Adalat LA 30 mg Prolonged-Release Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Nifedipine
Available from:
IMED Healthcare Ltd.
ATC code:
C08CA; C08CA05
INN (International Name):
Nifedipine
Dosage:
30 milligram(s)
Pharmaceutical form:
Prolonged-release tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Dihydropyridine derivatives; nifedipine
Authorization status:
Authorised
Authorization number:
PPA1463/058/002
Authorization date:
2012-04-05

Package leaflet - information for the user

Adalat® LA 30 mg Prolonged Release

Tablets

Nifedipine

Read all of this leaflet carefully before you start taking this

medicine.

Keep this leaflet. You may need to read it again.

If you have more questions, ask your doctor or pharmacist.

This medicine has been prescribed for you.

Do not pass it on to others. It may harm them, even if their symptoms are

the same as yours.

If any of the side effects gets serious, or if you notice any side effects not

listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet

1 What Adalat LA is

2 Before you take Adalat LA

3 How you take Adalat LA

4 Possible side effects

5 How to store Adalat LA

6 Further information

1 What Adalat LA is

Adalat LA contains nifedipine, which belongs to a group of medicines

called calcium antagonists.

Adalat LA is used to treat high blood pressure or angina (chest

pain).

For high blood pressure: Adalat LA works by relaxing and expanding the

blood vessels. This makes the blood flow more easily and lowers blood

pressure. Lower blood pressure reduces the strain on your heart.

For angina: Adalat LA works by relaxing and expanding the arteries

supplying the heart. This allows more blood and oxygen to reach the

heart and decreases the strain on it. Your angina attacks will be less

severe and less frequent if there is less strain on the heart.

2 Before you take Adalat LA

Do not take Adalat LA:

If you have had a heart attack within the last month.

If you get a sudden angina attack. Adalat LA will not help relieve

symptoms of angina quickly.

If you have unstable angina

If you are allergic to the active ingredient (nifedipine), to any other

similar medicines (known as dihydropyridines) or to any of the other

ingredients. The ingredients of Adalat LA are listed in section 6.

If you are taking rifampicin, an antibiotic.

If you have a liver disease that prevents your liver from working

properly.

If you have inflammation of the bowel or intestines, such as

Crohn’s disease.

If you have an obstruction or narrowing in your intestines, or have

had this in the past.

If you have ever had an obstruction in the gullet (the oesophagus -

the tube connecting the throat to the stomach).

If you have been told you have a narrowing of the aortic heart

valve (stenosis).

If you have ever had a collapse caused by a heart problem

(cardiogenic shock), during which you became breathless, pale and had

a cold sweat and dry mouth.

If you have a “Kock pouch” (a surgically constructed intestinal

reservoir with an opening through the abdominal wall) in your gut.

If your blood pressure continues to rise despite treatment

(malignant hypertension).

Tell your doctor and do not take Adalat LA if any of these apply

to you.

Your doctor will take special care:

If you have low blood pressure and you were prescribed Adalat LA

for your angina. Your blood pressure may be decreased further by this

treatment.

If you have a heart condition where your heart cannot cope with

increased strain (poor cardiac reserve).

If you are pregnant

If you are breastfeeding

If you are a diabetic. The treatment for your diabetes may need to

be adjusted. If you have any questions about this, ask your doctor.

If you are on kidney dialysis. If you have a very high blood

pressure and a low blood volume, you might experience a sudden drop

in blood pressure when you take Adalat LA.

Talk to your doctor before you take Adalat LA if any of these

apply to you.

Tell your doctor:

If your chest pain (angina) gets worse (comes on more often or more

severely) over a matter of hours or days. You may be advised not to take

Adalat LA.

If you have chest pains after taking your first dose of Adalat LA.

Your doctor may wish to change your treatment.

If you notice increased breathlessness.

If you notice swelling of the ankles.

Tell your doctor before you take the next dose if any of these

apply to you.

Also tell your doctor:

If you are giving a urine sample. Adalat LA may interfere with the

results of certain urine tests.

If you are to have a barium contrast x-ray (barium meal). These

tablets may affect the results of the test.

If you are a man who has been unable to father a child by in vitro

fertilisation. Drugs like Adalat LA have been shown to impair sperm

function.

Other medicines and Adalat LA

Tell your doctor about any other medicines that you are taking, or

took recently. This includes any products you bought without a

prescription.

Some medicines may affect the way Adalat LA works. Tell your doctor

if you are taking:

Other medicines to treat high blood pressure.

Rifampicin (an antibiotic)

Cimetidine (to treat stomach ulcers).

Digoxin, diltiazem, quinidine or beta-blockers (to treat heart

conditions).

Quinupristin/dalfopristin (a combination antibiotic).

Phenytoin, carbamazepine or valproic acid (to treat epilepsy).

Cisapride (to treat reduced movements of the gullet and stomach).

Magnesium sulphate injections during pregnancy (may cause a

severe fall in blood pressure).

Erythromycin (an antibiotic).

Ketoconazole, itraconazole or fluconazole (anti-fungal medicines).

Indinavir, nelfinavir, ritonavir, saquinavir or amprenavir (to treat

HIV).

Fluoxetine or nefazodone (to treat depression).

Tacrolimus (to prevent the rejection of transplanted organs).

Phenobarbital (usually used to treat insomnia or anxiety).

Food and drink with Adalat LA

You can take Adalat LA with or without food.

Do not drink grapefruit juice or eat grapefruit while taking Adalat

LA.

Do not start taking Adalat LA within 3 days of drinking grapefruit juice or

eating grapefruit. Tell your doctor if you have had grapefruit or grapefruit

juice in this time. Also, do not drink grapefruit juice or eat grapefruit

whilst taking Adalat LA. Grapefruit juice is known to increase the blood

levels of the active ingredient, nifedipine. This effect can last for at least

3 days.

One tablet of Adalat LA 30mg contains 9.4mg salt (sodium).

Tell your doctor if you are on a low-salt diet.

Pregnancy and breastfeeding

If you are pregnant, think you might be pregnant or are planning a family,

tell your doctor before taking Adalat LA.

If you need to take Adalat LA while breastfeeding, tell your doctor

before taking the tablets

Driving and using machines

Adalat LA may make you feel dizzy, faint, extremely tired or have visual

disturbances. Do not drive or operate machinery if you are affected in

this way. This may be more likely when you first start treatment, if you

change tablets, or if you have drunk alcohol.

3 How to take Adalat LA

Adalat is specially formulated so that you only have to take one dose

each day.

Adalat LA is not recommended for use in children and adolescents below

18 years of age, because there is only limited data on the safety and

efficacy in this population.

Take the tablets as prescribed by your doctor.

Dose for high blood pressure: the usual dose is 1 tablet, once a day.

Dose for angina: the dose depends on your individual requirements.

Your doctor will decide how much you should take.

Lower doses may be prescribed for elderly patients.

Swallow the tablets whole. Do not bite, chew or break them – if you

do they will not work properly. If you have difficulty swallowing tablets,

consult your doctor as he or she may wish to change your medicine.

Continue to take these tablets for as long as your doctor has told you

Take your dose at the same time each day, preferably in the morning.

Take your tablets with a glass of water. Do not take them with grapefruit

juice.

You can take Adalat LA with or without food.

You may see what looks like a complete tablet in the toilet or in your

stools. This is normal – it’s the outer shell of the tablet which is not

digested by the body

If you take too many tablets

Get medical help immediately. If possible, take your tablets or the

box with you to show the doctor.

Taking too many tablets may cause your blood pressure to become too

low and your heartbeats to speed up or slow down. It may also lead to

an increase in your blood sugar level or an increase in the acidity of your

blood, swelling in the lungs, low blood oxygen levels and disturbances in

consciousness, possibly leading to unconsciousness.

If you forget to take the tablets

Take your normal dose immediately and continue taking your tablets at

the usual time of day, waiting at least 12 hours before taking the next

dose.

Do not take a double dose to make up for the missed dose.

4 Possible side effects

Like all medicines, Adalat LA can have side effects, although not

everybody gets them.

If you notice:

hives on the body, lips, eyes or tongue

itching of the skin or rash

fast heart beat (tachycardia)

shortness of breath or difficulty breathing

Contact your doctor immediately and do not take the next dose

as these may be the first signs of allergic reaction which may

become severe.

Apart from the side effects listed above, these are the other side effects

of Adalat LA, starting with the more common ones:

Common side effects

(These may affect up to 1 in 10 people)

headache

flushing

general feeling of being unwell

constipation

swelling, particularly of the ankles and legs

Uncommon side effects

(These may affect up to 1 in 100 people)

stomach pain (abdominal pain)

unspecific pain

chills

low blood pressure when standing up (symptoms include fainting,

dizziness, light headedness, occasional palpitations, blurred vision and

sometimes confusion)

fainting

irregular heartbeat (palpitations)

dry mouth

indigestion or upset stomach

wind (flatulence)

feeling sick (nausea)

muscle cramps

joint swelling

sleep disorders

anxiety or nervousness

reddening of the skin

nose bleeds

nasal congestion

sensation of spinning or whirling motion (vertigo)

migraine

dizziness

trembling

increase in the need to pass water (urinate)

painful or difficult urination

inability to achieve or maintain an erection (impotence)

blurred vision

temporary increase in certain liver enzymes

Rare side effects

(These may affect up to 1 in 1,000 people)

pins and needles

unpleasant abnormal sensation

inflammation of the gums, tender or swollen gums, bleeding gums

Other side effects

(Frequency unknown)

stomach pain or distress caused by a mass of foreign material found

in the stomach which may require surgery for removal

difficulty swallowing

abdominal pain, caused by obstruction of the gut or ulcers in the gut

vomiting.

eye pain

chest pain

lowered white blood cell count

high blood sugar level

reduction in skin sensitivity to pain or touch

drowsiness or sleepiness

acid reflux

yellow discolouration of the skin (jaundice)

life-threatening skin reaction (toxic epidermal necrolysis)

allergic reaction to sunlight

purplish-red spots which can be felt

muscle / joint pain.

shortness of breath

All of these symptoms usually go away when treatment with Adalat LA is

stopped.

Reporting of side effectsIf you get any side effects, talk to your doctor,

pharmacist or nurse. This includes any possible side effects not listed in

this leaflet. You can also report side effects directly via HPRA

Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1

6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:

medsafety@hpra.ie. By reporting side effects you can help provide more

information on the safety of this medicine.

5 How to store Adalat LA

Keep this medicine out of the reach and sight of children.

Do not store above 30°C.

Store your medicine in its original container. Protect from strong light and

only remove the tablet from the blister strip when you are about to take it.

Do not use after the expiry date which is marked on both the outer carton

and on each blister strip of tablets.

Do not dispose of medicines in household rubbish. Any unused Adalat

LA tablets should be returned to a pharmacist (chemist) who will dispose

of them properly. This helps the environment.

6 Further information

What Adalat LA 30 contains

Adalat LA tablets contain the active ingredient, nifedipine.

Adalat LA tablets also contain propylene glycol, cellulose acetate,

hypromellose, hydroxypropylcellulose, polyethylene oxide, macrogol,

magnesium stearate, shellac, titanium dioxide (E171) , ferric oxide red

(E172) and iron oxide black (E172).

Each tablet also contains 24mg of sodium chloride (salt) to be taken into

consideration by patients on a controlled sodium diet.

What’s in the pack

Each prolonged release film-coated tablet contains 30 mg of nifedipine.

Each tablet is pink and round with a laser hole on one side and marked

‘Adalat 30’.

Each pack contains 28 tablets. Each tablet has the day of the week

printed next to it to remind you when to take it.

Parallel Product Authorisation Holder and Manufacturer

Product procured from within the EU by the Parallel Product

Authorisation Holder: IMED Healthcare Ltd, Unit 625 Kilshane Avenue,

Northwest Business Park, Ballycoolin, Dublin 15, Ireland

Manufacturer: Bayer Schering Pharma AG, D-51368 Leverkusen,

Germany

Repackaged by: IMED Healthcare Ltd, Unit 625 Kilshane Avenue,

Northwest Business Park, Ballycoolin, Dublin 15, Ireland.

This leaflet was last revised: March 2018

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Adalat LA 30 mg Prolonged-Release Tablet

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 30 mg nifedipine.

Each tablet contains 9.4mg sodium.

For a full list of excipients, see Section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release film-coated tablet.

Product imported from the UK:

Pink, round tablets with a laser hole on one side and marked ‘Adalat 30’.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

For the treatment of all grades of hypertension.

For the management of chronic stable angina pectoris either as monotherapy or in combination with a beta-blocker.

4.2 Posology and method of administration

Method of administration

Oral Use

As far as possible the treatment must be tailored to the needs of the individual.

Depending on the clinical picture in each case, the basic dose must be introduced gradually.

Unless otherwise prescribed, the following dosage guidelines apply for adults:

For coronary heart disease:

Chronic stable angina pectoris (angina of effort)

1 Adalat LA 30 mg tablet once daily (1 x 30 mg/day)

For hypertension:

1 Adalat LA 30 mg tablet once daily (1 x 30 mg/day)

In general therapy should be initiated with 30 mg once daily.

Where registered a starting dose of 20 mg once daily may be considered when medically indicated. Interim doses i.e. 40

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mg, 50 mg etc. can be applied by combinations of i.e. 20 mg + 20 mg or 20 mg + 30 mg tablets.

Depending on the severity of the disease and the patient's response the dose can be increased in stages up to 90 mg once

daily.

Co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers may result

in the recommendation to adapt

nifedipine dose or not

to use nifedipine at

(see "Interaction with other medicinal

products and other forms of

interaction").

Duration of Treatment

The attending doctor will determine the duration of use.

Administration

As a rule Adalat LA tablets are swallowed whole with a little liquid,

irrespective of meal times.

Grapefruit juice is to be

avoided (see "Interaction with other medicinal products and other forms of interaction").

Additional information on special populations

ii

Paediatric populations

The safety and efficacy of nifedipine in children below 18 years have not been established. Currently available data for

the use of nifedipine in hypertension are described in section 5.1.

Elderly (>65) patients

Based on pharmacokinetic data for Adalat LA no dose adaptation in elderly people above 65 years is necessary.

Patients with hepatic impairment

In patients with impaired liver function, careful monitoring and, in severe cases, a dose reduction may be necessary.

Patients with renal impairment

Based on pharmacokinetic data no dosage adjustment is required in patients with renal impairment (see "Pharmacokinetic

properties")

The tablets must not be chewed or broken up!

4.3 Contraindications

Adalat LA must not be administered to patients with known hypersensitivity to nifedipine or other dihydropyridines

because of the theoretical risk of cross-reactivity.

The safety of Adalat LA during pregnancy or in nursing mothers has not been established (see sections 4.4, 4.6 and

5.3).

Adalat LA must not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina, or

during or within one month of a myocardial infarction.

Adalat LA must not be used for the treatment of acute attacks of angina.

The safety of Adalat LA in malignant hypertension has not been established.

Adalat LA must not be used for secondary prevention of myocardial infarction.

Owing to the duration of action of the formulation, Adalat LA must not be administered to patients with hepatic

impairment.

Adalat LA must not be administered to patients with a history of gastro-intestinal obstruction, oesophageal obstruction,

or any degree of decreased lumen diameter of the gastro-intestinal tract.

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Adalat LA must not be used in patients with Kock pouch (ileostomy after proctocolectomy)

Adalat LA is contra-indicated in patients with inflammatory bowel disease or Crohn's disease.

Adalat LA must 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 LA tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.

The outer membrane of the Adalat LA tablet is not digested and, therefore, what appears to be the complete tablet may

be seen in the toilet or associated with the patient's stools.

Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90

mm HG), in cases of manifest heart failure and in the case of severe aortic stenosis.

Caution should be exercised in patients with hypotension as there is a risk of further reduction in blood pressure.

Adalat 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.

Adalat LA will not prevent possible rebound effects after cessation of other antihypertensive therapy.

Adalat LA should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has

occasionally been observed with nifedipine.

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.

Diabetic patients taking Adalat LA may require adjustment of their control.

In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.

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, also when administered nifedipine with i.v. magnesium

sulfate, owing to the possibility of an excessive fall in blood pressure which could harm both mother and fetus.

Co-administration of nifedipine with erythromycin, ketoconazole, itraconazole, fluconazole, fluoxetine, indinavir,

nelfinavir, ritonavir, amprenavir and saquinavir, may theoretically result in an increase in nifedipine plasma

concentrations. Upon co-administration with any of these cytochrome P450 3A4 inhibitors, blood pressure should be

monitored and, if necessary, a reduction in the nifedipine dose considered (see section 4.5).

As the outer membrane of the Adalat LA tablet is not digested, care should be exercised as obstructive symptoms may

occur, particularly in patients with pre-existing severe gastrointestinal narrowing. 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.

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Adalat LA must not be administered to patients with Kock pouch (ileostomy after proctocolectomy).

A false positive effect may be experienced when performing a barium contrast x-ray.

Patients with hepatic impairment

In patients with impaired liver function, careful monitoring and, in severe cases, a dose reduction may be necessary (see

section 5.2).

This medicinal product contains 9.4mg sodium per dose; this should be taken into consideration for patients on a

controlled sodium diet.

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 inhibitors of the cytochrome P450 3 A4 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.

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 weak to moderate inhibitors of the cytochrome P450 3A4 system (listed immediately

below), 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.

Macrolide antibiotics (e.g., erythromycin):

No interaction studies have been carried out between nifedipine and macrolide antibiotics. Certain macrolide antibiotics

are known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore the potential for an

increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (see section 4.4).

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Azithromycin, although structurally related to the class of macrolide antibiotics is void of CYP 3A4 inhibition.

Anti-HIV protease inhibitors (e.g., ritonavir):

A clinical study investigating the potential of a drug interaction between nifedipine and certain anti-HIV protease

inhibitors has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In

addition, drugs of this class have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of

nifedipine. When administered together with nifedipine, a substantial increase in plasma concentrations of nifedipine

due to a decreased first pass metabolism and a decreased elimination cannot be excluded (see section 4.4).

Azole anti-mycotics (e.g., ketoconazole):

A formal interaction study investigating the potential of a drug interaction between nifedipine and certain azole anti-

mycotics has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. When

administered orally together with nifedipine, a substantial increase in systemic bioavailability of nifedipine due to a

decreased first pass metabolism cannot be excluded (see section 4.4).

Fluoxetine:

A clinical study investigating the potential of a drug interaction between nifedipine and fluoxetine has not yet been

performed. Fluoxetine has been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine.

Therefore an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded

(see section 4.4).

Nefazodone:

A clinical study investigating the potential of a drug interaction between nifedipine and nefazodone has not yet been

performed. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore

an increase in nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (see section

4.4).

Quinupristin/dalfopristin

Simultaneous administration of quinupristin/dalfopristin and nifedipine, may lead to increased plasma concentrations of

nifedipine (see section 4.4).

Valproic acid:

No formal studies have been performed to investigate the potential interaction between nifedipine and valproic acid. As

valproic acid has been shown to increase the plasma concentrations of the structurally similar calcium channel blocker,

nimodipine, due to enzyme inhibition, an increase in nifedipine plasma concentrations and hence an increase in efficacy

cannot be excluded (see section 4.4).

Cimetidine:

Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may

potentiate the antihypertensive effect (see section 4.4).

Diltiazem:

Diltiazem decreases the clearance of nifedipine and, hence, increases plasma nifedipine levels. Therefore, caution

should be taken when both drugs are used in combination and a reduction of the nifedipine dose may be necessary.

Further studies:

Cisapride

Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.

Cytochrome P450 3A4 system-inducing anti-epileptic drugs, such as phenytoin, carbamazepine and phenobarbital:

phenytoin induces cytochrome P450 3A4 system. Upon co-administration with phenytoin, the bioavailability of

nifedipine is reduced and thus its efficacy weakened. When both drugs are administered concomitantly, the clinical

response to nifedipine should be monitored and, if necessary, an increase of 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 with phenytoin is discontinued.

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No formal studies have been performed to investigate the potential interaction between nifedipine and carbamazepine

or phenobarbital. As both drugs have been shown to reduce the plasma concentrations of the structurally similar

calcium channel blocker, nimodipine, due to enzyme induction, a decrease in nifedipine plasma concentrations and

hence a decrease in efficacy cannot be excluded.

Effects of nifedipine on other drugs

Blood pressure lowering drugs

Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives, such as:

-diuretics

-beta-blockers

-Ace-inhibitors

- Angiotensin 1 (AT1) receptor- antagonists

-other calcium antagonists

-alpha-adrenergic blocking agents

-PDE5 inhibitors

-alpha-methyldopa

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 checked for symptoms of digoxin overdosage as a

precaution and, if necessary, the glycoside dose should be reduced taking account of the plasma concentration of

digoxin.

Quinidine:

When nifedipine and quinidine have been administered simultaneously, lowered quinidine levels, or after

discontinuation of nifedipine, a distinct increase in plasma concentrations of quinidine, have been observed in

individual cases. For this reason, when nifedipine is either additionally administered or discontinued, monitoring of the

quinidine plasma concentration, and if necessary, adjustment of the quinidine dose are recommended. Some authors

reported increased plasma concentrations of nifedipine upon co-administration of both drugs, while others did not

observe an alteration in the pharmacokinetics of nifedipine.

Therefore the blood pressure should be carefully monitored, if quinidine is added to an existing therapy with nifedipine.

If necessary, the dose of nifedipine should be decreased.

Tacrolimus:

Tacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system. Data recently published 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).

Drugs shown not to interact with nifedipine

The following drugs have been shown to have no effect on the pharmacokinetics of nifedipine when administered

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concomitantly: ajmaline, aspirin, benazepril, candesartan cilexetil, debrisoquine, doxazosin, irbesartan, omeprazole,

orlistat, pantoprazole, ranitidine, rosiglitazone, talinolol and triamterene hydrochlorothiazide.

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

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).

Adalat LA should not be used by women who intend to get pregnant in the near future.

The safety of Adalat LA for use in human pregnancy has not been established.

There are no adequate and well controlled studies in pregnant women.

The available information is inadequate to rule out adverse drug effects on the unborn and newborn child.

In animal studies nifedipine has been shown to produce embryotoxicity, fetotoxicity and teratogenicity (see section 5.3).

Evaluation of experimental animal studies has shown reproductive toxicity consisting of embryotoxicity and

teratogenic effects at maternally toxic doses.

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 has been reported. It is unclear

whether these reports are due to the underlying hypertension, its treatment or to a specific drug effect.

Breast-feeding

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 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, can 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.

4.8 Undesirable effects

Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of

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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 system

disorders

Agranulocytosis

Leukopenia

Immune system

disorders

Allergic reaction

Allergic oedema /

angioedema (incl.

larynx oedema

Pruritus

Urticaria

Rash

Anaphylactic/

anaphylactoid

reaction

Psychiatric

disorders

Anxiety reactions

Sleep disorders

Metabolism and

nutrition

disorders

Hyperglycaemia

Nervous system

disorders

Headache

Vertigo

Migraine

Dizziness

Tremor

Par-/

Dysaesthesia

Hypoaesthesia

Somnolence

Eye disorders

Visual disturbances

Eye pain

Cardiac disorders

Tachycardia

Palpitations

Chest pain (Angina

Pectoris)

Vascular

disorders

Oedema (incl.

peripheral

oedema)

Vasodilatation

Hypotension

Syncope

Respiratory,

thoracic, and

mediastinal

disorders

Nosebleed

Nasal congestion

Dyspnea

Gastrointestinal

disorders

Constipation

Gastrointestinal and

abdominal pain

Nausea

Dyspepsia

Flatulence

Dry mouth

Gingival

hyperplasia

Bezoar

Dysphagia

Intestinal

obstruction

Intestinal ulcer

Vomiting

Gastrooesophageal

sphincter

insufficiency

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= 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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, tachycardiac/bradycardiac heart rhythm

disturbances, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.

Management of Overdose

As far as treatment is concerned, elimination of the active substance and the restoration of stable cardiovascular

conditions have priority.

After oral ingestion, thorough gastric lavage is indicated, if necessary in combination with irrigation of the small

intestine.

Particularly in cases of intoxication with slow-release products like Adalat LA, elimination must be as complete as

possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active

substance.

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

Hepatobiliary

disorders

Transient increase in

liver enzymes

Jaundice

Skin and

subcutaneous

tissue disorders

Erythema

Toxic Epidermal

Necrolysis

Photosensitivity

allergic reaction

Palpable purpura

Musculoskeletal

and connective

tissue disorders

Muscle cramps

Joint swelling

Arthralgia

Myalgia

Renal and urinary

disorders

Polyuria

Dysuria

Reproductive

system and breast

disorders

Erectile dysfunction

General disorders

and

administration

site conditions

Feeling unwell

Unspecific pain

Chills

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% calcium gluconate solution administered slowly I.V. and repeated if necessary). As a result the serum calcium can

reach the upper normal range to slightly elevated levels. 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 solely by the patient's response.

Symptomatic bradycardia may be treated with beta-sympathomimetics, and in life threatening bradycardiac

disturbances of heart rhythm, temporary cardiac pacemaker therapy can be advisable.

Additional liquid or volume must be administered with caution because of the danger of overloading the heart.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 Adalat LA tablet is formulated to achieve controlled delivery of nifedipine in a release

profile sufficient to enable once-daily administration to be effective in clinical use.

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, Adalat LA 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, Adalat LA 30 and 60 (nifedipine GITS) were shown to reduce

cardiovascular and cerebrovascular events to a comparable degree as a standard diuretic combination.

In the multicentre, randomized , placebo-controlled, double-blind ACTION trial with a follow-up of 5 years involving

7665 patients with stable angina pectoris on best practice standard treatment the effects on clinical outcomes of

nifedipine LA vs placebo were investigated.

The primary endpoint for efficacy (combined rate of death from any cause, acute myocardial infarction, refractory

angina, new overt heart failure, debilitating stroke, and peripheral revascularization) did not differ between patients

assigned nifedipine LA (n= 3825) and patients allocated placebo (n= 3840) (P =0.54).

In a predefined subgroup analysis which included 3997 angina patients with hypertension at baseline nifedipine LA led

to a significant 13% reduction of the primary endpoint for efficacy.

Nifedipine LA has been demonstrated to be safe as the primary endpoint for safety (combined rate of death from any

cause, acute myocardial infarction, and debilitating stroke) was similar in both treatment groups (P=0.86).

Nifedipine LA had a positive effect on two of the three predefined secondary endpoints. The combined rate of death,

major cardiovascular events, revascularization, and coronary angiography (CAG) was reduced by 11% (P=0.0012), the

main reason being the pronounced reduction in the need for coronary angiography. There were 150 fewer CAGs as the

first event in the nifedipine group when compared to placebo. Any vascular event was reduced by 9% (P=0.027), the

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main reason being the reduced need for percutaneous coronary interventions and bypass surgery. In total, there were 89

fewer procedures as first events in the nifedipine group compared to placebo. The outcome of the third secondary

endpoint 'major cardiovascular event'

did not show differences between the two treatment groups (P=0.26).

Paediatric populations:

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

General characteristics:

Adalat LA 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 Adalat LA 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.

Absorption

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 Adalat LA tablets ranges from 68-86% relative to Adalat capsules.

Administration in the presence of food slightly alters the early rate of absorption but does not influence the extent of

drug availability.

Distribution

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.

Biotransformation

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. Non-metabolised

nifedipine can be detected only in traces (below 1.0%) in the urine.

Elimination

The terminal elimination half-life is 1.7 to 3.4h in conventional formulations (nifedipine capsules). The terminal

halflife following Adalat LA administration does not represent a meaningful parameter as a plateau-like plasma

concentration is maintained during release from the tablets and absorption.

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, Adalat LA should not be administered in these patients.

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.

Following acute oral and intravenous administration of nifedipine in various animal species, the following LD

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(mg/kg) values were obtained:

In subacute and subchronic toxicity studies in rats and dogs, nifedipine was tolerated without damage at doses of up to

50 mg/kg (rats) and 100 mg/kg (dogs) p.o. over periods of thirteen and four weeks, respectively.

Following

intravenous administration, dogs tolerated up to 0.1 mg/kg nifedipine for six days without damage.

Rats tolerated daily

intravenous administration of 2.5 mg/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 100 mg/kg p.o.

In rats, toxic effects occurred at concentrations above 100 ppm in the feed

(approximately 5-7 mg/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 palate 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 fetotoxic effects, including

stunted fetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal

deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). All

of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic at several

times the recommended maximum dose for humans.

In in vitro and in vivo tests, nifedipine has not beenassociated with mutagenic properties.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet Core

Polyethylene oxide

Hypromellose (5 cp)

Magnesium stearate

Sodium chloride

Ferric oxide, red (E172)

Coating

Cellulose acetate

Macrogol (3350)

Hydroxypropylcellulose

Hypromellose (3 cp)

Propylene glycol

Hypromellose (5 cp)

Titanium dioxide (E171)

Ferric oxide, red (E172)

Mouse:

Oral:

494 (421-572)*;

i.v.:

4.2 (3.8-4.6)*.

Rat:

Oral:

1022 (950-1087)*;

i.v.:

15.5 (13.7-17.5)*.

Rabbit:

Oral:

250-500;

i.v.:

2-3.

Cat:

Oral:

~ 100;

i.v.:

0.5-8.

Dog:

Oral:

> 250;

i.v.:

2-3.

* 95% confidence interval.

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Polish and Print

Black ink for printing Opacode S-1-17823

(Contains: iron oxide black (E172) and Shellac)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

The shelf-life expiry date of this product is the date shown on the container and outer carton of the product on the

market in the country of origin.

6.4 Special precautions for storage

Store in the original container. The tablets should be protected from strong light. Do not store above 30°C.

6.5 Nature and contents of container

Blister packs composed of PP backed with aluminium foil, containing 28 tablets.

6.6 Special precautions for disposal and other handling

No special requirements.

7 PARALLEL PRODUCT AUTHORISATION HOLDER

IMED Healthcare Ltd.

Unit 625 Kilshane Avenue

Northwest Business Park

Ballycoolin

Dublin 15,

Ireland

8 PARALLEL PRODUCT AUTHORISATION NUMBER

PPA1463/058/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 5

April 2012

10 DATE OF REVISION OF THE TEXT

September 2014

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