Consumer medicine information

Adefin 10; Adefin 20

Nifedipine

BRAND INFORMATION

Brand name

Adefin

Active ingredient

Nifedipine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Adefin 10; Adefin 20.

What is in this leaflet

This leaflet answers some common questions about Adefin 10 and Adefin 20 tablets (described below as Adefin tablets).

It does not take the place of talking to your doctor or pharmacist.

This leaflet is for Adefin tablets. It is different from the leaflet for another form of Adefin known as Adefin XL. It is not to be used in relation to any other product, which may also contain the same active ingredient.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Adefin against the benefits expected for you.

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

Keep this leaflet with your medicine. You may need to read it again.

What Adefin is used for

Adefin tablets are used either to treat high blood pressure or to prevent chronic stable angina (chest pain).

Adefin tablets are not used for the relief of a sudden attack of angina or to manage unstable angina. Adefin tablets contain the active substance nifedipine that 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 Adefin have been prescribed for you. Your doctor may have prescribed Adefin for another reason.

Adefin is available only with a doctor's prescription.

Before you take Adefin

When you must not take it

Do not take Adefin if you are allergic to:

  • medicines containing nifedipine (eg. in Adalat, Adefin XL)
  • medicines similar to nifedipine such as amlodipine (Norvasc), felodipine (eg. Plendil, Felodur), lercanidipine (Zanidip), nimodipine (Nimotop)
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • Skin rash, itching or hives
  • Swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • Wheezing or shortness of breath.

Do not take Adefin 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 Adefin if you are taking another medicine containing rifampicin (Rifadin, Rimycin), an antibiotic used to treat tuberculosis and other serious infections.

Do not take Adefin if you are pregnant or plan to become pregnant. It may affect your developing baby if you take it during pregnancy.

Do not take Adefin if you are breastfeeding or plan to breastfeed. Adefin passes into breast milk and may affect your baby.

Do not take Adefin within eight days after a heart attack.

Do not take Adefin after the expiry date (EXP) printed on the pack has passed. If you take this medicine after the expiry date, it may not work as well.

Do not take Adefin if the packaging shows signs of tampering or if the tablets do not look quite right.

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 are allergic to any other medicines, foods, dyes or preservatives.

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

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

Tell your doctor if you plan to have surgery.

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

Adefin 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 Adefin. You should not eat grapefruit or drink grapefruit juice while you are taking Adefin because this can cause unwanted changes in the blood pressure lowering effect of the tablets.

Taking other medicines

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

Some medicines may be affected by Adefin or may affect how well it works. These include:

  • medicines used to treat heart failure, such as digoxin, beta-blockers
  • Other medicines used to treat high blood pressure or angina (chest pain), such as diltiazem, nitrates
  • medicines used to treat arrhythmia (fast or irregular heartbeats), such as quinidine
  • Other medicines used to treat heart disease, eg. digoxin
  • medicines used to treat stomach ulcers and heartburn, such as cimetidine cisapride
  • medicines used to treat tuberculosis, such as rifampicin
  • medicines used to treat bacterial infections, such as quinupristin and dalfopristin
  • medicines used to treat fungal infections, e.g. ketoconazole
  • medicines used to treat HIV, e.g. ritonavir
  • medicines used to treat epilepsy, such as phenytoin, carbamazepine, valproic acid, phenobarbitone
  • anti-depressants, e.g. fluoxetine, nefazodone
  • tacrolimus, used to prevent rejection after organ transplant
  • medicines used to treat asthma, such as theophylline

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Adefin.

How to take Adefin

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist.

How much to take

The dose of Adefin may vary from person to person.

Your doctor will decide the right dose for you. This may depend on your condition, other medicines you are taking and how you respond to Adefin.

The usual dosage is 10 mg to 20 mg twice daily.

If required, your doctor may increase the dose up to 40 mg twice daily. The maximum dose of Adefin is 80 mg (daily).

How to take it

The tablets are to be swallowed with some liquid, with or without food.

When to take it

The tablets are usually taken every 12 hours.

The tablets should generally be taken first thing in the morning, followed by the second dose before going to bed.

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it for

Keep taking Adefin for as long as your doctor recommends. Your doctor will determine how long you should take Adefin tablets.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take Adefin

If you have missed a dose by more than 6 hours, skip the dose you missed and take the next dose when you are meant to.

Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you have missed several doses, consult your doctor.

If you are not sure what to do or have any questions, ask your doctor or pharmacist.

If you take too much Adefin (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Adefin.

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 heartbeats, shortness of breath and even loss of consciousness.

While you are taking Adefin

Things you must do

Take Adefin tablets exactly as prescribed by your doctor. If you do not follow your doctor's instructions, you may not get control of your blood pressure or relief from your angina.

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

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

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Adefin.

The use of Adefin may affect the results of certain laboratory tests or x-rays. If you are about to have any tests or x-rays, tell your doctor that you are taking this medicine.

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

Things you must not do

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.

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

Do not give Adefin to anyone else, even if they have the same symptoms as you.

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 Adefin.

Things to be careful of

Make sure you know how Adefin affects you before you drive a car, operate machinery, or do anything else that could be dangerous. Adefin tablets may cause dizziness or fainting in some people who have low blood pressure, 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 Adefin tablets. 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 taking Adefin. Adefin helps most people with high blood pressure or chronic stable angina. However, like other medicines, they may have unwanted effects in some people.

All medicines have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of these side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

Tell your doctor if you notice any of the following and they worry you:

  • 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 arm, ankles or legs.

The above list includes the more common and mild side effects.

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

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • chest pain
  • signs of an allergic reaction such as skin rash, itching or hives; swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing; wheezing or shortness of breath
  • 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 are very serious side effects. You may need urgent medical attention or hospitalisation.

Very rarely, some people experience a 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 Adefin 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 if you notice anything that is making you feel unwell. This is not a complete list of all possible side effects.

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

After taking Adefin

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack, they will not keep well.

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

Do not store Adefin or any other medicine in the bathroom or near a sink.

Do not leave Adefin in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Adefin where children cannot reach it. 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 Adefin or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Adefin tablets are available in two strengths:

  • Adefin 10 - round, film-coated pink-grey tablets marked with "A 10" on one side.
  • Adefin 20 - round, film-coated pink-grey tablets marked with "1 U" on one side and the Bayer cross on the other.

Each pack contains 60 tablets.

Ingredients

The active ingredient in Adefin is nifedipine.

Each Adefin 10 tablet contains 10 mg of nifedipine.

Each Adefin 20 tablet contains 20 mg of nifedipine.

Adefin 10 and Adefin 20 tablets also contain the following inactive ingredients:

  • cellulose
  • maize starch
  • lactose monohydrate
  • polysorbate 80
  • hypromellose
  • macrogol 4000
  • magnesium stearate
  • iron oxide red (CI77491)
  • titanium dioxide.

Adefin tablets also contain sulfites.

Supplier

Adefin is supplied by:

Alphapharm Pty Limited
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

Adefin 10 - AUST R 92999

Adefin 20 - AUST R 93000

This leaflet was prepared in January 2020.

Adefin_cmi\Nov19/00

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Adefin

Active ingredient

Nifedipine

Schedule

S4

 

1 Name of Medicine

Nifedipine.

6.7 Physicochemical Properties

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

Chemical structure.


CAS number.

21829-25-4.

2 Qualitative and Quantitative Composition

Adefin (nifedipine) 10 or 20 is a calcium ion influx inhibitor (calcium channel blocker or calcium antagonist).
Adefin tablets contain micronised nifedipine 10 mg or 20 mg as the active ingredient.

Excipients with known effect.

Adefin tablets contain trace quantities of lactose and sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Adefin 10.

Pink-grey biconvex lacquered tablets, one side marked "A 10", the reverse side is blank, each containing 10 mg nifedipine.

Adefin 20.

Pink-grey lacquered tablets, one side marked "1 U", the reverse side with the Bayer cross; 6 mm diameter each containing 20 mg nifedipine.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 vasodilatation. 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 is:

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 beta-blockers, nifedipine does not abolish responsiveness of the heart to beta-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 reflux increase in heart rate and thus in the cardiac output. However this increase is not enough to compensate for the vasodilation.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

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%.

Distribution.

Nifedipine is about 95% bound to plasma protein (albumin). Protein binding may be greatly reduced in patients with renal or hepatic impairment.

Metabolism and excretion.

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 twelve 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.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro and in vivo mutagenicity studies were negative.

Carcinogenicity.

Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.3 Contraindications

Known hypersensitivity to nifedipine or any of the excipients.
Pregnancy and during lactation.
Cardiovascular shock.
Within the first 8 days after an acute episode of myocardial infarction.
Concomitant administration with rifampicin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Excessive hypotension.

Nifedipine 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.

Nifedipine 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.

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.

Other.

Adefin contains lactose monohydrate, patients with a rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Adefin.

Other nifedipine formulations.

Adefin XL 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.

Use in hepatic impairment.

Adefin 10 and 20 should be used with caution in patients with mild, moderate or severe impaired liver function (see Section 5 Pharmacological Properties). A dose reduction, may be required (see Section 4.2 Dose and Method of 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 nifedipine are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.

Paediatric use.

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

Effects on laboratory tests.

Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, 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.

4.5 Interactions with Other Medicines and Other Forms of 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, such as:
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 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 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.
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 is weakened. The use of rifampicin in combination with nifedipine is contraindicated.
Upon coadministration of the following weak to moderate inhibitors of CYP3A4 the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see Section 4.2 Dose and Method of 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 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 Section 4.4 Special Warnings and Precautions for Use).

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 phenobarbital (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 carbamazepine or phenobarbital (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;
α-methyldopa.
When nifedipine is administered simultaneously with β-receptor blockers, patients should be carefully monitored since fairly severe hypotension can occur, deterioration of heart failure is also known to develop in isolated cases.

Digoxin.

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 is 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.

Coumarin anticoagulants.

There have been rare reports of increased prothrombin time when nifedipine was administered to patients taking coumarin anticoagulants. However, the relationship to nifedipine therapy is uncertain.

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.

Drug-food interactions.

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.

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.

4.6 Fertility, Pregnancy and Lactation

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.
(Category C)
Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
Nifedipine carries the potential for foetal 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 foetotoxic effects, including stunted foetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and foetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). All of the doses associated with the teratogenic, embryotoxic or foetotoxic 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.
 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.

4.8 Adverse Effects (Undesirable 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 = 6,486; placebo n = 5,326) are listed in Table 1.
The frequencies are defined as: common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100; rare ≥ 1/10,000 to < 1/1000.

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 man. 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 beta-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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage should be individualised depending on severity of disease, patient's tolerance and responsiveness to Adefin (nifedipine) 10 or 20 and to concurrent antihypertensive medications (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Depending on the clinical picture in each case, the basic dose must be introduced gradually.
The recommended initial dose is 10 to 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, Adefin should be discontinued gradually, particularly when high doses are used.
Adefin 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 Adefin 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.7 Effects on Ability to Drive and Use Machines

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

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 (Adefin 10 and Adefin 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 plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution).
Bradycardiac heart rhythm disturbances may be treated symptomatically with β-sympathomimetics, and in life threatening bradycardiac 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/min). If an insufficient increase in blood pressure is achieved with calcium and isoprenaline, vasoconstricting sympathomimetics such as dopamine or noradrenaline (norepinephrine) 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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Adefin tablets also contain the following inactive ingredients: microcrystalline cellulose, polysorbate 80, magnesium stearate, hypromellose, macrogol 4000, titanium dioxide, maize starch, iron oxide red (CI 77491) and lactose monohydrate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Tablets should be stored below 25°C. Avoid freezing.
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.

6.5 Nature and Contents of Container

Adefin 10.

Packed in PVC/PVDC/Al blister strips of 10 tablets in boxes containing 60 tablets.

Adefin 20.

Packed in PVC/PVDC/Al blister strips of 10 tablets in boxes containing 60 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

Summary Table of Changes