Fortipine La 40mg Modified-Release Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fortipine LA 40mg Modified-Release Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Active Ingredient
Nifedipine (international non-proprietary name): 40mg chemical name: Dimethyl 1, 4 dihydro-2, 6-dimethyl-6 (2-nitrophenyl) pyridine-3, 5-dicarboxylate.
3. PHARMACEUTICAL FORM
Modified release tablets (matrix tablets) for oral administration.
4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
For the prophylaxis of chronic stable angina pectoris and the treatment of mild to moderate hypertension.
4.2. Posology and Method of Administration
Adults:
Patients should be treated individually depending on the severity of the disease and the therapeutic response. Nifedipine should not be taken with Grapefruit juice (see Section 4.5).
The following recommendations for dosing in adults and adolescents are applicable:
In general, one modified release tablet of FORTIPINE LA 40 (40mg) once daily should be adequate. If necessary this dose can be increased to 80 mg given once daily, or 40 mg twice daily.
The modified release tablets are to be taken after meals, e.g. breakfast. The modified release tablets should be swallowed whole with half a glass of water and must not be broken or chewed.
In patients with renal dysfunction, a slight alteration of the pharmacokinetics of nifedipine may be seen. However, dose adjustment in these patients is not usually required.
In patients with liver cirrhosis and chronic liver failure, significant alterations of the pharmacokinetics of nifedipine is usually seen. These patients should usually be carefully monitored when initiating therapy and during maintenance treatment with a dose that should not exceed one modified release tablet of 40mg.
Elderly Patients:
The pharmacokinetics of nifedipine are altered in the elderly, so that a maintenance dose should be once daily modified release tablet of 40mg. Regular assessment of the medical regime should be performed to minimise unwanted effects.
Paediatric population:
The safety and efficacy of nifedipine in children under the age 18 years have not been established.
Currently available data for the use of nifedipine in hypertension are described in section 5.1.
4.3. Contraindications
FORTIPINE LA 40 should not be administered to patients with hypersensitivity to nifedipine or other dihydropyridines because of the theoretical risk of cross-reactivity, nor to patients with a cardiogenic shock. It is contra-indicated in women with child-bearing potential and those breastfeeding their babies. FORTIPINE LA 40 is contra-indicated in patients with cardiac failure, with those with markedly severe hypotension with less than 90mm Hg systolic and with porphyria.
Nifedipine should not be used in clinically significant aortic stenosis, patients who develop unstable angina, or during or within 1 month of a myocardial infarction.
Fortipine LA 40 should not be used for secondary prevention of myocardial infarction.
Nifedipine should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction.
4.4. Special Warnings and Special Precautions for Use
Patients at risk of hypotensive crisis should begin any therapy under close medical supervision.
The safety of nifedipine in malignant hypertension has not been established.
Ischaemic pain has been reported in a small proportion of patients following the introduction of nifedipine therapy. Although a 'steal' effect has not been demonstrated, patients experiencing this effect should discontinue nifedipine therapy.
4.5. Interactions with other Medicaments and other forms of Interaction
FORTIPINE LA 40 can be administered concomitantly with other antihypertensives including beta-receptor blockers. These may have additive antihypertensive or potentiating effects and postural hypotension may therefore occur. Concomitant treatment of nifedipine with a beta-blocker occasionally results in the occurrence of heart failure. For this reason, a combination with a beta-blocker is only recommended in patients that are not suffering from any degree of heart failure or ventricular strain. After discontinuation of the beta-blocker, a deterioration with regard to the symptoms of angina pectoris may occasionally occur, due to the abrupt withdrawal of the beta-blocker. Therefore, it is not recommended to switch abruptly from a beta-blocker to nifedipine.
FORTIPINE LA 40 will not prevent the possibility that there might be a rebound effect when other antihypertensive treatment is stopped.
Concomitant therapy with cimetidine may potentiate the antihypertensive action of nifedipine. Nifedipine administration may suppress serum levels of quinidine and may increase plasma digoxin levels due to reduced drug clearance. Therefore, on combination therapy monitoring of quinidine levels, as well as digoxin levels is recommended.
FORTIPINE LA 40 may modify insulin and glucose responses, requiring adjustment in therapy of treated diabetics.
Grapefruit juice inhibits the oxidative metabolism of nifedipine; this may be potentially significant in some patients.
Nifedipine should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see contra-indications).
An enhanced hypotensive effect may be seen when nifedipine is coadministered with anti-psychotics and possibly ciclosporin.
Nifedipine clearance can be reduced when co-administered with diltiazem.
Nifedipine effect may be reduced when co-administered with carbamazepine.
Nifedipine increases the plasma concentration of phenytoin.
Nifedipine enhances the effect of non-depolarising muscle relaxants.
4.6. Pregnancy and Lactation
FORTIPINE LA 40 is contra-indicated in pregnant women and women of child-bearing potential because foetal risks, observed in animal experiments and during human use, far outweigh the potential benefits. Pregnancy category: B3
Nifedipine is secreted into breast milk, so FORTIPINE LA 40 should not be administered during lactation.
4.7. Effects on Ability to Drive and Use Machines
Nifedipine may cause headache, dizziness, nausea and tiredness to such a degree that reaction time is affected. These effects can be aggravated by concurrent consumption of alcohol. If this occurs, the patient should be advised not to drive or operate machines.
4.8. Undesirable Effects
Undesirable effects, usually mild and transient in nature, may occur and are more frequent at the beginning of therapy. Frequently, headache, flush (facial reddening), dizziness, as well as oedema, due to vasodilatation, may occur. Less common side effects include rash, nausea, lethargy and urinary frequency. In rare cases, in acute studies, a transient increase in glucose has been observed. This should be considered particularly in patients with diabetes mellitus. Nifedipine has no diabetogenic effect. Rarely gingival hyperplasia has been observed which was reversible after discontinuation of therapy. In elderly patients, very rarely gynaecomastia has been observed which was reversible after discontinuation of therapy. Chest pain due to myocardial ischaemia may occur 1-4 hours after ingestion of nifedipine. Cases of hypersensitivity to nifedipine resulting in jaundice have been reported.
List of undesirable effects according to body systems:
Cardiovascular System:
Tachycardia, hypotension. As with other vasodilators coronary ischaemia (steal phenomenon) resulting in retrosternal pain, may occur.
As with other sustained released dihydropyridines, exacerbation of angina pectoris may occur rarely at the start of treatment with sustained release formulations of nifedipine. The occurrence of myocardial infarction has been described although it is not possible to distinguish such an event from the natural course of ischaemic heart disease.
Central Nervous System:
Dizziness, tiredness, paraesthesia, tremor
Eyes:
Transient change in optical perception
Gastro-Intestinal Tract:
Nausea, Gastro-intestinal upsets
Skin:
Redness, itching, urticaria, exanthema, and exceptionally exfoliate dermatitis Urinary Tract:
An increase in the daily amount of urine so that nocturia may occur.
Legs:
Myalgia
Liver:
Very rarely liver function disturbances (intrahepatic cholestasis, or increases in transaminases) have occurred which were reversible after discontinuation of therapy.
Miscellaneous:
Gingival hyperplasia, gynaecomastia, increase in glucose in particular in patients with diabetes mellitus
4.9. Overdose
Toxic effects arise from the three main actions of nifedipine in overdose: dilatation of vascular smooth muscles (predominant effect); decreased myocardial contractility; and depression of AV nodal conduction. Hypotension and tachycardia or bradycardia are the most likely manifestations of overdose. Other toxic effects include nausea, vomiting, drowsiness, dizziness, confusion, lethargy, flushing, coma and convulsions. Cardiac effects may include heart block, AV dissociation and asystole; metabolic disturbances include hyperglycaemia, acidosis, hypo- or hyperkalaemia and hypocalcaemia; pulmonary oedema has been reported.
Primary treatment involves removal of nifedipine by gastric lavage or ipecacuanha and administration of activated charcoal (50 g adults; 10 - 15 g children). FORTIPINE LA 40 is a modified release matrix tablet, therefore activated charcoal should be repeated at 4 hourly intervals (25 g adults; 10 g children). The patient should be closely monitored and treated according to predominating signs: for hypotension: the feet should be raised and plasma expanders given. If this is not effective, 10 % calcium gluconate or chloride can be given intravenously (calcium chloride should not be given to acidotic patients). If this fails, dopamine may be tried (large doses may be needed). Glucagon may be also of value; for bradycardia: treatment with atropine, isoprenaline and cardiac pacing should be given as required.
The value of extracorporeal methods of removal of nifedipine have not been established.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC code: C08CA05
Nifedipine is a specific and potent calcium antagonist of the 1, 4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell. Nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels.
In hypertension, the main action of Fortipine LA 40 is to cause peripheral vasodilatation and thus reduce peripheral resistance.
In angina, Fortipine LA40 reduces peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume, whilst decreasing after-load.
Additionally, nifedipine dilates submaximally both clear and atherosclerotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.
Nifedipine reduces the frequency of painful attacks and the ischaemic ECG changes irrespective of the relative contribution from coronary artery spasm or atherosclerosis.
Fortipine LA40 administered twice-daily provides 24-hour control of raised blood pressure. It causes reduction in blood pressure such that the percentage lowering is directly related to its initial level. In normotensive individuals, Fortipine LA40 has little or no effect on blood pressure.
Paediatric population:
Limited information on comparison of nifedipine with other antihypertensives is available for both acute hypertension and long-term hypertension with different formulations in different dosages. Antihypertensive effects of nifedipine have been demonstrated but dose recommendations, long term safety and effect on cardiovascular outcome remain unestablished. Pediatric dosing forms are lacking.
5.2. Pharmacokinetic Properties
Absorption: FORTIPINE LA 40 is absorbed rapidly and almost completely following oral administration. FORTIPINE LA 40 reaches maximal concentrations (29.4 ± 12.0) X ± SD) ng/ml) 5.0 ± 2.7 hours after drug intake at steady state.
The release of nifedipine from the FORTIPINE LA 40 modified release tablet is almost linear, this means that the drug is delivered at a constant rate. The relative bioavailability of the modified release form compared to the slow release forms of nifedipine is not statistically different in steady state.
Trough levels after FORTIPINE LA 40 (24 h post-dose) in steady state (12.0 ± 6.5 ng/ml) are achieved already after the first dose.
Based on its pharmacokinetic profile, an effect due to FORTIPINE LA 40 is expected over 24 hours.
Concomitant intake of food results in higher maximum plasma concentrations of nifedipine, which occurs earlier compared to administration in the fasted state, but the concentrations at the end of the dose interval are similar.
Distribution: The protein binding of nifedipine amounts to 94 - 99 %. Animal studies with labelled nifedipine have shown that distribution of the fraction not protein bound is throughout all organs and tissues, with higher concentrations in myocardium than in skeletal muscle. Neither nifedipine nor its metabolites are stored selectively in any tissue.
Metabolism: Nifedipine is almost completely metabolised to inactive metabolites.
Elimination: An apparent half-life of 14.9 ± 6.0 hours was found. The apparent half-life of FORTIPINE LA 40 did not change after repeated dosing. Only < 1 % of the dose is excreted in the urine as the parent compound. 70 - 80 % of the dose is excreted in the urine as metabolites. The remainder is excreted as metabolites in the faeces. Elimination may be retarded by renal failure or insufficiency.
5.3 Preclinical safety data
Preclinical data reveal no special hazards for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.
Reproduction toxicology:
Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum, and malformation of the ribs. Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after the end of the organogenesis period.
Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and foetotoxic effects, including stunted foetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and foetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). The risk to humans cannot be ruled out if a sufficiently high systemic exposure is achieved, however, all of the doses associated with the teratogenic, embryotoxic or foetotoxic effects in animals were maternally toxic and were several times the recommended maximum dose for humans (see Section 4.6).
6. PHARMACEUTICAL PARTICULARS 6.1. List of Excipients
- Microcrystalline Cellulose
- Cellulose
- Methylhydroxypropylcellulose
- Lactose
- Magnesium Stearate
- Colloidal Anhydrous Silica
- Macrogol 400 (Polyethyleneglycol 400)
- Macrogol 6000 (Polyethyleneglycol 6000)
- Ferric Oxide Red (E172)
- Titanium Dioxide (E171)
- Talc
6.2. Incompatibilities
None Known.
6.3. Shelf Life
Three years
6.4. Special Precautions for Storage
FORTIPINE LA40 should be stored in the original pack below 25°C, in a dry place and protected from light.
Nifedipine is highly sensitive to light and is therefore protected both by materials in the tablet and in the packaging. Nonetheless tablets should not be exposed to direct sunlight and should only be removed from the blister pack when about to be taken.
6.5. Nature and Contents of Container
Thermoformed blister packs of red transparent, light protective PVC/PVDC film/aluminium in boxes of 28, 30, 56, 60 or 100 tablets.
6.6. Instructions for Use/Handling
None.
7. MARKETING AUTHORISATION HOLDER
Mercury Pharmaceuticals Ltd Capital House, 85 King William Street,
London EC4N 7BL, UK
8. MARKETING AUTHORISATION NUMBER
PL 12762/0014
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
June 1998
10 DATE OF REVISION OF THE TEXT
30/05/2014