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5mg: light pink, coated, round, biconvex 9mm tablets, imprinted 5.
10mg: reddish brown, coated, round, biconvex 9mm tablets, imprinted 10.
Do not halve tablet. This product is not able to deliver all approved dose regimens.
Felodipine is a highly 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.
Felodipine is effective in all grades of hypertension. It can be used as monotherapy or in combination with other antihypertensive agents, e.g. beta-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 maintains its antihypertensive effect during concomitant therapy with non-steroidal anti-inflammatory agents (NSAID).
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. Felodipine effectively counteracts coronary vasospasm. 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. 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 beta-adrenoceptor blockers in patients with stable angina pectoris.
Felodipine is effective and well tolerated in adult patients irrespective of age and race and is also well tolerated in the presence of concomitant diseases such as congestive heart failure, asthma and other obstructive pulmonary disease, impaired renal function, diabetes mellitus, gout, hyperlipidaemia, Raynaud's disease and in renal transplant recipients. Felodipine has no effect on blood glucose levels or lipid profile.
The predominant pharmacodynamic feature of felodipine is its pronounced vascular vs 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 cell membranes.
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. Plasma concentrations of felodipine are positively correlated to the decrease in total peripheral resistance and blood pressure.
Felodipine in therapeutic doses has no effect on cardiac contractility or atrioventricular conduction or refractoriness. In patients with heart failure, felodipine favourably affects left ventricular function, as assessed by ejection fraction or stroke volume, and does not cause neurohormonal activation. However, felodipine does not seem to affect survival. Therefore felodipine can be used in patients with hypertension or angina pectoris who also have impaired left ventricular function. Antihypertensive treatment with felodipine is associated with significant regression of pre-existing left ventricular hypertrophy.
Felodipine has a natriuretic and diuretic effect due to reduced tubular reabsorption of filtered sodium. This counteracts the salt and water retention observed with other vasodilators. Felodipine does not affect daily potassium excretion. The renal vascular resistance is decreased by felodipine. Normal glomerular filtration rate is unchanged. In patients with impaired renal function, the glomerular filtration rate may increase.
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.
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 to 80 years were followed for a mean period of 3.8 years (range 3.3 to 4.9).
Felodipine was given as monotherapy or in combination with a beta-blocker and/or ACE-inhibitor and/or diuretic. The study showed benefits of lowering the SBP and DBP down to 139 and 83 mmHg, respectively. When the baseline DBP was lowered from 105 mmHg to 83 mmHg, it suggests that from five to ten major cardiovascular events can be prevented in every 1 000 patients treated for 1 year. This implies a 30% risk reduction. Active lowering of blood pressure was particularly beneficial in the subgroup of patients with diabetes mellitus.
According to the 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 preventative effect on cardiovascular mortality and morbidity as other commonly used classes of antihypertensive drugs - ACE inhibitors, beta-blockers and diuretics.
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 plasma protein binding of felodipine is approximately 99%. It is bound predominantly to the albumin fraction. The time to maximum plasma concentration (tmax) is between 2.5 and 5 hours.
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. Plasma concentrations are directly proportional to dose within the therapeutic dose range 2.5-10 mg.
In humans felodipine has a volume of distribution of approximately 10 L/kg at steady state.
Felodipine is extensively metabolised by the liver and all identified metabolites are inactive. Felodipine is a high clearance agent with an average blood clearance of 1200 mL/min. The average half-life of felodipine in the terminal phase is 24 hours. 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 kinetics of felodipine are not changed in patients with renal impairment, including those treated with haemodialysis.
The bioavailability, time to peak plasma concentration and volume of distribution do not appear to be significantly affected by age.
Since there is often significant inter-individual variation in pharmacokinetic characteristics, dosage of felodipine should be individually adjusted rather than based only on patient's age.
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.
Felodipine 2.5 mg is not proven to be effective in treating angina.
Hypertension
Chronic, stable angina pectoris. Felodipine may be used alone or in combination with other anti-anginal medication.
This product is not able to deliver all approved dose regimens.
The tablets should be taken in the morning, be swallowed with water and 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.
The dose should be adjusted individually. Treatment should be started with 5 mg once daily. If necessary the dose may be further increased or another anti-hypertensive agent added. The usual maintenance doses are 5 mg to 10 mg once daily. In elderly patients initial treatment with 2.5 mg daily should be considered.
The dose should be adjusted individually. Treatment should be started with 5 mg once daily, increasing to 10 mg once daily if needed.
Elderly patients should have their dose adjusted individually taking the patient's age into consideration. The lowest effective dose for angina is felodipine 5 mg daily and it is recommended that this dose be employed as the initial dose and alternative treatment considered if this dose is not well tolerated in the individual.
There is no experience of felodipine treatment in children.
Pregnancy
Hypersensitivity to felodipine or any other component of the product
Uncompensated heart failure
Acute myocardial infarction
Unstable angina pectoris
Felodipine, like other effective arteriolar dilators, may in rare cases precipitate significant hypotension, which, in susceptible individuals, may result in myocardial ischaemia.
Felodipine should not be given during pregnancy. Felodipine is detected in breast milk. When taken in therapeutic doses by the nursing mother it is, however, not likely to affect the infant.
Felodipine is not likely to affect the ability to drive or use machines.
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.
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.
The following adverse events have been reported from clinical trials and from Post Marketing Surveillance.
The following definitions of frequencies are used:
Common ≥ 1/100
Uncommon ≥ 1/1 000 and < 1/100
Rare ≥ 1/10 000 and < 1/1 000
Very rare < 1/10 000
Common: flush
Uncommon: rash, pruritus.
Rare: urticaria
Very rare: photosensitivity reactions, leucocytoclastic vasculitis
Rare: arthralgia, myalgia.
Common: headache.
Uncommon: dizziness, paraesthesia
Gastrointestinal
Uncommon: nausea, abdominal pain
Rare: vomiting
Very rare: gingival hyperplasia, gingivitis
Very rare: increased liver enzymes.
Uncommon: tachycardia, palpitations
Rare: syncope.
Vascular (extra cardiac)
Common: peripheral oedema.
Rare: impotence/sexual dysfunction
Very rare: pollakiuria
Uncommon: fatigue.
Very rare: hypersensitivity reactions e.g. angio-oedema, fever.
Concomitant administration of substances which interfere with the cytochrome P450 enzyme system may affect plasma concentrations of dihydropyridine calcium antagonists such as felodipine.
Enzyme inhibitors (e.g. cimetidine, erythromycin, itraconazole, ketoconazole and certain flavonoids present in grapefruit juice) have been shown to cause an increase in felodipine plasma concentrations. Enzyme inducers (e.g. phenytoin, carbamazepine, rifampicin, barbiturates) may cause a decrease in plasma concentrations of felodipine.
Felodopine 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 cyclosporin. The high degree of plasma protein binding of felodipine does not appear to affect the unbound fraction of other extensively bound drugs such as warfarin.
Overdosage may cause excessive peripheral vasodilatation with marked hypotension and sometimes bradycardia.
Activated charcoal, if necessary gastric lavage.
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 agents with predominant effect on the alpha1-adrenoceptor may be given if the above mentioned measures are insufficient.
Store below 25°C. Protect from light & moisture.
Prescription Medicine.
5 mg: packs of 30 or 90 extended release tablets.
10 mg: packs of 30 or 90 extended release tablets.
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).
Studies have been performed in mice and rats. In the rat, interstitial cell tumours in the testes were observed. This species-specific effect is caused by an endocrinological effect of felodipine in the rat.
Lactose, magnesium stearate, silicon dioxide, microcrystalline cellulose, povidone, propyl gallate, hypromellose, propylene glycol, purified talc, titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172).
Mylan New Zealand Ltd
PO Box 11-183
Ellerslie
AUCKLAND
Telephone: 09-579-2792
2 February 2009