on cardiac contractility or atrioventricular conduction or refractoriness.

Antihypertensive treatment with Renedil is associated with significant regression of pre-existing left ventricular hypertrophy.

Renal effects

Renedil has a natriuretic and diuretic effect due to reduced tubular reabsorption of filtered sodium. Renedil does not affect daily potassium excretion. The renal vascular resistance is decreased by Renedil. Renedil does not influence urinary albumin excretion.

In cyclosporine-treated renal transplant recipients, Renedil reduces blood pressure and improves both the renal blood flow and the glomerular filtration rate. Renedil may also improve early renal graft function.

Clinical efficacy and safety

In the HOT (Hypertension Optimal Treatment) study, the effect on major cardiovascular events (ie, acute myocardial infarction, stroke and cardiovascular death) was studied in relation to diastolic blood pressure targets < 90 mmHg, < 85 mmHg and < 80 mmHg and achieved blood pressure, with Renedil as baseline therapy.

A total of 18,790 hypertensive patients (DBP 100-115 mmHg), aged 50-80 years were followed for a mean period of 3.8 years (range 3.3-4.9). Renedil was given as monotherapy or in combination with a betablocker, and/or an ACE-inhibitor and/or a diuretic. The study showed benefits of lowering SBP and DBP down to 139 and 83 mmHg, respectively.

According to the STOP-2 (Swedish Trial in Old Patients with Hypertension-2 study), performed in 6614 patients, aged 70-84 years, dihydropyridine calcium antagonists (Renedil and isradipine) have shown the same preventive effect on cardiovascular mortality and morbidity as other commonly used classes of antihypertensive medicinal products - ACE inhibitors, beta-blockers and diuretics.

Paediatric population

There is limited clinical trial experience of the use of Renedil in hypertensive paediatric patients. In a randomised, double-blind, 3-week, parallel group study in children aged 6-16 years with primary hypertension, the antihypertensive effects of once daily Renedil 2.5 mg (n = 33), 5 mg (n = 33) and 10 mg (n = 31) were compared with placebo (n = 35). The study failed to demonstrate the efficacy of Renedil in lowering blood pressure in children aged 6-16 years

The long-term effects of Renedil on growth, puberty and general development have not been studied. The long-term efficacy of antihypertensive therapy as therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.

Absorption

Felodipine is administered as extended-release tablets, from which it is completely absorbed in the gastrointestinal tract. The systemic availability of felodipine is approximately 15% and is independent of dose in the therapeutic dose range. The extended-release tablets produce a prolonged absorption phase of felodipine. This results in even felodipine plasma concentrations within the therapeutic range for 24 hours. Maximum blood plasma levels (t_max) are achieved with the prolonged-release form after 3 to 5 hours. The rate but not the extent of absorption of felodipine is increased when taken simultaneously with food with a high fat content.

Distribution

The plasma protein binding of felodipine is approximately 99%. It is bound pre-dominantly to the albumin fraction. Volume of distribution at steady state is 10 L/kg.

Biotransformation

Felodipine is extensively metabolised in the liver by cytochrome P450 3A4 (CYP3A4) and all identified metabolites are inactive. Felodipine is a high clearance medicinal product with an average blood clearance of 1200 ml/min. There is no significant accumulation during long-term treatment.

Elderly patients and patients with reduced liver function have on average higher plasma concentrations of felodipine than younger patients. The pharmacokinetics of felodipine is not changed in patients with renal impairment, including those treated with haemodialysis.

Elimination

The half-life of felodipine in the elimination phase is approximately 25 hours and steady state is reached after 5 days. There is no risk of accumulation during long-term treatment. About 70% of a given dose is excreted as metabolites in the urine; the remaining fraction is excreted in the faeces. Less than 0.5% of a dose is recovered unchanged in urine.

Linearity/non-linearity

Plasma concentrations are directly proportional to dose within the therapeutic dose range 2.5-10 mg.

Paediatric population

In a single dose (felodipine prolonged-release 5 mg) pharmacokinetic study with a limited number of children aged between 6 and 16 years (n=12) there was no apparent relationship between the age and AUC, C_max or half-life of felodipine.

Absorption

Renedil is administered as extended-release tablets, from which it is completely absorbed in the gastrointestinal tract. The systemic availability of Renedil is approximately 15 % and is independent of dose in the therapeutic dose range. The extended-release tablets produce a prolonged absorption phase of Renedil. This results in even Renedil plasma concentrations within the therapeutic range for 24 hours. Maximum blood plasma levels (t_max) are achieved with the prolonged-release form after 3 to 5 hours. The rate but not the extent of absorption of Renedil is increased when taken simultaneously with food with a high fat content.

Distribution

The plasma protein binding of Renedil is approximately 99 %. It is bound pre-dominantly to the albumin fraction. Volume of distribution at steady state is 10 L/kg.

Biotransformation

Renedil is extensively metabolised in the liver by cytochrome P450 3A4 (CYP3A4) and all identified metabolites are inactive. Renedil is a high clearance medicinal product with an average blood clearance of 1200 ml/min. There is no significant accumulation during long-term treatment.

Elderly patients and patients with reduced liver function have on average higher plasma concentrations of Renedil than younger patients. The pharmacokinetics of Renedil is not changed in patients with renal impairment, including those treated with haemodialysis.

Elimination

The half-life of Renedil in the elimination phase is approximately 25 hours and steady state is reached after 5 days. There is no risk of accumulation during long-term treatment. About 70 % of a given dose is excreted as metabolites in the urine; the remaining fraction is excreted in the faeces. Less than 0.5 % of a dose is recovered unchanged in urine.

Linearity/non-linearity

Plasma concentrations are directly proportional to dose within the therapeutic dose range 2.5-10 mg.

Paediatric population

In a single dose (Renedil prolonged-release 5 mg) pharmacokinetic study with a limited number of children aged between 6 and 16 years (n = 12) there was no apparent relationship between the age and AUC, C_max or half-life of Renedil.

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

No special requirements