Consumer medicine information

ADALAT™ TABLETS

Nifedipine

BRAND INFORMATION

Brand name

Adalat Tablets

Active ingredient

Nifedipine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using ADALAT™ TABLETS.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Adalat tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

This leaflet is for Adalat tablets. It is different from the leaflet for another form of Adalat known as Adalat Oros.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Adalat against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

WHAT ADALAT IS USED FOR

Adalat tablets are used either to treat high blood pressure or to manage a type of angina (chest pain), known as chronic stable angina.

Adalat tablets are not used for the relief of a sudden attack of angina or to manage unstable angina.

Adalat tablets contain the active substance nifedipine which belongs to a group of medicines called calcium channel blockers. They work by opening up blood vessels in the body to lower blood pressure and improve the supply of blood and oxygen to the heart.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

BEFORE YOU TAKE ADALAT

When you must not take it

Do not take Adalat if you have an allergy to:

  • nifedipine, the active ingredient in Adalat
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take Adalat if you are in cardiogenic shock (very low blood pressure due to a failing heart). Tell your doctor if you have had a heart attack in the last week or so.

Do not take Adalat tablets if you are taking another medicine containing the active substance rifampicin, an antibiotic used to treat tuberculosis and other serious infections.

Do not take this medicine if you are pregnant.

It may affect your developing baby if you take it during pregnancy.

Do not breast-feed if you are taking this medicine.

The active ingredient in Adalat passes into breast milk and there is a possibility that your baby may be affected.

Do not take this medicine after the expiry date printed on the pack and blister.

The expiry date is printed on the carton and on each blister after “EXP” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not take this medicine if the packaging is torn or shows signs of tampering.

If the packaging is damaged, return it to your pharmacist for disposal.

Do not take tablets that show visible signs of deterioration (e.g. are broken or discoloured).

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • heart failure
  • other heart or blood vessel disorders
  • low blood pressure
  • stroke
  • mini-stroke (also known as TIA or transient ischaemic attack)
  • liver disease
  • diabetes

If you have not told your doctor about any of the above, tell him/her before you start taking Adalat.

Adalat contains lactose.

If you have been told by your doctor that you have intolerance to some sugars, tell your doctor before taking it.

Tell your doctor if you eat grapefruit or drink grapefruit juice regularly, including in the last 3 days before starting Adalat.

You should not have grapefruit while you are taking Adalat because this can cause unwanted changes in the blood pressure lowering effect of the tablets.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Adalat may interfere with each other. Examples are given below but this is not a complete list. Talk to your doctor or pharmacist if you have any questions.

Medicines to be careful with or avoid while taking Adalat include:

  • beta-blockers, e.g. metoprolol, atenolol
  • other medicines used to treat high blood pressure or angina, e.g. diltiazem
  • medicines used to treat arrhythmia (fast or irregular heartbeats), e.g. quinidine
  • other medicines used to treat heart disease, e.g. digoxin
  • some medicines used to treat stomach ulcers and heartburn, e.g. cimetidine, cisapride
  • rifampicin, used to treat tuberculosis and other serious infections
  • other medicines used to treat bacterial infections, e.g. erythromycin, quinupristin, dalfopristin
  • medicines used to treat fungal infections, e.g. ketoconazole
  • medicines used to treat HIV, e.g. ritonavir
  • medicines used to treat epilepsy, e.g. phenytoin, carbamazepine, valproic acid, phenobarbitone
  • anti-depressants, e.g. fluoxetine, nefazodone
  • tacrolimus, used to prevent rejection after organ transplant

These medicines may be affected by Adalat or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines.

Your doctor or pharmacist has a more complete list of medicines to avoid while taking Adalat.

HOW TO TAKE ADALAT

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions printed on the pharmacist label, ask your doctor or pharmacist for help.

How much to take

The correct dose of Adalat to take has been decided by your doctor. Make sure you follow the instructions given to you by your doctor.

The usual dosage is 10 mg to 20 mg twice daily. Your doctor may increase the dose if required.

How to take it

Swallow the tablets whole with some liquid, either with or without a meal. Do not break or chew the tablets.

When to take it

The tablets are usually taken every 12 hours.

How long to take it

Your doctor will determine how long you should take Adalat tablets. Do not stop taking the tablets unless you are told to do so by your doctor.

If you forget to take it

If you have forgotten to take your Adalat tablet(s) at the right time, take it as soon as you remember, then continue as normal for the next dose. If you do not remember until it is almost time to take your next dose [i.e. within 6 (six) hours of your next dose], then skip the dose that you forgot but be sure to take the next dose when it is due.

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

If you have missed several doses, consult your doctor.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre for advice (Australia: 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too many Adalat tablets. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Signs of an overdose include feeling dizzy and fainting due to drop in blood pressure, irregular or rapid heart beats, shortness of breath, shock and loss of consciousness.

WHILE YOU ARE TAKING ADALAT

Things you must do

Take Adalat tablets exactly as told by your doctor.

If you do not follow your doctor’s instruction, you may not get control of your blood pressure or relief from your angina.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Adalat.

Tell your doctor if you continue to have angina attacks or if they become more frequent while you are taking Adalat tablets.

Tell all doctors, dentists and pharmacists who are treating you that you are taking Adalat tablets.

The use of Adalat may affect the results of certain laboratory tests.

If you are about to have any tests, tell your doctor that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Things you must not do

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use it to treat any other medical conditions unless your doctor tells you to.

Do not eat grapefruit or drink grapefruit juice while you are taking this medicine.

Grapefruit can cause unwanted changes in the blood pressure lowering effect of Adalat.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how Adalat affects you.

Adalat tablets may cause dizziness or fainting in some patients, especially when they first start taking the medicine, change dose, or drink alcohol.

If you have angina, be careful not to overdo physical activities when you first start taking Adalat. You may feel better when you start taking it, but you will need time to improve your physical fitness.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Adalat.

All medicines have side effects. Sometimes they are serious, most of the time they are not. In serious cases, you may need medical attention.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you.

The list below includes the more common side effects of your medicine. They are usually mild and short-lived.

  • headache
  • feeling dizzy
  • fast or irregular heartbeats
  • feeling sick (nausea)
  • flushing
  • constipation
  • generally feeling unwell
  • unusual tiredness or weakness
  • general swelling and/or swelling of the arms, ankles or legs

Your doctor may need to monitor your liver function, as Adalat can increase your liver enzymes. You may not experience any specific symptoms.

If any of the following happen, stop taking Adalat and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • chest pain
  • rash, itching or hives on the skin
  • swelling of the face, lips, tongue, or other parts of the body
  • shortness of breath, wheezing, or trouble breathing
  • signs of liver problems such as yellowing of the skin and/or eyes (jaundice)
  • signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers

These serious side effects are not common. If you have these side effects you may need urgent medical attention.

There have been reports of purple/brown discolouration of the skin or redness, flaking and itching of the skin. Also, it has been reported for some people to develop a rash or blistering of the skin when they are exposed to sunlight.

Tell your doctor if you experience any of these symptoms.

In a small number of cases of in vitro fertilisation, medicines like nifedipine appeared to have interfered with the normal function of sperm. This effect went away after the medicine was stopped. In those men who are taking Adalat tablets and are repeatedly unsuccessful in fathering a child by in vitro fertilisation, the medicine should be considered as one of the possible causes if no other explanation can be found.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

AFTER TAKING ADALAT

Storage

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the pack they may not keep well.

Keep the medicine in a cool dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car.

Heat and damp can destroy some medicines.

Keep the tablets where children cannot reach them.

A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Adalat or the expiry date has passed, ask your pharmacist what to do with any tablets left over.

PRODUCT DESCRIPTION

What it looks like

  • Adalat 10 tablets are round, film-coated tablets in pink-grey colour marked with “A 10” on one side. The tablets are supplied in blister packs of 60’s with each tablet containing 10 mg of nifedipine.
  • Adalat 20 tablets are round, film-coated tablets, pink-grey in colour, marked with “1 U” on one side and the BAYER cross on the reverse. The tablets are supplied in blister packs of 60’s with each tablet containing 20 mg of nifedipine.

Ingredients

Active Ingredient:

  • ADALAT 10 - nifedipine 10 mg
  • ADALAT 20 - nifedipine 20 mg

Inactive ingredients:

  • cellulose
  • maize starch
  • lactose
  • polysorbate 80
  • hypromellose
  • macrogol 4000
  • magnesium stearate
  • iron oxide red
  • titanium dioxide

Supplier

Made in Germany for:
Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Australian Registration Numbers

  • ADALAT 10 mg tablets–
    AUST R 43103
  • ADALAT 20 mg tablets –
    AUST R 18691

Date of preparation

November 2012

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

® Registered Trademark of Bayer AG, Germany

© Bayer Australia Ltd

All rights reserved

BRAND INFORMATION

Brand name

Adalat Tablets

Active ingredient

Nifedipine

Schedule

S4

 

Name of the medicine

Nifedipine.

Excipients.

Microcrystalline cellulose, maize starch, polysorbate 80, magnesium stearate, hypromellose, macrogol 4000, titanium dioxide, iron oxide red (CI 77491) and lactose.

Description

Chemical name: dimethyl-1,4-dihydro-2,6-dimethyl- 4-(2'-nitrophenyl)-3,5-pyridine dicarboxylate. Molecular formula: C17H18N2O6. MW: 346.3. CAS: 21829-25-4. Nifedipine is a yellow crystalline substance practically insoluble in water, and sparingly soluble in absolute ethanol. It is sensitive to light.

Pharmacology

Adalat (nifedipine) 10 or 20 is a calcium ion influx inhibitor (calcium channel blocker or calcium antagonist).

Pharmacokinetics.

After oral administration, the absorption of nifedipine from the tablet is delayed (Tmax 1.5 to 4.2 hours) compared to a liquid capsule formulation (Tmax 0.5 to 2.17 hours). The bioavailability of the tablet is 45 to 56%.
Nifedipine is about 95% bound to plasma protein (albumin). Protein binding may be greatly reduced in patients with renal or hepatic impairment.
Nifedipine is almost completely metabolised in the body with only traces detected in the urine in an unchanged form. 70 to 80% of the dose is excreted via the kidneys in the form of highly water soluble pharmacologically inactive metabolites. The remainder is excreted in the faeces, also in a metabolised form. The half-life of an immediate release dose form shows a mean of approximately 1.7 to 3.4 hours. Administration of the tablet results in a half-life of about 6 to 12 hours. (Continuing absorption of residual nifedipine from the gastrointestinal tract probably contributes to the prolonged half-life observed.)
The pharmacological action of nifedipine persists for up to 12 hours after administration of the tablet.
In cases of impaired liver function, the elimination half-life is distinctly prolonged and the total clearance is reduced. A dose reduction may be necessary in severe cases.

Pharmacological actions.

Cardioprotective coronary treatment.

The contractile processes of vascular smooth muscle and cardiac muscle are dependent upon calcium ions. Calcium ions enter these cells during depolarisation as slow ionic transmembrane currents. Nifedipine specifically inhibits slow inward calcium ion channels without changing serum calcium concentrations. In so doing, two distinct beneficial effects are produced which reduce anginal pain in individuals with ischaemic heart disease.

Nifedipine improves myocardial oxygen supply.

Nifedipine is a potent relaxant of arterial smooth muscle. It dilates main coronary arteries and arterioles both in normal and in ischaemic myocardial regions without inducing a steal phenomenon. Nifedipine is also a potent inhibitor of coronary artery spasm. These effects increase myocardial oxygen delivery at rest and during exercise in patients with chronic stable angina, and in patients with episodes of coronary artery spasm.

Nifedipine reduces myocardial work through afterload reduction.

As with myocardial cell contraction, regulation of the contraction of vascular smooth muscle is also dependent upon intracellular calcium ion concentration. By reducing the influx of calcium ions into vascular smooth muscle, nifedipine causes relaxation and peripheral vasodilation. Peripheral vasodilatation reduces the impedance (afterload) against which the heart works. This unloading of the heart indirectly reduces myocardial energy consumption and oxygen requirements. Ventricular emptying is also facilitated by the reduction in impedance.
A third possible effect seen experimentally follows.

Nifedipine directly decreases myocardial oxygen consumption.

During myocardial fibre depolarisation, elevation of intracellular calcium ion concentration triggers the contractile process and increases the amount of adenosine-5'-triphosphate (ATP) hydrolysed.
By inhibiting the transmembrane flux of calcium that enters myocardial cells and hence decreasing intracellular calcium concentration, nifedipine reduces the amount of ATP hydrolysed and thereby decreases the amount of oxygen consumed by the heart. The clinical significance of this effect is as yet undecided. Unlike β-blockers, nifedipine does not abolish responsiveness of the heart to β-adrenergic stimulation.

Antihypertensive effect.

Nifedipine reduces the smooth muscle tone of the arterioles, thus lowering the increased peripheral resistance and consequently the blood pressure. At the beginning of the nifedipine treatment there may be a transient reflex increase in heart rate and thus in the cardiac output. However, this increase is not enough to compensate for the vasodilatation.

Indications

Adalat 10 and 20 are indicated for: management of chronic stable angina pectoris and vasospastic angina pectoris (Prinzmetal angina, variant angina) due to coronary heart disease; treatment of hypertension.

Contraindications

Known hypersensitivity to nifedipine or any of the excipients.
Pregnancy and during lactation.
Cardiovascular shock.
Within the first eight days after an acute episode of myocardial infarction.
Concomitant administration with rifampicin (see Interactions with Other Medicines).

Precautions

Excessive hypotension.

Adalat may be used in combination with beta-blocking medicines and other antihypertensive agents, but the possibility of potentiation of existing antihypertensive therapy should be noted. Care must also be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mmHg), in cases of manifest heart failure and in the case of severe aortic stenosis.

Increased angina.

As with other vasoactive substances, angina pectoris attacks may very rarely occur at the start of the treatment with nifedipine. The occurrence of myocardial infarction has been described in isolated cases, although it was not possible to distinguish this from the natural course of the underlying disease.

Beta-blocker withdrawal.

When nifedipine is administered simultaneously with beta-blockers the patient should be carefully monitored, since deterioration of heart failure may develop in isolated cases.
Nifedipine has no inherent antiarrhythmic action and therefore gives no protection against any arrhythmias which may result from abrupt withdrawal of beta-blockers. Any such withdrawal of beta-blockers should be gradual over a period of several days.

Congestive heart failure.

The onset of cardiac insufficiency has occasionally been observed during clinical use. Care should be observed with patients whose cardiac reserve is poor, or who are receiving large doses of beta-blockers.

Outflow obstruction.

Adalat should be used with caution in the presence of fixed left ventricular outflow obstruction.

Peripheral oedema.

Mild to moderate peripheral oedema typically associated with arterial vasodilatation and not due to left ventricular dysfunction occurs in one in ten patients treated with nifedipine. This oedema occurs primarily in the lower extremities and usually responds to diuretic therapy.

Other.

Adalat contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/ galactose malabsorption should not take Adalat.

Other nifedipine formulations.

Adalat Oros modified release tablets are not bioequivalent to immediate release nifedipine capsules and tablets and patients should be carefully monitored if it is decided to switch between immediate release and modified release nifedipine or vice versa.

Effects on 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.

Use in pregnancy.

(Category C)
Nifedipine carries the potential for fetal hypoxia, caesarean deliveries, prematurity and intrauterine growth retardation, which may be associated with maternal hypotension. Accordingly, it is contraindicated throughout pregnancy.
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 are possibly a result of compromised uterine blood flow. 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 and several times the recommended maximum dose for humans. There are no adequate and well controlled studies in pregnant women.

Use in lactation.

Nifedipine passes into breast milk. Insufficient evidence is available to determine whether effects of nifedipine occur in infants. Breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period.

Paediatric use.

The safety and efficacy of Adalat in children below 18 years has not been established.

Use in patients with impaired liver function.

Adalat 10 and 20 should be used with caution in patients with mild, moderate or severe impaired liver function (see Pharmacology). A dose reduction may be required (see Dosage and Administration). Close monitoring of response and metabolic effect should apply. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment. Therefore, nifedipine should be used with caution in patients with severe hepatic impairment.

Use in the elderly.

The pharmacokinetics of Adalat are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.

Use in diabetes.

A possible interference with glucose induced insulin release should be taken into account when treating diabetic patients with nifedipine but based on extensive experience it is probably more accurate to conclude that nifedipine has no true diabetogenic potential.

Carcinogenicity/ mutagenicity.

Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. In vitro and in vivo mutagenicity studies were negative.

Effect on ability to drive and use machines.

Reactions to medicine, 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 the treatment, on changing the medication and in combination with alcohol.

Interactions

Nifedipine is metabolised via cytochrome P450 3A4 (CYP3A4), located in the intestinal mucosa and the liver. Medicines that are known to inhibit or induce CYP3A4 may therefore alter the first-pass or the clearance of nifedipine.
Drugs, which are inhibitors of CYP3A4 and therefore may lead to increased plasma concentrations of nifedipine, are, e.g. 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 and cimetidine.
Upon coadministration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.

Drugs that affect nifedipine.

Nifedipine is metabolised via CYP3A4, located in the intestinal mucosa and the liver. Medicines that are known to inhibit or induce CYP3A4 may therefore alter the first pass 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 CYP3A4. Upon coadministration 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.
Upon coadministration of the following weak to moderate inhibitors of CYP3A4, blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see Dosage and Administration).

Macrolide antibiotics (e.g. erythromycin).

No interaction studies have been carried out between nifedipine and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit CYP3A4 mediated metabolism of other medicines, and could increase plasma concentrations of nifedipine if administered concomitantly.
Azithromycin, although structurally related to the class of macrolide antibiotics does not inhibit CYP3A4.

Anti-HIV protease inhibitors.

A clinical study investigating the potential interaction between nifedipine and certain anti-HIV protease inhibitors has not yet been performed. Medicines of this class are known to inhibit the CYP3A4. In addition, drugs of this class have been shown to inhibit in vitro the CYP3A4 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 decreased elimination cannot be excluded.

Azole antimycotics (e.g. ketoconazole).

A formal interaction study investigating the potential of a drug interaction between nifedipine and these medicines has not yet been performed. These medicines are known to inhibit CYP3A4. When administered orally with nifedipine, a substantial increase in systemic bioavailability of nifedipine due to a decreased first pass metabolism cannot be excluded.

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 CYP3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma concentrations upon coadministration of both medicines cannot be excluded (see Precautions).

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 CYP3A4 mediated metabolism of other medicines. Therefore an increase of nifedipine plasma concentrations upon coadministration of both medicines cannot be excluded.

Quinupristin/ dalfopristin.

Simultaneous administration of quinupristin/ dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine, with the effect varying markedly between individuals.

Valproic acid.

No formal studies have been performed to investigate the interaction of nifedipine with valproic acid, but it has been shown to increase the plasma concentrations of another dihydropyridine calcium channel blocker (nimodipine) through enzyme inhibition. Therefore an increase in the plasma concentrations of nifedipine is possible which may mean that an adjustment in the dosage of nifedipine may be required.

Cimetidine.

Elevation of plasma nifedipine levels during cimetidine administration has been reported. It is suggested that patients taking both nifedipine and cimetidine should be carefully monitored. In case of hypotension, the dosage of nifedipine should be reduced or the patient should be treated with ranitidine, as the interaction with this medicine and nifedipine is less pronounced.

Diltiazem.

Diltiazem decreases the clearance of nifedipine and, hence, increases plasma nifedipine levels. Therefore caution should be exercised when the two medicines are used concomitantly and a reduction in the dose of nifedipine may be necessary.

Further studies.

Cisapride.

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

CYP3A4 inducing antiepileptic drugs such as phenytoin, carbamazepine and phenobarbitone.

Phenytoin induces CYP3A4. Coadministration of phenytoin with nifedipine reduces the bioavailability of nifedipine. When both medicines are concomitantly administered, the clinical response to nifedipine should be monitored and an increase in the nifedipine dose considered, if necessary. If the dose of nifedipine is increased during coadministration of both medicines, a reduction of the nifedipine dose should be considered when phenytoin is discontinued. No formal studies have been performed to investigate the potential interaction between nifedipine and carbamazeipine or phenobarbitone. As both drugs have been shown to reduce the plasma concentrations of the structurally similar calcium channel blocker, nimodipine, through 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, β-blockers, ACE inhibitors, angiotensin I (ATI) receptor antagonists, other calcium antagonists, α-adrenergic blocking agents, PDE5 inhibitors and α-methyldopa.
When nifedipine is administered simultaneously with β-receptor blockers, the patient should be carefully monitored, since fairly severe hypotension can occur; deterioration of heart failure is also known to develop in isolated cases.

Digoxin.

The simultaneous administration of nifedipine and digoxin can lead to reduced digoxin clearance and hence an increase in the plasma digoxin level. The patient should therefore be checked for symptoms of digoxin overdose as a precaution and, if necessary, the glycoside dose should be reduced taking account of the plasma digoxin concentration.

Quinidine.

When nifedipine and quinidine have been administered simultaneously, lowered quinidine levels or, after discontinuation of nifedipine, a distinct increase in the plasma quinidine level have been observed in individual cases. For this reason, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine concentration and, if necessary, adjustment of the dose are recommended. Some authors reported increased plasma levels of nifedipine upon coadministration of both medicines, while others did not observe an alteration in the pharmacokinetics of nifedipine. Therefore, if quinidine is added to existing nifedipine therapy, blood pressure should be monitored, and if necessary the dose of nifedipine should be reduced.

Tacrolimus.

Tacrolimus is metabolised by CYP3A4. Published data indicate that the dose of nifedipine administered simultaneously with tacrolimus may be reduced in individual cases. Upon coadministration of both medicines, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose should be considered.

Drug-food interactions.

Grapefruit.

Concomitant intake of grapefruit juice inhibits the oxidative metabolism of nifedipine resulting in increased plasma concentration which may cause an increased blood pressure lowering effect. After regular intake of grapefruit juice this effect may last for at least 3 days after the last ingestion of grapefruit juice.
Ingestion of grapefruit/ grapefruit juice is therefore to be avoided while taking nifedipine.

Interactions shown not to exist.

In drug interaction studies, aspirin, omeprazole, pantoprazole, ranitidine, and cerivastatin did not have clinically significant effects on the pharmacokinetics of nifedipine. Nifedipine did not have clinically significant effects on the pharmacokinetics of cerivastatin, or on the effect of 100 mg aspirin on platelet aggregation and bleeding time.

Candesartan cilexetil, irbesartan, doxazosin.

The blood pressure lowering effect of these agents may be potentiated by coadministration with nifedipine, so caution should be used in initiating combination therapy. Concomitant administration of irbesartan or doxazosin and nifedipine has no effect on the pharmacokinetics of nifedipine, and concomitant administration of candesartan cilexetil and nifedipine has no effect on the pharmacokinetics of either medicine.

Others.

Case reports of increased plasma theophylline concentrations due to nifedipine administration have been reported. Nifedipine has also been reported to have a potentiating effect on terbutaline and salbutamol induced bronchodilation in asthmatics.

Other forms of interactions.

Nifedipine may cause falsely increased spectrophotometric values of urinary vanillylmandelic acid. However, measurement with HPLC is unaffected.

Effect on laboratory tests.

Rare, usually transient, but occasionally significant elevations of enzymes such as AP, CPK, LDH, AST (SGOT) and ALT (SGPT) have been noted. The relationship to nifedipine therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms; however, cholestasis with or without jaundice has been reported. Rare instances of allergic hepatitis have been reported.
Nifedipine like other calcium channel blockers, decreases platelet aggregation in vitro. Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and increase in bleeding time in nifedipine treated patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated.

Adverse Effects

Adverse drug reactions (ADRs) listed under common were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%). ADR is defined as a response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man. Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility.
Adverse drug reactions (ADRs) based on placebo controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial database: nifedipine n = 6486; placebo n = 5326) are listed below. The frequencies are defined as: common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100; rare ≥ 1/10000 to < 1/1000 (see Table 1).

Serious or life threatening reactions.

Anaphylactic reactions have occurred with other formulations of nifedipine.
In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation.
The medicine has, like other members of its class, negative inotropic effects on isolated myocardial tissue. Such effects have not been seen in studies in intact animals or in humans. Nevertheless, it may theoretically precipitate cardiac failure. Aggravation of cardiac insufficiency has occasionally been reported in patients with compromised cardiac function or when nifedipine is given in combination with β-blockers.
Acute pulmonary oedema precipitated by nifedipine in a patient with fixed outflow obstruction has been reported. Care should therefore be taken with patients whose cardiac reserve is poor.

Postmarketing experience.

A small number of events identified during ongoing postmarketing surveillance associated with nifedipine for which a frequency could not be estimated are listed in Table 2.

Dosage and Administration

Dosage should be individualised depending on severity of disease, patient's tolerance and responsiveness to Adalat (nifedipine) 10 or 20 and to concurrent antihypertensive medications (see Interactions with Other Medicines).
Depending on the clinical picture in each case, the basic dose must be introduced gradually.
The recommended initial dose is 10-20 mg twice daily swallowed with a little fluid, with or without food. The tablets must not be chewed or broken up. Grapefruit juice is to be avoided. The usual adult dose is 20 mg twice daily. If required, the dose may be increased up to 40 mg twice daily. The maximum daily dose of 80 mg should not be exceeded. The recommended dose interval is about 12 hours.
Due to its pronounced anti-ischaemic and antihypertensive action, Adalat should be discontinued gradually, particularly when high doses are used.
Adalat 10 tablets permit dosage titration. Dose titration is particularly recommended for patients with severe cerebrovascular disease or patients of low bodyweight, on multiple therapies with other antihypertensive medicines, or for whom adverse reactions would occur at the higher initial dose. These patients are likely to have an excessive reaction to nifedipine. In addition, a finer dose adjustment is desirable in patients who experience side effects in response to the nifedipine treatment and should be individually stabilised with Adalat 10 tablets. Patients with hepatic dysfunction should commence therapy at 10 mg twice daily with careful monitoring.
Coadministration with CYP3A4 inhibitors or inducers may require nifedipine dose adjustment or for nifedipine not to be used at all (see Interactions with Other Medicines).

Overdosage

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, tachycardic/ bradycardic 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 (Adalat 10 and Adalat 20), 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 plasmaphaeresis is advisable (high plasma protein binding, relatively low volume of distribution).
Bradycardic heart rhythm disturbances may be treated symptomatically with β-sympathomimetics, and in life threatening bradycardic disturbances of heart rhythm, temporary pacemaker therapy may be advisable.
Hypotension, as a result of cardiogenic shock and arterial vasodilatation, can be treated with calcium (10 to 20 mL of a 10% calcium gluconate solution administered slowly intravenously and repeated if necessary). As a result, the serum calcium can reach the upper normal range to slightly elevated levels. If the effects are inadequate, the treatment can be continued with ECG monitoring and additional β-sympathomimetics if necessary (e.g. isoprenaline 0.2 mg slowly intravenously as a continuous infusion of 5 microgram/minute). If an insufficient increase in blood pressure is achieved with calcium and isoprenaline, vasoconstricting sympathomimetics such as dopamine or noradrenaline are additionally administered. The dosage of these medicines is determined solely by the effect obtained.
Additional liquid or volume must be administered with caution because of the danger of overloading the heart.
Contact Poisons Information Centre 131 126 for advice on management.

Presentation

Tablets (pink grey, round, biconvex, film coated), 10 mg (marked A10 on one side), 20 mg (marked 1U on one side, Bayer cross on reverse): 20's*, 60's (red blister strips of 10 tablets in box, PVC/Al blister pack*; PVC/PVDC/Al blister pack*; PP/Al blister pack).
*Not currently marketed in Australia.

Storage

Nifedipine is highly light sensitive. The tablets should be protected from light and should be stored in the manufacturer's original container. Tablets must only be removed from the packaging immediately before use. Broken tablets should not be used. Tablets should be stored below 25°C. Avoid freezing.

Poison Schedule

S4.