LOGIMAX Prolonged-release tablet Ref.[28235] Active ingredients: Felodipine Metoprolol

The fixed combination of felodipine and metoprolol, can like other antihypertensives, cause hypotension. Felodipine may cause significant hypotension with subsequent tachycardia. This may in susceptible patients result in myocardial ischaemia.

In cases of bronchial asthma, adequate bronchodilator therapy (tablets or inhalation) must be given concomitantly. The dose of β 2-agonists may need to be increased when treatment with Logimax is started. The risk for interaction between Logimax and β2-agonists is, however, less than with conventional tablet formulations of β1-selective blockers.

Treatment with Logimax may affect carbohydrate metabolism or mask hypoglycaemia, but the risk is less than with conventional tablet formulations of β1-selective blockers and much less than with non-selective β-receptor blockers.

Logimax should not be given to patients with latent or manifest cardiac insufficiency without concomitant treatment of this condition.

An existing moderate disturbance of AV-conduction time may be exacerbated (possibly leading to AV block).

Logimax should be given with caution to patients with severe acute states of metabolic acidosis.

Intravenous administration of calcium antagonists of the verapamil type must not be given to patients being treated with Logimax.

If patients develop pronounced bradycardia, the dose of Logimax should be reduced or gradually withdrawn.

Logimax may aggravate symptoms of worsened peripheral arterial circulation.

Logimax should not be given in combination with CYP3A4- inhibitors or- inducers, see section 4.5

If Logimax is given to patients with phaeochromocytoma, concomitant treatment with α- blockers should be given.

Prior to surgery, the anaesthetist must be informed that the patient is on Logimax. It is recommended that beta-blockade is not withdrawn in patients who are undergoing surgery. Treatment with β-blockers may aggravate the treatment of an anaphylactic reaction. Adrenaline treatment in normal doses does not always produce the expected therapeutic effect.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

β1-selective receptor blockers should be used with caution in patients with Prinzmetal’s angina. Mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful dental hygiene.

LOGIMAX contains lactose and should not be given to patients with hereditary galactose intolerance or glucose-galactose malabsorption.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Concomitant administration of substances that influence the cytochrome P450 system can affect the plasma concentration of both felodipine and metoprolol. Felodipine and metoprolol do not interact with each other, since they utilise different isoenzymes of cytochrome P450.

Interactions with felodipine

Felodipine is metabolised in the liver by cytochrome P450 3A4 (CYP3A4)2. Interactions leading to increased plasma concentration of felodipine
Enzyme inhibitors of the cytochrome P450 3A4 system have been shown to cause an increase in felodipine plasma concentrations.

Examples:

Strong CYP3A4-inhibitor

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

Other CYP3A4-inhibitors

• Cimetidine
• Erythromycin
• Certain flavonides present in grapefruit juice

During concomitant administration of itraconazole, the felodipine C_max increased 8-fold and the AUC 6-fold.

During concomitant administration of erythromycin, the felodipine C_max and AUC increased approximately 2.5-fold.

During concomitant administration of grapefruit juice the felodipine C_max and AUC increased approximately 2-fold.

During concomitant administration of cimetidine the felodipine C_max and AUC increased by approx. 55%.

Interactions leading to decreased plasma concentrations of felodipine

Enzyme inducers of the cytochrome P450 3A4 system may cause a decrease in felodipine plasma concentrations.

Examples:

• Phenytoin
• Carbamazepine
• Rifampicin
• Barbiturates
• Efavirenz
• Nevirapine
• Hypericum perforatum (Saint John’s worth)

During concomitant administration of carbamazepine, phenytoin, and phenobarbital, the felodipine decreased AUC by 93% and C_max by 82%.

Additional interactions with 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.

Cyclosporin: During concomitant administration of cyclosporin and felodipine, C_max for felodipine increased by 150% and AUC by approx. 60%. Felodipine, however, does not affect plasma concentrations of cyclosporin.

Interactions with metoprolol

Metoprolol is a substrate for cytochrome P450 isoenzyme 2D6. Drugs that act as enzyme-inducing or enzyme-inhibiting substances on CYP2D6 may exert an influence on the plasma level of metoprolol.

CYP2D6-inhibitors may cause an increase in metoprolol plasma concentration.

Examples:

• Antiarrhythmics (e.g. quinidine, propafenon)
• Antihistamines (e.g. diphenhydramine)
• Histamine-2-receptor antagonists
• Antidepressants (e.g. paroxetin, fluoxetin, sertraline)
• Antipsychotics
• COX-2-inhibitors (e.g. celecoxib)
• Antifungals (e.g. terbinafine)

When propafenone treatment was initiated in four patients who were already treated with metoprolol, the plasma concentrations of metoprolol increased 2-5-fold, and two patients experienced typical metoprolol side effects. The interaction was confirmed in tests on eight healthy subjects.

Diphenhydramine reduces (2.5-fold) clearance of metoprolol to alpha-hydroxymetoprolol in rapid hydroxylators via CYP2 D6.

The plasma concentration of metoprolol may be raised by alcohol and hydralazine.

The plasma concentration of metoprolol is lowered by rifampicin.

Additional interactions with metoprolol:

The following combinations with Logimax may require adjustment of doses:

Ganglion blocking agents, MAO-inhibitors, other β-blockers: Patients receiving concomitant treatment with Logimax and ganglion blocking agents, other β-blockers (e.g. eye drops), or MAO-inhibitors should be kept under close supervision.

Clonidine: If concomitant treatment with clonidine must be discontinued, Logimax must be withdrawn several days before clonidine.

Calcium antagonists: Increased negative inotropic and chronotropic effects may occur when Logimax is given together with calcium antagonists of the verpamil- or diltiazem type. Intravenous administration of calcium blockers of the verapamil type should not be given together with Logimax.

Antiarrhythmic agents: Logimax may increase the negative inotropic and dromotropic effects of antiarrhythmic agents (of quinidine type and amiodarone).

Digitalis glycosides: Digitalis glycosides in association with β-blockers, may increase atrioventricular conduction time and may induce bradycardia.

Inhalation anaesthetic agents: Inhalation anaesthetic agents enhance the cardiodepressant effect in patients treated with Logimax.

Prostaglandin synthetase inhibitors: Concomitant treatment with indomethacin or other prostaglandin synthetase inhibiting drugs may decrease the antihypertensive effect of Logimax.

Adrenaline: Under certain conditions, when adrenaline is administered to patients treated with β-blockers, pronounced hypertension and bradycardia may occur. Cardioselective β-blockers interfere much less with blood pressure control than non-selective β-blockers.

Oral antidiabetics: The dosage of oral antidiabetics may have to be readjusted in patients receiving Logimax.

Phenylpropanolamine: Phenylpropanolamine (norephedrine) at single doses of 50 mg may increase diastolic blood pressure to reach pathologic levels in healthy subjects. Propranolol normally counteracts that increase of blood pressure triggered by phenylpropanolamine.

β-blockers may, however trigger paradoxical hypertensive reactions in patients who take high doses of phenylpropanolamine. Hypertensive crises during treatment with phenylpropanolamine alone have been described in a few cases.

Fertility

Data on male and female fertility in patients are missing (see section 5.3).

Pregnancy

Logimax should not be given during pregnancy.

Breast-feeding

Felodipine passes into human milk. When taken in therapeutic doses by the nursing mother it is not likely to affect the infant. β-blockers may cause side effects e.g. bradycardia in the foetus and in the newborn and breast-fed infant. The amount of metoprolol ingested via human milk, however, seems to be negligible as regards β-blocking effect in the infant if the mother is treated with metoprolol in doses within the therapeutic range.

Since dizziness and fatigue can occur during treatment with Logimax, this should be taken into account when increased alertness is required, for instance when driving a vehicle or using a machine. The patient must evaluate for himself/herself whether the alertness changes when taking Logimax.

Logimax is well tolerated and adverse reactions have generally been mild and reversible.

The most common undesirable effects reported in clinical trials with Logimax are headache, swelling of the ankles, facial redness, dizziness, nausea and fatigue. Most of these effects are attributable to the vasodilator properties of felodipine, they are usually dose related and appear at the beginning of treatment or when the dose is increased. If they appear, they are usually transient and diminish in intensity over time.

From the clinical and marketing experience with the individual components the adverse drug reactions below have been reported.

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. Very common (≥1/10) Common (≥1/100 and <1/10), Uncommon (≥1/1,000 and <1/100) Rare (≥1/10,000 and <1/1,000) and Very rare (<1/10,000).

Felodipine

Metoprolol

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 to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

Not applicable.