Consumer medicine information

Amlodipine Sandoz

Amlodipine

BRAND INFORMATION

Brand name

Amlodipine Sandoz

Active ingredient

Amlodipine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Amlodipine Sandoz.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risk of you taking Amlodipine Sandoz against the benefits it is expected to 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 want to read it again.

What Amlodipine Sandoz is used for

What it does

The name of your medicine is Amlodipine Sandoz. It contains the active ingredient amlodipine besilate.

Amlodipine Sandoz is used to treat high blood pressure. Everyone has blood pressure. This pressure helps to circulate the blood all around your body. Your blood pressure may be different at different times of the day, depending on how busy or worried you are. You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems. You may feel fine and have no symptoms, but eventually hypertension can cause stroke, heart disease and kidney failure. Amlodipine Sandoz helps to lower your blood pressure.

Amlodipine Sandoz is also used to treat angina pectoris. Angina is caused by a shortage of the supply of oxygen to the heart and is characterised by a painful and uncomfortable feeling in the chest. This feeling often spreads to the arms or neck, and sometimes also to the shoulders and back.

Amlodipine Sandoz is not for the relief of a sudden attack of angina. If such an attack occurs, you should take other medication that your doctor will have given to you.

Your doctor may have prescribed Amlodipine Sandoz for another reason. Ask your doctor if you have any questions about why Amlodipine Sandoz was prescribed for you.

Amlodipine Sandoz is available only with a doctor's prescription.

How Amlodipine Sandoz works

Amlodipine Sandoz belongs to a group of medicines called calcium channel blockers or calcium ion antagonists. It works by relaxing the blood vessels in your body, making it easier for your heart to pump blood around the body. It also widens the blood vessels leading to your heart and so helps to increase the supply of oxygen-rich blood to the heart.

Calcium channel blockers do not change the amount of calcium in your blood or bones.

There is no evidence that Amlodipine Sandoz is addictive.

Before you take Amlodipine Sandoz

When you must not take Amlodipine Sandoz

Do not take Amlodipine Sandoz if:

  • You are allergic to the active ingredient or any of the inactive ingredients mentioned at the end of this leaflet under Product Description.
  • You ever had an allergic reaction to other medicines of this drug class. Examples of these medicines are felodipine, nifedipine, or lercanidipine. If you are not sure whether you have ever taken any of these medicines, check with your doctor or pharmacist.
  • You are pregnant or breastfeeding, unless permitted by your doctor.
  • It is past its expiry date or the packaging appears to have been tampered with.

Amlodipine Sandoz is not recommended for the use in children as the safety and efficacy in this age group have not been established.

Before you start to take Amlodipine Sandoz

Tell your doctor if you have allergies to:

  • Any other medicines, especially if they are in the same drug class as Amlodipine Sandoz.
  • Any other substances, including foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant. This medicine may affect your developing baby if you take it during pregnancy. Your doctor can discuss with you the risks and benefits involved.

Do not breast-feed if you are taking this medicine. The active ingredient in Amlodipine Sandoz passes into breast milk. Your baby may be affected.

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

  • heart problems, including heart failure
  • liver problems.

Taking other medicines

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

Some medicines may be affected by Amlodipine Sandoz, or may affect how well it works. You may need to use different amounts of your medicine, or you may need to take different medicines.

Tell your doctor or pharmacist if you are taking any of the following:

  • other medicines used to treat angina, such as diltiazem
  • some antibiotics, such as erythromycin, clarithromycin or rifampicin
  • some antifungals, such as ketoconazole or itraconazole
  • anti-proteases, medicines used to treat HIV infection, such as ritonavir
  • simvastatin, a medicine used to lower cholesterol
  • ciclosporin, tacrolimus, sirolimus or everolimus, medicines used tosuppress the immune system
  • temsirolimus, a medicine used to treat kidney cancer
  • St John's Wort.

Your doctor or pharmacist has a complete list of medicines to be careful with or avoid while taking Amlodipine Sandoz.

If you have not told your doctor or pharmacist about any of the above, tell them before you start to take Amlodipine Sandoz.

How to take Amlodipine Sandoz

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

If you do not understand the instructions on the box/bottle, ask your doctor or pharmacist for help.

How much to take

The usual dose of Amlodipine Sandoz is one 5 mg tablet each day. Your doctor may increase this to one 10 mg tablet each day.

Your doctor may prescribe another dose of Amlodipine Sandoz depending on your condition and how you respond to this medicine.

How to take it

Swallow the tablet with a full glass of water.

If you need to break Amlodipine Sandoz, hold tablet with both hands and snap along break line.

Take your tablets about the same time each day, either morning or evening. This will help you to get the best effect and also makes it easier to remember when to take it.

Amlodipine Sandoz can be taken with or without food.

How long to take it

You must take Amlodipine Sandoz every day.

Continue taking your medicine for as long as your doctor tells you.

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

If you forget to take your dose

If less than 12 hours have passed since the time when you should have taken your dose, then take your dose as soon as you remember, and continue to take it as you would normally.

Otherwise, skip the dose you missed and take your next dose when you are meant to.

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

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

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much

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

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

If you take too much Amlodipine Sandoz, you may feel dizzy, light-headed or faint or have an irregular heart beat.

While you are using Amlodipine Sandoz

Things you must do

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

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

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

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests (add specific tests as per PI) from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take Amlodipine Sandoz to treat any other complaints unless your doctor tells you to.

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

Things to be careful of

Avoid eating large quantities of grapefruit or drinking large quantities of grapefruit juice. Grapefruit juice contains one or more components that alter the metabolism of some medicines, including Amlodipine Sandoz.

Drinking very large quantities (over 1.2 litres) of grapefruit juice each day while taking Amlodipine Sandoz may increase the effects of this medicine.

Be careful driving or operating machinery until you know how Amlodipine Sandoz affects you. Amlodipine Sandoz may cause dizziness or light-headedness in some people, especially after the first dose or after the dose has been increased.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

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

Amlodipine Sandoz helps most people but it may have some unwanted side effects in a few people. 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.

It can be difficult to tell whether side effects are the result of taking Amlodipine Sandoz, effects of your condition or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

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

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

  • headache
  • dizziness
  • flushing
  • tiredness
  • drowsiness or sleepiness
  • stomach pain or nausea.

These are the more common side effects of Amlodipine Sandoz. Mostly, these are mild and short-lived.

Tell your doctor if you notice any of the following:

  • indigestion
  • sexual problems.

These may or may not be due to Amlodipine Sandoz but you should tell your doctor if they worry you.

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

  • changes in heart beat (fast or slow)
  • swelling of the ankles, feet, face or hands
  • tingling or numbness of the hands or feet
  • dizziness or light-headedness on standing up from a sitting or lying position
  • unusual tiredness or weakness
  • muscle cramps or aches
  • joint pain
  • eye pain or change in vision
  • changes in mood, feeling anxious or nervous
  • symptoms of liver disease such as itching, yellowing of the skin and eyes, and dark coloured urine
  • unusual movements, including trembling and shaking of the hands, and fingers, twisting movements of the body, shuffling walk and stiffness of the arms and legs.

These may be serious side effects of Amlodipine Sandoz. You may need urgent medical attention. Serious side effects are rare.

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

  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing.
  • shortness of breath
  • symptoms of allergy such as skin rash and/or itching
  • severe upper stomach pain, often with nausea and vomiting
  • fast or irregular heart beats
  • chest pain
  • chest pain associated with exertion (angina) that lasts longer, is more severe or occurs more often.

These are very serious side effects. You may need urgent medical attention or hospitalisation. All of these side effects are very rare.

If you are 65 years or older, you should be especially careful when you are taking Amlodipine Sandoz.

Some people in this age group are more likely to experience side effects such as swelling of the feet and ankles, muscle cramps and dizziness.

Make sure to tell your doctor if you experience any side effects.

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 using Amlodipine Sandoz

Storage

Keep Amlodipine Sandoz in the original packaging until you need to take it.

Store below 25°C in a dry place, where it is protected from light. Keep your 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.

Do not leave your medicines on a window sill or in the car. Heat and dampness can destroy some medicines.

Disposal

Return any unused or out of date medicine to your pharmacist.

Product description

What Amlodipine Sandoz looks like

Amlodipine Sandoz 5mg: A white or almost white, oblong tablet, scored on one side and coded "5" on the other. Available in blisters of 30 tablets.

Amlodipine Sandoz 10mg: A white or almost white, oblong tablet, scored on one side and coded "10" on the other. Available in blisters of 30 tablets.

Ingredients

Active Ingredient

Each Amlodipine Sandoz 5mg tablet contains 5 mg amlodipine as amlodipine besilate.

Each Amlodipine Sandoz 10mg tablet contains 10 mg amlodipine as amlodipine besilate.

Inactive Ingredients

Each Amlodipine Sandoz tablet also contains sodium starch glycollate, calcium hydrogen phosphate, cellulose-microcrystalline and magnesium stearate.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in September 2018.

Australian Register Numbers

Amlodipine Sandoz 5 mg tablets: AUST R 124578 (blisters)

Amlodipine Sandoz 10 mg tablets: AUST R 124582 (blisters)

Published by MIMS November 2018

BRAND INFORMATION

Brand name

Amlodipine Sandoz

Active ingredient

Amlodipine

Schedule

S4

 

1 Name of Medicine

Amlodipine besilate.

2 Qualitative and Quantitative Composition

Each Amlodipine Sandoz 2.5 mg tablet contains 2.5 mg amlodipine.
Each Amlodipine Sandoz 5 mg tablet contains 5 mg amlodipine.
Each Amlodipine Sandoz 10 mg tablet contains 10 mg amlodipine.
Not all strengths may be available in Australia.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Amlodipine Sandoz 2.5 mg tablet: A white or almost white, oblong, bevelled tablet, coded “2.5” on one side.
Amlodipine Sandoz 5 mg tablet: A white or almost white, oblong, bevelled tablet, scored on one side and coded “5” on the other.
Amlodipine Sandoz 10 mg tablet: A white or almost white, oblong, bevelled tablet, scored on one side and coded “10” on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension.

First line treatment of hypertension. It can be used as the sole agent to control blood pressure in the majority of patients. Patients not adequately controlled on a single antihypertensive agent may benefit from the addition of amlodipine besilate, which has been used in combination with a thiazide diuretic, beta-adrenoreceptor blocking agent or an angiotensin converting enzyme inhibitor.

Angina.

First line treatment of chronic stable angina. Amlodipine besilate may be used alone, as monotherapy, or in combination with other antianginal drugs.

4.2 Dose and Method of Administration

Dosage.

For hypertension or angina the usual initial dose is 2.5 to 5 mg once daily which may be increased to a maximum dose of 10 mg depending on the individual patient's response.
Small, fragile or elderly individuals, or patients with hepatic insufficiency should be started on 2.5 mg once daily and this dose may be used when adding amlodipine besilate to other antihypertensive therapy.
Dosage should be adjusted according to each patient's need. In general, titration should proceed over 7 to 14 days so that the doctor can fully assess the patient's response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently. (See Section 4.8 Adverse Effects (Undesirable Effects)).

Coadministration with other antihypertensive and/or antianginal drugs.

Amlodipine besilate has been safely administered with thiazides, angiotensin converting enzyme (ACE) inhibitors, beta-blockers, long acting nitrates, and/or sublingual nitroglycerine (glyceryl trinitrate).
No dose adjustment of amlodipine besilate is required upon concomitant administration of thiazide diuretics, beta-blockers, long acting nitrates and ACE inhibitors.

4.3 Contraindications

Known hypersensitivity to amlodipine, other dihydropyridines, or any of the inactive ingredients.

4.4 Special Warnings and Precautions for Use

Increased angina.

Rarely patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Outflow obstruction (aortic stenosis).

Amlodipine besilate should be used with caution in the presence of a fixed left ventricular outflow obstruction (aortic stenosis).

Use in patients with congestive heart failure.

In general, calcium channel blockers should be used with caution in patients with heart failure. Amlodipine (5 to 10 mg/day) has been studied in a placebo controlled trial of 1,153 patients with NYHA class III or IV heart failure on stable doses of ACE inhibitor, digoxin and diuretics. Follow-up was at least six months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life threatening arrhythmia, acute myocardial infarction, or hospitalisation for worsened heart failure). Amlodipine besilate has been compared to placebo in four 8 to 12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms or LVEF.

Beta-blocker withdrawal.

Amlodipine besilate is not a beta-blocker and, therefore, provides no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Peripheral oedema.

Mild to moderate peripheral oedema was the most common adverse event in the clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). The incidence of peripheral oedema was dose dependent and ranged in frequency from 3.0 to 10.8% in the 5 to 10 mg dose range. Care should be taken to differentiate this peripheral oedema from the effects of increasing left ventricular dysfunction.

Use in hepatic impairment.

There are no adequate studies in patients with liver dysfunction and dosage recommendations have not been established. In a small number of patients with mild to moderate hepatic impairment given single doses of amlodipine 5 mg, half-life has been prolonged. Worsening of liver function test values may occur. Amlodipine besilate should, therefore, be administered with caution in these patients and careful monitoring should be performed. A lower starting dose may be required (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

Amlodipine is extensively metabolised to inactive metabolites with 10% excreted as unchanged drug in the urine. Changes in amlodipine plasma concentrations are not correlated with the degree of renal impairment. Amlodipine besilate may be used at normal doses in patients with renal failure. Amlodipine is not dialysable.

Use in the elderly.

In elderly patients (≥ 65 years) clearance of amlodipine is decreased with a resulting increase in AUC. In clinical trials the incidence of adverse events in elderly patients was approximately 6% higher than that of younger population (< 65 years). Adverse events include oedema, muscle cramps and dizziness. Amlodipine besilate should be used cautiously in elderly patients.

Paediatric use.

Amlodipine is not indicated in children. Safety and effectiveness have not been established in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Amlodipine besilate has been safely administered with thiazide diuretics, beta-blockers, ACE inhibitors, long acting nitrates, sublingual nitroglycerine (glyceryl trinitrate), non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycaemic drugs.
Special studies have indicated that the co-administration of amlodipine besilate with digoxin did not change serum digoxin levels or digoxin renal clearance in healthy volunteers, and that co-administration of cimetidine did not alter the pharmacokinetics of amlodipine; and that coadministration with warfarin did not change the warfarin prothrombin response time.
In vitro data from studies with human plasma indicate that amlodipine has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin or indomethacin).

Simvastatin.

Co-administration of multiple doses of amlodipine and simvastatin resulted in an increase in exposure to simvastatin compared to simvastatin alone. The product information for simvastatin should be reviewed for the appropriate dose of simvastatin when the patient is prescribed amlodipine concurrently.

Grapefruit juice.

Grapefruit juice is known to inhibit the cytochrome P450 system, thereby affecting the pharmacokinetics of drugs such as calcium channel blockers.
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

CYP3A4 inhibitors.

With concomitant use with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients respectively the plasma concentration of amlodipine increased. However, the clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors.

Clarithromycin.

Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.

CYP3A4 inducers.

There are no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum [St John's wort]) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

Aluminium/ magnesium (antacid).

Coadministration of an aluminium/ magnesium antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil.

A single 100 mg dose of sildenafil in 16 patients with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin.

Coadministration of multiple 10 mg doses of amlodipine with atorvastatin 80 mg resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Ethanol (alcohol).

Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Ciclosporin.

No drug interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations, with the exception of renal transplant patients. Various studies in renal transplant patients report that co-administration of amlodipine with ciclosporin affects the trough concentrations of ciclosporin, and consideration should be given for monitoring ciclosporin levels in renal transplant patients on amlodipine.

Tacrolimus.

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic target of rapamycin (mTOR) inhibitors.

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use of mTOR inhibitors and amlodipine may increase exposure of mTOR inhibitors.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In animal studies, amlodipine did not affect fertility in rats at oral doses up to 18 mg/kg (base) and had no teratogenic effects in rats (18 mg/kg) or rabbits (10 mg/kg).
(Category C)
Calcium channel blockers carry the potential to produce fetal hypoxia associated with maternal hypotension. Accordingly they should not be used in pregnant women unless the potential benefit outweighs the risk to the fetus.
Safety of amlodipine besilate in human pregnancy or lactation has not been established. Amlodipine (10 mg/kg as besilate salt, 7 mg/kg base) administered orally to rats at or near parturition induced a prolongation of gestation time, a prolonged duration of labour, an increase in the number of stillbirths and a decreased postnatal survival.
 Experience in humans indicates that amlodipine is transferred into human breast milk.
Breast-feeding should be discontinued during treatment with amlodipine besilate.

4.7 Effects on Ability to Drive and Use Machines

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired.

4.8 Adverse Effects (Undesirable Effects)

Amlodipine besilate has been evaluated for safety in more than 11,000 patients in clinical trials worldwide.
In general, treatment with amlodipine besilate was well tolerated at doses up to 10 mg daily. Most adverse events reported during therapy with amlodipine besilate were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besilate (n = 1,730) in doses up to 10 mg to placebo (n = 1,250), discontinuation of amlodipine besilate due to adverse events was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). Amlodipine besilate therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, uric acid, blood urea nitrogen, creatinine or liver function tests.
The most common side effects are headache and oedema. The incidence (%) of side effects which occurred in a dose related manner are listed in Table 1.
Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo controlled clinical trials include the following (see Table 2).
The following events occurred in ≤ 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the doctor to a possible relationship.

Cardiac disorders.

Tachycardia, palpitations.

Vascular disorders.

Hot flushes, hypotension, peripheral ischaemia, postural hypotension, vasculitis.

Ear and labyrinth disorders.

Tinnitus, vertigo.

Nervous system disorders.

Hypoesthesia, paraesthesia, postural dizziness, syncope, tremor, peripheral neuropathy.

Eye disorders.

Abnormal vision, conjunctivitis, diplopia, eye pain.

Gastrointestinal disorders.

Anorexia, altered bowel habits, constipation, diarrhoea, dry mouth, dyspepsia*, dysphagia, flatulence, gingival hyperplasia, pancreatitis, vomiting.

General disorders and administration site conditions.

Asthenia*, chest pain, malaise, pain, rigors, thirst.

Immune system disorders.

Allergic reactions.

Musculoskeletal connective tissue and bone disorders.

Arthralgia, arthrosis, back pain, muscle cramps*, myalgia, ankle swelling.

Psychiatric disorders.

Abnormal dreams, anxiety, depersonalisation, depression, insomnia, mood changes., nervousness.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea*, epistaxis.

Skin and subcutaneous tissue disorders.

Alopecia, angioedema, pruritus*, purpura, skin discolouration, hyperhydrosis, exanthema, rash*, rash erythematous, rash maculopapular, sweating increased.

Renal and urinary disorders.

Micturition disorder, micturition frequency, nocturia, increased urinary frequency.

Metabolism and nutritional disorders.

Hyperglycaemia, anorexia.

Blood and lymphatic system disorders.

Leucopenia, thrombocytopenia.

Reproductive system and breast disorder.

Gynaecomastia, sexual dysfunction (male* and female), impotence.

Investigations.

Weight increase, weight decrease.
*These events occurred in less than 1% of patients in placebo controlled trials, but the incidence of these side effects was between 1 and 2% in all multiple dose studies.
The following events occurred in ≤ 0.1% of patients.
Cardiac failure, pulse irregularity, extrasystoles, skin discolouration, urticaria, skin dryness, dermatitis, erythema multiforme, Stevens-Johnson syndrome, photosensitivity, Quinke oedema, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, xerophthalmia and weight decrease.
As with other calcium channel blockers the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) chest pain, and vasculitis.
There have been infrequent postmarketing reports of hepatitis, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis). Some cases severe enough to require hospitalisation have been reported in association with use of amlodipine. In many instances, causal association is uncertain.
There have been post-marketing reports of extrapyramidal disorder in association with use of amlodipine.
Amlodipine besilate has been used safely in patients with chronic obstructive pulmonary disease, well compensated congestive heart failure, peripheral vascular disease, diabetes mellitus and abnormal lipid profiles.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Available data suggest that overdose might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. Dysrhythmias may occur following overdose with any calcium antagonists. Hypotension and bradycardia are usually seen within 1 to 5 hours following overdose. Hypotension can persist for longer than 24 hours despite treatment. Cardiac rhythm disturbances have been noted to persist for up to 7 days. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalised; another (120 mg) was hospitalised, underwent gastric lavage and remained normotensive; the third one (105 mg) was hospitalised and had hypotension (90/50 mmHg) which normalised following plasma expansion. Death resulted from a mixed overdose of 140 mg and 10 mefenamic acid capsules in a 15 year old girl, and from a mixed overdose of amlodipine 70 mg and an unknown quantity of oxazepam in a 63 year old woman. A case of accidental drug overdose has been documented in a 19 month old male who ingested amlodipine besilate 30 mg (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 beats per minute.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium may help to reverse the effects of calcium entry blockade. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. Ipecac emesis is not recommended since haemodynamic instability and CNS depression may rapidly develop. Since amlodipine is highly protein bound, dialysis is not likely to be of benefit.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Amlodipine is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiological pH range, amlodipine is an ionised compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterised by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces the total ischaemic burden by the following two actions.
Firstly, it dilates peripheral arterioles and thus reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
Secondly, amlodipine has been shown to block constriction in main coronary arteries and coronary arterioles, induced by calcium, potassium, adrenaline, serotonin and thromboxane A2 analogue both in normal and in ischaemic regions.

Haemodynamics.

Following administration of therapeutic doses to patients with hypertension, amlodipine besilate produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreased arterial blood pressure and increased heart rate in haemodynamic studies of patients with chronic stable angina, chronic administration of oral amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients.
The magnitude of reduction in blood pressure with amlodipine besilate is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine besilate have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine besilate has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when coadministered with beta-blockers to humans. Similar findings, however, have been observed in normal or well compensated patients with heart failure with agents possessing significant negative inotropic effects.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine besilate resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

Electrophysiological effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In patients with chronic stable angina, intravenous administration of amlodipine 10 mg and a further 10 mg after a 30 minute interval produced peripheral vasodilation and afterload reduction, but did not significantly alter atrial-His (A-H) and His-ventricular (H-V) conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine besilate and concomitant beta-blockers. In clinical studies in which amlodipine besilate was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine besilate therapy did not alter electrocardiographic intervals or produce higher degrees of atrioventricular blocks.

Effects in hypertension.

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval postdose. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration. The blood pressure effect is maintained over the 24 hour dosing interval, with little difference in peak and trough effect. Tolerance has not been demonstrated in patients studied for up to one year. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure.

Effects in chronic stable angina.

In patients with angina, once daily administration of amlodipine increases total exercise time to angina onset and total work time to 1 mm ST segment depression and decreases both angina attack frequency and nitroglycerine (glyceryl trinitrate) tablet consumption. The sustained efficacy of amlodipine besilate in angina patients has been demonstrated over long-term dosing. In patients with angina there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+ 0.3 beats per minute).

Other.

In clinical trials amlodipine has shown no harmful effect on lipid levels. Dihydropyridine calcium channel blockers have not been associated with any adverse metabolic effects and are suitable for use in patients with asthma, diabetes and gout.

Clinical trials.

Studies in patients with congestive heart failure.

Amlodipine besilate has been compared to placebo in four 8 to 12 week studies of patients with New York Heart Association (NYHA) class II/III heart failure, involving a total of 697 patients. Although efficacy in regard to the primary and secondary endpoints was not demonstrated, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms or LVEF. In a long-term (follow-up at least six months, mean 13.8 months) placebo controlled mortality/ morbidity study of amlodipine besilate 5 to 10 mg in 1,153 patients with NYHA classes III (n = 931) or IV (n = 222) heart failure on stable doses of diuretics, digoxin and ACE inhibitors, amlodipine besilate had no effect on the primary endpoint of the study which was the combined endpoint of all cause mortality and cardiac morbidity (as defined by life threatening arrhythmia, acute myocardial infarction or hospitalisation for worsened heart failure), or on NYHA classification or symptoms of heart failure. Total combined all cause mortality and cardiac morbidity events were 222/571 (39%) for patients on amlodipine besilate and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.
In this study amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours postdose. This may reflect significant initial uptake by the liver, followed by a phase of redistribution. This interval is shorter (two to eight hours) in patients with hepatic insufficiency. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.

Distribution.

The volume of distribution is approximately 20 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism.

Amlodipine is extensively metabolised by the liver to inactive metabolites.

Excretion.

10% of the parent compound and 60% of metabolites is excreted in the urine.
The terminal plasma elimination half-life is about 35 to 50 hours and is consistent with once daily dosing. Steady-state plasma levels are reached after seven to eight days of consecutive dosing.

Special populations.

Elderly ≥ 65 years.

In elderly hypertensive patients (mean age 69 years) there was a decrease in clearance of amlodipine from plasma as compared to young volunteers (mean age 36 years) with a resulting increase in the area under the curve (AUC) of about 60%.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

The carcinogenic potential of amlodipine has not been fully elucidated. Amlodipine did not induce any tumours when tested in rats at oral doses up to 2.5 mg/kg. This dose gave rise to plasma levels that are similar to those achieved clinically.

6 Pharmaceutical Particulars

6.1 List of Excipients

Amlodipine Sandoz tablets also contain sodium starch glycollate, calcium hydrogen phosphate, cellulose-microcrystalline and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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. Protect from light.

6.5 Nature and Contents of Container

Amlodipine Sandoz tablets are available in PA/Al/PVC/Al or PVC/Al blister packs or HDPE bottles of 30 tablets.
Not all presentations may be available in Australia.

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

Amlodipine besilate is a white or almost white powder, slightly soluble in water, freely soluble in methanol, sparingly soluble in ethanol, slightly soluble in 2-propanol.
The chemical name of Amlodipine besilate is 3-ethyl 5-methyl-2-(2-aminoethoxymethyl)-4(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzene sulfonate. Its empirical formula is C20H25ClN2O5.C6H6O3S (MW: 567.1) (free base 408.9).

Chemical structure.


CAS number.

111470-99-6 (amlodipine besilate); 88150-42-9 (amlodipine).

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes