Parmid XL 10 mg Prolonged Release Tablets

Each prolonged release tablet contains 10mg of felodipine.

Excipient(s) lactose monohydrate (21.45 mg/tablet)

For a full list of excipients, see section 6.1.

Prolonged release tablets

Round, reddish brown, biconvex tablet with imprint 10

Essential hypertension

The dose should be adjusted to the individual requirements of the patient.

Parmid XL Tablets should usually be administered as follows:

The recommended initial 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.

Elderly:

The recommended initial dose should be adapted in the elderly. Subsequent dose increases should be undertaken with particular caution.

Impaired Renal Function:

The pharmacokinetics are not significantly affected in patients with mild to impaired renal function. Caution should be taken in patients with severe renal impairment (see Sections 4.4 & 5.2).

Impaired hepatic function:

In patients with mild to moderate hepatic impairment, the recommended initial 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 section5.2). It is contraindicated in patients with severe hepatic impairment.

Children:

Felodipine should not be used in children, as its safety and efficacy in this population has not been established.

Method 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)

The prolonged release tablets should be swallowed whole and not chewed or crushed.

The tablets may be taken on an empty stomach or with a light meal. However a high-fat meal should be avoided (see section 5.2).

Felodipine is contra-indicated in patients:

• With hypersensitivity to felodipine (or other dihydropyridines) or to any of the excipients

• With cardiogenic shock (as with all other calcium channel blockers, treatment should be discontinued in patients who develop cardiogenic shock)

• With severe aortic or mitral stenosis

• With obstructive hypertrophic cardiomyopathy

• With unstable angina pectoris

• Who have had an acute myocardial infarction (within 4-8 weeks of a myocardial infarction)

• With decompensated heart failure

• With severe hepatic impairment

• During pregnancy (see section 4.6)

Felodipine should be used with caution in patients with:

• Conduction disorders, compensated heart failure, tachycardia and aortic or mitral valve stenosis.

• Mild to moderare hepatic impairment, as the anti-hypertensive effect may be enhanced. Adjustment of the dose 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).

Dihydropyridines may cause acute hypotension. In some cases there is a risk of hypoperfusion accompanied by refex tachycardia (paradoxical angor) (see section 5.1).

Felodipine 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).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Felodipine is a CYP3A4 substrate. Drugs that induce or inhibit CYP3A4 will have a large influence on felodipine 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) 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 barbituates (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.

Hydrochlorthiazide may enhance the anti-hypertensive effect of felodipine.

Felodipine can induce an increase of Cmax of cyclosporin. Additionally, cyclosporin may inhibit felodipine metabolism which may create a potential risk of felodipine toxicity.

Blood levels of digoxin increase during concomitant administration of felodipine. Therefore decreasing digoxin dosage should be taken into account when the two drugs are administered concurrently.

Felodipine is contra-indicated throughout pregnancy, as animal experiments have demonstrated foetal damage (see section 5.3.). Pregnancy must be excluded before starting treatment with felodipine.

Felodipine is excreted into breast milk. If the breast-feeding mother is taking therapeutic doses of felodipine, a totally 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 new born, therefore, as a precaution, breast-feeding should be discontinued during treatment.

Treatment with felodipine requires regular medical supervision. In individual cases felodipine can influence a patient's reactions to such an extent that the ability to drive or to operate machines or to work without suitable safeguards may be impaired. This is particularly the case at the start of therapy, or when the dose is increased, or when medication is changed as well as after the concomitant ingestion of alcohol.

Adverse reactions have been ranked under headings of frequency using the following convention:

Flushing, headache or tinnitus may occur, particularly at the beginning of treatment, when the dose is increased or when high doses are administered. Generally, these effects subside on continued treatment

Particularly at the beginning of treatment, angina pectoris attacks may occur. In patients with pre-existing angina pectoris there may be an increase in the frequency, duration and severity of the attacks.

Symptoms of overdose:

Overdose may lead to excessive peripheral vasodilation and then marked hypotension and in rare cases bradycardia.

Management of overdose:

The therapeutic measures should be focussed on the elimination of the active ingredient and the restoration of the circulation. 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 – 1.0mg) should be given intravenously. Additional intravenous fluids should be cautiously administered under haemodynamic supervision to prevent cardiac overloading. Sympathomimetic drugs with predominant effect on the α₁-adrenoreceptor (such as dobutamin, dopamine, norepinephrine or adrenaline) may also be given. Dosage depends on the efficacy obtained.

Felodipine is only dialyzable to a minimal extent (approx. 9 %).

Pharmacotherapeutic group: dihydropyridine derivative

ATC-Code:C08C A02

Felodipine is a calcium antagonist of the dihydropyridine class. 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 vasodilation.

Felodipine is a vasoselective calcium antagonist: it has a stronger effect on the vascular smooth muscle than the myocardial muscle. Felodipine selectively dilates the arterioles with no effects on venous vessels.

Felodipine leads to a dose-related lowering of blood pressure via vasodilation 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 weak natiuretic/diuretic effect and does not provoke fluid retention.

Felodipine can be used as a monotherapy but also concomitantly with beta-blockers, diuretics and AEC.

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.

Absorption:

Felodipine is completely absorbed following oral administration. With the extended release tablets the absorption phase is prolonged. This results in even felodipine plasma concentrations within the therapeutic range for 24 hours. Peak plasma levels are reached with the prolonged release formulation after 3-5 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 systematically available.

Distribution:

The plasma protein binding of felodipine is > 99 %. The volume of distribution is approx. 10 l/kg at steady state, so that felodipine is indicating a 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 fuction.

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, C_max or half-life of felodipine.

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 simultaneous ingestion of fatty foods. The Cmax was 2 to 2.5 times higher following intake of a high-fat meal compared to a fasting state.

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.

Lactose monohydrate

Microcrystalline cellulose

Hypromellose,

Povidone

Propyl gallate

Colloidal anhydrous silica

Magnesium stearate

Talc

Propylene glycol

Titanium dioxide (E171)

Iron yellow oxide (E 172)

Iron oxide red (E172).

Not applicable

4 years

Do not store above 25 °C.

PVC/PE/PVDC aluminium blister

Original packs containing either 10, 20, 28, 30, 50, 56, 100 or 100x1 prolonged release tablets

Not all pack sizes may be marketed.

No special requirements

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

PL 4416/0459

29^th November 2009

02/2011 (To be amended after approval)