Plendil 2.5mg, Plendil 5mg and Plendil 10mg.

Plendil 2.5mg contains Felodipine Ph. Eur. 2.5mg

Plendil 5mg contains Felodipine Ph. Eur. 5mg

Plendil 10mg contains Felodipine Ph. Eur. 10mg

Circular biconvex film coated extended-release tablets.

Plendil 2.5mg - yellow tablets coded A/FL and 2.5 on the reverse.

Plendil 5mg - pink tablets coded A/FM and 5 on the reverse.

Plendil 10mg - red-brown tablets coded A/FE and 10 on the reverse.

In the management of hypertension and prophylaxis of chronic stable angina pectoris.

For oral administration.

The tablets should be taken in the morning irrespective of food intake. Plendil tablets must not be chewed or crushed. They should be swallowed whole with half a glass of water.

Hypertension

Adults (including elderly) The dose should be adjusted to the individual requirements of the patient. The recommended starting dose is 5mg once daily. If necessary the dose may be further increased or another antihypertensive agent added. The usual maintenance dose is 5 - 10 mg once daily. Doses higher than 20mg daily are not usually needed. For dose titration purposes a 2.5mg tablet is available. In elderly patients an initial treatment with 2.5mg daily should be considered.

Angina pectoris

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

Children The safety and efficacy of Plendil in children has not been established.

Plendil can be used in combination with β-blockers, ACE inhibitors or diuretics. The effects on blood pressure are likely to be additive and combination therapy will usually enhance the antihypertensive effect. Care should be taken to avoid hypotension.

In patients with severely impaired liver function the dose of felodipine should be low. The pharmacokinetics are not significantly affected in patients with impaired renal function.

Unstable angina pectoris.

Pregnancy.

Patient with a previous allergic reaction to Plendil or other dihydropyridines because of the theoretical risk of cross-reactivity.

Plendil should not be used in patients with clinically significant aortic stenosis, uncompensated heart failure, and during or within one month of a myocardial infarction.

As with other calcium channel blockers, Plendil should be discontinued in patients who develop cardiogenic shock.

As with other vasodilators, Plendil may, in rare cases, precipitate significant hypotension with tachycardia which in susceptible individuals may result in myocardial ischaemia.

There is no evidence that Plendil is useful for secondary prevention of myocardial infarction.

The efficacy and safety of Plendil in the treatment of malignant hypertension has not been studied.

Plendil should be used with caution in patients with severe left ventricular dysfunction.

Concomitant administration of substances which interfere with the cytochrome P4503A4 enzyme system may affect plasma concentrations of felodipine. Enzyme inhibitors such as cimetidine, erythromycin, itraconazole and ketoconazole impair the elimination of felodipine, and Plendil dosage may need to be reduced when drugs are given concomitantly. Conversely, powerful enzyme inducing agents such as some anticonvulsants (phenytoin, carbamazepine, phenobarbital) can increase felodipine elimination and higher than normal Plendil doses may be required in patients taking the drugs.

No dosage adjustment is required when Plendil is given concomitantly with digoxin.

Felodipine does not appear to affect the unbound fraction of other extensively plasma protein bound drugs such as warfarin.

Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.

Grapefruit juice results in increased peak plasma levels and bioavailability possibly due to an interaction with flavonoids in the fruit juice. This interaction has been seen with other dihydropyridine calcium antagonists and represents a class effect. Therefore grapefruit juice should not be taken together with Plendil tablets.

Felodipine should not be given during pregnancy.

In a study on fertility and general reproductive performance in rats, a prolongation of parturition resulting in difficult labour, increased foetal deaths and early postnatal deaths were observed in the medium-and high-dose groups. Reproductive studies in rabbits have shown a dose-related reversible enlargement of the mammary glands of the parent animals and dose-related digital abnormalities in the foetuses when felodipine was administered during stages of early foetal development.

Felodipine has been detected in breast milk, but it is unknown whether it has harmful effects on the new-born.

None.

As with other calcium antagonists, flushing, headache, palpitations, dizziness and fatigue may occur. These reactions are usually transient and are most likely to occur at the start of treatment or after an increase in dosage.

As with other calcium antagonists ankle swelling, resulting from precapillary vasodilation, may occur. The degree of ankle swelling is dose related.

In patients with gingivitis/periodontitis, mild gingival enlargement has been reported with Plendil, as with other calcium antagonists. The enlargement can be avoided or reversed by careful dental hygiene.

As with other dihydropyridines, aggravation of angina has been reported in a small number of individuals especially after starting treatment. This is more likely to happen in patients with symptomatic ischaemic heart disease.

The following adverse events have been reported from clinical trials and from Post Marketing Surveillance. In the great majority of cases a causal relationship between these events and treatment with felodipine has not been established.

Skin: very rarely - leucocytoclastic vasculitis, rarely - rash and/or pruritus, and isolated cases of photosensitivity.

Musculoskeletal: in isolated cases arthralgia and myalgia.

Psychiatric: rarely impotence/sexual dysfunction.

Central and peripheral nervous system: headache, dizziness. In isolated cases paraesthesia.

Gastrointestinal: very rarely - gingivitis, in isolated cases abdominal pain, nausea, vomiting, gum hyperplasia.

Hepatic: in isolated cases increased liver enzymes.

Urinary system: very rarely urinary frequency.

Cardiovascular: rarely - tachycardia, palpitations and syncope.

Vascular (extracardiac): peripheral oedema, flush.

Other: very rarely - fever, rarely - fatigue, in isolated cases hypersensitivity reactions e.g. urticaria, angio-oedema.

Symptoms: Overdosage may cause excessive peripheral vasodilatation with marked hypotension which may sometimes be accompanied by bradycardia.

Management: Activated charcoal, induction of vomiting or gastric lavage, if appropriate or indicated. Severe hypotension should be treated symptomatically, with the patient placed supine and the legs elevated. Bradycardia, if present, should be treated with atropine 0.5-1mg i.v. If this is not sufficient, plasma volume should be increased by infusion of e.g. glucose, saline or dextran. Sympathomimetic drugs with predominant effect on the α₁-adrenoceptor may be given e.g. metaraminol or phenylephrine.

Felodipine is a vascular selective calcium antagonist, which lowers arterial blood pressure by decreasing peripheral 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.

It can be used as monotherapy or in combination with other antihypertensive drugs, e.g. β-receptor 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. In a study of 12 patients, felodipine maintained its antihypertensive effect during concomitant therapy with indomethacin.

Because there is no effect on venous smooth muscle or adrenergic vasomotor control, felodipine is not associated with orthostatic hypotension.

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 as well as myocardial oxygen supply are increased by felodipine due to dilation of both epicardial arteries and arterioles. Felodipine effectively counteracts coronary vasospasm. The reduction in systemic blood pressure caused by felodipine leads to decreased left ventricular afterload.

Felodipine improves exercise tolerance and reduces anginal attacks in patients with stable effort induced angina pectoris. Both symptomatic and silent myocardial ischaemia are reduced by felodipine in patients with vasospastic angina. Felodipine can be used as monotherapy or in combination with β-receptor blockers in patients with stable angina pectoris.

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

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 felodipine as therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.

Felodipine is well tolerated in patients with concomitant disease such as congestive heart failure well-controlled on appropriate therapy, asthma and other obstructive pulmonary diseases, diabetes, gout, hyperlipidemia impaired renal function, renal transplant recipients and Raynaud's disease. Felodipine has no significant effect on blood glucose levels or lipid profiles.

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. In patients with mild to moderate essential hypertension, a reduction in blood pressure usually occurs 2 hours after the first oral dose and lasts for at least 24 hours with a trough/peak ratio usually above 50%.

Plasma concentration of felodipine and decrease in total peripheral resistance and blood pressure are positively correlated.

Electrophysiological and other cardiac effects: Felodipine in therapeutic doses has no effect on cardiac contractility or atrioventricular conduction or refractoriness.

Renal effects: Felodipine has a natriuretic and diuretic effect. Studies have shown that the tubular reabsorption of filtered sodium is reduced. This counteracts the salt and water retention observed for other vasodilators. Felodipine does not affect the daily potassium excretion. The renal vascular resistance is decreased by felodipine. Normal glomerular filtration rate is unchanged. In patients with impaired renal function glomerular filtration rate may increase.

Felodipine is well tolerated in renal transplant recipients.

Site and mechanism of action: The predominant pharmacodynamic feature of felodipine is its pronounced vascular versus myocardial selectivity. Myogenically active smooth muscles in arterial resistance vessels are particularly sensitive to felodipine.

Felodipine inhibits electrical and contractile activity of vascular smooth muscle cells via an effect on the calcium channels in the cell membrane.

Absorption and distribution: Felodipine is completely absorbed from the gastrointestinal tract after administration of felodipine extended release tablets.

The systemic availability of felodipine is approximately 15% in man and is independent of dose in the therapeutic dose range.

With the extended-release tablets the absorption phase is prolonged. This results in even felodipine plasma concentrations within the therapeutic range for 24 hours.

The plasma protein binding of felodipine is approximately 99%. It is bound predominantly to the albumin fraction.

Elimination and metabolism: The average half-life of felodipine in the terminal phase is 25 hours. There is no significant accumulation during long-term treatment. Felodipine is extensively metabolised by the liver and all identified metabolites are inactive. Elderly patients and patients with reduced liver function have an average higher plasma concentration of felodipine than younger patients.

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 the urine.

The kinetics of felodipine are not changed in patients with renal impairment.

In a single dose (felodipine extended release 5 mg) pharmacokinetic study in twelve children aged between 6 and 16 years there was no apparent relationship between age and AUC, C_max or half-life of felodipine.

Felodipine is a calcium antagonist and lowers arterial blood pressure by decreasing vascular resistance. In general a reduction in blood pressure is evident 2 hours after the first oral dose and at steady state lasts for at least 24 hours after dose.

Felodipine exhibits a high degree of selectivity for smooth muscles in the arterioles and in therapeutic doses has no direct effect on cardiac contractility. Felodipine does not affect venous smooth muscle and adrenergic vasomotor control.

Electrophysiological studies have shown that felodipine has no direct effect on conduction in the specialised conducting system of the heart and no effect on the AV nodal refractories.

Plendil possesses a mild natriuretic/diuretic effect and does not produce general fluid retention, nor affect daily potassium excretion. Plendil is well tolerated in patients with congestive heart failure.

Polyoxyl 40 hydrogenated castor oil, Hydroxypropyl cellulose, Propyl gallate, Hydroxypropyl methylcellulose, Sodium aluminium silicate, Microcrystalline cellulose, Lactose anhydrous, Sodium stearyl fumarate, Macrogol, Colour Titanium dioxide (E171), Colour Iron oxide yellow (E172) and Carnauba wax.

None stated.

Plendil 2.5mg – 24 months

Plendil 5mg – 3 years

Plendil 10mg – 3 years

Do not store above 25°C.

1. HDPE Bottles - White, high density polyethylene (PE) bottles with PE screw caps. A break-off ring guarantees the integrity of the unopened package. Each bottle contains 100 tablets.

2. Aclar^®Blisters - Press through blister package of aluminium form foil with an aluminium foil as enclosure web. Each blister strip contains 7 tablets. A single pack may contain 7, 14, 28, 56 or 112 tablets as multiplies of blisters of 7.

3. Tristar^®Blisters - Press through packages of thermoformed PVC/PVDC with an aluminium foil as enclosure web. Each blister strip contains 7 tablets. A single pack may contain 7, 14, 28, 56 or 112 tablets as multiples of blisters of 7.

4. PVC/PVDC Blisters - Press through blister package of PVC/PVDC form foil with an aluminium foil as enclosure web. Each blister strip contains 7 tablets. A single pack may contain 7, 14, 28, 56 or 112 tablets as multiples of blisters of 7.

None Stated

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

3^rd February 2002

27^th September 2007