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1. Plendil 2.5mg
2. Plendil 2.5mg

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Plendil 2.5mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Felodipine Ph. Eur. 2.5mg

3. PHARMACEUTICAL FORM

Yellow, circular biconvex film coated extended-release tablets coded A/FL and 2.5 on the reverse.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

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

4.2 Posology and method of administration

For oral administration.

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

Adults:

Hypertension:

The dose should be adjusted to the individual requirements of the patient. The recommended starting dose is 5mg 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 - 10 mg once daily.

Doses higher than 20mg daily are not usually needed. For dose titration purposes a 2.5mg tablet is available.

Stable angina pectoris:

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

Plendil can be used in combination with ^-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.

Elderly population

Initial treatment with lowest available dose should be considered.

Hepatic Impairment

Patients with impaired hepatic function may have elevated plasma concentrations of felodipine and may respond to lower doses (see section 4.4 and section 5.2).

Renal Impairment

Dose adjustment is not needed in patients with impaired renal function. The pharmacokinetics are not significantly affected in patients with impaired renal function.

Paediatric Population

There is limited clinical trial experience of the use of felodipine in hypertensive paediatric patients (see sections 5.1 and 5.2).

4.3 Contraindications

Unstable angina pectoris.

Pregnancy.

Known hypersensitivity to felodipine or any other component of the product.

Other dihydropyridines because of the theoretical risk of cross-reactivity.

Plendil should not be used in patients with clinically significant aortic stenosis, haemodynamically significant cardiac valvular obstruction, dynamic cardiac outflow obstruction, uncompensated heart failure, and during or within one month of an acute myocardial infarction.

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

4.4 Special warnings and precautions for use

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

Felodipine must be used with caution in patients with a propensity for tachycardia.

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.

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

Felodipine is cleared by the liver. Consequently higher therapeutic concentrations and response can be expected in patients with clearly reduced liver function (see also section 4.2).

Plendil contains lactose and patients with hereditary galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Plendil.

4.5 Interaction with other medicinal products and other forms of interaction Enzyme interactions

Felodipine is metabolised in the liver by cytochrome P450 3A4 (CYP3A4). Enzyme inhibiting and enzyme inducing substances of cytochrome P450 isoenzyme 3A4 may exert an influence on the plasma level of felodipine.

Interactions leading to increased plasma concentrations of felodipine. Enzyme inhibitors of the cytochrome P450 3A4 systems have been shown to cause an increase in felodipine plasma concentrations such as cimetidine, erythromycin, itraconazole, ketoconazole and anti HIV/protease inhibitors (e.g. ritonavir) impair the elimination of felodipine, and Plendil dosage may need to be reduced when drugs are given concomitantly.

Interactions leading to decreased plasma concentrations of felodipine Enzyme inducers of the cytochrome P450 3A4 system may cause a decrease in plasma concentrations of felodipine such phenytoin, carbamazepine, phenobarbital, rifampicin, barbiturates, efavirenz, nevirapine and hypericum perforatum (St John’s wort). Higher than normal Plendil doses may be required in patients taking these drugs.

Additional interactions

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

The high degree of plasma protein binding of 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.

Felodipine does not affect plasma concentrations of ciclosporin.

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.

4.6 Fertility, pregnancy and lactation Fertility

Data on male and female fertility in patients are missing (see section 5.3). Pregnancy

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.

Lactation

Felodipine has been detected in breast milk. When taken in therapeutic doses by the nursing mother it is, however, not likely to affect the infant.

4.7 Effects on ability to drive and use machines

Patients should know how they react to felodipine before they drive or use machines because occasionally dizziness or fatigue may occur.

4.8 Undesirable effects

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

As with other dihydropyridines, 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. Experience from clinical trials has shown that 2 % of patients interrupted treatment due to ankle swelling.

As with other calcium antagonists, mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. 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. The following definitions of frequencies are used: Very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1A0000 and <1/1000) and very rare (<1/10000).

System Organ class	Frequency	Adverse Drug Reaction
Nervous system disorders	Common	Headache
	Uncommon	Dizziness, paraesthesia
Cardiac disorders	Uncommon	Tachycardia, palpitations
Vascular disorders	Common	Flush
	Uncommon	Hypotension
	Rare	Syncope
Gastrointestinal disorders	Uncommon	Nausea, abdominal pain
	Rare	Vomiting
	Very rare	Gingival hyperplasia, gingivitis
Hepatobiliary disorders	Very rare	Increased liver enzymes
Skin and subcutaneous tissue disorders	Uncommon	Rash, pruritus
	Rare	Urticaria
	Very rare	Photosensitivity reactions, leucocytoclastic 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

4.9 Overdose

Symptoms: Overdosage may cause excessive peripheral vasodilatation with marked hypotension and sometimes 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. In case of accompanying Bradycardia, atropine 0.5-1mg should be administered intravenously. 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 a_radrenoceptor may be given e.g. metaraminol or phenylephrine if the above-mentioned measures are insufficient.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Calcium antagonist.

ATC code: C08C A02

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. ^-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 ^-receptor blockers in patients with stable angina pectoris.

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

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.

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.

5.2 Pharmacokinetic properties

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 in the liver by cytochrome P450 3A4 (CYP3A4) 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 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.

5.3. Pre-clinical safety data

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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Macrogolglycerol hydroxystearate, Hydroxypropyl cellulose, Propyl gallate, Hypromellose, Sodium aluminium silicate, Microcrystalline cellulose, Lactose anhydrous, Sodium stearyl fumarate, Macrogol, Colour Titanium dioxide (E171), Colour Iron oxide yellow (E172) and Carnauba wax.

6.2. Incompatibilities

None stated.

6.3. Shelf life

24 months

Special precautions for storage

Do not store above 25°C.

6.5. Nature and contents of container

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.

6.6 Special precautions for disposal

None Stated.

7.    MARKETING AUTHORISATION HOLDER

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

8.    MARKETING AUTHORISATION NUMBER

PL 17901/0156

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

3^rd June 2002

DATE OF REVISION OF THE TEXT

08/07/2013