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.
Prolonged-release tablets 2.5 mg (blister): 2 years
Prolonged-release tablets 2.5 mg (bottle): 3 years
Prolonged-release tablets 5 mg (blister and bottle): 3 years
Prolonged-release tablets 10 mg (blister and bottle): 3 years
Not applicable.
Tablet core
Hydroxypropylcellulose
Hypromellose 50 mPa·s
Hypromellose 10000 mPa·s
Lactose anhydrous
Macrogolglycerol hydroxystearate
Microcrystalline cellulose
Propyl gallate
Sodium aluminium silicate
Sodium stearyl fumarate
Coating
Carnauba wax
Iron oxide yellow (E172)
Hypromellose 6 mPa·s
Macrogol 6000
Titanium dioxide (E171)
Plendil 5 mg and 10 mg:
Carnauba wax
Iron oxide reddish-brown (E172)
Iron oxide yellow (E172)
Hypromellose 6 mPa·s
Macrogol 6000
Titanium dioxide (E171)
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
|
System organ class |
Frequency |
Adverse reaction |
|
Nervous system disorders |
Common Uncommon |
Headache Dizziness, paraesthesia |
|
Cardiac disorders |
Uncommon |
Tachycardia, palpitations |
|
Vascular disorders |
Common Uncommon Rare |
Flush Hypotension Syncope |
|
Gastrointestinal disorders |
Uncommon Rare Very rare |
Nausea, abdominal pain Vomiting Gingival hyperplasia, gingivitis |
|
Hepatobiliary disorders |
Very rare |
Increased liver enzymes |
|
Skin and subcutaneous tissue disorders |
Uncommon Rare Very rare |
Rash, pruritus Urticaria Photosensitivity reactions, leukocytoclastic vasculitis |
|
Musculoskeletal and connective tissue disorders |
Rare |
Arthralgia, myalgia |
|
Renal and urinary disorders |
Very rare |
Pollakisuria |
|
Reproductive system and breast disorders |
Rare |
Impotence/sexual dysfunction |
|
General disorders and administration site conditions |
Very common Uncommon Very rare |
Peripheral oedema Fatigue Hypersensitivity reactions, e.g. angio-oedema, fever |
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.
Reproduction toxicity
In a study on fertility and general reproductive performance in rats treated with felodipine, a prolongation of parturition resulting in difficult labour/increased foetal deaths and early postnatal deaths was observed in the medium and high dose groups. These effects were attributed to the inhibitory effect of felodipine in high doses on uterine contractility. No disturbances of fertility were observed when doses within the therapeutic range were given to rats.
Reproduction studies in rabbits have shown a dose-related reversible enlargement of the mammary glands of the parent animals and dose-related digital anomalies in the foetuses. The anomalies in the foetuses were induced when felodipine was administered during early foetal development (before day 15 of pregnancy). In a reproduction study in monkeys, an abnormal position of the distal phalange(s) was noticed.
There were no other pre-clinical findings considered to be of concern and the reproductive findings are considered to be related to the pharmacological action of felodipine, when given to normotensive animals. The relevance of these findings for patients receiving felopidine is unknown. However, there have been no reported clinical incidences of phalangeal changes in foetus/neonate exposed to felodipine in-utero, from the information maintained within the internal patient safety databases.
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.
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 (tmax) 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, Cmax or half-life of felodipine.
9th November 2016
AstraZeneca UK Ltd.,
600 Capability Green,
Luton, LU1 3LU, UK.
This medicinal product does not require any special storage conditions.
High-density polyethylene bottle with a standard cap of polypropylene
PVC/PVDC/Aluminium blister
Prolonged-release tablets 2.5 mg
Blister pack
20 tablets (blister pack)
28 tablets (calendar blister pack)
30 tablets (blister pack)
50 tablets (unit-dose pack)
98 tablets (calendar blister pack)
100 tablets (blister pack)
Plastic bottle
30 tablets (bottle)
100 tablets (bottle)
500 tablets (bottle for dose dispensing)
Prolonged-release tablets 5 mg
Blister pack
14 tablets (calendar blister pack)
20 tablets (blister pack)
28 tablets (calendar blister pack)
30 tablets (blister pack)
50 tablets (unit-dose pack)
90 tablets (blister pack)
98 tablets (calendar blister pack)
100 tablets (blister pack)
Plastic bottle
30 tablets (bottle)
100 tablets (bottle)
500 tablets (bottle for dose dispensing)
Prolonged-release tablets 10 mg
Blister pack
14 tablets (calendar blister pack)
20 tablets (blister pack)
28 tablets (calendar blister pack)
30 tablets (blister pack)
50 tablets (unit-dose pack)
90 tablets (blister pack)
98 tablets (calendar blister pack)
100 tablets (blister pack)
Plastic bottle
30 tablets (bottle)
100 tablets (bottle and bottle for dose dispensing)
500 tablets (bottle for dose dispensing)
Not all pack sizes may be marketed.
Plendil 2.5 mg prolonged-release tablets: PL 17901/0156
Plendil 5 mg prolonged-release tablets: PL 17901/0157
Plendil 10 mg prolonged-release tablets: PL 17901/0155
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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Date of latest renewal: 03 June 2002
