This information is intended for use by health professionals

1. Name of the medicinal product

Neofel XL 2.5 mg Prolonged Release Tablets

2. Qualitative and quantitative composition

Neofel XL 2.5 mg Prolonged Release Tablets contain 2.5mg of felodipine.

3. Pharmaceutical form

Yellow, round, biconvex, film coated prolonged-release tablets with imprint 2.5.

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

The tablets should be taken in the morning and be swallowed with water. 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. If necessary another antihypertensive agent may be added. The standard maintenance dose is 5 mg once daily.

Angina pectoris

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

Elderly population

Initial treatment with lowest available dose should be considered.

Renal Impairment

Dose adjustment is not needed in patients with impaired renal function.

Hepatic Impairment

Patients with impaired hepatic function may have elevated plasma concentrations of felodipine and may respond to lower doses (see section 4.4 Special warnings and precautions for use).

Paediatric Population

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

Neofel XL 2.5 mg Prolonged Release Tablets can be used in combination with β-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. In patients with severely impaired liver function the dose of felodipine should be low. The pharmacokinetics are not significantly affected in patients with impaired renal function.

4.3 Contraindications

• Pregnancy

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

• Uncompensated heart failure

• Acute myocardial infarction

• Unstable angina pectoris Haemodynamically significant cardiac valvular obstruction

• Dynamic cardiac outflow obstruction

• 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 Neofel XL 2.5 mg Prolonged Release Tablets are useful for secondary prevention of myocardial infarction.

The efficacy and safety of Neofel XL 2.5 mg Prolonged Release Tablets in the treatment of malignant hypertension has not been studied.

Neofel XL 2.5 mg Prolonged Release Tablets should be used with caution in patients with severe left ventricular dysfunction.

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

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

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 concentration of felodipine

Enzyme inhibitors have been shown to cause an increase in felodipine plasma concentrations.

Examples:

• Cimetidine

• Erythromycin

• Itraconazole

• Ketoconazole

• Anti HIV/protease inhibitors (e.g.ritonavir)

• Certain flavonoids present in grapefruit juice

Interactions leading to decreased plasma concentration of felodipine

Enzyme inducers may cause a decrease in plasma concentrations of felodipine.

Examples:

• Phenytoin

• Carbamazepine

• Rifampicin

• Barbiturates

• Efavirenz

• Nevirapine

• Hypericum Perforatum (Saint John's wort)

Additional interactions

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.

Cyclosporin: Felodipine does not affect plasma concentrations of cyclosporin.

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.

4.6 Fertility, pregnancy and lactation

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.

Breastfeeding

Felodipine is 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).

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.

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, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000), very rare (<1/10,000)

Table 1 Undesirable effects

Frequency

System Organ Class

Adverse Drug Reaction

Very common

General disorders and administration site conditions:

Peripheral oedema

Nervous system disorders:

Headache

Vascular disorders:

Flush

Uncommon

Cardiac disorders:

Tachycardia, palpitations

Nervous system disorders:

Dizziness, paraesthesia

Gastrointestinal disorders:

Nausea, abdominal pain

Skin and subcutaneous system disorders:

Rash, pruritus

General disorders and administration site conditions:

Fatigue

Rare

Cardiac disorders:

Myocardial ischemia

Vascular disorders:

Syncope, hypotension

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

Gastrointestinal disorders:

Gingival hyperplasia, gingivitis

Hepatobiliary disorders:

Increased liver enzymes

Skin and subcutaneous system disorders:

Photosensitivity reactions, leucocytoclastic vasculitis

Renal and urinary disorders:

Pollakisuria

General disorders and administration site conditions:

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, 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 drugs with predominant effect on the α1-adrenoceptor may be given if the abovementioned measures are insufficient.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Felodipine is a vascular selective calcium antagonist, which lowers arterial blood pressure by decreasing peripheral vascular residence. 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. β-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 β-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 bland 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 by the liver 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 Preclinical 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.

Neofel XL 2.5 mg Prolonged Release Tablets possess a mild natriuretic/diuretic effect and does not produce general fluid retention, nor affect daily potassium excretion. Neofel XL 2.5 mg Prolonged Release Tablets are well tolerated in patients with congestive heart failure.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate, Cellulose microcrystalline, Hypromellose, Povidone, Propyl gallate, Silica colloidal anhydrous, Magnesium stearate, Ferric oxide yellow (E172), Titanium dioxide (E171), Talc, Propylene glycol.

6.2 Incompatibilities

None stated.

6.3 Shelf life

48 months.

6.4 Special precautions for storage

Do not store above 25 °C. Store in the original package.

6.5 Nature and contents of container

PVC/PE/PVDC Aluminium Blisters.

A single pack contains 10, 20, 28, 30, 50, 56 or 100 tablets.

6.6 Special precautions for disposal and other handling

None stated.

7. Marketing authorisation holder

Fannin (UK) Limited

42-46 Booth Drive

Park Farm South

Wellingborough

NN8 6GT

8. Marketing authorisation number(s)

PL 20417/0056

9. Date of first authorisation/renewal of the authorisation

27 February 2009

10. Date of revision of the text

31/12/2015