Consumer medicine information

Adefin XL

Nifedipine

BRAND INFORMATION

Brand name

Adefin XL

Active ingredient

Nifedipine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Adefin XL.

What is in this leaflet

This leaflet answers some common questions about ADEFIN XL 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 ADEFIN XL. It is different from the leaflet for other forms of ADEFIN products.

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 XL against the benefits expected for you.

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

Please read this leaflet carefully and keep it with your medicine. You may need to read it again.

What ADEFIN XL is used for

ADEFIN XL is used to:

  • treat high blood pressure
  • prevent chronic stable angina, a type of angina (chest pain).

ADEFIN XL is not used to relieve sudden attacks of angina or to manage unstable angina.

ADEFIN XL contains the active ingredient nifedipine which belongs to a group of medicines called calcium channel blockers.

Calcium channel blockers work by opening up blood vessels in the body to lower blood pressure and improve the supply of blood and oxygen to the heart.

ADEFIN XL tablets are specially designed with a strong outer shell. This outer shell allows the medicine to be released slowly into the body over a longer period of time after it is taken. The outer shell is excreted or passed out in the faeces (or bowel motions), as it does not dissolve in the body. Therefore, it is normal to find a "tablet-like" object in the faeces. The active substance contained in them has been absorbed by the body before excretion.

Ask your doctor if you have any questions about why ADEFIN XL has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is only available with a doctor's prescription.

Before you take ADEFIN XL

When you must not take it

Do not take ADEFIN XL if you are allergic to:

  • medicines containing nifedipine (eg. in Adefin XL, Adefin)
  • medicines similar to nifedipine such as amlodipine (Norvasc), felodipine (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 XL if you are in cardiogenic shock (very low blood pressure due to a failing heart). Symptoms of cardiogenic shock include rapid, shallow breathing, cold, clammy skin, a rapid, weak pulse, dizziness, weakness and fainting.

Do not take ADEFIN XL if you have had a heart attack in the last week or so.

Do not take ADEFIN XL if you have a Kock Pouch or ileostomy (a surgically created reservoir in the small intestine).

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

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

Do not take ADEFIN XL 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 XL if the packaging shows signs of tampering or the tablets are broken, discoloured or show any other sign of deterioration.

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 medical conditions, especially the following:

  • heart failure
  • other heart or blood vessel disorders
  • low blood pressure
  • stroke
  • mini-stroke (also known as TIA or transient ischaemic attack)
  • liver problems
  • diabetes
  • blockage of the oesophagus or intestines, e.g. due to previous injury, infection or surgery
  • prolonged diarrhoea (e.g. Crohn's disease or ulcerative colitis)
  • narrowing of the aorta
  • kidney disease
  • any surgical operations carried out on your bowel.

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

Tell your doctor if you eat grapefruit or drink grapefruit juice regularly, including in the last 3 days before starting ADEFIN XL. You should not have grapefruit juice while you are taking ADEFIN XL 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 can buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by ADEFIN XL or may affect how it works. These 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

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 XL.

How to take ADEFIN XL

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

Do not remove tablets from the blister pack until you are ready to take them.

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

How much to take

The dose varies from person to person.

Your doctor will decide the right dose for you.

This may depend on your condition, age, other medicines you are taking and how you respond to ADEFIN XL.

For the treatment of high blood pressure, the dose range is between 20 mg to 120 mg once daily.

For the treatment of chronic stable angina, the dose range is between 30 mg to 90 mg once daily.

Elderly people over 65 years of age and people with liver problems may require lower doses.

How to take it

Immediately after removing a tablet from the blister pack, swallow ADEFIN XL tablets whole with some water.

ADEFIN XL tablets must not be chewed, halved or broken up. Your chances of getting unwanted side effects are increased if you chew or break the tablets. ADEFIN XL tablets are specially designed with a strong outer shell, which allows the medicine to be released slowly into the body.

When to take it

Take ADEFIN XL once a day, about the same time each day. The tablets should generally be taken in the morning.

ADEFIN XL can be taken either with or without a meal.

How long to take it

Keep taking ADEFIN XL for as long as your doctor recommends. 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 forgot to take it

If you forget to take your daily dose of ADEFIN XL at the right time and remember in less than 12 hours, take it straight away, then continue as normal the next day.

Otherwise, skip that day's dose but be sure to take the next day's dose when it is due. Do not take a double dose to make up for the dose 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, check with your doctor or pharmacist.

If you have trouble remembering to take your ADEFIN XL, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 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 much ADEFIN XL.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Signs of an overdose include dizziness and fainting due to a drop in blood pressure; irregular or rapid heartbeats; shortness of breath and even loss of consciousness.

While you are taking ADEFIN XL

Things you must do

Take ADEFIN XL exactly as prescribed by your doctor.

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

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

Tell all doctors, dentists and pharmacists who are treating you that you are taking ADEFIN XL.

If you are about to have any blood tests or x-rays, tell your doctor that you are taking ADEFIN XL. It may interfere with the results of some tests.

If you become pregnant while taking ADEFIN XL, tell your doctor immediately. It may affect your developing baby if you take it during pregnancy.

Things you must not do

Do not take ADEFIN XL to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if they have the same symptoms or condition as you.

Do not eat grapefruit or drink grapefruit juice while you are taking this medicine. Grapefruit can cause unwanted changed in the blood pressure lowering effect of ADEFIN XL.

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

Make sure you know how ADEFIN XL affects you before driving a car, operating machinery, or do anything else that could be dangerous. ADEFIN XL may cause dizziness or fainting in some people, 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 XL. 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 ADEFIN XL. ADEFIN XL helps most people, but it 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 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:

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

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

Your doctor may need to monitor your liver function, as ADEFIN XL can increase your liver enzymes.

You may not experience any specific symptoms.

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

  • chest pain
  • signs of an allergic reaction such as 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 are very serious side effects. If you have these 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 that some people develop a rash or blistering of the skin when they are exposed to sunlight. Tell your doctor if you experience any of these symptoms.

Very rarely, the undissolved tablet shell may not pass out in the faeces and collect in the stomach. Tell your doctor if you experience symptoms of bowel blockage. Surgical intervention may be necessary to remove these shells.

In a small number of cases of in vitro fertilization, medicines like nifedipine may have interfered with the normal function of sperm. This effect went away after the medicine was stopped. In those men who are taking Adefin XL and are repeatedly unsuccessful in fathering a child by in vitro fertilization, 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 else that is making you feel unwell. Other side effects not listed above may also occur in some people.

After taking ADEFIN XL

Storage

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

Heat and moisture can affect ADEFIN XL tablets. Contact with moisture can release the active ingredient (nifedipine) from the tablets. To prevent this, the tablets must be kept in the original pack until immediately before use.

Keep your tablets in a cool dry place, away from sunlight where the temperature stays below 30°C (ADEFIN XL 30) or below 25°C (ADEFIN XL 60).

Do not leave ADEFIN XL in the car or on window sills.

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

Keep ADEFIN XL 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 XL, 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 XL is available in two strengths:

  • ADEFIN XL 30 - round, pink coloured tablet, with "30" printed in black on one side and blank on the other side.
  • ADEFIN XL 60 - round, pink coloured tablet, with "60" printed in black on one side and blank on the other side.

Each pack contains 30 tablets.

Ingredients

The active ingredient in ADEFIN XL is nifedipine.

  • Each ADEFIN XL 30 tablet contains 30 mg of nifedipine.
  • Each ADEFIN XL 60 tablet contains 60 mg nifedipine.

ADEFIN XL also contains the following inactive ingredients:

  • polyethylene oxide
  • magnesium stearate
  • hypromellose
  • iron oxide red CI77491 (E172)
  • hydroxypropylcellulose
  • cellulose acetate
  • macrogol 3350
  • titanium dioxide (171)
  • propylene glycol
  • sodium chloride

Supplier

ADEFIN XL 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 XL 30 - AUST R 91779

ADEFIN XL 60 - AUST R 91778

This leaflet was prepared in January 2020.

Adefin XL_cmi\Nov19/00

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Adefin XL

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-pyridinedicarboxylate.
Molecular formula: C17H18N2O6. Molecular Weight: 346.3.

Chemical structure.


CAS number.

21829-25-4.
Nifedipine is a yellow crystalline substance practically insoluble in water, and sparingly soluble in absolute ethanol. It is sensitive to light.

2 Qualitative and Quantitative Composition

Adefin XL tablets are a controlled release formulation (GITS, GastroIntestinal Therapeutic System) containing nifedipine USP 30 mg or 60 mg as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Adefin XL 30.

Round, biconvex, rose-pink, film-coated tablet with "30" printed in black on one side, the tablet diameter being 9 mm.

Adefin XL 60.

Round, biconvex, rose-pink, film-coated tablet with "60" printed in black on one side, the tablet diameter being 11 mm.
Adefin XL tablets are similar in appearance to conventional tablets. Each tablet consists of a semipermeable membrane surrounding an osmotically active core. The core itself is divided into two layers: an "active" layer containing nifedipine, and a "push" layer containing pharmacologically inert but osmotically active components. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and "pushes" against the nifedipine layer, releasing nifedipine through a precision laser drilled tablet orifice in the "active" layer. The coating of Adefin XL remains intact during the gastrointestinal passage and is eliminated in the faeces.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nifedipine is a calcium ion influx inhibitor (calcium channel blocker or calcium antagonist) which inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The contractile processes of these tissues are dependent upon the movement of extracellular calcium into the muscle cells through specific ion channels. Nifedipine selectively inhibits the transmembrane influx of calcium through the slow channel without affecting the transmembrane influx of sodium through the fast channel to any significant degree. This results in a reduction of free calcium ions available within the muscle cells and an inhibition of the contractile process. Nifedipine does not affect total serum calcium. The specific mechanisms by which nifedipine relieves angina and reduces blood pressure have not been fully determined but are believed to be brought about largely by its vasodilatory action.

Hypertension.

The mechanisms by which nifedipine reduces arterial blood pressure involve peripheral arterial vasodilatation and the resulting reduction in peripheral vascular resistance. The increased peripheral resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle. Studies have demonstrated that the increase in acute tension reflects an increase in free calcium in the cytosol.
The binding of nifedipine to voltage dependent and possibly receptor operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels. The reduction in calcium influx by nifedipine causes arterial vasodilatation and decreased peripheral vascular resistance which results in reduced arterial blood pressure.

Angina.

The precise mechanism by which inhibition of calcium influx relieves angina has not been fully determined. Some of the possible mechanisms include vasodilatation and reduction of oxygen utilisation.
Nifedipine dilates the main coronary arteries and coronary arterioles, both in normal and ischaemic regions, resulting in an increase in blood flow and hence in myocardial oxygen delivery in patients with coronary artery spasm.
Nifedipine reduces arterial blood pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral vascular resistance (afterload) against which the heart works. This unloading of the heart reduces myocardial energy consumption and oxygen requirements, and probably accounts for the effectiveness of nifedipine in chronic stable angina.

Clinical trials.

The pivotal clinical studies were performed in patients with chronic stable angina. In these studies, Adefin XL at doses of 30 mg and 60 mg once daily improved exercise tolerance test (ETT) parameters in reference to baseline. Adefin XL 30 mg daily showed small but suboptimal benefit. When titrated to the dose of 60 mg once daily, Adefin XL was as effective as atenolol 100 mg once daily. In patients already on beta-blocker therapy, Adefin XL improved ETT parameters and time to 1 mm ST depression, and at doses of up to 90 mg once daily, Adefin XL was more effective than modified release nitrates (isosorbide mononitrate 50 mg once daily, isosorbide dinitrate 20 to 40 mg twice daily). However in this particular study, ETT performance was measured at 22 to 24 hours after the last dose of Adefin XL and isosorbide mononitrate, and about 15 hours after last dose of isosorbide dinitrate. Therefore, the higher efficacy observed for Adefin XL may be attributable to the difference in pharmacokinetics between Adefin XL and nitrates. In pivotal and supportive clinical studies, the duration of treatment with Adefin XL was limited to 2 to 12 weeks only, and the majority of patients in these studies were already on background beta-blocker therapy. Data in patients with unstable angina, asymptomatic ischaemia, vasospastic angina and postmyocardial infarction are limited. Data on monotherapy with Adefin XL are limited and based on trials of short duration (≤ 4 weeks).

5.2 Pharmacokinetic Properties

Absorption and distribution.

Nifedipine is almost completely absorbed after oral administration. Plasma drug concentrations rise at a gradual, controlled rate exhibiting zero order absorption kinetics after Adefin XL administration and reach a plateau at approximately six hours after the first dose. For subsequent doses, relatively constant plasma concentrations at this plateau are maintained with minimal fluctuations over the 24 hour dosing interval. At steady-state, the bioavailability of Adefin XL is 86% relative to an immediate release dosage form which has a systemic availability of 45 to 68%. Administration of Adefin XL in the presence of food slightly alters the early rate of drug absorption, but does not influence the extent of drug bioavailability. Markedly reduced gastrointestinal retention times over prolonged periods (i.e. short bowel syndrome) may, however, influence the pharmacokinetic profile of the medicine, which could result in lower plasma concentrations. Pharmacokinetics of Adefin XL are linear over the dose range of 30 to 180 mg in that plasma concentrations are proportional to dose administered. There is no evidence of dose dumping either in the presence or absence of food.
Nifedipine is about 95% bound to plasma protein (albumin).

Metabolism and excretion.

The active substance nifedipine is almost completely metabolised in the liver, primarily by oxidative processes (the cytochrome P450 enzyme CYP3A4). Some metabolic activity within the gut wall may also contribute to the presystematic metabolism. These metabolites show no pharmacodynamic activity. The main metabolite (95%) is the hydroxycarbolic acid derivative; the remaining 5% is the corresponding lactone.
Nifedipine is excreted in the form of its metabolites predominantly via the kidneys (60 to 80%) and about 5 to 15% via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1%) in the urine.
The terminal elimination half-life is 1.7 to 3.4 hours in an immediate release formulation. In cases of impaired kidney function, no substantial changes have been detected in comparison with healthy volunteers.
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.
Patients on haemodialysis or chronic ambulatory peritoneal dialysis have not reported significantly altered pharmacokinetics of nifedipine.
Some published studies have reported slower elimination of nifedipine in different ethnic groups (e.g. Mexican, Japanese and South Asians). Currently, confirmatory studies only exist for the South Asian population. In comparison to Caucasians, there were increases in AUC due to a decrease in the activity of cytochrome P450 (IIIA), while increases in Cmax were less pronounced. Elimination half-lives of both nifedipine and its pyridine metabolite were prolonged by approximately twofold. Although haemodynamic responses in the South Asian healthy volunteers were similar to those reported in Caucasians, lower doses of nifedipine may be required in South Asian patients at the beginning of Adefin XL therapy.

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 XL is indicated for:
1. The treatment of mild to moderate hypertension.
2. The prophylaxis of chronic stable angina pectoris.

4.3 Contraindications

Adefin XL is contraindicated in:
patients with known hypersensitivity to nifedipine or related dihydropyridine calcium channel blockers or to any of the excipients;
female patients throughout pregnancy;
breastfeeding;
patients with cardiogenic shock;
patients with a Kock pouch (ileostomy after proctocolectomy);
patients being administered rifampicin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
patients within the first 8 days of an acute episode of myocardial infarction.

4.4 Special Warnings and Precautions for Use

Excessive hypotension.

Caution should be exercised in patients with severe hypotension (systolic pressure < 90 mmHg) as there is a risk of further reduction in blood pressure.
Adefin XL 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.

Increased angina and/or myocardial infarction.

Rare cases of increased frequency, duration and/or severity of angina or acute myocardial infarction on starting nifedipine or at the time of dosage increase have been reported. These well documented cases are mainly in those patients who have severe obstructive coronary artery disease. The mechanism of this effect is not established.

Chest pain.

There have been a small number of reports of chest pain not associated with myocardial infarction (in certain circumstances, angina pectoris-like symptoms) occurring soon after administration of a single dose. In this case, Adefin XL should be withdrawn if a causal relationship is suspected.

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.
Adefin XL 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 achieved gradually over a period of several days.

Congestive heart failure.

The onset of heart failure 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.

Peripheral oedema.

Mild to moderate peripheral oedema occurs in a dose dependent manner with an incidence ranging from approximately 10% on 30 mg to about 33% on Adefin XL 120 mg daily. This is due to arteriolar vasodilatation and is not due to heart failure. With patients whose hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral oedema from the effects of increasing left ventricular dysfunction.

Hypotension/heart rate.

Because Adefin XL (nifedipine) is an arterial and arteriolar vasodilator, hypotension and a compensatory increase in heart rate may occur. Thus, blood pressure and heart rate should be monitored carefully during nifedipine therapy. Close monitoring is especially recommended for patients who are prone to develop hypotension, those with a history of cerebrovascular insufficiency and those who are taking medications that are known to lower blood pressure.

Acute treatment of angina pectoris.

Adefin XL is not suitable for the acute treatment of angina pectoris due to delayed absorption of the medicine from the modified release dosage formulation.

Use in diabetes.

Treatment with nifedipine can theoretically impair glucose metabolism, which may be of clinical relevance in some cases.

Aortic stenosis.

Patients with severe aortic stenosis are at risk of developing heart failure or hypotension because of the vasodilating effects of Adefin XL.

Severe gastrointestinal narrowing.

As with any other nondeformable material, caution should be used when administering Adefin XL to patients with a previous history of severe gastrointestinal narrowing or obstruction. Bezoars can occur in very rare cases and may require surgical intervention.
There have been rare reports of bowel obstruction requiring surgery in patients with known oesophageal stricture, small bowel stenosis, and after gastroplexy, due to the nondeformable nature of Adefin XL. In single cases obstructive symptoms have been described without known history of gastrointestinal disorders.

Shortened transit times.

The sustained release of Adefin XL may be impaired in chronic diarrhoea (e.g. Crohn's disease, ulcerative colitis) or short bowel syndrome, when the gastrointestinal transit time is less than 18 to 22 hours. Monitoring of trough blood pressure (24 hour) is advised in these patients. If control of trough blood pressure is not satisfactory, then conventional Adefin tablets taken twice daily should be used.

Other nifedipine formulations.

Adefin XL 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. Adefin XL may not be bioequivalent to modified release nifedipine preparations available overseas.

Use in hepatic impairment.

Use in patients with liver impairment.

Adefin XL 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.

Caution should be exercised in the use of Adefin XL in elderly patients, especially those with a history of hypotension or cerebral vascular insufficiency. Lower doses may be required in patients with reduced drug clearance.

Paediatric use.

The safety and efficacy of Adefin XL 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 (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. A limited number of 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

Effects of other drugs on nifedipine.

Nifedipine is metabolised via the cytochrome P450 CYP3A4 system, 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.
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 also reduced. 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 certain azole antimycotics 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 used in conjunction with β-receptor blockers, patients should be carefully monitored since 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. It is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine and, if necessary, the dose of digoxin adjusted.

Quinidine.

Quinidine levels have been observed to decrease upon introduction of nifedipine and increase upon its withdrawal. For this reason, it is recommended that when nifedipine is either added to quinidine therapy or withdrawn from it, quinidine concentrations are monitored and the dose adjusted accordingly. 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 and ranitidine did not have clinically significant effects on the pharmacokinetics of nifedipine. Nifedipine did not have a clinically significant effect 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.

Grapefruit.

Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of nifedipine together with grapefruit juice thus results in elevated plasma concentrations of nifedipine due to a decreased first-pass metabolism. As a consequence, the blood pressure lowering effect may be increased. 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.

Other forms of interactions.

Barium contrast X-ray.

Adefin XL may cause false positive findings (e.g. filling defects interpreted as polyp) when barium contrast X-ray is undertaken.

Spectrophotometric test for vanillylmandelic acid.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In isolated cases of in vitro fertilisation, calcium channel blockers like nifedipine have been associated with reversible biochemical changes in the head section of the spermatozoa 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, the use of calcium channel blockers such as 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 is contraindicated throughout pregnancy. Medicines in this class carry the potential to produce foetal hypoxia, caesarean deliveries, prematurity and intrauterine growth retardation, which may be associated with maternal hypotension. Nifedipine was 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 has been 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 the breast milk. So far, insufficient evidence is available to determine whether nifedipine has an effect on breastfed infants. Breastfeeding should be stopped first 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.
In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation.
The most common adverse effect reported was oedema which was dose related and ranged in frequency from approximately 10% (30 mg) to 30% at the highest dose studied (180 mg). In clinical trials of 20 mg the frequency of peripheral oedema ranged from 0% to 4%.
There have been a small number of reports of chest pain not associated with myocardial infarction occurring soon after administration of a single dose. In such an event, the medicine must be discontinued if a causal relationship is suspected.
Aggravation of cardiac insufficiency has occasionally been reported in patients with compromised cardiac function or when nifedipine is given in combination with beta-blockers.
A small (5.4%) increase in mean alkaline phosphatase has been noted in patients treated with controlled release nifedipine tablets. These cases are rare and not associated with clinical symptoms and they rarely result in values outside the normal range.
In controlled studies, controlled release nifedipine tablets did not adversely affect serum uric acid, glucose or cholesterol. Serum potassium was unchanged in patients receiving controlled release nifedipine tablets in the absence of concomitant diuretic therapy, and slightly decreased in patients receiving concomitant diuretics.
Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. A limited number of clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation in some nifedipine patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for this finding has been demonstrated.
In a double blind comparison of Adefin XL and Adefin tablets, the incidence of vasodilator reactions did not differ.

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

As far as possible the treatment must be tailored to the needs of the individual and depending on the clinical picture in each case, the basic dose must be introduced gradually. In patients with impaired liver function, careful monitoring is advised and, in severe cases, a dose reduction may be necessary.
As a rule, the tablets are swallowed whole without chewing or being broken up with a little liquid. They may be taken with or without food, however grapefruit juice is to be avoided.

Hypertension.

In general, Adefin XL should be initiated with 30 mg once daily. A starting dose of 20 mg may be considered when medically indicated. Monitoring of trough blood pressure should be done initially to ensure blood pressure control lasts over the dosing interval. Depending on the severity of the disease and the patient's response, the dose can be decreased to 20 mg or increased in stages to 120 mg daily. In general, titration should proceed over a 7 to 14 day period so that the physician can fully assess the response to each dose level and monitor the blood pressure before proceeding to higher doses. Since steady-state levels are achieved on the second day of dosing, titration may proceed more rapidly if symptoms so warrant, provided the patient is assessed frequently. Titration to doses above 120 mg per day is not recommended.

Note.

Nifedipine 20 mg tablets is not available with this brand.

Chronic stable angina.

Adefin XL should be initiated with 30 mg once daily. If necessary, the dosage can be increased in stages to a maximum of 90 mg once daily. Experience with doses greater than 90 mg per day in patients with angina is limited.
The initiation of Adefin XL therapy in South Asians who have not previously taken nifedipine should start at low doses (see Section 5.2 Pharmacokinetic Properties).
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 the 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 treatment, on changing doses, 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, severe hypotension, 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 restoration of stable cardiovascular conditions have priority.
After oral ingestion of a potentially dangerous amount, thorough gastric lavage is indicated particularly in cases of intoxication with controlled release products like Adefin XL. Elimination must be as complete as possible, including the irrigation of the small intestine, to prevent the subsequent absorption of the active substance. Symptoms and signs of overdose may be delayed due to the controlled release properties of these products, so patients should be kept under observation for at least 24 hours.
Haemodialysis is ineffective in removing nifedipine in the body because nifedipine is not dialysable (high plasma protein binding, relatively low volume of distribution), but plasmapheresis may be considered.
Bradycardiac heart rhythm disturbances may be treated symptomatically with beta-sympathomimetics and, in life threatening situations, 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, with the addition of a beta-sympathomimetic medicine (e.g. isoprenaline 0.2 mg slowly intravenously, repeated if necessary as a continuous infusion at 5 microgram/min). If this is still insufficient to return the blood pressure to normal, vasoconstricting sympathomimetics such as dopamine or norepinephrine (noradrenaline) may be 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

Besides the active ingredient, Adefin XL 30 mg and 60 mg tablets also contain the following inactive ingredients: polyethylene oxide, magnesium stearate, sodium chloride, hypromellose, iron oxide red (CI 77491), cellulose acetate, macrogol 3350, Opacode monograming ink S-1-17823 Black (ID 12108) and Opadry LY-S-24914 (ID 2928).

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

Adefin XL 30.

Store below 30°C. Protect from light.

Adefin XL 60.

Blister packs (PP/Al) - Store below 25°C. Protect from light.
Blister packs (PVC/PVDC/Al) - Store below 25°C.
Blister packs (PA/Al/PVC/Al) - Store below 30°C.
Blister packs (PVC/PE/PCTFE (Aclar)/Al) - Store below 30°C.
The drug release mechanism of Adefin XL is triggered by moisture. Contact of the tablets with moisture may not be apparent but loss of contents may have already occurred. To prevent this, the tablet must be kept in its original blister-foil packaging until immediately before use.

6.5 Nature and Contents of Container

Adefin XL 30.

Packed in Al/Al blister packs supplied in packs of 10* or 30 tablets.

Adefin XL 60.

Packed in blister packs supplied in packs of 30 tablets.
Blister packs (PP/Al)*.
Blister packs (PA/Al/PVC/Al).
Blister packs (PVC/PVDC/Al)*.
Blister packs (PVC/PE/PCTFE (Aclar)/Al)*.
*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