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NIFOPRESS RETARD TABLETS 20MG

Active substance(s): NIFEDIPINE

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1.

NAME OF THE MEDICINAL PRODUCT
Nifopress Retard 20mg Modified-release tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each modified-release tablet contains 20mg nifedipine.
Excipients with known effect: Lactose
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Modified-release tablets.
Nifopress Retard are circular biconvex coated tablets, pink-brownish in colour
embossed with "NR" on one face and "20" on the other face

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
For the prophylaxis of chronic stable angina pectoris and the treatment of
hypertension.

4.2. Posology and method of administration

Posology
Dosage regimen
The recommended starting dose of is 10mg every 12 hours swallowed with water
with subsequent titration of dosage according to response. Nifopress Retard
tablets permit titration of the initial dosage, which may be adjusted to 40mg every
12 hours, to a maximum daily dose of 80mg.
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 on special populations
Paediatric population
The safety and efficacy of Nifopress Retard 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 Nifopress Retard are altered in the elderly so that lower
maintenance doses of nifedipine may be required.
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
Oral use.
As a rule, tablets are swallowed whole with a little liquid, either with or without
food.
Nifopress Retard should not be taken with grapefruit juice (see Section 4.5).
4.3.

Contraindications

Nifopress Retard 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 section
6.1.
Nifopress Retard must not be used in cases of cardiogenic shock, clinically
significant aortic stenosis, unstable angina, or during or within 4 weeks of a
myocardial infarction.
Nifopress Retard should not be used for the treatment of acute attacks of angina.
The safety of Nifopress Retard in malignant hypertension has not been
established.
Nifopress Retard should not be used for secondary prevention of myocardial
infarction.

Nifopress Retard 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 warning and precautions for use

Nifopress Retard 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.
Nifopress Retard 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. Nifopress Retard 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).
Nifopress Retard should not be used during pregnancy unless the clinical
condition of the woman requires treatment with nifedipine. Nifopress Retard
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.
Nifopress Retard is 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.
Nifopress Retard 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 Nifopress Retard 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 glucosegalactose malabsorption should not take this medicine.
For use in special populations see section 4.2.

4.5.

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. (see Section 4.4)
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)

-

fluoxetine

-

nefazodone

-

quinupristin/dalfopristin

-

cisapride

-

valproic acid

-

cimetidine

-

diltiazem

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)

-

phenytoin

-

carbamazepine

-

phenobarbital

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 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.
4.6.

Fertility, pregnancy and lactation

Pregnancy
Nifopress Retard 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 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 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.

Breast-feeding
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 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).
Fertility
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 alcohol.

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)

Common

Uncommon

Rare

Not Known

Blood and
Lymphatic

Agranulocytosis

System

Leucopenia

Disorders

Immune System

Allergic

Disorders

reaction
Allergic oedema
/ angioedema
(incl. larynx

Pruritus
Urticaria

Anaphylactic/
anaphylactoid

Rash

reaction

oedema*)
Psychiatric

Anxiety reactions

Disorders

Sleep disorders

Metabolism and
Nutrition

Hyperglycaemia

Disorders

Nervous System
Disorders

Vertigo
Headache

Migraine
Dizziness

Par/Dysaesthesia

Hypoaesthesia
Somnolence

Tremor
Eye Disorders

Visual
disturbances

Eye pain

Cardiac

Tachycardia

Chest pain

Disorders

Palpitations

(Angina Pectoris)

Vascular
Disorders

Oedema (incl.
peripheral
Hypotension
oedema)
Syncope
Vasodilatation

Respiratory,

Nasal congestion

Thoracic and

Nosebleed

Mediastinal

Dyspnoea

Disorders

Gastrointestinal

Gastrointestinal

Disorders

and abdominal
pain
Constipation

Nausea
Dyspepsia

Vomiting
Gingival
hyperplasia

Gastroesophageal
sphincter
insufficiency

Flatulence
Dry mouth
Hepatobiliary

Transient

Disorders

increase in liver

Jaundice

enzymes
Skin and

Toxic Epidermal

Subcutaneous

Necrolysis
Erythema

Tissue Disorders

Photosensitivity
allergic reaction
Palpable purpura

Musculoskeletal
and Connective
Tissue Disorders

Muscle cramps

Arthralgia

Joint swelling

Myalgia

Renal and

Polyuria

Urinary Disorders

Dysuria

Reproductive

Erectile

System and

dysfunction

Breast Disorders

General
Disorders and

Feeling

Unspecific pain

Administration

unwell

Chills

Site Conditions

* = may result in life-threatening outcome
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 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.
4.9.

Overdose

Symptoms:
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.
Treatment:
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 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
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 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: selective calcium channel blockers with
mainly vascular effect, dihydropyridine derivatives, ATC code: C08CA05
Nifedipine is a specific and potent calcium antagonist of the 1, 4dihydropyridine 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 Nifopress Retard is to cause peripheral
vasodilatation and thus reduce peripheral resistance.
In angina, Nifopress Retard 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.
Nifopress Retard administered twice-daily provides 24-hour control of raised
blood pressure. Nifopress Retard causes reduction in blood pressure such that
the percentage lowering is directly related to its initial level. In normotensive
individuals, Nifopress Retard 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. Paediatric dosing forms are
lacking.

5.2.

Pharmacokinetic properties

Absorption
After oral administration nifedipine is rapidly and almost completely absorbed.
The systemic availability of orally administered nifedipine is 45 – 56 % owing to
a first pass effect. Maximum plasma and serum concentrations are reached at 1.5
to 4.2 hours with Nifopress Retard 20mg tablets. Simultaneous food intake leads
to delayed, but not reduced absorption.
Distribution
Nifedipine is about 95 % bound to plasma protein (albumin). The distribution
half-life after intravenous administration was determined to be 5 to 6 minutes.
Biotransformation
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 urine.
Elimination
The terminal elimination half-life is 6 - 11 hours (Nifopress Retard), because of
delayed absorption. 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 volunteers.
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 section 4.4).
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

Tablet core:
Polysorbate 80
Maize Starch
Microcrystalline Cellulose 101
Lactose
Magnesium Stearate
Tablet coating:
Red iron oxide (E172)
Polyethylene glycol 4000
Titanium dioxide (E171)
Hydroxpropylmethyl cellulose (E5)

6.2

Incompatibilities
Not applicable.

6.3.

Shelf life

4 years - Nifopress Retard Tablets should not be used after the ' Use Before' date
given on the container.
6.4.

Special precautions for storage



Protect from light.



Store below 25°C.

6.5.

Nature and contents of container

PVC blisters (250µm) with Aluminium foil lids (20µm). Packs of 100 tablets
contains 10 strips of 10 tablets
Tablets are in pack sizes of 56, 100 or 112 tablets.
Not all pack sizes may be marketed.

6.6.

Special precautions for disposal and other handling

No special requirements.

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
3&4 Quidhampton Business Units
Polhampt limiton Lane
Overton
Hampshire
RG25 3ED
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 20416/0317

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
26 September 1997

10

DATE OF REVISION OF THE TEXT
17/02/2017

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