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Active substance(s): NIFEDIPINE

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Fortipine LA 40mg Modified-Release Tablets


Active Ingredient
Nifedipine (international non-proprietary name): 40mg chemical name:
Dimethyl 1, 4 dihydro-2, 6-dimethyl-6 (2-nitrophenyl) pyridine-3, 5dicarboxylate.


Modified release tablets (matrix tablets) for oral administration.




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
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
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

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
Currently available data for the use of nifedipine in hypertension are described in section 5.1.


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
Fortipine LA 40 should not be used for secondary prevention of myocardial
Nifedipine should not be administered concomitantly with rifampicin since
effective plasma levels of nifedipine may not be achieved owing to enzyme

4.4. Special warnings and precautions for use
Patients at risk of hypotensive crisis should begin any therapy under close medical

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.
Fortipine LA is not a beta-blocker and therefore gives no protection against the
dangers of abrupt beta-blocker withdrawal; any such withdrawal should be a gradual
reduction of the dose of beta-blocker preferably over 8 - 10 days.
Fortipine LA may be used in combination with beta-blocking drugs and other
antihypertensive agents but the possibility of an additive effect resulting in postural
hypotension should be borne in mind. Fortipine LA will not prevent possible rebound
effects after cessation of other antihypertensive therapy.
Care must be exercised in patients with very low blood pressure (severe hypotension
with systolic pressure less than 90 mm Hg.
Nifedipine should not be used during pregnancy unless the clinical condition of the
woman requires treatment with nifedipine. Nifedipine should be reserved for women
with severe hypertension who are unresponsive to standard therapy (see section 4.6).
Nifedipine is not recommended for use during breastfeeding because nifedipine has
been reported to be excreted in human milk and the effects of oral absorption of small
amounts of nifedipine are not known (see section 4.6).
Careful monitoring of blood pressure must be exercised when administering
nifedipine with I.V. magnesium sulphate, owing to the possibility of an excessive fall
in blood pressure, which could harm both mother and foetus. For further information
regarding use in pregnancy, refer to section 4.6.
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 (see Section 4.5).
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. (see Section 4.5)
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.


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 LA40 is contraindicated in pregnancy before week 20.
Nifedipine should not be used during pregnancy unless the clinical condition of the
woman requires treatment with nifedipine. Nifedipine should be reserved for women
with severe hypertension who are unresponsive to standard therapy (see section 4.4).
There are no adequate and well controlled studies in pregnant women.
Acute pulmonary oedema has been observed when calcium channel blockers, among
others nifedipine, have been used as tocolytic during pregnancy (see section 4.8),
especially in cases of multiple pregnancy (twins or more), with the intravenous route
and/or concomitant use of beta-2 agonists.
In animal studies, nifedipine has been shown to produce embryotoxicity,
foetotoxicity and teratogenicity (see Section 5.3 Preclinical safety data).
From the clinical evidence available a specific prenatal risk has not been identified,
although an increase in perinatal asphyxia, caesarean delivery, as well as prematurity
and intrauterine growth retardation have been reported.
It is unclear whether these reports are due to the underlying hypertension, its
treatment, or to a specific drug effect.
The available information is inadequate to rule out adverse drug effects on the
unborn and newborn child. Therefore any use in pregnancy after week 20 requires a
very careful individual risk benefit assessment and should only be considered if all
other treatment options are either not indicated or have failed to be efficacious.
In single cases of in-vitro fertilisation calcium antagonists like nifedipine have been
associated with reversible biochemical changes in the spermatozoa's head section
that may result in impaired sperm function. In those men who are repeatedly
unsuccessful in fathering a child by in vitro fertilisation, and where no other
explanation can be found, calcium antagonists like nifedipine should be considered
as possible causes.

Nifedipine passes into the breast milk. The nifedipine concentration in the milk is
almost comparable with mother serum concentration. For immediate release
formulations, it is proposed to delay breastfeeding or milk expression for 3 to 4 hours
after drug administration to decrease the nifedipine exposure to the infant (see
section 4.4).


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

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.



> 1% to <10%

>0.1% to <1%

>0.01% to <0.1%

Frequency Not Known

Blood and lymphatic system disorders
Immune System Disorders
Allergic reaction
oedema/angioedema Urticaria
(Incl. Larynx
Psychiatric Disorders
Anxiety reactions


d reaction

Sleep disorders
Metabolism and nutrition disorders
Nervous System Disorders


Par-/Dys aesthesia


Eye Disorders
Visual disturbances

Eye Pain


Chest Pain (Angina

Cardiac Disorders

Vascular Disorders




Respiratory, thoracic, and mediastinal disorders


Nasal congestion

Pulmonary oedema**

Gastrointestinal Disorders
Gastrointestinal and
abdominal pain


Intestinal obstruction
Gingival hyperplasia Intestinal ulcer



Dry mouth

sphincter insufficiency

Hepatobiliary Disorders
Transient increase in
liver enzymes
Skin and Subcutaneous Tissue Disorders


Toxic Epidermal

Photosensitivity allergic
Palpable purpura

Musculoskeletal, Connective Tissue and Bone Disorders
Muscle cramps


Joint swelling


Renal and Urinary Disorders
Reproductive System and Breast Disorders
Erectile dysfunction
General Disorders and Administration Site Conditions
Feeling unwell

Unspecific pain

*= may result in life threatening outcome
**= cases have been also reported when used as tocolytic during pregnancy (see
section 4.6)
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:


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




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.


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
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


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).




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


None Known.


Shelf Life
Three years


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.


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.


Instructions for Use/Handling


Mercury Pharmaceuticals Ltd
Capital House, 85 King William Street,
London EC4N 7BL, UK


PL 12762/0014


June 1998




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