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.
Three years
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.
- 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
Modified release tablets (matrix tablets) for oral administration.
Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n = 2,661; placebo n = 1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n = 3,825; placebo n = 3,840) are listed below:
ADRs listed under "common" were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%).
ADRs derived from post marketing reports are printed in bold italic.
| Common > 1% to <10% | Uncommon >0.1% to <1% | Rare >0.01% to <0.1% | Frequency Not Known |
| Blood and lymphatic system disorders | |||
| Agranulocytosis Leukopenia | |||
| Immune System Disorders | |||
| Allergic reaction Allergic oedema/angioedema (Incl. Larynx oedema*) | Pruritus Urticaria Rash | Anaphylactic/anaphylactoid reaction | |
| Psychiatric Disorders | |||
| Anxiety reactions Sleep disorders | |||
| Metabolism and nutrition disorders | |||
| Hyperglycaemia | |||
| Nervous System Disorders | |||
| Headache | Vertigo Migraine Dizziness Tremor | Par-/Dys aesthesia | Hypoaesthesia Somnolence |
| Eye Disorders | |||
| Visual disturbances | Eye Pain | ||
| Cardiac Disorders | |||
| Tachycardia Palpitations | Chest Pain (Angina Pectoris) | ||
| Vascular Disorders | |||
| Oedema Vasodilatation | Hypotension Syncope | ||
| Respiratory, thoracic, and mediastinal disorders | |||
| Nosebleed Nasal congestion | Dyspnoea Pulmonary oedema** | ||
| Gastrointestinal Disorders | |||
| Constipation | Gastrointestinal and abdominal pain Nausea Dyspepsia Flatulence Dry mouth | Gingival hyperplasia | Bezoar Dysphagia Intestinal obstruction Intestinal ulcer Vomiting Gastrooesophageal sphincter insufficiency |
| Hepatobiliary Disorders | |||
| Transient increase in liver enzymes | Jaundice | ||
| Skin and Subcutaneous Tissue Disorders | |||
| Erythema | Toxic Epidermal Necrolysis Photosensitivity allergic reaction Palpable purpura | ||
| Musculoskeletal, Connective Tissue and Bone Disorders | |||
| Muscle cramps Joint swelling | Arthralgia Myalgia | ||
| Renal and Urinary Disorders | |||
| Polyuria Dysuria | |||
| Reproductive System and Breast Disorders | |||
| Erectile dysfunction | |||
| General Disorders and Administration Site Conditions | |||
| Feeling unwell | Unspecific pain Chills | ||
*= may result in life threatening outcome
**= cases have been also reported when used as tocolytic during pregnancy
In dialysis patients with malignant hypertension and hypovolaemia, a distinct fall in blood pressure can occur as a result of vasodilatation.
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.
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.
For the prophylaxis of chronic stable angina pectoris and the treatment of mild to moderate hypertension.
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.
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.
19/09/2016
Fortipine LA 40mg Modified-Release Tablets
Mercury Pharmaceuticals Ltd
Capital House, 85 King William Street,
London EC4N 7BL, UK
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.
Thermoformed blister packs of red transparent, light protective PVC/PVDC film/aluminium in boxes of 28, 30, 56, 60 or 100 tablets.
PL 12762/0014
Active Ingredient
Nifedipine (international non-proprietary name): 40mg chemical name: Dimethyl 1, 4 dihydro-2, 6-dimethyl-6 (2-nitrophenyl) pyridine-3, 5-dicarboxylate.
Patients at risk of hypotensive crisis should begin any therapy under close medical supervision.
Ischaemic pain has been reported in a small proportion of patients following the introduction of nifedipine therapy.
In patients with impaired liver function, careful monitoring, and in severe cases, a dose reduction may be necessary.
Fortipine LA should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.
The use of Fortipine LA in diabetic patients may require adjustment of their control.
In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.
Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine.
Drugs that are known inhibitors of the cytochrome P450 3A4 system, and which may therefore lead to increased plasma concentrations of nifedipine include, for example:
- macrolide antibiotics (e.g., erythromycin)
- anti-HIV protease inhibitors (e.g., ritonavir)
- azole antimycotics (e.g., ketoconazole)
- the antidepressants, nefazodone and fluoxetine
- quinupristin/dalfopristin
- valproic acid
- cimetidine
Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.
Since this medicinal product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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.
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.
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.
None.
June 1998
