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ADANIF XL 30MG TABLETS
Active substance(s): NIFEDIPINE
NAME OF THE MEDICINAL PRODUCT
Adanif XL 30mg Tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains 30mg nifedipine.
For a full list of excipients, see Section 6.1.
Prolonged release film-coated tablet.
Pale red, round biconvex tablets.
For the treatment of all grades of hypertension.
For the prophylaxis of chronic stable angina pectoris either as monotherapy or in
combination with a beta-blocker.
Posology and method of administration
Method of administration
For oral administration, the tablets should be swallowed whole with a glass of water,
either with or without food. The tablets should be taken at approximately 24-hour
intervals, i.e. at the same time each day, preferably during the morning. Adanif XL
Tablets must be swallowed whole; under no circumstances should they be bitten,
chewed or broken up.
Adanif XL should not be taken with grapefruit juice (see section 4.5).
In mild to moderate hypertension, the recommended initial dose is one 20mg tablet
once-daily. In severe hypertension, the recommended initial dose is one 30mg tablet
once-daily. If necessary, the dosage can be increased according to individual
requirements up to a maximum of 90mg once-daily.
For the prophylaxis of angina pectoris, the recommended initial dose is one 30mg
tablet once-daily. The dosage can be increased according to individual requirements
up to a maximum of 90mg once-daily.
Patients in whom hypertension or anginal symptoms are controlled on other
nifedipine containing preparations may be safely switched to Adanif XL.
Prophylactic anti-anginal efficacy is maintained when patients are switched from
other calcium antagonists such as diltiazem or verapamil to Adanif XL. Patients
switched from other calcium antagonists should initiate therapy at the recommended
initial dose of 30mg Adanif XL once-daily. Subsequent titration to a higher dose may
be initiated as warranted clinically.
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
Duration of treatment
Treatment may be continued indefinitely.
Additional information on special populations
The safety and efficacy of nifedipine in children under the age of 18 years have not
been established. Currently available data for the use of nifedipine in hypertension
are described in section 5.1.
Elderly (>65 years)
Based on pharmacokinetic data for Adanif XL no dose adaptation in elderly people
above 65 years is necessary.
Patients with renal impairment
Patients with renal impairment should not required adjustment of dosage.
• Adanif XL should not be administered to patients with known hypersensitivity to
nifedipine, or to other dihydropyridines because of the theoretical risk of crossreactivity, or to any of the excipients (see Section 4.4 and 6.1).
• Adanif XL should not be used in cases of cardiogenic shock, clinically significant
aortic stenosis, unstable angina, or during or within one month of a myocardial
• Adanif XL should not be used for the treatment of acute attacks of angina.
• The safety of Adanif XL in malignant hypertension has not been established.
• Adanif XL should not be used for secondary prevention of myocardial infarction.
• Owing to the duration of action of the formulation, Adanif XL should not be
administered to patients with hepatic impairment.
• Adanif XL should not be administered to patients with a history of gastrointestinal obstruction, oesophageal obstruction, or any degree of decreased lumen
diameter of the gastro-intestinal tract.
• Adanif XL must not be used in patients with a Kock pouch (ileostomy after
• Adanif XL is contra-indicated in patients with inflammatory bowel disease or
• Adanif XL 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).
Special warnings and precautions for use
Adanif XL Tablets must be swallowed whole; under no circumstances should they be
bitten, chewed or broken up.
Caution should be exercised in patients with hypotension as there is a risk of further
reduction in blood pressure and care must be exercised in patients with very low
blood pressure (severe hypotension with systolic blood pressure less than 90mm Hg).
Adanif XL should not be used during pregnancy unless the clinical condition of the
woman requires treatment with nifedipine. Adanif XL should be reserved for women
with severe hypertension who are unresponsive to standard therapy (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.
Adanif XL is not recommended for use during breastfeeding 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 impaired liver function careful monitoring and, in severe cases, a
dose reduction may be necessary.
Adanif XL 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. Adanif XL will not prevent possible rebound
effects after cessation of other antihypertensive therapy.
Adanif XL should be used with caution in patients whose cardiac reserve is poor.
Deterioration of heart failure has occasionally been observed with nifedipine.
Diabetic patients taking Adanif XL 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, which are known inhibitors of the cytochrome P450 3A4 system, and which
may therefore lead to increased plasma concentrations of nifedipine include, for
- 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.
As the outer membrane of the Adanif XL Tablet is not digested, what appears to be
the complete tablet may be seen in the toilet or associated with the patient's stools.
Also, as a result of this, care should be exercised when administering Adanif XL to
patients, as obstructive symptoms may occur. Bezoars can occur in very rare cases
and may require surgical intervention. In single cases, obstructive symptoms have
been described without known history of gastrointestinal disorders.
A false positive effect may be experienced when performing a barium contrast x-ray.
For use in special populations see Section 4.2.
Adanif XL contains Lactose monohydrate. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
should not take this medicine.
Interaction with other medicinal products and other forms of interaction
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.
The extent as well as the duration of interactions should be taken into account when
administering nifedipine together with the following drugs:
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 coadministration 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 ß-receptor
blockers the patient should be carefully monitored, since deterioration of heart failure
is also known to develop in isolated cases.
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 decreased.
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 unaffected.
Fertility, pregnancy and lactation
Nifedipine should not be used during pregnancy unless the clinical condition of the
woman requires treatment with nifedipine (see Section 4.4).
Acute pulmonary oedema has been observed when calcium 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). There are no adequate
well controlled studies in pregnant women.
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
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.
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 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 breastfeeding or milk expression for 3 to 4 hours
after drug administration to decrease the nifedipine exposure to the infant (see Section
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. This applies particularly at the
start of treatment, on changing the medication and in combination with alcohol.
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; 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 <10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to 1/1,000).
ADRs derived from post marketing reports and for which a frequency could not be
estimated are listed in the Frequency Not Known column.
≥ 1% to <10%
>0.1% to <1%
>0.01% to <0.1%
Blood and Lymphatic System Disorders
Immune System Disorders
Metabolism and Nutrition Disorders
Nervous System Disorders
Chest pain (Angina
Respiratory Thoracic and Mediastinal
Gastrointestinal and Gingival hyperplasia Bezoar
Transient increase in
Skin and Subcutaneous Tissue Disorders
Musculoskeletal and Connective Tissue Disorders
Renal and Urinary Disorders
Reproductive System Disorders
General Disorders and Administration Site Conditions
* may result in life-threatening outcome
**cases have been also reported when used as tocolytic during pregnancy (see section
In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in
blood pressure can occur as a result of vasodilation.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after authorisations 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 Website: www.mhra.gov.uk/yellowcard.
The following symptoms are observed in cases of severe nifedipine intoxication:
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
1. Consider activated charcoal (50g for adults, 1g/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 lifethreatening 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 sulphate).
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 plasmaspheresis
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 (10-20ml 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 patient's response.
Symptomatic bradycardia may be treated with atropine, beta-sympathomimetics or a
temporary cardiac pacemaker, as required. Additional fluids should be administered
with caution to avoid cardiac overload.
ATC code: C08 CA05
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 nifedipine
is to relax arterial smooth muscle, both in the coronary and peripheral circulation. The
Adanif XL Tablet is formulated to achieve controlled delivery of nifedipine in a
release profile sufficient to enable once-daily administration to be effective in clinical
In hypertension, the main action of nifedipine is to cause peripheral vasodilatation
and thus reduce peripheral resistance. Nifedipine administered once-daily provides
24-hour control of raised blood pressure. Nifedipine causes reduction in blood
pressure such that the percentage lowering is proportional to its initial level. In
normotensive individuals, nifedipine has little or no effect on blood pressure.
In angina, Adanif XL 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.
In a multi-national, randomised, double-blind, prospective study involving 6321
hypertensive patients with at least one additional risk factor followed over 3 to 4.8
years, Adanif XL 30 and 60 (nifedipine GITS) were shown to reduce blood pressure
to a comparable degree as a standard diuretic combination.
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.
Adanif XL Tablets are formulated to provide nifedipine at an approximately constant
rate over 24 hours. Nifedipine is released from the tablet at a zero-order rate by a
membrane-controlled, osmotic push-pull process. The pharmacokinetic profile of this
formulation is characterized by low peak-trough fluctuation. 0-24 hour plasma
concentration versus time profiles at steady state are plateau-like, rendering the
Adanif XL Tablet appropriate for once-a-day administration.
The delivery rate is independent of gastrointestinal pH or motility. Upon swallowing,
the biologically inert components of the tablet remain intact during gastrointestinal
transit and are eliminated in the faeces as an insoluble shell. Orally administered
nifedipine is almost completely absorbed in the gastro-intestinal tract. The systemic
availability of orally administered nifedipine immediate release formulations
(nifedipine capsules) is 45–56% owing to a first pass effect. At steady-state, the
bioavailability of Adanif XL Tablets ranges from 68-86% relative to Nifedipine
capsules. Administration in the presence of food slightly alters the early rate of
absorption but does not influence the extent of drug availability.
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 metabolised in the gut wall and in the liver,
primarily by oxidative processes. These metabolites show no pharmacodynamic
activity. Nifedipine is eliminated in the form of its metabolites, predominantly via the
kidneys, with approximately 5-15% being excreted via the bile in the faeces. Nonmetabolised nifedipine can be detected only in traces (below 1.0%) in the urine.
The terminal elimination half-life is 1.7 to 3.4 hours in conventional formulations
(nifedipine capsules). The terminal half-life following Adanif XL administration does
not represent a meaningful parameter as a plateau-like plasma concentration is
maintained during release from the tablets and absorption. After release and
absorption of the last dose the plasma concentration finally declines with an
elimination half-life as seen in conventional formulations.
Characteristics in patients:
There are no significant differences in the pharmacokinetics of nifedipine between
healthy subjects and subjects with renal impairment. Therefore, dosage adjustment is
not needed in these patients.
In patients with hepatic impairment, the elimination half-life is distinctly prolonged
and the total clearance is reduced. Owing to the duration of action of the formulation,
Adanif XL should not be administered in these patients.
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.
Following acute oral and intravenous administration of nifedipine in various animal
species, the following LD50 (mg/kg) values were obtained:
Oral: 494 (421-572)*;
i.v.: 4.2 (3.8-4.6)*.
Oral: 1022 (950-1087)*;
i.v.: 15.5 (13.7-17.5)*.
Oral: ~ 100;
Oral: > 250;
* 95% confidence interval.
In subacute and subchronic toxicity studies in rats and dogs, nifedipine was tolerated
without damage at doses of up to 50mg/kg (rats) and 100mg/kg (dogs) p.o. over
periods of thirteen and four weeks, respectively. Following intravenous
administration, dogs tolerated up to 0.1mg/kg nifedipine for six days without damage.
Rats tolerated daily intravenous administration of 2.5mg/kg nifedipine over a period
of three weeks without damage.
In chronic toxicity studies in dogs with treatment lasting up to one year, nifedipine
was tolerated without damage at doses up to and including 100mg/kg p.o. In rats,
toxic effects occurred at concentrations above 100ppm in the feed (approximately 57mg/kg bodyweight).
In a carcinogenicity study in rats (two years), there was no evidence of a carcinogenic
effect of nifedipine.
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
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.
In in vitro and in vivo tests, nifedipine has not been associated with mutagenic
List of excipients
Anhydrous colloidal silica
Ferric oxide (red) (E172)
Titanium dioxide (E171)
Special precautions for storage
Do not store above 25oC. Store in the original package to protect from light.
Nature and contents of container
28 tablets in PVC/PVdC – Aluminium blisters.
Special precautions for disposal
No additional information.
MARKETING AUTHORISATION HOLDER
Focus Pharmaceuticals Ltd
85 King William Street,
London EC4N 7BL,
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT