Pinefeld Xl 10mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Pinefeld XL 10mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged release tablet contains 10mg felodipine
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Prolonged release tablet
grey-red, round, biconvex tablets with an approximate diameter of 9mm, with the imprint F10 on one side
4.1 Therapeutic indications
Essential hypertension and prophylaxis of chronic stable angina pectoris.
4.2 Posology and method of administration
Posology
The dose should be adjusted to the individual requirements of the patient. Felodipine should usually be administered as follows:
The recommended starting dose is 5 mg felodipine once daily.
Depending on the patient’s response, the dosage can, where applicable, be decreased to 2.5 mg or 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.. Doses higher than 20 mg daily are not usually needed.
Stable angina pectoris:
The dose should be adjusted individually. Treatment should be started with 5 mg once daily and if needed be increased to 10 mg once daily.
Pinefeld XL can be used in combination with p-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.
Different modified-release preparations do not necessarily have the same effect in practice. When changing therapy from different modified-release preparations of felodipine to Pinefeld XL 10mg tablets, the blood pressure control should be checked and the dosage schedule changed as appropriate (see particularly section 5.2).
Older people
The recommended starting dose should be adapted in the elderly.
Subsequent dose increases should be undertaken with particular caution.
Patients with 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 Sections 4.4 (Special Warning and Precautions for Use) and 5.2 (Pharmacokinetic Properties). Dose adjustment is not needed in patients with impaired renal function.
Patients with impaired hepatic function:
Patients with impaired hepatic function may have elevated plasma concentrations of felodipine and may response to lower doses (see section 4.4 Special warnings and precautions for use). 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 5.2 Pharmacokinetic Properties). It is contraindicated in patients with severe hepatic impairment.
Paediatric population:
Felodipine should not be used in children, as its safety and efficacy in this population have not been established (see sections 5.1 and 5.2).
Methods of 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 4.5).
In order to keep the prolonged release properties, the tablets should be swallowed whole and must not be divided, chewed or crushed. The tablet may be taken on an empty stomach or with a light meal; however a high-fat or carbohydrate meal should be avoided (see 5.2).
4.3 Contraindications
• Hypersensitivity to the active substance, other dihydropyridines or to any of the excipients listed in section 6.1.
• Cardiogenic shock
• Clinically significant aortic stenosis
• Unstable angina pectoris
• Acute myocardial infarction (during or within one month of a myocardial infarction)
• Uncompensated heart failure
• Pregnancy
• Acute porphyria
• Haemodynamically significant cardiac valvular obstruction
• Dynamic cardiac outflow obstruction
4.4 Special warnings and precautions for use
Felodipine should be used with caution in patients with severe left ventricular dysfunction.
If treatment with felodipine is discontinued abruptly, a hypertensive crisis may occur in individual cases.
As with other vasodilators, Felodipine may, in rare cases, precipitate 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).
Felodipine must be used with caution in patients with a propensity for tachycardia.
There is no evidence that Felodipine Prolonged Release Tablets are useful for secondary prevention of myocardial infarction.
The efficacy and safety of Felodipine Prolonged Release Tablets in the treatment of malignant hypertension has not been studied.
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 Posology and method of administration).
Patients with hereditary galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Felodipine.
Mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful dental hygiene.
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 plasma concentrations. The anti-hypertensive effect of felodipine may be enhanced by other anti-hypertensives 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) , anti HIV protease inhibitors (e.g. ritonavir), leads to increased felodipine plasma levels and impairs the elimination of Felodipine. As a result, Felodipine may need to be reduced when these drugs are given concomitantly.
Concomitant treatment with drugs such as carbamazepine, phenytoin, Efavirenz, Nevirapine, Hypericum Perforatum (Saint John’s wort) and barbiturates (e.g.phenobarbital) and rifampicin reduces the plasma levels of felodipine via enzyme induction in the liver (cytochrome P450-System). Therefore a dose increase of felodipine may be necessary.
Grapefruit juice results in increased peak plasma levels and bioavailability possibly due to interactions with flavanoids in the fruit juice. The grape fruit interaction has been seen with other dihydropyridine calcium antagonists and represents a class effect.Therefore grapefruit juice should not be taken together with felodipine. Hydrochlorothiazide may enhance the antihypertensive effect of felodipine
No dosage adjustment is required when Felodipine Prolonged Release Tablets are 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 cyclosporin and can induce an increased C-max of ciclosporin. Additionally, ciclosporin may inhibit felodipine metabolism which may create a potential risk of felodipine toxicity.
4.6 Fertility, pregnancy and lactation
Pregnancy
Felodipine is contraindicated during the entire duration of pregnancy.
Breast-feeding
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.
Fertility
Data on fertility in patients are missing (see also section 5.3). 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.
4.7 Effects on ability to drive and use machines
The treatment requires regular medical supervision. Felodipine can influence individual reactions to such an extent that the ability to take an active part in road traffic or to operate machines (or work without suitable safeguards) may be impaired as occasionally dizziness or fatigue may occur. This is particularly
the case at start of therapy, or when the dose is increased, or medication is changed as well as after concomitant ingestion of alcohol.
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 dihydropyridines, aggravation of angina has been reported in a small number of individuals especially after starting treatment particularly at the beginning of treatment, angina pectoris attacks may occur, or in patients with pre-existing angina pectoris or symptomatic ischaemic heart disease there may be an increase in the frequency, duration and severity of the attacks.
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 Undesirable effects
|
Frequency |
System Organ Class |
Adverse drug reaction |
|
Very common |
General disorders and administration site conditions |
Peripheral oedema |
|
Ear and labyrinth disorders |
Tinnitus | |
|
Common |
Nervous system disorders |
Headache |
|
Vascular disorders |
Flushing | |
|
Uncommon |
Cardiac disorders |
Tachycardia, palpitations, |
|
Nervous system disorders: |
Dizziness, paraesthesia , tremors | |
|
Vascular disorders |
Hypotension | |
|
Gastrointestinal disorders |
Abdominal pain, Nausea, diarrhoea and constipation. | |
|
Respiratory, thoracic and mediastinal disorders |
Dyspnoea | |
|
Psychiatric disorders |
Restlessness | |
|
Investigations |
Weight gain | |
|
Skin and subcutaneous system disorders |
Rash, pruritus, exanthema and sweating | |
|
General disorders and administration site conditions |
Fatigue | |
|
Rare |
Vascular disorders |
Syncope |
|
Reproductive system and breast disorders |
Impotence/sexual dysfunction | |
|
Skin and subcutaneous system disorders |
urticaria, | |
|
Gastrointestinal disorders: |
vomiting | |
|
Musculoskeletal: and connective tissue disorders |
Myalgia, arthralgia | |
|
Very rare |
Gastrointestinal disorders: |
Gingival hyperplasia, gingivitis |
|
Hepatobilliary disorders |
Increased liver enzymes, Hepatic function disorders (elevated transaminase levels) | |
|
Renal and urinary disorders |
Pollakisuria | |
|
General disorders and administration site conditions |
Hypersensitivity reactions e.g. angio-oedema, fever | |
|
Skin and subcutaneous system disorders |
Exfoliative dermatitis, Photosensitivity reactions, leucocytoclastic Vasculitis | |
|
Reproductive system and breast disorders |
Gynecomastia, menorrhagia | |
|
Cardiac disorders |
Myocardial infarction |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov .uk/yellowcard
4.8 Overdose
Symptoms of intoxication
Overdose may lead to excessive peripheral vasodilatation with marked hypotension and in rare cases bradycardia.
Management of intoxication
Activated charcoal, induction of vomiting or gastric lavage, if appropriate or indicated.
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 volume should be increased by infusion of e.g. glucose, saline or dextran. Sympathomimetic drugs with predominant effect on the (od-adrenoceptor may be given e.g. metaraminol or phenylephrine if the above-mentioned measures are insufficient.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
1,4-didydropyridine derivative/calcium antagonist
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 2.5 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 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 1100 ml/l and depends on the hepatic blood flow.
Elderly
Increased plasma concentrations have been measured in elderly patients. Children
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.
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.
Bioequivalence
The table below shows the 90% confidence intervals for Pinefield XL 10mg tablets in three different studies compared with a marketed modified-release preparation of felodipine, as reference.
|
Comparison |
AUC0-24 |
AUC0-¥ |
C max | |||
|
Ratio |
90% CI |
Ratio |
90% CI |
Ratio |
90% CI | |
|
Fasted single dose |
0.93 |
0.87-0.99 |
0.89 |
0.92-0.96 | ||
|
Fasted steady state |
0.91 |
0.85-0.98 |
0.90 |
0.82-0.99 | ||
|
Fed single dose |
0.93 |
0.86-1.01 |
0.86 |
0.76-0.97 | ||
In these studies Pinefield XL 10mg tablets provide around 90% of the active substance compared to the reference product, which is within the overall acceptable limits for comparative bioavailability.
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.
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.
Pinefeld XL 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.
6.1 List of excipients
Tablet core:
Cellulose microcrystalline Lactose monohydrate Sodium laurilsulfate Hypromellose Magnesium stearate
Tablet coating:
Lactose monohydrate Hypromellose Macrogol 4000
Colouring agents: iron oxide (E172), titanium dioxide (E171)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
The prolonged-release film-coated tablets are packed in a polyvinylchloride / aluminium blister and inserted into a carton.
Original packages containing
7, 14, 28, 98 prolonged-release film-coated tablets
Not all pack sizes may be marketed.
6.6 Instructions for use and handling Not applicable.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Limited 3 Howard Road Eaton Socon, St Neots Cambridgeshire, PE19 8ET.
United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 11311/0342
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 20/01/2005
10 DATE OF REVISION OF THE TEXT
13/10/2014