Felogen Xl 5mg Prolonged Release Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Felogen XL 5mg Prolonged Release Tablet
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 prolonged release tablet contains 5mg of felodipine For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Prolonged release tablets
Light pink, round, biconvex, film-coated prolonged release tablet with embossed 5
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension
4.2 Posology and method of administration
The tablets should be taken in the morning and be swallowed with water. The tablets should NOT be taken with grapefruit juice (see section 4.5). In order to keep the prolonged release properties, the tablets 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.
Hypertension
The dose should be adjusted individually. Treatment can be started with 5 mg 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. Dose increases should occur at intervals of at least 2 weeks. If necessary another antihypertensive agent may be added.
The standard maintenance dose is 5 mg once daily. The maximum daily dose is 10 mg felodipine.
Elderly population
Initial treatment with lowest available dose should be considered. Subsequent dose increases should be undertaken with particular caution.
Renal Impairment
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 Sections 4.4 and 5.2.
Dose adjustment is not needed in patients with impaired renal function.
Hepatic Impairment
In patients with mild to moderate hepatic impairment, the recommended starting dose should be lowered to the minimum 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.
Patients with impaired hepatic function may have elevated plasma concentrations of felodipine and may respond to lower doses (see section 4.4).
Paediatric Population
There is limited clinical trial experience of the use of felodipine in hypertensive paediatric patients, see sections 5.1 and 5.2. Felogen XL is not recommended for use in children due to lack of data on safety and efficacy.
4.3 Contraindications
• Pregnancy
• Known hypersensitivity to felodipine (or other dihydropyridines) or any other component of the product
• Uncompensated heart failure
• Acute myocardial infarction (within 4-8 weeks of myocardial infarction)
• Unstable angina pectoris
• Haemodynamically significant cardiac valvular obstruction
• Dynamic cardiac outflow obstruction
• Cardiogenic shock
• Severe hepatic impairment
4.4 Special warnings and precautions for use
Felogen XL 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 Felogen XL is discontinued abruptly, a hypertensive crisis may occur in individual cases.
Felogen XL may cause significant hypotension with subsequent tachycardia. This may lead to myocardial ischaemia in susceptible patients.
Dihydropyridines may cause acute hypotension. In some cases there is a risk of hypoperfusion accompanied by reflex tachycardia (paradoxal angor) (see section 5.1).
Felogen XL is metabolised by CYP3A4 enzymes. Therefore, combination with medicinal products which are potent CYP3A4 inhibitors or inducers should be avoided (see section 4.5). Due to the same reason the concomitant intake of grapefruit juice should be avoided (see section 4.5).
Felogen XL must be used with caution in patients with a propensity for tachycardia.
Felogen XL is cleared by the liver. Consequently higher therapeutic concentrations and response be expected in patients with clearly reduced liver function (see section 4.2).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Enzyme interactions
Felogen XL is a CYP3A4 substrate. Enzyme inhibiting and enzyme inducing substances of cytochrome P450 isoenzyme 3A4 may exert an influence on the plasma level of felodipine. The anti-hypertensive effect of Felogen XL may be enhanced by other anti-hypertensives and tricyclic antidepressants.
Interactions leading to increased plasma concentration of felodipine Enzyme inhibitors have been shown to cause an increase in felodipine plasma concentrations.
Examples:
• Cimetidine
• Erythromycin
• Clarithromycin
• Telithromycin
• Itraconazole
• Ketoconazole
• Anti HIV/protease inhibitors (e.g.ritonavir)
• Certain flavonoids present in grapefruit juice. Therefore grapefruit juice should not be taken together with Felogen XL.
Interactions leading to decreased plasma concentration of felodipine Enzyme inducers may cause a decrease in plasma concentrations of felodipine. Therefore a dose increase of Felogen XL may be necessary Examples:
• Phenytoin
• Carbamazepine
• Rifampicin
• Barbiturates
• Efavirenz
• Nevirapine
• Hypericum Perforatum (Saint John’s wort)
Additional interactions
Hydrochlorothiazide: May enhance the antihypertensive effect of felodipine. Tacrolimus: 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.
Ciclosporin: Felodipine does not affect plasma concentrations of ciclosporin. Ciclosporin may inhibit felodipine metabolism which may create a potential risk of felodipine toxicity.
Other extensively bound drugs: 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 two drugs are administered concurrently.
4.6 Fertility, pregnancy and lactation
Pregnancy
Felogen XL should not be given during pregnancy.
Felogen XL 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 Felogen XL.
Breastfeeding
Felogen XL is detected in breast milk. When taken in therapeutic doses by the nursing mother it is, however, not likely to affect the infant. There is no experience of the risk this may pose to the newborn, therefore, as a precaution breastfeeding should be discontinued during treatment.
Fertility
Data on fertility in patients are missing (see also section 5.3).
4.7 Effects on ability to drive and use machines
Patients should know how they react to Felogen XL before they drive or use machines because occasionally dizziness or fatigue may occur. 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, Felogen XL 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.
The adverse drug 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 and <1/10 Uncommon >1/1000 and <1/100 Rare >1/10000 and <1/1000 Very rare <1/10000
|
Table 1 Undesirab |
e effects | |
|
Frequency |
System Organ Class |
Adverse drug reaction |
|
Very common |
Ear and labyrinth disorders: |
Tinnitus (Particularly at the beginning of treatment, when the dose is increased or when high doses are administered). Generally, this effect subsides on continuous treatment. |
|
General disorders and administration site conditions: |
Peripheral oedema (The degree of ankle swelling is dose related). | |
|
Common |
Nervous system disorders: |
Headache (Particularly at the beginning of treatment, when the dose is increased or when high doses are administered). Generally, this effect subsides on continuous treatment. |
|
Cardiac disorders: |
Angina Pectoris (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.) | |
|
Vascular disorders: |
Flushing (Particularly at the beginning of treatment, when the dose is increased or when high doses are administered). Generally, this effect subsides on continuous treatment.) | |
|
Uncommon |
Metabolism and nutrition disorders: |
Weight gain |
|
Psychiatric disorders: |
Restlessness | |
|
Cardiac disorders: |
Tachycardia, palpitations | |
|
Vascular disorders: |
Hypertension | |
|
Nervous system disorders: |
Dizziness, paraesthesia | |
|
Respiratory, thoracic and mediastinal disorders: |
Dyspnoea | |
|
Gastrointestinal disorders: |
Nausea, abdominal pain, diarrhoea, constipation | |
|
Skin and subcutaneous system disorders: |
Rash, pruritus, sweating | |
|
Musculoskeletal and connective tissue disorders: |
Tremors | |
|
General disorders and administration site conditions: |
Fatigue |
|
Rare |
Vascular disorders: |
Syncope |
|
Gastrointestinal disorders: |
Vomiting | |
|
Musculoskeletal and connective tissue disorders: |
Arthralgia, myalgia | |
|
Reproductive system and breast disorders: |
Impotence/sexual dysfunction | |
|
Skin and subcutaneous system disorders: |
Urticaria | |
|
Very rare |
Cardiac disorders: |
Myocardial infarction |
|
Gastrointestinal disorders: |
Gingival hyperplasia, gingivitis | |
|
Hepatobilliary disorders: |
Hepatic function disorder (Increased liver enzymes) | |
|
Skin and subcutaneous system disorders: |
Photosensitivity reactions, leucocytoclastic vasculitis, exfoliative dermatitis | |
|
Renal and urinary disorders: |
Pollakisuria | |
|
Reproductive system and breast disorders: |
Gynaecomastia, menorrhagia | |
|
General disorders and administration site conditions: |
Hypersensitivity reactions e.g. angio-oedema, fever |
4.9 Overdose
Symptoms
Overdose may cause excessive peripheral vasodilatation with marked hypotension and in rare sometimes bradycardia.
Management
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. Additional intravenous fluids should be administered under haemodynamic supervision to prevent cardiac overloading. If this is not
sufficient, plasma volume should be increased by infusion of eg, glucose, saline, or dextran.
Sympathomimetic drugs with predominant effect on the a1-adrenoceptor may be given if the above-mentioned measures are insufficient. Dosage depends in the efficacy obtained.
Felogen XL is only dialysable to a minimal extent (approx. 9 %).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
didydropyridine derivative
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 which leads to 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.
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 2.5mg (n=33), 5mg (n=33) and 10mg (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 results in even felodipine plasma concentrations within the therapeutic range for 24 hours. Steady state is reached approximately 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, indicating large tissue distribution. There is no significant accumulation during long-term treatment.
Metabolism
Felodipine is extensively metabolised in the liver by CYP3A4. All identifiable 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 1100ml/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.
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 with a fasting state.
Children
In a single dose (felodipine prolonged release 5mg) 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 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
Propyl gallate
Colloidal anhydrous silica
Magnesium stearate
Tablet coating:
Hypromellose Iron oxide red (E172)
Iron oxide yellow (E172)
Titanium dioxide (E171)
Talc
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, 98, 100 prolonged release tablets Not all pack sizes may be marketed
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0574
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
27/08/2002 / 19/01/2006
10 DATE OF REVISION OF THE TEXT
05/11/2012