Vascalpha 10mg Prolonged Release Tablets (Felodipine)
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Vascalpha 10mg prolonged release tablets (felodipine)
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One prolonged release tablet contains 10 mg of felodipine.
Lactose-monohydrate 21.45 mg.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Prolonged release tablet.
Reddish brown, round, biconvex, film coated prolonged release tablets with imprint 10
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
- Essential hypertension.
- Stable angina pectoris.
4.2. Posology and method of administration
Vascalpha (felodipine) prolonged release tablets should usually be administered as follows:
The recommended starting dose is 5 mg felodipine once daily.
If necessary, the dose may be increased to 10 mg felodipine once daily or another antihypertensive agent added. Dose increases should occur at intervals of at least 2 weeks. The usual maintenance dose is 5-10mg once daily.
The maximum daily dose is 10 mg felodipine.
The dose should be adjusted to the individual requirements of the patient.
Angina Pectoris:
It is recommended to initiate treatment with Felodipine 5 mg once daily and in case of insufficient effect increase the dose to 10 mg once daily. The dose should be adjusted individually. Felodipine can be used as monotherapy or in combination with beta-blockers in patients with stable angina pectoris
Elderly
The recommended starting dose should be 2.5mg.
Subsequent dose increases should be undertaken with particular caution.
Note: Other medicinal products may be available for the starting dose of 2.5 mg felodipine, as Vascalpha is not available in this strength.
Impaired hepatic function
In patients with mild to moderate hepatic impairment, the recommended starting dose should be lowered to the minimal therapeutic effective dose of felodipine. The dose should only be increased after carefully balancing the benefits against the risks (see section 5.2). It is contraindicated in patients with severe hepatic impairment (see section 4.3).
Impaired renal function
The pharmacokinetics are not significantly affected in patients with mild to moderate impaired renal function. Caution should be taken in patients with severe renal impairment (see section 4.4 and section 5.2).
Children
Felodipine is not recommended for use in children due to lack of data on safety and efficacy.
Administration
The prolonged release tablets should be taken in the morning with a sufficient amount of fluid (e.g. a glass of water, but it should NOT be taken with grapefruit juice!) (see section 4.5).The prolonged release tablets should be swallowed whole and not chewed, crushed or divided.
The tablets may be taken on empty stomach or with a light meal, however a high-fat meal should be avoided (see section 5.2).
4.3 Contraindications
Felodipine is contra-indicated in patients with:
- hypersensitivity to felodipine (or other dihydropyridines) or to any of the excipients
- cardiogenic shock
- severe aortic and mitral stenosis
- obstructive hyperthrophic cardiomyopathy
- unstable angina pectoris
- acute myocardial infarction (within 4-8 weeks of a myocardial infarction)
- decompensated heart failure
- severe hepatic impairment
- pregnancy (see section 4.6)
4.4
Special warnings and precautions for use
Felodipine should be used with caution in patients with:
• conduction disorders, compensated heart failure, tachycardia and aortic or mitral valve stenosis.
• mild to moderate hepatic impairment, as the anti-hypertensive effect may be enhanced. Adjustment of the dosage should be considered.
• severe renal impairment (GFR <30ml/min)
• AV block of the second or third degree
If treatment with felodipine is discontinued abruptly, a hypertensive crisis may occur in individual cases.
Felodipine could cause significant hypotension (vasodilation effect) with consecutive tachycardia, leading to myocardial ischaemia in sensitive patients, therefore predisposed patients may suffer from myocardial infarction (see section 5.1 Pharmacodynamic properties).
Dihydropyridines may cause acute hypotension. In some cases there is a risk of hypoperfusion accompanied by reflex tachycardia (paradoxical angor) (see section 5.1 Pharmacodynamic properties).
Poor oral hygiene increases the risk of development of gingival hyperplasia.
Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Felodipine is a CYP3A4 substrate. Drugs that induce or inhibit CYP3A4 will have large influence on felodipine concentrations.
The anti-hypertensive effect of felodipine may be enhanced by other antihypertensives and tricyclic antidepressants.
The concomitant intake of felodipine and drugs which inhibit the cytochrome P450 isoenzyme 3A4 of the liver (such as cimetidine, azole antifungals [itraconazole, ketoconazole], macrolide antibiotics [erythromycin, clarithromycin, telithromycin] or HIV protease inhibitors leads to increased felodipine plasma levels (see section 4.4)).
Grapefruit juice results in increased peak plasma levels and bioavailability possibly due to interaction with flavonoids in the fruit juice. Therefore grapefruit juice should not be taken together with felodipine.
Concomitant treatment with drugs such as carbamazepine, phenytoin and barbiturates (e.g. phenobarbital) and rifampicin reduces the plasma levels of felodipine via enzyme induction in the liver (cytochrome P450-System). A similar effect is expected with St. John’s wort. Therefore a dose increase of felodipine may be necessary. Hydrochlorothiazide may enhance the anti-hypertensive effect of felodipine.
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 has no clinically significant effect on plasma concentrations of ciclosporin. Ciclosporin may inhibit felodipine metabolism which may create a potential risk of felodipine toxicity.
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.
Blood levels of digoxin increase during concomitant administration of felodipine. Therefore, decreasing of digoxin dosage should be taken into account when the two drugs are administered concurrently.
4.6 Pegnancy and lactation
Pregnancy
Felodipine is contra-indicated during the entire duration of pregnancy, as animal experiments have demonstrated foetal damage (see section 5.3). Pregnancy must be excluded before starting treatment with felodipine.
Lactation
Felodipine is excreted in breast milk. If the breast-feeding mother is taking therapeutic doses of felodipine, a fully breast-fed infant absorbs only a very low dose of the active substance with the breast milk. There is no experience of the risk this may pose to the newborn, therefore as a precaution breast-feeding should be discontinued during treatment.
4.7 Effects on ability to drive and use machines
Felodipine can cause dizziness or tiredness. These adverse effects are more likely to occur after initiation of the treatment, after dose increases, or after concomitant ingestion of alcohol. Should they occur, one should refrain from driving and other activities requiring alertness.
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.
Adverse drug reactions identified from clinical trials and from post marketing surveillance are listed below by system organ class and frequency. Frequencies are defined as: 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), not known (cannot be estimated from the available data).
Nervous system disorders
Very common: Headache.
Uncommon: Paraesthesia, dizziness, syncope, restlessness.
Ear and labyrinth disorders Very common: Tinnitus1.
Cardiac disorders
Uncommon: Palpitations, tachycardia, hypotension.
Very rare: Myocardial infarction
Vascular disorders Very common: Flushing.
Respiratory, thoracic and mediastinal disorders Uncommon: Dyspnoea.
Gastrointestinal disorders
Uncommon: Nausea, vomiting, diarrhoea, constipation, abdominal pain, gingival
hyperplasia and gingivitis.
Hepatobiliary disorders
Very rare: Hepatic function disorders (elevated transaminase levels).
Skin and subcutaneous tissue disorders
Uncommon: Skin and hypersensitivity reactions such as pruritus, urticaria, exanthema,
photosensitisation.
Rare: Leucocytoclastic vasculitis.
Very rare: Exfoliative dermatitis.
Musculoskeletal and connective tissue disorders Uncommon: Myalgia, arthralgia, tremors.
Renal and urinary disorders Uncommon: Pollakisuria.
Reproductive system and breast disorders
Very rare: Erection disorders, gynaecomastia, menorrhagia.
General disorders and administration site conditions
Very common: Peripheral oedema.
Uncommon: Weight gain, fatigue, sweating.
Very rare: Angiooedema, fever. 1 2
volume should be increased by infusion of e.g. glucose, saline or dextran. Additional intravenous fluids should be cautiously administered under haemodynamic supervision to prevent cardiac overloading. Sympathomimetic drugs with predominant effect on the a1-adrenoreceptor (such as dobutamin, dopamin, norepinephrin or adrenalin) may also be given if the above mentioned measures are insufficient. Dosage depends on the efficacy obtained.
Felodipine is only dialysable to a minimal extent (approx. 9 %).
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group:Didydropyridine derivates ATC code:C08C A02
Felodipine is a calcium antagonist of the dihydropyridine class of calcium channel blockers. Calcium antagonists interfere with the voltage-dependent L-type (slow) calcium channels in the plasma membranes of smooth muscle cells and reduce the inflow of calcium ions. This results in vasodilatation.
Felodipine has a greater selectivity for vascular smooth muscle than myocardial muscle. Felodipine selectively dilates arterioles with no effects on venous vessels. Felodipine leads to a dose-related lowering of blood pressure via vasodilatation and consequently a reduction of peripheral vascular resistance. It reduces both systolic and diastolic blood pressure. The haemodynamic effect of felodipine is accompanied by reflex (baroreceptor-mediated) tachycardia. In therapeutic doses, felodipine has no direct effect on either cardiac contractility or cardiac conduction. Felodipine reduces renal vascular resistance. The glomerular filtration rate remains unchanged.
Felodipine has a weak natriuretic/diuretic effect and does not provoke fluid retention.
Felodipine can be used as a monotherapy but also concomitantly with beta-blockers, diuretics and ACE inhibitors.
Felodipine improves the exercise tolerance and reduces the frequency of anginal attacks in patients with stable angina pectoris. Felodipine can be used as monotherapy or in combination with beta-blockers in patients with stable angina pectoris.
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
Felodipine is completely absorbed following oral administration. Peak plasma levels are reached with the prolonged release formulation after 3 - 5 hours and result in even felodipine plasma concentrations within the therapeutic range for 24 hours. Steady state is reached approx. 3 days after starting treatment. Due to an extensive first-pass effect, only approx. 15 % of the administered dose is systemically available.
Distribution
The plasma protein binding of felodipine is > 99 %. The volume of distribution is approximately 10 l/kg at steady state, so that felodipine is indicating large tissue distribution. There is no significant accumulation during long-term treatment.
Metabolism
Felodipine is extensively metabolised in the liver by CYP3A4. All identified metabolites are inactive.
Elimination
No unchanged parent substance is detectable in the urine. The average half-life of felodipine in the terminal phase is 25 hours. The inactive hydrophilic metabolites formed by hepatic biotransformation are mainly eliminated renally (to approx. 70 %), and the remainder is excreted in the faeces. The mean plasma clearance is 1100 ml/l and depends on the hepatic blood flow.
Elderly
Increased plasma concentrations have been measured in elderly patients. Impaired hepatic function
Increased plasma concentrations of up to 100% have been measured in patients with impaired hepatic function.
Impaired renal function
Renal impairment does not affect the pharmacokinetics of felodipine, although accumulation of inactive metabolites occurs in renal failure.
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.
Effect of food
The rate, but not the extent of absorption is affected by the simultaneous ingestion of fatty food. Cmax was 2 to 2.5 times higher following intake of a high-fat meal compared to a fasting state.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In animal studies with respect to the reproduction, adverse effects were found. Effects in rats (prolonged duration of pregnancy and difficult labour) and rabbits (impaired development of distal phalanges, presumably due to decreased uteroplacental perfusion) revealed no evidence of a direct teratogenic effect, but indicate secondary consequences of the pharmacodynamic effect. In monkeys, an abnormal position of the distal phalanges was found. The significance of these observations for humans is unknown.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Microcrystalline cellulose Hypromellose Povidone K25 Propyl gallate (Ph.Eur.)
Colloidal anhydrous silica Magnesium stearate (Ph.Eur.)
Tablet coat:
Hypromellose Iron oxide red (E172)
Iron oxide yellow (E172)
Titanium dioxide (E171)
Talcum
Propylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
6.4 Special precautions for storage
Do not store above 25 °C.
6.5 Nature and contents of container
PVC/PE/PVDC aluminium blister.
Pack sizes: 10, 14, 20, 28, 30, 50, 56, 60, 90, 98, 100, 250, 500 and 1000 prolonged release tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited (Trading style: Actavis)
Whiddon Valley Barnstaple North Devon EX32 8NS
8 MARKETING AUTHORISATION NUMBER
PL 00142/0542
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/09/2006
10 DATE OF REVISION OF THE TEXT
23/03/2012
Particularly at the beginning of treatment, when the dose is increased or when high doses are administered. Generally, those effects subside on continued treatment.
Particularly at the beginning of treatment, angina pectoris attacks may occur, or in patients with pre-existing angina pectoris there may be an increase in the frequency, duration and severity of the attacks.
4.9 Overdose
Symptoms of intoxication
Overdose may lead to excessive peripheral vasodilatation with marked hypotension and in rare cases bradycardia.
Management of intoxication
The therapeutic measures should focus on elimination of the active ingredient (e.g. administration of charcoal, bowel irrigation) and monitoring of the vital signs. If severe hypotension occurs, symptomatic treatment should be provided, the patient should be placed supine with the legs elevated. In case of accompanying bradycardia, atropine (0.5 - 1.0 mg) should be given intravenously. If this is not sufficient, plasma