Consumer medicine information

Addos XR

Nifedipine

BRAND INFORMATION

Brand name

Addos XR

Active ingredient

Nifedipine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Addos XR.

What is in this leaflet

This leaflet answers some common questions about ADDOS XR.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

Talk to your doctor or pharmacist if you have any concerns about taking this medicine.

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

What ADDOS XR is used for

ADDOS XR is used either to treat high blood pressure or to prevent chronic stable angina, one of the different types of angina (chest pain).

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

ADDOS XR 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.

This medicine is designed to allow the slow release of the nifedipine from the tablet after it is taken.

Your doctor may have prescribed ADDOS XR for another reason. Ask your doctor if you have any questions about why ADDOS XR has been prescribed for you.

It is available only with a doctor's prescription.

This medicine is not addictive.

Before you take it

When you must not take it

Do not take ADDOS XR if you are allergic to:

  • medicines containing nifedipine
  • other calcium channel blockers such as amlodipine, felodipine or israldipine
  • 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 that may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take ADDOS XR if you are taking another medicine containing rifampicin.

Do not take this medicine if you have or have had:

  • heart attack in the last 8 days
  • cardiogenic shock (very low blood pressure due to a failing heart)
  • Kock Pouch or an ileostomy.

Do not take ADDOS XR if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not take it if you are breastfeeding. ADDOS XR passes into breast milk and may affect your baby.

Do not take it if the expiry date (Exp.) printed on the pack has passed. It may not work as well if you do.

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

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you have or have had 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 of surgery
  • prolonged diarrhoea e.g. due to Crohn’s disease or ulcerative colitis.

Tell your doctor if you are pregnant or intend to become pregnant.

Tell your doctor if you are breastfeeding or intend to breastfeed.

If you have not told your doctor about any of the above, tell them before you start taking ADDOS XR.

Taking other medicines

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

Some medicines may be affected by ADDOS XR, or may affect how well 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

Your doctor can tell you what to do if you are taking any of these medicines.

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 ADDOS XR.

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

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

How to take it

How much to take

The usual starting dose is 30 mg (one tablet) daily. Your doctor may increase the dose slowly over several weeks depending on how you respond to this medicine.

Your doctor may have prescribed a different dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

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

Follow the instructions they give you. If you take the wrong dose, ADDOS XR may not work as well and your problem may not improve.

How to take it

Swallow the tablets whole with a glass of liquid, with or without food. ADDOS XR should not be chewed or broken up.

When to take it

The tablets are generally taken in the morning.

Take the tablets at about the same time of each day. Taking your tablets at the same time each day will have the best effect on your conditions. It will also help you to remember when to take them.

How long to take it for

ADDOS XR helps control your condition, but does not cure it. Therefore, you must take it every day. Continue taking your tablets for as long as your doctor tells you to.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take the missed dose as soon as you remember (if less than 12 hours to the next dose), and then go back to taking your tablets as you would normally.

Do not take more than one dose at a time to make up for the dose you missed.

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

If you take too much ADDOS XR (overdose)

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

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

Symptoms of overdose may include feeling dizzy 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 ADDOS XR

Things you must do

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

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

Before starting any new medicine, tell your doctor or pharmacist that you are taking ADDOS XR.

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

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

The use of ADDOS XR may affect 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 ADDOS XR, tell your doctor immediately.

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed. Otherwise, your doctor may think that it is not working and change your treatment unnecessarily.

Things you must not do

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

Do not stop taking the tablets suddenly, or change the dosage, without checking with your doctor. You may suffer unwanted side effects if you do.

Do not give ADDOS XR to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how ADDOS XR affects you. ADDOS XR may cause dizziness, light-headedness or fainting in some patients who have low blood pressure, especially when they first start taking the medicine, change dose, or drink alcohol.

Make sure you know how you react to ADDOS XR before driving a car, operating machinery, or doing anything else that could be dangerous if you are affected.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

This may be more noticeable when you first start taking ADDOS XR.

Standing up slowly, especially when you get up from lying down or sitting, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

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

Things that may help your condition

Some self-help measures suggested below may help your condition.

Talk to your doctor or pharmacist about them:

  • Alcohol - your doctor may advise you to limit your alcohol intake.
  • Smoking - your doctor may advise you to stop smoking or at least cut down.
  • Exercise - regular exercise helps reduce blood pressure and helps get the heart fitter, but it is important not to overdo it. Walking is good exercise, but try to find a route that is fairly flat. Before starting any exercise, ask your doctor for the program that best suits you.
  • Weight – if you are overweight, your doctor may suggest losing some weight to help lower your blood pressure and lessen the amount of work your heart has to do. Some people may need a dietician’s help to lose weight.
  • Diet - eat a healthy low-fat diet that includes plenty of fresh vegetables, fruit, bread, cereals and fish. Also eat less fat and sugar.
  • Salt - your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake, you can use minimum salt in cooking and avoid salt at the table.

Side effects

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

Like other medicines, ADDOS XR can cause some side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

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

  • headache
  • dizziness or light-headedness
  • feeling sick (nausea)
  • flushing
  • loss of energy, unusual weakness, tiredness
  • constipation
  • numbness in the hands and feet
  • generally feeling unwell
  • General swelling and/or swelling of the arms, ankles or legs.

These are the more common side effects of ADDOS XR. They are usually mild.

Bleeding, tender or swollen gums may occur some time after starting ADDOS XR. Muscle pain, trembling, visual disturbances and an increase in the need to pass water may also occur.

Occasionally, the treatment of high blood pressure may lead to slight breast swelling in older men. This side effect goes away when treatment is stopped.

Tell your doctor immediately if you notice any of the following:

  • fast or irregular heartbeat
  • fainting
  • signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers.

These side effects are rare but could be serious. You may need medical attention.

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

  • chest pain
  • symptoms of allergy 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
  • symptoms 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 side effects are rare but very serious. You may need urgent medical attention or hospitalisation.

Very rarely, some people experience a purple or 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 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 ADDOS XR and are repeatedly unsuccessful in fathering a child by in vitro fertilisation, the medicine should be considered as one of the possible causes if no other explanation can be found.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some patients.

After using it

Storage

Keep ADDOS XR 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.

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

Keep the tablets in their packs until it is time to take them. If you take the tablets out of the packs, they may not keep well.

Do not store ADDOS XR or other medicines in the bathroom or near a sink.

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

Disposal

If your doctor tells you to stop taking ADDOS XR, 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

ADDOS XR comes in two strengths of tablets:

  • ADDOS XR 30 – round, pale red tablet marked “30” on one side
  • ADDOS XR 60 - round pale red tablet marked “60” on one side.

Each blister pack contains 30 tablets.

Ingredients

The active ingredient in ADDOS XR is nifedipine.

  • each ADDOS XR 30 tablet contains 30 mg of nifedipine
  • each ADDOS XR 60 tablet contains 60 mg of nifedipine.

The tablets also contain:

  • purified talc
  • lactose monohydrate
  • povidone
  • carbomer 934P
  • hypromellose
  • colloidal anhydrous silica
  • magnesium stearate
  • titanium dioxide
  • iron oxide red CI77491
  • macrogol 4000
  • Eudragit E100.

ADDOS XR tablets contains lactose. The tablets do not contain gluten, sucrose,tartrazine or any azo dyes.

Sponsor

Arrow Pharma Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121 Australia

Australian registration numbers:
ADDOS XR 30 - AUST R 114825
ADDOS XR 60 - AUST R 98806

This leaflet was revised in November 2021.

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Addos XR

Active ingredient

Nifedipine

Schedule

S4

 

1 Name of Medicine

Nifedipine.

2 Qualitative and Quantitative Composition

Addos XR 30 mg tablets contain 30 mg of nifedipine.
Addos XR 60 mg tablets contain 60 mg of nifedipine.
Excipients with known effect: lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Addos XR 30 mg tablets are pale red, round biconvex tablet marked "30" on one side.
Addos XR 60 mg tablets are pale red, round biconvex tablet marked "60" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of hypertension. Prophylaxis of chronic stable angina pectoris.

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.
The tablets are swallowed whole, without chewing or being broken up, with a little liquid, independently of meal times. Grapefruit juice is to be avoided.

Hypertension.

Addos XR 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.

Note.

Nifedipine 20 mg tablets are not available with this brand.

Chronic stable angina.

Addos XR 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 Addos XR therapy in South Asian patients 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).

Children and adolescents.

The safety and efficacy of Addos XR in children and adolescents below 18 years has not been established.

Elderly patients.

Caution should be exercised in the use of Addos XR 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.

4.3 Contraindications

Known hypersensitivity to nifedipine or related dihydropyridine calcium channel blockers or to any of the excipients. Pregnancy and lactation. Cardiogenic shock. Kock pouch (ileostomy after proctocolectomy). Concomitant administration with rifampicin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Within the first eight 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.
Addos XR may be used in combination with beta-blocking drugs 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, Addos XR 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.
Nifedipine extended release tablets have no inherent antiarrhythmic action and, therefore, give no protection against any arrhythmias that 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% with nifedipine extended release tablets 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 nifedipine extended release tablets are 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.

Addos XR is not suitable for the acute treatment of angina pectoris due to delayed absorption of the drug from the modified release dosage formulation.

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 Addos XR.

Severe gastrointestinal narrowing.

As with any other nondeformable material, caution should be used when administering Addos XR 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 nifedipine extended release tablets. In single cases obstructive symptoms have been described without known history of gastrointestinal disorders.

Shortened transit times.

The sustained release of Addos XR 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 nifedipine tablets taken twice daily should be used.

Other nifedipine formulations.

Addos XR 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 and vice versa. Addos XR may not be bioequivalent to modified release nifedipine preparations available overseas.

Use in hepatic impairment.

Addos XR should be used with caution in patients with mild, moderate or severe impaired liver function (see Section 5 Pharmacological Properties). The total systemic plasma clearance is reduced and elimination half-life is increased in severe liver disease. A dose reduction may be required (see Section 4.2 Dose and Method of Administration). Close monitoring of response and metabolic effect should apply. 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 Addos XR in elderly patients, especially those with a history of hypotension or cerebrovascular insufficiency. Lower doses may be required in patients with reduced drug clearance.

Paediatric use.

The safety and efficacy of Addos XR in children and adolescents below 18 years has not been established.

Effects on laboratory tests.

Barium contrast X-ray.

Nifedipine extended release tablets may cause false positive findings (e.g. filling defects interpreted as polyps) when barium contrast X-ray is undertaken.

Spectrophotometric test for vanillylmandelic acid.

Nifedipine may falsely increase spectrophotometric assay values of urinary vanillylmandelic acid (VMA). However measurement with high pressure liquid chromatography (HPLC) is unaffected.
Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), AST and ALT 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

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 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 co-administration 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 the cytochrome 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 co-administration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus it's efficacy is also reduced. The use of rifampicin in combination with nifedipine is therefore contraindicated.
Upon co-administration 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 anti-mycotics (ketoconazole, itraconazole, fluconazole).

A formal interaction study investigating the potential of a drug interaction between nifedipine and these drugs has not yet been performed. These drugs are known to inhibit CYP3A4. When administered orally with nifedipine, a substantial increase in systemic bioavailability of nifedipine is possible. Co-administration of these drugs with nifedipine requires careful monitoring and, if necessary, a reduction in the nifedipine dose should be considered.

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 co-administration of both medicines cannot be excluded (see Section 4.4 Special Warnings and Precautions for Use).

Nefazadone.

A clinical study investigating the potential of a drug interaction between nifedipine and nefazadone has not yet been performed. Nefazadone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded. When nefazadone is given together with nifedipine, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered.

Quinupristin/dalfopristin.

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

Sodium valproate.

No formal studies have been performed to investigate the interaction of nifedipine with sodium valproate, 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 and hence an increase in efficacy is possible.

Cimetidine.

Elevation of plasma nifedipine levels during cimetidine administration has been reported. It is suggested that patients taking 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 drug 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 drugs 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. Blood pressure should be monitored upon co-administration of both drugs, and the nifedipine dose reduced if necessary.
CYP3A4-inducing anti-epileptic drugs such as phenytoin, carbamazepine and phenobarbital (phenobarbitone).

Phenytoin.

Phenytoin induces CYP3A4. Co-administration of phenytoin with nifedipine reduces the bioavailability of nifedipine. When both drugs 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 co-administration of both drugs, 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.

Carbamazepine, phenobarbitone.

No formal studies have been performed to investigate the interaction of nifedipine with these drugs. These drugs have been shown to reduce the plasma concentrations of another dihydropyridine calcium channel blocker (nimodipine) through enzyme induction. Therefore, a decrease in the plasma concentrations of nifedipine and hence a decrease in efficacy is possible.

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.

Beta-blockers and nitrates.

Although there is a possibility of additive effects with antihypertensive and negative inotropic agents, nifedipine extended release tablets may be used in conjunction with nitrates and beta-blocking drugs. Patients should be carefully monitored when such concomitant therapies are initiated.

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.

Digoxin.

The 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 the 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 drugs, 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 co-administration of both drugs, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose should be considered.

Theoretical potential interactions.

Erythromycin.

No interaction studies have been carried out between nifedipine and erythromycin. As both nifedipine and erythromycin undergo metabolism by CYP3A4, the potential for drug interaction cannot be ruled out at this stage. Erythromycin is known to inhibit CYP3A4 mediated metabolism of other drugs and could increase plasma concentrations of nifedipine if administered concomitantly.

Amprenavir, indinavir, nelfinavir, ritonavir, saquinavir.

A clinical study investigating the potential interaction between nifedipine and amprenavir, indinavir, nelfinavir, ritonavir or saquinavir has not yet been performed. Drugs of this class are known to inhibit the CYP3A4 system. In addition, amprenavir, indinavir, nelfinavir, ritonavir and saquinavir 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. Upon coadministration, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered.

Interactions shown not to exist.

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

Drug-food interactions.

Grapefruit juice.

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.

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 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 a possible cause.
(Category C)
Nifedipine is contraindicated throughout pregnancy. Drugs 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 has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum and malformation of the ribs. Digital anomalies are possibly a result of compromised uterine blood flow. Nifedipine administration 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.
Acute pulmonary oedema has been observed when calcium channel blockers, among others nifedipine (primarily in IR formulation), have been used as a tocolytic agent during pregnancy, especially in cases of multiple pregnancy (twins or more), with the intravenous route and/or concomitant use of beta-2 agonists.
Category C: Drugs which owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
 Nifedipine passes into the breast milk. So far, insufficient evidence is available as to whether nifedipine has an effect on breastfed infants. Breastfeeding should be stopped first if nifedipine treatment becomes necessary during the breastfeeding period.

4.7 Effects on Ability to Drive and Use Machines

Reactions to the drug, which vary in intensity from individual to individual, can impair the ability to drive or to operate machinery. This applies particularly at the start of treatment, on changing doses, and in combination with alcohol.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The most common adverse reactions to nifedipine extended release tablets based on clinical studies sorted by CIOMS III frequency categories (n = 9,566 patients as of 13 Oct 98) are listed below.

Reactions occurring in greater than or equal to 1% and < 10% of patients.

Cardiovascular system.

Palpitation.

Digestive system.

Constipation.

Nervous system.

Headache, dizziness.

General disorders and administration site conditions.

Feeling unwell, asthenia.

Reactions occurring in greater than or equal to 0.1% and < 1% of patients.

Immune system disorders.

Allergic reaction, allergic oedema/angioedema (incl. larynx oedema*).

Psychiatric disorders.

Anxiety reactions, sleep disorders.

Cardiovascular system.

Chest pain, tachycardia, angina pectoris.

Digestive system.

Diarrhoea, dry mouth, dyspepsia, flatulence, nausea, vomiting.

Hepatobiliary disorders.

Transient increases in liver enzymes.

Musculoskeletal system.

Leg cramps, muscle cramps, joint swelling.

Nervous system.

Paraesthesia, somnolence, vertigo, migraine, tremor.

Eye disorders.

Visual disturbances.

Respiratory system.

Dyspnoea, nosebleed, nasal congestion.

Skin and appendages.

Pruritus, rash, erythema.

Urogenital system.

Dysuria, polyuria.

Reproductive system and breast disorders.

Erectile dysfunction.

General disorders and administration site conditions.

Unspecific pain, chills, leg pain.
*May result in life threatening outcome.

Reactions occurring in greater than or equal to 0.01% and < 0.1% of patients.

Immune system disorders.

Urticaria.

Cardiovascular system.

Chest pain substernal, cardiovascular disorder.

Digestive system.

Anorexia, eructation, gastrointestinal disorder, gingivitis, gum hyperplasia, GGT increased, gingival hyperplasia.

Musculoskeletal system.

Arthralgia, joint disorder, myalgia.

Nervous system.

Hypaesthesia, dysaesthesia.

Skin and appendages.

Angioedema, maculopapular rash, pustular rash, sweating, urticaria, vesiculobullous rash.

Urogenital system.

Urinary frequency.

General disorders and administration site conditions.

Fever.
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 of nifedipine. 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.
Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase (AP), creatine phosphokinase (CPK), lactate dehydrogenase (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 intrahepatic cholestasis with or without jaundice has been reported. Rare instances of allergic hepatitis have also been reported.
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 treated 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 nifedipine extended release and immediate release tablets, the incidence of vasodilator reactions did not differ.

Postmarketing reports.

A small number of events identified during ongoing post-marketing surveillance associated with nifedipine for which a frequency could not be estimated are listed in Table 1.

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.

4.9 Overdose

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.

Treatment.

As far as treatment is concerned, elimination of the poison 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 Addos XR. 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), but plasmaphaeresis may be considered.
Bradycardic 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 (calcium gluconate 10% solution 10 to 20 mL administered slowly intravenously and repeated if necessary). If the effects are inadequate, the treatment can be continued with ECG monitoring, with the addition of a beta-sympathomimetic drug (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 drugs 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 13 11 26.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nifedipine 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.

Angina clinical trials.

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

5.2 Pharmacokinetic Properties

Absorption.

Nifedipine is almost completely absorbed after oral administration. Plasma drug concentrations rise at a gradual, controlled rate exhibiting zero order absorption kinetics after nifedipine extended release tablet 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 nifedipine extended release tablets is 86% relative to an immediate release dosage form which has a systemic availability of 45 to 68%. Administration of nifedipine extended release tablets 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 drug, which could result in lower plasma concentrations. The pharmacokinetics of nifedipine extended release tablets 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.

Distribution.

Nifedipine is about 95% bound to plasma protein (albumin).

Metabolism.

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 presystemic metabolism. These metabolites show no pharmacodynamic activity. The main metabolite is the hydroxycarbolic acid derivative (95%); the remaining 5% is the corresponding lactone.

Excretion.

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 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 Addos XR therapy.

5.3 Preclinical Safety Data

Genotoxicity.

No data available

Carcinogenicity.

Carcinogenesis/mutagenesis. 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Addos XR tablets contain purified talc, povidone, lactose monohydrate, carbomer 934P, hypromellose, colloidal anhydrous silica, magnesium stearate, titanium dioxide, iron oxide red CI77491, macrogol 4000 and Eudragit E100.
The tablets are gluten free.

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

Store below 25°C.

6.5 Nature and Contents of Container

Addos XR 30 tablets are available in blister pack (PVC/PVDC/Al) of 30 tablets.
Addos XR 60 tablets are available in blister pack (PVC/PVDC/Al) of 30 tablets.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Nifedipine is a yellow, crystalline powder which is practically insoluble in water and sparingly soluble in absolute ethanol. It is sensitive to light.

Chemical structure.


Chemical Name: dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Structural formula:
Molecular Formula: C17H18N2O6.
Molecular Weight: 346.3.

CAS number.

CAS Registry Number: 21829-25-4.

7 Medicine Schedule (Poisons Standard)

S4: Prescription Only Medicine.

Summary Table of Changes