Consumer medicine information

Adalat Oros Controlled release tablets

Nifedipine

BRAND INFORMATION

Brand name

Adalat Oros Controlled release tablets

Active ingredient

Nifedipine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Adalat Oros Controlled release tablets.

WHAT IS IN THIS LEAFLET

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

This leaflet is for Adalat Oros. It is different from the leaflet for other forms of Adalat products.

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

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

Keep this leaflet with the medicine.

You may need to read it again.

WHAT ADALAT OROS IS USED FOR

Adalat Oros is used either to treat high blood pressure or to prevent a type of angina (chest pain), known as chronic stable angina.

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

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

Adalat Oros is specially designed to allow the slow release of the active substance from the tablet after it is taken. It is composed of a strong outer shell which does not dissolve in the body and is excreted in the faeces. It is normal to find these “ghost-tablets” in the faeces. The active substance contained in them has been absorbed by the body before excretion.

Your doctor, however, may prescribe Adalat Oros for another purpose.

Ask your doctor if you have any questions about why Adalat Oros has been prescribed for you.

BEFORE YOU TAKE ADALAT OROS

When you must not take it

Do not take Adalat Oros if you have an allergy to:

  • nifedipine, the active ingredient in Adalat Oros
  • any of the ingredients listed at the end of this leaflet
  • active substances similar to nifedipine such as: amlodipine, felodipine and israpidine.

Some of the symptoms of an allergic reaction may include:

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

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

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

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

Do not take this medicine if you are pregnant.

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

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

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

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

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

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

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

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

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

Before you start to take it

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

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

  • heart failure
  • other heart or blood vessel disorders
  • low blood pressure
  • stroke
  • mini-stroke (also known as TIA or transient ischaemic attack)
  • liver disease
  • diabetes
  • narrowing of your oesophagus or intestine, e.g. due to previous injury, infection or surgery
  • prolonged diarrhoea, e.g. due to Crohn’s disease or ulcerative colitis

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Adalat Oros.

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

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

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

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

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

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

HOW TO TAKE ADALAT OROS

Follow all directions given to you by your doctor or 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 pharmacist label, ask your doctor or pharmacist for help.

How much to take

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

The usual dose is 30 mg or 60 mg once daily. Your doctor may increase the dose if required.

How to take it

Immediately after removing a tablet from the blister pack, swallow it whole with some liquid.

Do not break or chew the tablets.

When to take it

Take Adalat Oros once a day, at about the same time each day. Adalat Oros can be taken either with or without a meal.

How long to take it

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

If you forget to take it

If you forget to take your daily dose of Adalat Oros 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.

If you have missed several doses, consult your doctor.

If you take too much (overdose)

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

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

WHILE YOU ARE TAKING ADALAT OROS

Things you must do

Take Adalat Oros exactly as told by your doctor. If you do not follow your doctor’s instruction, you may not get control of your blood pressure or relief from your angina.

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

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

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

The use of Adalat Oros 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 this medicine, tell your doctor immediately.

Things you must not do

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

Do not use it to treat any other medical conditions unless your doctor says so.

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

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

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

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

Things to be careful of

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

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

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

SIDE EFFECTS

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

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

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

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

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

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

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

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

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

In very rare cases, the undissolved shell of the Adalat Oros tablet or “ghost-tablets” may not be excreted in the faeces and may collect in the stomach. Tell your doctor if you experience symptoms of bowel blockage. Surgery may be necessary to remove these shells.

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

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

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

AFTER TAKING ADALAT OROS

Storage

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

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

Keep the medicine in a cool dry place.

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

Do not leave it in the car.

Heat and damp can destroy some medicines.

Keep the tablets where children cannot reach them.

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

Disposal

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

PRODUCT DESCRIPTION

What it looks like

  • Adalat Oros 20 mg tablets are round, biconvex film-coated tablets in rose-pink colour marked with “Adalat 20” on one side and a pin-prick hole on the other side to aid in delivery of your medicine. The tablets are supplied in blister packs of 30 tablets, with each tablet containing 20 mg of nifedipine.
  • Adalat Oros 30 mg tablets are round, biconvex film-coated tablets in rose-pink colour marked with “30” on one side and a pin-prick hole on the other side to aid in delivery of your medicine. The tablets are supplied in blister packs of 30 tablets, with each tablet containing 30 mg of nifedipine.
  • Adalat Oros 60 mg tablets are round, biconvex film-coated tablets in rose-pink colour marked with “60” on one side and a pin-prick hole on the other side to aid in delivery of your medicine. The tablets are supplied in blister packs of 30 tablets, with each tablet containing 60 mg of nifedipine.

Ingredients

Active Ingredient per tablet:

  • Adalat Oros 20 - nifedipine 20 mg
  • Adalat Oros 30 - nifedipine 30 mg
  • Adalat Oros 60 - nifedipine 60 mg

Inactive ingredients:

  • polyethylene oxide
  • magnesium stearate
  • sodium chloride
  • hypromellose
  • iron oxide red (CI 77491)
  • hydroxypropylcellulose
  • cellulose acetate
  • macrogol 3350
  • titanium dioxide
  • propylene glycol

Supplier

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

Australian Registration Numbers

  • ADALAT OROS 20 -
    AUST R 60101
  • ADALAT OROS 30 -
    AUST R 76041
  • ADALAT OROS 60 -
    AUST R 76040

Date of preparation

June 2013

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

® Registered Trademark of Bayer AG, Germany

© Bayer Australia Ltd

All rights reserved

BRAND INFORMATION

Brand name

Adalat Oros Controlled release tablets

Active ingredient

Nifedipine

Schedule

S4

 

Name of the medicine

Nifedipine.

Excipients

Polyethylene oxide, magnesium stearate, sodium chloride, hypromellose, iron oxide red (CI77491), hydroxypropylcellulose, cellulose acetate, macrogol 3350, titanium dioxide and propylene glycol.

Description

Chemical name: dimethyl-1,4-dihydro- 2,6-dimethyl-4- (2'-nitrophenyl) -3,5-pyridine dicarboxylate. Molecular formula: C17H18N2O6. MW: 346.3. CAS: 21829-25-4. Nifedipine is a yellow crystalline substance practically insoluble in water and sparingly soluble in absolute ethanol. It is sensitive to light.
Adalat Oros tablets are a controlled release formulation (GITS (gastrointestinal therapeutic system)) containing nifedipine 20, 30 or 60 mg. Adalat Oros 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 Adalat Oros remains intact during the gastrointestinal passage and is eliminated in the faeces.
All strengths of Adalat OROS are round, biconvex shaped, rose-pink, film-coated tablets. Tablet diameters are 8.4 mm (20 mg), 9 mm (30 mg) and 11 mm (60 mg). Adalat OROS 20 mg tablets are marked in black with the product name on one side (“Adalat 20”) and the Adalat OROS 30 mg and 60 mg tablets are marked with the dose strength on one side (“30” or “60”).

Pharmacology

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 active 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 in both 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 in angina.

The pivotal clinical studies were performed in patients with chronic stable angina. In these studies, Adalat Oros at doses of 30 and 60 mg once daily improved exercise tolerance test (ETT) parameters in reference to baseline. Adalat Oros 30 mg daily showed a small but suboptimal benefit. When titrated to the dose of 60 mg once daily, Adalat Oros was as effective as atenolol 100 mg once daily. In patients already receiving β-blocker therapy, Adalat Oros improved ETT parameters and time to 1 mm ST depression, and at doses of up to 90 mg once daily, Adalat Oros was more effective than modified release nitrates (isosorbide mononitrate 50 mg once daily or 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 Adalat Oros and isosorbide mononitrate, and about 15 hours after the last dose of isosorbide dinitrate. Therefore the higher efficacy observed for Adalat Oros may be attributable to the difference in pharmacokinetics between Adalat Oros and nitrates. In pivotal and supportive clinical studies, the duration of treatment with Adalat Oros was limited to two to twelve weeks only, and the majority of patients in these studies were already on background β-blocker therapy. Data in patients with unstable angina, asymptomatic ischaemia, vasospastic angina and postmyocardial infarction are limited. Data on monotherapy with Adalat Oros are limited and based on trials of short duration (four weeks or less).

Pharmacokinetics.

Nifedipine is almost completely absorbed after oral administration. Plasma drug concentrations rise at a gradual, controlled rate exhibiting zero order absorption kinetics after Adalat Oros 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 Adalat Oros is 86% relative to an immediate release dosage form which has a systemic availability of 45 to 68%. Administration of Adalat Oros 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. The pharmacokinetics of Adalat Oros 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 in either the presence or the absence of food.
Nifedipine is about 95% bound to plasma protein (albumin).
The active substance nifedipine is almost completely metabolised in the liver, primarily by oxidative processes: cytochrome P450 3A4 (CYP3A4). Some metabolic activity within the gut wall may also contribute to the presystemic metabolism. These metabolites show no pharmacodynamic activity. The main metabolite is the hydroxycarbolic acid derivative (95%); 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% is excreted 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 Asian patients). Currently, confirmatory studies only exist for the South Asian population. In comparison to Caucasian patients, there were increases in area under the curve (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 Caucasian patients, lower doses of nifedipine may be required in South Asian patients at the beginning of Adalat Oros therapy.

Indications

Adalat OROS is indicated for the treatment of mild to moderate hypertension. Prophylaxis of chronic stable angina pectoris.

Contraindications

Adalat OROS 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 Interactions with Other Medicines); patients within the first eight days of an acute episode of myocardial infarction.

Precautions

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.
Adalat Oros may be used in combination with β-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, Adalat Oros should be withdrawn if a causal relationship is suspected.

Beta-blocker withdrawal.

When nifedipine is administered simultaneously with β-blockers the patient should be carefully monitored, since deterioration of heart failure may develop in isolated cases.
Adalat Oros has no inherent antiarrhythmic action and therefore gives no protection against any arrhythmias that may result from abrupt withdrawal of β-blockers. Any such withdrawal of β-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 β-blockers.

Peripheral oedema.

Mild to moderate peripheral oedema occurs in a dose dependent manner with an incidence ranging from approximately 10% at Adalat Oros 30 mg daily to about 33% at 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 Adalat Oros (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.

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

Aortic stenosis.

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

Severe gastrointestinal narrowing.

As with any other nondeformable material, caution should be used when administering Adalat Oros 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 Adalat Oros. In single cases obstructive symptoms have been described without known history of gastrointestinal disorders.

Shortened transit times.

The sustained release of Adalat Oros may be impaired in chronic diarrhoea (e.g. Crohn's disease, ulcerative colitis) or the 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 the trough blood pressure is not satisfactory, then conventional Adalat tablets taken twice daily should be used.

Other nifedipine formulations.

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

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.

Use in pregnancy.

(Category C)
Nifedipine is contraindicated throughout pregnancy. Medicines in this class carry the potential to produce fetal 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 fetotoxic effects, including stunted fetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits) and prolonged pregnancy/ decreased neonatal survival (rats; not evaluated in other species). All of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic and several times the recommended maximum dose for humans. There are no adequate and well controlled studies in pregnant women.

Use in lactation.

Nifedipine passes into 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.

Paediatric use.

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

Use in patients with liver impairment.

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

Use in the elderly.

Caution should be exercised in the use of Adalat Oros 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.

Use in diabetes.

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

Carcinogenicity/ mutagenicity.

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

Effect on ability to drive and use machines.

Reactions to 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.

Interactions

Nifedipine is metabolised via CYP3A4, located in the intestinal mucosa and the liver. Medicines that are known to inhibit or induce CYP3A4 may therefore alter the first pass or the clearance of nifedipine.
Drugs which are inhibitors of CYP3A4 and therefore may lead to increased plasma concentrations of nifedipine, are, e.g. macrolide antibiotics (e.g. erythromycin);
anti-HIV protease inhibitors (e.g. ritonavir);
azole antimycotics (e.g. ketoconazole);
the antidepressants nefazodone and fluoxetine;
quinupristin/ dalfopristin;
valproic acid;
cimetidine.
Upon coadministration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.

Drugs that affect nifedipine.

Nifedipine is metabolised via CYP3A4, located in the intestinal mucosa and the liver. Medicines that are known to inhibit or induce CYP3A4 may therefore alter the first pass or the clearance of nifedipine.
The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following drugs.

Rifampicin.

Rifampicin strongly induces CYP3A4. Upon coadministration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy is also reduced. The use of nifedipine in combination with rifampicin is therefore 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 Dosage and Administration).

Macrolide antibiotics (e.g. erythromycin).

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

Anti-HIV protease inhibitors.

A clinical study investigating the potential interaction between nifedipine and certain anti-HIV protease inhibitors has not yet been performed. Medicines of this class are known to inhibit 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 nifedipinedue to a decreased first pass metabolism cannot be excluded.

Fluoxetine.

A clinical study investigating the potential of a drug interaction between nifedipine and fluoxetine has not yet been performed. Fluoxetine has been shown to inhibit in vitro the CYP3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma concentrations upon coadministration of both medicines cannot be excluded (see Precautions).

Nefazodone.

A clinical study investigating the potential of a drug interaction between nifedipine and nefazodone has not yet been performed. Nefazodone is known to inhibit CYP3A4 mediated metabolism of other medicines. Therefore an increase of nifedipine plasma concentrations upon coadministration of both medicines cannot be excluded.

Quinupristin/ dalfopristin.

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

Valproic acid.

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

Cimetidine.

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

Diltiazem.

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

Further studies.

Cisapride.

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

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

Phenytoin induces CYP3A4. Coadministration of phenytoin with nifedipine reduces the bioavailability of nifedipine. When both medicines are concomitantly administered, the clinical response to nifedipine should be monitored and an increase in the nifedipine dose considered, if necessary. If the dose of nifedipine is increased during coadministration of both medicines, a reduction of the nifedipine dose should be considered when phenytoin is discontinued. No formal studies have been performed to investigate the potential interaction between nifedipine and carbamazepine or phenobarbitone. As both drugs have been shown to reduce the plasma concentrations of the structurally similar calcium channel blocker, nimodipine, through enzyme induction, a decrease in nifedipine plasma concentrations and hence a decrease in efficacy cannot be excluded.

Effects of nifedipine on other drugs.

Blood pressure lowering drugs.

Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives, such as diuretics;
β-blockers;
ACE inhibitors;
angiotensin I (ATI) receptor antagonists;
other calcium antagonists;
α-adrenergic blocking agents;
PDE5 inhibitors;
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.

Drug-food interactions.

Grapefruit.

Grapefruit juice inhibits CYP3A4. 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.

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.

Other forms of interactions.

Barium contrast X-ray.

Adalat Oros 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.

Effect on laboratory tests.

Rare, usually transient, but occasionally significant elevations of enzymes such as AP, CPK, LDH, AST (SGOT) and ALT (SGPT) have been noted. The relationship to nifedipine therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms, however cholestasis with or without jaundice has been reported. Rare instances of allergic hepatitis have been reported.
Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. 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.

Adverse Effects

Adverse drug reactions (ADRs) listed under common were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%). ADR is defined as a response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man. Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility. Adverse drug reactions (ADRs) based on placebo controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial database: nifedipine n = 6,486; placebo n = 5,326) are listed below.
The frequencies are defined as: common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000.

ADRs reported based on clinical trial data.

Immune system disorders.

Uncommon: allergic reaction, allergic oedema/ angioedema (including larynx oedema*). *May result in life threatening outcome.
Rare: urticaria.

Psychiatric disorders.

Uncommon: anxiety reactions, sleep disorders.

Nervous system disorders.

Common: headache, dizziness.
Uncommon: paraesthesia, somnolence, tremor, vertigo, migraine.
Rare: hypaesthesia, dysaethesia.

Eye disorders.

Uncommon: visual disturbances.

Cardiac disorders.

Common: palpitation.
Uncommon: chest pain, angina pectoris, tachycardia.
Rare: chest pain substernal, cardiovascular disorder.

Vascular disorders.

Common: oedema, vasodilatation.
Uncommon: syncope, hypotension.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea, nosebleed, nasal congestion.

Gastrointestinal disorders.

Common: constipation.
Uncommon: gastrointestinal and abdominal pain, nausea, dry mouth, dyspepsia, vomiting, flatulence, diarrhoea.
Rare: gingival hyperplasia, anorexia, eructation, gastrointestinal disorder, GGT increased, gingivitis.

Hepatobiliary disorders.

Uncommon: increase in transaminases.

Skin and cutaneous tissue disorders.

Uncommon: pruritus, rash, erythema.
Rare: sweating, maculopapular rash, pustular rash, vesiculobullous rash.

Musculoskeletal and connective tissue disorders.

Uncommon: muscle cramps, joint swelling, leg cramps.
Rare: arthralgia, myalgia, joint disorder.

Renal and urinary disorders.

Uncommon: polyuria, dysuria.
Rare: urinary frequency increased.

General disorders and administration site conditions.

Common: feeling unwell, asthenia.
Uncommon: unspecific pain, chills, leg pain.
Rare: fever.

Reproductive system and breast disorders.

Uncommon: erectile dysfunction.
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% on 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 β-blockers.
A small (5.4%) increase in mean AP 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 Adalat Oros and Adalat 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 below.

ADRs reported based on postmarketing experience.

System organ class (MedDRA), frequency not known.

Blood and lymphatic system disorders.

Agranulocytosis, leukopenia.

Immune system disorders.

Anaphylactic/ anaphylactoid reactions.

Metabolism and nutrition disorders.

Hyperglycaemia.

Nervous system disorders.

Hypoaesthesia, somnolence.

Eye disorders.

Eye pain, blurred vision.

Cardiac disorders.

Chest pain (angina pectoris).

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Vomiting, gastrooesophageal sphincter insufficiency, gum hyperplasia, bezoar, dysphagia, intestinal obstruction, intestinal ulcer, oesophagitis, gum disorder.

Hepatobiliary disorders.

Jaundice.

Skin and subcutaneous tissue disorders.

Toxic epidermal necrolysis (exfoliative dermatitis), erythromelalgia, photosensitivity, allergic reaction, palpable purpura, gynaecomastia.

Musculoskeletal and connective tissue disorders.

Arthralgia, myalgia, muscle cramps.

Investigations.

Weight loss, ALT increased.

Dosage and 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.
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 Adalat Oros therapy 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 doctor 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/day is not recommended.

Chronic stable angina.

Adalat Oros 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/day in patients with angina is limited.
The initiation of Adalat Oros therapy in South Asian patients who have not previously taken nifedipine should start at low doses (see Pharmacokinetics).
Coadministration with CYP3A4 inhibitors or inducers may require nifedipine dose adjustment or for nifedipine not to be used at all (see Interactions with Other Medicines).

Overdosage

Symptoms.

The following symptoms are observed in cases of severe nifedipine intoxication: disturbances of consciousness to the point of coma, severe hypotension, tachycardic/ bradycardic heart rhythm disturbances, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.

Management of overdose.

As far as treatment is concerned, elimination of the active substance and the restoration of stable cardiovascular conditions have priority.
After oral ingestion of a potentially dangerous amount, thorough gastric lavage is indicated, particularly in cases of intoxication with controlled release products like Adalat Oros. 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 from the body because nifedipine is not dialysable (high plasma protein binding, relatively low volume of distribution), but plasmaphaeresis may be considered.
Bradycardic heart rhythm disturbances may be treated symptomatically with β-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 (calcium gluconate 10% solution 10 to 20 mL 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 β-sympathomimetic medicine (e.g. isoprenaline 0.2 mg slowly intravenously, repeated if necessary as a continuous infusion at 5 microgram/minute). If this is still insufficient to return the blood pressure to normal, vasoconstricting sympathomimetics such as dopamine or 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.

Presentation

Adalat OROS tablets are round, biconvex, rose-pink, film-coated tablets, supplied in packs of 10 or 30 tablets. Adalat OROS 20 mg tablets are marked in black with the product name on one side (“Adalat 20”) and the Adalat OROS 30 mg and 60 mg tablets are marked with the dose strength on one side (“30” or “60”).
Not all pack sizes may be marketed.
The drug release mechanism of Adalat OROS 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.

Storage

Container types and storage conditions for Adalat Oros 20 mg.

Blister pack (PA/Al/PVC/Al): store below 30°C.
Blister pack (PVC/PVDC/Al): store below 30°C.

Container types and storage conditions for Adalat Oros 30 mg.

Blister pack (PA/Al/PVC/Al): store below 30°C.
Blister pack (PVC/PE/PCTFE/Al): store below 30°C.
Blister pack (PVC/PVDC/Al): store below 25°C.

Container types and storage conditions for Adalat Oros 60 mg.

Blister pack (PA/Al/PVC/Al): store below 30°C.
Blister pack (PVC/PVDC/Al): store below 25°C.
Blister pack (PP/Al): store below 25°C. Protect from light.
Blister pack (PVC/PE/PCTFE/Al): store below 30°C.
Not all packaging material types may be marketed. Refer to medicine carton for storage instructions.

Poison Schedule

S4.