GMP Nifedipine 25mg tablet Prophylaxis of chronic stable angina
pectoris treat Raynaud's phenomenonessential hypertension
1. Name of the medicinal product
Nifedipine 20mg tablet
2. Qualitative and quantitative composition
Each tablet contains 20 mg nifedipine.
Excipient with known effect: Yellow orange S (E110)
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Orange film-coated tablet
4. Clinical particulars
4.1 Therapeutic indications
For the prophylaxis of chronic stable angina pectoris, the
treatment of Raynaud's phenomenon and essential hypertension.
For patients suffering from essential hypertension or chronic
stable angina pectoris, and treated with fast release forms of
nifedipine (Adalat capsules), a dose dependent increase in the risk
of cardiovascular complications (e.g., myocardial infarction) and
mortality may occur. Due to this, Adalat capsules should only be
used for treatment of patients with essential hypertension or
chronic stable angina pectoris if no other treatment is
4.2 Posology and method of administration
The maximum total daily dose is 60 mg. The recommended starting
dose is 5 mg every eight hours with subsequent titration of dose
according to response permitting an increase to a maximum of 20 mg
every eight hours.
Co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers may
result in the recommendation to adapt the nifedipine dose or not to
use nifedipine at all (see section 4.5).
Duration of treatment
Treatment may be continued indefinitely.
Additional information for special populations
The safety and efficacy of Adalat capsules in children below 18
years of age has not been established. Currently available data for
the use of nifedipine in hypertension are described in section 5.1
Older people (>65 years)
The pharmacokinetics of Adalat capsules are altered in the older
people so that lower maintenance doses of nifedipine may be
Patients with hepatic impairment
Nifedipine is metabolised primarily by the liver and therefore
patients with mild, moderate or severe liver dysfunction should be
carefully monitored and a dose reduction may be necessary. The
pharmacokinetics of nifedipine has not been investigated in
patients with severe hepatic impairment (see section 4.4 and 5.2).
Patients with renal impairment
Based on pharmacokinetic data, no dosage adjustment is required in
patients with renal impairment (see section 5.2).
Method of administration
Adalat capsules should be swallowed whole with a little liquid,
either with or without food.
Adalat capsules should not be taken with grapefruit juice (see
Adalat capsules must not be administered to patients with known
hypersensitivity to the active substance, or to other
dihydropyridines because of the theoretical risk of
cross-reactivity, or to any of the excipients listed in sections
4.4 and 6.1.
Adalat capsules must not be used in cases of cardiogenic shock,
clinically significant aortic stenosis, unstable angina, or during
or within 4 weeks of an acute myocardial infarction.
Adalat capsules should not be used for the treatment of acute
attacks of angina.
The safety of Adalat capsules in malignant hypertension has not
Adalat capsules should not be used for secondary prevention of
Adalat capsules should not be administered concomitantly with
rifampicin since effective plasma levels of nifedipine may not be
achieved owing to enzyme induction (see section 4.5).
4.4 Special warnings and precautions for use
Adalat capsules are not beta-blockers and therefore give 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.
Adalat capsules 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. Adalat capsules 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).
Treatment with short-acting nifedipine may induce an exaggerated
fall in blood pressure and reflex tachycardia, which can cause
cardiovascular complications such as myocardial and cerebrovascular
As with other vasoactive substances, angina pectoris may very
rarely occur (data from spontaneous reports) with immediate release
nifedipine, especially at the start of the treatment. Data from
clinical studies confirm that the occurrence of angina pectoris
attacks is uncommon.
In patients suffering from angina pectoris an increase in
frequency, duration and severity of angina pectoris attacks may
occur, especially at the start of the treatment.
The occurrence of myocardial infarction has been described in
isolated cases, although it was not possible to distinguish this
from the natural course of the underlying disease.
Adalat capsules should not be used during pregnancy unless the
clinical condition of the woman requires treatment with nifedipine.
Adalat capsules should be reserved for women with severe
hypertension who are unresponsive to standard therapy (see section
Careful monitoring of blood pressure must be exercised when
administering nifedipine with I.V. magnesium sulfate, 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.
Adalat capsules are not recommended for use during breast-feeding
because nifedipine has been reported to be excreted in human milk
and the effects of nifedipine exposure to the infant are not known
(see section 4.6).
In patients with mild, moderate or severe impaired liver function,
careful monitoring and a dose reduction may be necessary. The
pharmacokinetics of nifedipine has not been investigated in
patients with severe hepatic impairment (see section 4.2 and 5.2).
Therefore, nifedipine should be used with caution in patients with
severe hepatic impairment.
Adalat capsules should be used with caution in patients whose
cardiac reserve is poor. Deterioration of heart failure has
occasionally been observed with nifedipine.
At doses higher than those recommended, there is some concern about
increased mortality and morbidity in the treatment of ischaemic
heart disease, in particular after myocardial infarction.
The use of Adalat capsules 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
- valproic acid
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).
Adalat capsules contain yellow orange S (E110) which may cause
For use in special populations see section 4.2.
4.5 Interaction with other medicinal products and other forms of
Drugs that affect nifedipine
Nifedipine is metabolised via the cytochrome P450 3A4 system,
located both in the intestinal mucosa and in the liver. Drugs that
are known to either inhibit or to induce this enzyme system may
therefore alter the first pass (after oral administration) or the
clearance of nifedipine (see Section 4.4).
The extent as well as the duration of interactions should be taken
into account when administering nifedipine together with the
Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon
co-administration with rifampicin, the bioavailability of
nifedipine is distinctly reduced and thus its efficacy weakened.
The use of nifedipine in combination with rifampicin is therefore
contraindicated (see Section 4.3).
Upon co-administration of known inhibitors of the cytochrome P450
3A4 system the blood pressure should be monitored and, if
necessary, a reduction in the nifedipine dose considered (see
Sections 4.2 and 4.4). In the majority of these cases, no formal
studies to assess the potential for a drug interaction between
nifedipine and the drug(s) listed have been undertaken, thus far.
Drugs increasing nifedipine exposure:
• macrolide antibiotics (e.g., erythromycin)
• anti-HIV protease inhibitors (e.g., ritonavir)
• azole anti-mycotics (e.g., ketoconazole)
• valproic acid
Upon co-administration of inducers of the cytochrome P450 3A4
system, the clinical response to nifedipine should be monitored
and, if necessary, an increase in the nifedipine dose considered.
If the dose of nifedipine is increased during co-administration of
both drugs, a reduction of the nifedipine dose should be considered
when the treatment is discontinued.
Drugs decreasing nifedipine exposure:
• rifampicin (see above)
Effects of nifedipine on other drugs
Nifedipine may increase the blood pressure lowering effect of
concomitant applied antihypertensives.
When nifedipine is administered simultaneously with beta-receptor
blockers the patient should be carefully monitored, since
deterioration of heart failure is also known to develop in isolated
Digoxin: The simultaneous administration of nifedipine and digoxin may
lead to reduced digoxin clearance and, hence, an increase in the
plasma digoxin level. The patient should therefore be subjected to
precautionary checks for symptoms of digoxin overdosage and, if
necessary, the glycoside dose should be reduced.
Quinidine: Co-administration of nifedipine with quinidine may lower
plasma quinidine levels, and after discontinuation of nifedipine, a
distinct increase in plasma quinidine levels may be observed in
individual cases. Consequently, when nifedipine is either
additionally administered or discontinued, monitoring of the
quinidine plasma concentration, and if necessary, adjustment of the
quinidine dose are recommended. Blood pressure should be carefully
monitored and, if necessary, the dose of nifedipine should be
Tacrolimus: Tacrolimus is metabolised via the cytochrome P450 3A4
system. Published data indicate that the dose of tacrolimus
administered simultaneously with nifedipine may be reduced in
individual cases. Upon co-administration of both drugs, the
tacrolimus plasma concentrations should be monitored and, if
necessary, a reduction in the tacrolimus dose considered.
Drug food interactions
Grapefruit juice inhibits the cytochrome P450 3A4 system.
Administration of nifedipine together with grapefruit juice thus
results in elevated plasma concentrations and prolonged action of
nifedipine due to a decreased first pass metabolism or reduced
clearance. As a consequence, the blood pressure lowering effect of
nifedipine may be increased. After regular intake of grapefruit
juice, this effect may last for at least three days after the last
ingestion of grapefruit juice.
Ingestion of grapefruit/grapefruit juice is therefore to be avoided
while taking nifedipine (see Section 4.2).
Other forms of interaction
Nifedipine may increase the spectrophotometric values of urinary
vanillylmandelic acid falsely. However, HPLC measurements are
4.6 Fertility, pregnancy and lactation
Adalat capsules should not be used during pregnancy unless the
clinical condition of the woman requires treatment with nifedipine
(see section 4.4).In animal studies, nifedipine has been shown to produce
embryotoxicity, foetotoxicity and teratogenicity (see section 5.3).
There are no adequate and well-controlled studies in pregnant
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 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.
Acute pulmonary oedema has been observed when calcium channel
blockers, among others nifedipine, have been used as a tocolytic
agent 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.
Nifedipine is excreted in 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 breast-feeding or milk expression for 3 to 4 hours after
drug administration to decrease the nifedipine exposure to the
infant (see section 4.4).
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.
4.7 Effects on ability to drive and use machines
Reactions to the drug, which vary in intensity from individual to
individual, may impair the ability to drive or to operate machinery
(see section 4.8). This applies particularly at the start of
treatment, on changing the medication and in combination with
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%).
The frequencies of ADRs reported with nifedipine-containing
products are summarised in the table below. Within each frequency
grouping, undesirable effects are presented in order of decreasing
seriousness. Frequencies are defined as common (≥1/100 to <
1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to
< 1/1,000). The ADRs identified only during the ongoing
postmarketing surveillance, and for which a frequency could not be
estimated, are listed under “Not known”.
System Organ Class (MedDRA)
Blood and Lymphatic System Disorders
Immune System Disorders
Allergic oedema / angioedema (incl. larynx oedema*)
Anaphylactic/ anaphylactoid reaction
Metabolism and Nutrition Disorders
Nervous System Disorders
Oedema (incl. peripheral oedema)
Respiratory, Thoracic, and Mediastinal Disorders
Gastrointestinal and abdominal pain
Gastroesophageal sphincter insufficiency
Transient increase in liver enzymes
Skin and Subcutaneous Tissue Disorders
Toxic Epidermal Necrolysis
Photosensitivity allergic reaction
Musculoskeletal and Connective Tissue Disorders
Renal and Urinary Disorders
Reproductive System and Breast Disorders
General Disorders and Administration Site Conditions
* = may result in life-threatening outcome
**cases have been 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
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.
The following symptoms are observed in cases of severe nifedipine
Disturbances of consciousness to the point of coma, a drop in blood
pressure, tachycardia, bradycardia, hyperglycaemia, metabolic
acidosis, hypoxia, cardiogenic shock with pulmonary oedema.
As far as treatment is concerned, elimination of nifedipine and the
restoration of stable cardiovascular conditions have priority.
Elimination must be as complete as possible, including the small
intestine, to prevent the otherwise inevitable subsequent
absorption of the active substance.
The benefit of gastric decontamination is uncertain.
1. Consider activated charcoal (50 g for adults, 1 g/kg for
children) if the patient presents within 1 hour of ingestion of a
potentially toxic amount.
Although it may seem reasonable to assume that late administration
of activated charcoal may be beneficial for sustained release (SR,
MR) preparations there is no evidence to support this.
2. Alternatively consider gastric lavage in adults within 1 hour of
a potentially life-threatening overdose.
3. Consider further doses of activated charcoal every 4 hours if a
clinically significant amount of a sustained release preparation
has been ingested with a single dose of an osmotic laxative (e.g.
sorbitol, lactulose or magnesium sulfate).
4. Asymptomatic patients should be observed for at least 4 hours
after ingestion and for 12 hours if a sustained release preparation
has been taken.
Haemodialysis serves no purpose as nifedipine is not dialysable,
but plasmapheresis is advisable (high plasma protein binding,
relatively low volume of distribution).
Hypotension as a result of cardiogenic shock and arterial
vasodilatation can be treated with calcium (10-20 ml of a 10 %
calcium gluconate solution administered intravenously over 5-10
minutes). If the effects are inadequate, the treatment can be
continued, with ECG monitoring. If an insufficient increase in
blood pressure is achieved with calcium, vasoconstricting
sympathomimetics such as dopamine or noradrenaline should be
administered. The dosage of these drugs should be determined by the
Symptomatic bradycardia may be treated with atropine,
beta-sympathomimetics or a temporary cardiac pacemaker, as
Additional fluids should be administered with caution to avoid
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective calcium channel blockers with
mainly vascular effect, dihydropyridine derivatives, ATC code:
Nifedipine is a 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. As a
specific and potent calcium antagonist, nifedipine acts
particularly on the cells of the myocardium and the smooth muscle
cells of the coronary arteries and the peripheral resistance
vessels. The main action of Adalat capsules is to relax arterial
smooth muscle both in the coronary and peripheral circulation.
In angina pectoris, Adalat capsules relax peripheral arteries so
reducing the load on the left ventricle. Additionally, Adalat
capsules dilate submaximally both clear and pre-stenotic coronary
arteries, and stenotic and post-stenotic coronary arteries, thus
protecting the heart against coronary artery spasm and improving
perfusion to the ischaemic myocardium.
Adalat capsules reduce the frequency of painful attacks and
ischaemic ECG changes, irrespective of the relative contribution
from coronary artery spasm or atherosclerosis.
Adalat capsules cause a reduction in blood pressure such that the
percentage lowering is directly related to its initial level. In
normotensive individuals, Adalat capsules have little or no effect
on blood pressure.
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. Paediatric dosing
forms are lacking.
5.2 Pharmacokinetic properties
After oral administration nifedipine is almost completely absorbed.
The systemic availability of orally administered nifedipine
immediate release formulation (Adalat capsules) is 45 – 56 % owing
to a first pass effect. Maximum plasma and serum concentrations are
reached at 30 to 60 minutes. Simultaneous food intake leads to
delayed, but not reduced absorption.
Nifedipine is about 95 % bound to plasma protein (albumin). The
distribution half-life after intravenous administration has been
determined to be 5 to 6 minutes.
After oral administration nifedipine is metabolized in the gut wall
and in the liver, primarily by oxidative processes. These
metabolites show no pharmacodynamic activity. Nifedipine is
excreted in the form of its metabolites predominantly via the
kidneys and about 5 – 15 % via the bile in the faeces. The
unchanged substance is recovered only in traces (below 0.1 %) in
The terminal elimination half-life is 1.7 to 3.4 hours. No
accumulation of the substance after the usual dose was reported
during long-term treatment. In cases of impaired kidney function no
substantial changes have been detected in comparison with healthy
In a study comparing the pharmacokinetics of nifedipine in patients
with mild (Child Pugh A) or moderate (Child Pugh B) hepatic
impairment with those in patients with normal liver function, oral
clearance of nifedipine was reduced by on average 48% (Child Pugh
A) and 72% (Child Pugh B). As a result AUC and Cmax of nifedipine
increased on average by 93% and 64% (Child Pugh A) and by 253% and
171% (Child Pugh B), respectively, compared to patients with normal
hepatic function. The pharmacokinetics of nifedipine has not been
investigated in patients with severe hepatic impairment (see
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on
conventional studies of single and repeated dose toxicity,
genotoxicity and carcinogenic potential.
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.
6. Pharmaceutical particulars
6.1 List of excipients
The capsule shell contains:
Titanium dioxide (E171)
Yellow orange S (E110)