Consumer medicine information

Carvedilol Sandoz

Carvedilol

BRAND INFORMATION

Brand name

Carvedilol Sandoz

Active ingredient

Carvedilol

Schedule

SUMMARY CMI

Carvedilol Sandoz^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Carvedilol Sandoz?

Carvedilol Sandoz contains the active ingredient carvedilol. Carvedilol Sandoz is used to treat heart failure and high blood pressure (hypertension).

For more information, see Section 1. Why am I using Carvedilol Sandoz? in the full CMI.

2. What should I know before I use Carvedilol Sandoz?

Do not use if you have ever had an allergic reaction to carvedilol or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Carvedilol Sandoz? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Carvedilol Sandoz and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Carvedilol Sandoz?

Take Carvedilol Sandoz exactly as your doctor has prescribed.
Your doctor will tell you how many Carvedilol Sandoz tablets to take each day. This depends on your condition and whether or not you are taking other medicines.

More instructions can be found in Section 4. How do I use Carvedilol Sandoz? in the full CMI.

5. What should I know while using Carvedilol Sandoz?

Things you should do	Remind any doctor, dentist, pharmacist, surgeon, or anaesthetist you visit that you are using Carvedilol Sandoz, especially if you are going to have any laboratory tests or surgery. Drink enough water during exercise and hot weather. Tell your doctor if you haven't taken your medicine or if you feel it is not helping your condition.
Things you should not do	Do not stop using this medicine suddenly. Do not change the dose without first checking with your doctor. Do not run out of medicine over the weekend or on holidays.
Driving or using machines	Carvedilol Sandoz may affect your ability to drive a car or operate machinery when started or when the dosage is increased.
Looking after your medicine	Keep your tablets in the blister pack until it is time to take them. Store it in a cool dry place below 30°C away from moisture, heat, or sunlight.

For more information, see Section 5. What should I know while using Carvedilol Sandoz? in the full CMI.

6. Are there any side effects?

Shortness of breath, swelling of the mouth or tongue, fluid retention, severe blisters & bleeding in the lips, eyes, mouth, nose and genitals, itching, dark urine, loss of appetite, yellowing of skin or eyes, feeling “flu-like” with no clear cause, bleeding or bruising more easily, slow heart rate, irregular heartbeat, chest pain, feeling dizzy or lightheaded, headache, tiredness, drowsiness, abnormal or blurry vision, diarrhoea, nausea or vomiting, bronchitis, weight increase, unusual hair loss or thinning.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

Carvedilol Sandoz^®

Active ingredient(s): carvedilol

Consumer Medicine Information (CMI)

This leaflet provides important information about using Carvedilol Sandoz. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Carvedilol Sandoz.

Where to find information in this leaflet:

1. Why am I using Carvedilol Sandoz?
2. What should I know before I use Carvedilol Sandoz?
3. What if I am taking other medicines?
4. How do I use Carvedilol Sandoz?
5. What should I know while using Carvedilol Sandoz?
6. Are there any side effects?
7. Product details

1. Why am I using Carvedilol Sandoz?

Carvedilol Sandoz contains the active ingredient carvedilol.

Carvedilol Sandoz belongs to a group of medicines called beta-blockers. These medicines work by relaxing tightened blood vessels and slowing the heart rate. Carvedilol Sandoz has the additional effect of being an antioxidant.

Carvedilol Sandoz^® is used to treat:

heart failure,
high blood pressure, which is called hypertension.

Heart Failure

Heart failure occurs when the heart can no longer pump blood strongly enough for the body's needs. Often the heart grows in size to try to improve the blood flow, but this can make the heart failure worse.

Symptoms of heart failure include shortness of breath and swelling of the feet or legs due to fluid build-up.

Carvedilol Sandoz reduces the pressure that the heart has to pump against as well as controlling your heart rate. Over 6 months or more this will reduce the size of an oversized heart and increase its efficiency.

Carvedilol Sandoz reduces the chances of you being admitted to hospital and/or dying from this condition.

Carvedilol Sandoz is often used with other medicines to treat heart failure.

Hypertension

All people have blood pressure. This pressure helps to push blood all around your body. Your blood pressure changes during the day, depending on how busy you are or how you are feeling.

You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

Regular blood pressure checks are the only way of knowing that you have hypertension. There are usually no symptoms of hypertension and you may feel fine. If hypertension is not treated, serious health problems such as stroke, heart disease and kidney failure may occur.

Carvedilol Sandoz helps to lower your blood pressure.

Your doctor, however, may have prescribed Carvedilol Sandoz for another purpose.

Ask your doctor if you have any questions about why Carvedilol Sandoz has been prescribed for you.

Carvedilol Sandoz is not addictive.

2. What should I know before I use Carvedilol Sandoz?

Warnings

Do not use Carvedilol Sandoz if:

you are allergic to carvedilol, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
you are under 18 years of age.
you have asthma or other conditions which make you short of breath from time to time.
you have a history of allergic problems, including hay fever. Symptoms of an allergy may include: rash, itching, watery eyes, or sneezing.
you have a history of a very slow heart rate or uneven heart beating.
you have certain other heart conditions.
you have liver problems including liver failure.
you have very low blood pressure.
the package is torn or shows signs of tampering.
the expiry date (EXP) printed on the pack has passed or if the tablets appear damaged in some way

Use in Children

Do not give Carvedilol Sandoz to people under 18 years of age.

Safety and effectiveness in children have not been established.

Check with your doctor if you have other medical conditions, especially:

angina or chest pain/tightness which occurs even when you are at rest (also called unstable angina)
low blood pressure
high blood pressure which varies widely
very poor circulation to your fingers and/or toes (also called peripheral vascular disease)
a history of poor kidney function
chronic bronchitis or emphysema causing breathing difficulties
diabetes
sudden low blood sugar levels (also called hypoglycaemia)
thyroid disorders
severe allergic reactions causing swelling and/or difficulty breathing
a rare cancer of the adrenal gland called phaeochromocytoma which is not being treated with other medicines
skin disease such as psoriasis (hardened patches of red skin).

Check with your doctor if you take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

It is not known whether Carvedilol Sandoz is harmful to an unborn baby when taken by a pregnant woman. Your doctor will discuss the risks and benefits of using Carvedilol Sandoz during your pregnancy.

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

Carvedilol Sandoz passes into the breastmilk. Your doctor will discuss the risks and benefits of taking Carvedilol Sandoz if you are breast-feeding.

Surgery

Check with your doctor if you plan to have surgery.

Your surgeon and anaesthetist should know well ahead of the date of your surgery so they can allow for your condition and medications.

3. What if I am taking other medicines?

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

Some medicines may interfere with Carvedilol Sandoz and affect how it works. These medicines include:

rifampicin, a medicine used to treat tuberculosis
cimetidine, a medicine used to treat stomach ulcers or reflux
digoxin, a medicine used to treat heart failure
monoamine-oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine, medicines used to treat depression
clonidine, a medicine used to treat high blood pressure, migraine, or menopausal symptoms
diltiazem, a medicine used to treat high blood pressure or angina
verapamil, a medicine used to treat high blood pressure, angina, or fast heart rate
ciclosporin or tacrolimus, medicines used to treat certain problems with the immune system
aspirin and other pain relievers or non-steroidal anti-inflammatory medicines such as ibuprofen or naproxen medicines which may relieve asthma or help your breath better such as salbutamol and salmeterol.
fluoxetine or paroxetine, medicines used to treat depression and other conditions
drugs for when your heart doesn't beat smoothly, including disopyramide, mexiletine, lignocaine, flecainide, and amiodarone
drugs for diabetes, including insulin injections, glibenclamide, metformin, gliclazide, glipizide
other medicines that may help lower your blood pressure.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins, or supplements you are taking and if these affect Carvedilol Sandoz.

You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Carvedilol Sandoz.

4. How do I use Carvedilol Sandoz?

How much to take

Take Carvedilol Sandoz exactly as your doctor has prescribed.
Your doctor will tell you how many Carvedilol Sandoz tablets to take each day. This depends on your condition and whether or not you are taking other medicines.

Heart Failure:

The usual starting dose in heart failure is 3.125 mg (half a 6.25 mg tablet) twice daily.
The dose is usually increased every two weeks to 6.25 mg twice daily, 12.5 mg twice daily and then 25 mg twice daily. However, this may be done more slowly if side effects occur.
If the tablets slow your heart too much you may go back to a lower dose.

High Blood Pressure:

Adults: The recommended dose for initiation of therapy is 12.5 mg a day for the first two days. Thereafter, the recommended dosage is 25 mg once a day.
If necessary, the dosage may be increased every two weeks up to the recommended maximum daily dose of 50 mg given once a day or in divided doses (twice daily).
Elderly: The recommended dose for initiation of therapy is 12.5 mg once daily, which has provided satisfactory control in some patients. If the response is inadequate, the dose may be increased every two weeks up to the recommended maximum daily dose.
Your doctor will monitor you carefully each time the dose is increased.
Follow the instructions provided and use Carvedilol Sandoz until your doctor tells you to stop.

When to take Carvedilol Sandoz

Carvedilol Sandoz tablets should be taken with food at about the same time each day.
Taking your medicine at the same time each day will have the best effect. It will also help you to remember when to take it.
If you take Carvedilol Sandoz on an empty stomach, it may increase the risk of some of the side effects.

How to take Carvedilol Sandoz

Swallow the tablets whole or halved with a glass of water.
Do not crush or chew the tablets.

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

How to long to take Carvedilol Sandoz

Continue taking your medicine for as long as your doctor tells you.
Make sure you have enough to last over weekends and holidays
It is very important that Carvedilol Sandoz is not ceased suddenly. If you are to stop taking Carvedilol Sandoz, your doctor will advise you to reduce the dose slowly over approximately two weeks.

If you forget to use Carvedilol Sandoz

Carvedilol Sandoz should be used regularly at the same time each day.

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 it as soon as you remember then go back to taking your medicine as you would normally.

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 use too much Carvedilol Sandoz

If you think that you have used too much Carvedilol Sandoz, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(By calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

The following are some symptoms, which may or may not occur as a result of taking too much Carvedilol Sandoz:

low blood pressure, causing dizziness or fainting
a very slow heart rate
difficulty breathing
vomiting
shock
seizures

5. What should I know while using Carvedilol Sandoz?

Things you should do

Make sure you drink enough water during exercise and hot weather when you are taking Carvedilol Sandoz, especially if you sweat a lot.

Tell your doctor that you are taking Carvedilol Sandoz if you are going to have any laboratory tests.

Remind any doctor, dentist, or pharmacist you visit that you are using Carvedilol Sandoz. You should also tell your surgeon and anaesthetist if you are having surgery.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel the tablets are not helping your condition.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Your doctor may examine your eyes and test your blood glucose and kidney function from time to time.

Call your doctor straight away if you:

feel light-headed, dizzy, or faint when getting out of bed or standing up, get up slowly.
become pregnant while taking Carvedilol Sandoz.

Things you should not do

Do not stop using this medicine suddenly.
Do not stop taking Carvedilol Sandoz or change the dose without first checking with your doctor.
Do not let yourself run out of medicine over the weekend or on holidays.
Carvedilol Sandoz should only be stopped by gradually reducing the amount over a two-week period.
Do not give Carvedilol Sandoz to anyone else even if they have the same condition as you.
Do not use Carvedilol Sandoz to treat other complaints unless your doctor says to.
Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Contact lenses

If you wear contact lenses you may also notice a reduction in the amount of tear fluid in your eyes.

Drinking grapefruit juice

When taken with grapefruit juice the amount of Carvedilol Sandoz absorbed by your body may be increased.

Drinking alcohol

Talk to your doctor about drinking alcohol before taking Carvedilol Sandoz

Alcohol can change how the medicine affects your condition. Your doctor may advise you to limit your alcohol intake.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Carvedilol Sandoz affects you.

Carvedilol Sandoz may affect your ability to drive a car or operate machinery when started or when the dosage is increased.

Looking after your medicine

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

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place below 30°C away from moisture, heat, or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor tells you to stop taking Carvedilol Sandoz, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

General well-being related:

headache (this is usually mild and happens at the start of your treatment)
unusual weakness
tiredness, drowsiness
faintness

Mood related:

hallucination
depression

Heart related:

low blood pressure. The signs include feeling dizzy or lightheaded especially after you stand up.
slow heart rate

Eye related:

abnormal or blurry vision
dry or irritated eyes

Gut related:

diarrhoea
nausea or vomiting
indigestion
stomach pain or discomfort

Bladder related:

frequent need to urinate, difficulty or pain when passing urine

Lungs related:

asthma

Infection related:

bronchitis

Others:

fluid retention (the signs include overall swelling of parts of your body for example your hands, feet, ankles and legs.)
unusual hair loss or thinning
excessive sweating
loss of control of blood sugar in diabetics
general pain or discomfort, pain in extremities
weight increase

Speak to your doctor if you have any of these less serious side effects and they worry you.

These are the more common side effects of Carvedilol Sandoz. Mostly these are mild and will decrease as you get used to your medicine.

Serious side effects

Serious side effects

What to do

Infection related:

Fever, chills, shortness of breath and a cough produce yellow green phlegm and occasionally blood.

Heart related:

Irregular heartbeat, slow heartbeat, or heartbeat pause/stops, especially in older people or people with other heart conditions.

Breathing related:

Difficulty breathing or breathlessness usually worsens on lying down.
Chest tightness

Allergy related:

Shortness of breath or swelling of the mouth of tongue.

Blood related:

Bleeding or bruising more easily than normal

Others:

Itching, dark urine, loss of appetite, yellowing of skin or eyes, or feeling “flu-like” with no clear cause.
Severe blisters and bleeding in the lips, eyes, mouth, nose, and genitals.
Swelling of the feet or legs due to fluid build up

Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Carvedilol Sandoz contains

Active ingredient (Main ingredient)	Each Carvedilol Sandoz 6.25mg tablet contains 6.25mg carvedilol. Each Carvedilol Sandoz 12.5mg tablet contains 12.5mg carvedilol. Each Carvedilol Sandoz 25mg tablet contains 25mg carvedilol.
Other ingredients (Inactive ingredients)	lactose monohydrate microcrystalline cellulose crospovidone povidone colloidal anhydrous silica magnesium stearate iron oxide yellow (6.25 and 12.5mg) iron oxide red (12.5mg).
Potential allergens	This medicine contains sugars as lactose

Do not take this medicine if you are allergic to any of these ingredients.

What Carvedilol Sandoz looks like

Carvedilol Sandoz 6.25mg tablets: a yellow, round, convex, scored tablet, coded C2 on one side. (AUST R 104391)

Carvedilol Sandoz 12.5mg tablets: a red-brown, round, convex, scored tablet, coded C3 on one side. (AUST R 104396)

Carvedilol Sandoz 25mg tablets: a white to almost white, round, convex, scored tablet, coded C4 on one side. (AUST R 104399)

Carvedilol Sandoz is available in 60 tablet blister packs.

Who distributes Carvedilol Sandoz

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

This leaflet was prepared in June 2022

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Carvedilol Sandoz

Active ingredient

Carvedilol

Schedule

1 Name of Medicine

Carvedilol.

2 Qualitative and Quantitative Composition

For the full list of excipients, see Section 6.1 List of Excipients.

Excipients of known effect.

Lactose.

3 Pharmaceutical Form

Carvedilol Sandoz 6.25 mg tablets.

Yellow, round, convex, scored tablet, coded C2 on one side.

Carvedilol Sandoz 12.5 mg tablets.

Red/brown, round, convex, scored tablet, coded C3 on one side.

Carvedilol Sandoz 25 mg tablets.

White to almost white, round, convex, scored tablet, coded C4 on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Carvedilol Sandoz is indicated for the treatment of hypertension. Data have not been provided to support the use of this drug in renovascular disease.
Carvedilol Sandoz is indicated for the treatment of patients with symptomatic mild to severe (NYHA class II - IV) congestive heart failure (CHF) as an adjunct to conventional treatments (e.g. diuretics, digoxin, ACE inhibitors and vasodilators).

4.2 Dose and Method of Administration

Dosage.

Hypertension. Once daily dosing is recommended.

Adults.

The recommended dose for initiation of therapy is 12.5 mg once a day for the first two days. Thereafter, the recommended dosage is 25 mg once a day. If necessary, the dosage may subsequently be increased at intervals of at least two weeks up to the recommended maximum daily dose of 50 mg given once or twice daily.

Elderly.

The recommended dose for initiation of therapy is 12.5 mg once daily, which has provided satisfactory control in some patients. If the response is inadequate, the dose may be titrated at intervals of at least two weeks up to the recommended maximum daily dose.
Carvedilol can be combined with other antihypertensive agents, thiazide diuretics in particular.
Symptomatic congestive heart failure (CHF). Dosage must be individualised and closely monitored by the doctor during up-titration.
For patients receiving digitalis, diuretics and ACE inhibitors, dosing of these agents should be stabilised prior to initiation of Carvedilol Sandoz.
The recommended starting dose is 3.125 mg twice daily for two weeks. If this dose is tolerated, the dosage may subsequently be increased, at intervals of not less than two weeks, to 6.25 mg twice daily, followed by 12.5 mg twice daily, then 25 mg twice daily. Dosing should be increased to the highest level tolerated by the patient.
The recommended maximum dose is 25 mg twice daily in patients with mild or moderate CHF weighing less than 85 kg. In patients with mild or moderate CHF weighing more than 85 kg, the recommended maximum daily dose is 50 mg twice daily. For all patients with severe CHF the recommended maximum daily dose is 25 mg twice daily.
For severe CHF, before commencement of therapy, patients should be fully clinically evaluated to ensure that they have sitting systolic blood pressure ≥ 85 mmHg, no more than trace oedema of the peripheral limbs, no new pulmonary rales or ascites, optimisation of diuretic therapy and other established therapy such as ACE inhibitors and angiotensin II antagonists, no recent unstable angina, cardiac surgery or ventricular arrhythmias and no recent use of intravenous positive inotropic or vasodilator agents (other than digitalis).
Before each dose increase, the patient should be evaluated by the physician for symptoms of worsening heart failure, vasodilation or bradycardia. If either heart failure or vasodilation occurs, the dose of Carvedilol Sandoz should not be increased until symptoms of heart failure or vasodilation have been stabilised.
If bradycardia (pulse rate < 55 beats/minute) occurs, the dose of Carvedilol Sandoz should be reduced.
Transient worsening of heart failure or fluid retention should be treated with increased doses of diuretics. Occasionally it may be necessary to lower the dose of Carvedilol Sandoz or temporarily discontinue Carvedilol Sandoz. If carvedilol treatment is discontinued for more than one week, therapy should be recommenced at a lower dose level (twice daily) and up-titrated in line with the above dosing recommendation. If Carvedilol Sandoz is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg twice daily and up-titrated in line with the above dosing recommendations. Such episodes do not preclude subsequent successful up-titration of carvedilol.
Symptoms of vasodilation may be managed initially by a reduction in the dose of diuretics. If symptoms persist the dose of ACE inhibitor (if used) may be reduced, followed by a reduction in the dose of Carvedilol Sandoz if necessary.

Method of administration.

It is recommended that Carvedilol Sandoz be taken with food to slow the rate of absorption and to reduce the risk of orthostatic effects. The tablets should be swallowed with sufficient fluid.

Dosage adjustment.

Renal impairment.

Dosage adjustments are not required for mild to moderate impairment, however, in patients with underlying renal insufficiency, renal function should be monitored during up-titration of Carvedilol Sandoz and the drug discontinued or dosage reduced if worsening of renal function occurs.

Hepatic impairment.

Since plasma levels have been shown to be increased in patients with cirrhosis, Carvedilol Sandoz is contraindicated in patients with significant liver disease.

4.3 Contraindications

Carvedilol must not be used in patients with:
New York Heart Association (NYHA) Class IV decompensated heart failure requiring intravenous inotropic support.
Bronchial asthma (two cases of death from status asthmaticus have been reported in patients receiving single doses of carvedilol) or related bronchospastic conditions including chronic obstructive pulmonary disease (COPD) with a bronchospastic component.
Allergic disorders (including asthma and allergic rhinitis) which may suggest a predisposition to bronchospasm.
Severe sinus bradycardia (less than 45 to 50 beats per minute) or sick sinus syndrome (unless a permanent pacemaker is in place).
Shock (including cardiogenic and hypovolaemic shock).
Second and third degree atrioventricular block.
Known hypersensitivity to Carvedilol Sandoz.
Hepatic impairment. Carvedilol is contraindicated in patients with clinically manifest liver dysfunction.
Severe hypotension (systolic blood pressure < 85 mmHg).

4.4 Special Warnings and Precautions for Use

Beta-blockers can cause worsening heart failure. Since carvedilol has beta-blocking properties, care must be taken during initiation and up-titration of the drug in heart failure patients, since worsening heart failure has been observed in this phase of treatment. In order to minimise the risk of these events, it is critical to carefully follow the recommended dosing for carvedilol in patients with CHF (see Section 4.2 Dose and Method of Administration).
There are a number of important pharmacokinetic and pharmacodynamic interactions with other drugs (e.g. digoxin, ciclosporin, rifampicin, anaesthetic drugs, anti-arrhythmic drugs), see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Abrupt withdrawal.

In patients with heart failure, ischaemic heart disease or angina pectoris, abrupt cessation of therapy may lead to deterioration. There have been reports of severe exacerbation of angina, and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of beta-blocker therapy. Therefore, when discontinuing carvedilol in patients with angina pectoris the dosage should be gradually reduced over a period of about 2 weeks and the patient should be carefully observed. The same frequency of administration should be maintained. If angina markedly worsens or acute coronary insufficiency develops, re-institute carvedilol therapy promptly, at least temporarily.

Prinzmetal variant angina.

Agents with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There has been no clinical experience with carvedilol in these patients, although the alpha-blocking activity of carvedilol may prevent such symptoms. Caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina.

Bradycardia.

In clinical trials, carvedilol caused bradycardia in about 2% of hypertensive patients and 9% of congestive heart failure patients. If pulse rate drops below 55 beats/minute, the dosage should be reduced.

Hypotension.

Hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of congestive heart failure patients receiving carvedilol compared to 3.6 and 2.5% of placebo patients, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up-titration period, and was a cause for discontinuation of therapy in 0.7% of carvedilol patients, compared to 0.4% of placebo patients.
To decrease the likelihood of syncope or excessive hypotension, treatment should be initiated with 3.125 mg b.i.d. (twice daily) for congestive heart failure patients. Dosage should then be increased slowly, according to the recommendations in Section 4.2 Dose and Method of Administration, and the drug should be taken with food. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.

Labile hypertension.

Carvedilol should be used with caution in patients with labile or secondary hypertension until further clinical experience is available.

Peripheral vascular disease and Raynaud's phenomenon.

Carvedilol should be used with caution in patients with peripheral vascular disease (e.g. Raynaud's phenomenon) as β-blockers can precipitate or aggravate symptoms of arterial insufficiency.

Hypertensive patients with left ventricular failure.

In hypertensive patients who have congestive heart failure controlled with digitalis, diuretics and/or an angiotensin converting enzyme inhibitor, carvedilol may be used. However, since it is likely that such patients are dependent, in part, on sympathetic stimulation for circulatory support, it is recommended that dosing follow the instructions for patients with congestive heart failure.

Left ventricular dysfunction following acute myocardial infarction.

Before treatment with carvedilol is initiated the patient must be clinically stable and should have received an ACE inhibitor for at least the preceding 48 hours, and the dose of the ACE inhibitor should have been stable for at least the preceding 24 hours.

Psoriasis.

Patients with a history of psoriasis associated with β-blocker therapy should take carvedilol only after consideration of the risk-benefit ratio.

Ocular effects.

Animal studies have shown that carvedilol binds to the melanin of the uveal tract. The significance of this in humans is not known but periodic ophthalmic examinations are advisable while the patient is taking carvedilol.
Oculomucocutaneous syndrome, whose signs include conjunctivitis sicca, psoriasiform rashes, and sclerosing serositis, has occurred with the chronic use of one beta-adrenergic blocking agent (practolol). This syndrome has not been observed in association with carvedilol or any other such agent. However, physicians should be alert to the possibility of such reactions and discontinue treatment in the event that they occur.
Wearers of contact lenses should bear in mind the possibility of reduced lacrimation.

Diabetes and hypoglycaemia.

Care should be taken in the administration of carvedilol to patients with diabetes as it may be associated with worsening control of blood glucose, or the early signs and symptoms of acute hypoglycaemia may be masked or attenuated. Beta-blockers may mask some of the manifestations of hypoglycaemia, particularly tachycardia. Non-selective beta-blockers may potentiate insulin induced hypoglycaemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycaemia, or diabetic patients receiving insulin or oral hypoglycaemic agents, should be cautioned about these possibilities and carvedilol should be used with caution. In congestive heart failure patients with diabetes, the use of Carvedilol Sandoz may lead to worsening hyperglycaemia, which responds to intensification of hypoglycaemic therapy. It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted or discontinued. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacodynamic interactions).

Thyrotoxicosis.

Beta-adrenergic blockade may mask the clinical signs of hyperthyroidism such as tachycardia. Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

Hypersensitivity reactions.

Care should be taken in administering carvedilol to patients with a history of serious hypersensitivity reactions, and in those patients undergoing desensitisation therapy, as β-blockers may increase both the sensitivity towards allergens and the severity of hypersensitivity reactions. Such patients may be unresponsive to the usual doses of adrenaline used to treat allergic reaction.

Severe cutaneous adverse reactions (SCARs).

Very rare cases of severe cutaneous adverse reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment of carvedilol (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience). Carvedilol should be permanently discontinued in patients who experience severe cutaneous adverse reactions possibly attributable to carvedilol.

Risk of anaphylactic reaction.

While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens, and in those undergoing desensitisation therapy, may be more reactive to repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of adrenaline used to treat allergic reaction.

Non-allergic bronchospasm (e.g. chronic bronchitis and emphysema).

Patients with bronchospastic disease should in general not receive beta-blockers. Carvedilol may be used with caution.
In clinical trials of patients with congestive heart failure, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacodynamic interactions.)

Anaesthesia and major surgery.

If Carvedilol Sandoz treatment is to be continued perioperatively, particular care should be taken when anaesthetic agents which depress myocardial function such as ether, cyclopropane and trichloroethylene are used. See Section 4.9 Overdose for information on treatment of bradycardia and hypotension.

Phaeochromocytoma.

In patients with this condition, an alpha-blocking drug (e.g. phentolamine or phenoxybenzamine) should be administered before the beta-blocker to avoid exacerbation of hypertension. Although carvedilol has both alpha and beta-blocking pharmacological activities, there is no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having phaeochromocytoma.

Concomitant use of calcium channel blockers.

Careful monitoring of ECG and blood pressure is necessary in patients receiving concomitant therapy with calcium channel blockers of the verapamil or diltiazem type or other antiarrhythmic drugs.

Lactose.

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hepatic injury.

Mild hepatocellular injury, confirmed by rechallenge, has occurred rarely with carvedilol therapy.
In controlled studies of congestive heart failure, the incidence of liver function abnormalities reported as adverse experiences was 5.0% (38 of 765 patients) in patients receiving carvedilol and 4.6% (20 of 437 patients) in those receiving placebo. Three patients receiving carvedilol (0.4%) and two patients receiving placebo (0.5%) in placebo-controlled trials withdrew for abnormal hepatic function.
Hepatic injury has been reversible and has occurred after short and/or long-term therapy with minimal clinical symptomatology. No deaths due to liver function abnormalities have been reported.
At the first symptom/ sign of liver dysfunction (e.g. pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained "flu-like" symptoms) laboratory testing should be performed. If the patient has laboratory evidence of liver injury or jaundice, carvedilol should be stopped and not restarted.

Renal function.

Rarely, use of carvedilol in patients with congestive heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic BP < 100 mmHg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors, it is recommended that renal function should be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs.

Use in the elderly.

In congestive heart failure trials of carvedilol worldwide, there were no notable differences in efficacy or the incidence of adverse events between older (≥ 65 years) and younger patients. With the exception of dizziness (incidence 8.8% in the elderly vs. 6% in younger patients), there were no events in the world-wide hypertensive trial population for which the incidence in the elderly exceeded that in the younger population by greater than 2%.

Paediatric use.

Safety and efficacy of Carvedilol Sandoz in patients younger than 18 years of age have not been established. Use of Carvedilol Sandoz in paediatric patients is not recommended as substantial information regarding benefits and risks is missing. (See Section 5.1 Pharmacodynamic Properties, Clinical trials).

Effects on laboratory tests.

Carvedilol does not affect laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interactions.

Effects of carvedilol on the pharmacokinetics of other drugs. Carvedilol is a substrate as well as an inhibitor of P-glycoprotein. Therefore, the bioavailability of drugs transported by P-glycoprotein may be increased with concomitant administration of carvedilol. In addition, the bioavailability of carvedilol can be modified by inducers or inhibitors of P-glycoprotein.

Digoxin.

An increased exposure of digoxin of up to 56% has been shown in some studies in healthy subjects and patients with heart failure, when given carvedilol. A significantly larger effect has been seen in male patients compared to female patients. Therefore, monitoring of digoxin levels and signs and symptoms of digoxin toxicity is recommended when initiating, adjusting or discontinuing carvedilol (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacodynamic interactions). Carvedilol had no effect on digoxin administered intravenously.

Ciclosporin and tacrolimus.

Two studies in renal and cardiac transplant patients receiving oral ciclosporin have shown an increase in ciclosporin plasma concentration following the initiation of carvedilol. It appears that carvedilol increases the absorption of ciclosporin (po) through inhibition of P-glycoprotein activity in the intestine. In an attempt to maintain therapeutic ciclosporin levels, an average 10-20% reduction of the ciclosporin dose was necessary. Therefore, due to wide interindividual variability of ciclosporin levels, it is recommended that ciclosporin concentrations are monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin be adjusted as appropriate. In case of IV administration of ciclosporin, no interaction with carvedilol is anticipated. Furthermore, there is evidence that CYP3A4 is involved in the metabolism of carvedilol. As tacrolimus is a substrate of P-glycoprotein and CYP3A4, its pharmacokinetics may also be affected by carvedilol through these interaction mechanisms.
Effects of other drugs and other substances on the pharmacokinetics of carvedilol. Inhibitors as well as inducers of CYP2D6 and CYP2C9 can modify the systemic and/or presystemic metabolism of carvedilol stereoselectively, leading to increased or decreased plasma concentrations of R and S-carvedilol. Retrospective analysis of side effects in clinical trials showed that poor CYP2D6 metabolisers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the alpha-blocking R(+) enantiomer.
Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.

Grapefruit juice.

Consumption of a single dose of 300 mL of grapefruit juice (an inhibitor of CYP3A4 and CYP1A2) was shown to result in a 16% increase of the AUC of carvedilol in comparison to water. While the clinical relevance of this observation is unclear, it is advisable that patients should avoid concomitant intake of grapefruit juice at least until a stable dose-response relationship is established.

Rifampicin.

In a study in 12 healthy subjects, exposure to carvedilol decreased by around 60% during concomitant administration with rifampicin and a decrease effect of carvedilol on the systolic blood pressure during exercise was observed. The mechanism for the interaction is not known but it may be due to the induction of the intestinal P-glycoprotein by rifampicin. A close monitoring of the β-blockade activity in patients receiving concomitant administration of carvedilol and rifampicin is appropriate.

Cimetidine.

The AUC of carvedilol was increased by 30% without associated increase in C_max in healthy male subjects receiving concomitant cimetidine, which is not a potent CYP2D6 inhibitor.

Amiodarone.

An in vitro study with human liver microsomes has shown that amiodarone and desethylamiodarone inhibited the oxidation of R- and S-carvedilol. The trough concentration of S-carvedilol was significantly increased by 2.2-fold in heart failure patients receiving carvedilol and amiodarone concomitantly as compared to patients receiving carvedilol monotherapy. The effect on S-carvedilol was attributed to desethylamiodarone, a metabolite of amiodarone, which is a strong inhibitor of CYP2C9. Monitoring of the β-blockade activity in patients treated with the combination carvedilol and amiodarone is advised.

Fluoxetine and paroxetine.

In a randomised, cross-over study in 10 patients with heart failure, co-administration of fluoxetine, a strong inhibitor of CYP2D6, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in mean R(+) enantiomer's AUC, and a non-statistically 35% increase of the S(-) enantiomer's AUC as compared to the placebo group. However, no differences in adverse events and no statistically significant differences in blood pressure and heart rate were noted between treatment groups. The effect of paroxetine, a strong CYP2D6 inhibitor, on carvedilol pharmacokinetics was investigated in 12 healthy subjects following single oral carvedilol administration. In the study, the AUC of R-carvedilol and S-carvedilol were increased by approximately 2.5-fold and 1.9-fold, respectively. Despite significant increase in R- and S-carvedilol exposure, no clinical effects were observed in these healthy subjects. Care should be taken when carvedilol is combined with fluoxetine or paroxetine in clinically unstable patients.

Alcohol.

Concomitant consumption of alcohol can potentiate the antihypertensive action of carvedilol and cause different adverse reactions, such as syncope and hypotension. Alcohol intake was shown to have acute hypotensive effects which possibly augment the blood pressure reduction caused by carvedilol. As carvedilol is only sparingly soluble in water but soluble in ethanol, the presence of alcohol could affect the rate and/or extent of intestinal absorption of carvedilol by increasing its solubility. Furthermore, carvedilol was shown to be partly metabolized by CYP2E1, an enzyme known to be both induced and inhibited by alcohol.

Pharmacodynamic interactions.

Clonidine.

Concomitant administration of clonidine with agents with beta-blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with beta-blocking properties and clonidine is to be terminated, the beta-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.

Catecholamine depleting agents.

Patients treated with both carvedilol and a drug that can deplete catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.

Non-dihydropyridines calcium channel blockers, amiodarone or other antiarrhythmic drugs.

Care should be taken when prescribing beta-blockers with non-dihydropyridines calcium blockers, amiodarone or other antiarrhythmics because their combination with carvedilol can increase the risk of AV conduction disturbances. Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when carvedilol and diltiazem were co-administered. As with other drugs with beta-blocking activity, if carvedilol is to be administered orally with non-dihydropyridines calcium channel blockers of the verapamil or diltiazem type, amiodarone or other antiarrhythmics, it is recommended that ECG and blood pressure be monitored.
Interactions have been reported during concomitant beta-blocker therapy with the Class IA agents disopyramide, and less frequently quinidine; Class IB agents tocainide, mexiletine and lignocaine; the Class IC agent flecainide; the Class III agent amiodarone; and the Class IV antiarrhythmic agents.

Insulin or oral hypoglycaemics.

Agents with beta-blocking properties may enhance the blood sugar reducing effect of insulin and oral hypoglycaemics. The signs of hypoglycaemia may be masked or attenuated (especially tachycardia). Therefore, in patients taking insulin or oral hypoglycaemics, regular monitoring of blood glucose is recommended. (See Section 4.4 Special Warnings and Precautions for Use, Diabetes and hypoglycaemia).

Antihypertensives.

As with other agents with β-blocking activity, carvedilol may potentiate the effect of other concomitantly administered drugs that are anti-hypertensive in action (e.g. α₁-receptor antagonists) or have hypotension as part of their adverse effect profile.

NSAIDs.

The concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and beta-adrenergic blockers may result in an increase in blood pressure and impairment of blood pressure control.

Beta-agonist bronchodilators.

Non-cardioselective beta-blockers oppose the bronchodilator effects of beta-agonist bronchodilators. Careful monitoring of patients is recommended.

Anaesthetic agents.

Careful monitoring of vital signs is recommended during anaesthesia due to the synergistic negative inotropic and hypotensive effects of carvedilol and anaesthetic drugs.

Digoxin.

The combined use of beta-blockers and digoxin may result in additive prolongation of atrioventricular (AV) conduction time (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacokinetic interactions, Effects of carvedilol on the pharmacokinetics of other drugs above).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

When mated with similarly treated male rats, oral administration of carvedilol to adult female rats at a toxic dose (300 mg/kg/day, 55 times the MRHD on a body surface area basis) resulted in impairment of fertility (poor mating, fewer corpora lutea and fewer implants). No adverse effects on fertility were seen at 60 mg/kg/day (11 times the MRHD on a body surface area basis).
(Category C)
There is no adequate clinical experience with carvedilol in pregnant women. Carvedilol should not be used during pregnancy unless the potential benefit outweighs the potential risk. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.
Beta-blockers reduce placental perfusion, which may result in intrauterine fetal death, and immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in the fetus and neonate. There may be an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. There is no evidence from animal studies that carvedilol has any teratogenic effects.
Studies in rats have shown that carvedilol and/or its metabolites cross the placental barrier. Carvedilol was embryotoxic and foetotoxic at doses greater than 60 mg/kg/day in rats and 15 mg/kg/day in rabbits (11 and 5 times, respectively, the MRHD based on body surface area). Maternal toxicity was noted in rats and rabbits at doses greater than 60 and 75 mg/kg/day, respectively.
Carvedilol is excreted in breast milk, although the risk of affecting the child appears unlikely at therapeutic doses, the possibility of the consequences of alpha and beta-blockade should be borne in mind. Carvedilol must not be used during lactation unless the anticipated benefits outweigh the possible risks.

4.7 Effects on Ability to Drive and Use Machines

Individually varying reactions can impair alertness (e.g. patients' capacity for driving or operating machinery). This applies particularly when starting or changing treatment and in conjunction with alcohol.

4.8 Adverse Effects (Undesirable Effects)

Carvedilol is well tolerated by most patients. Most of the adverse reactions are transient and occur at the beginning of treatment. Adverse reactions are related to the pharmacological effects and to the dose.
Carvedilol has been evaluated for safety in mild to moderate congestive heart failure in more than 1,900 patients worldwide, of whom 1,300 participated in US clinical trials. Approximately 54% of the total treated population received carvedilol for at least 6 months and 20% received carvedilol for at least 12 months. The adverse experience profile of carvedilol in congestive heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In US clinical trials comparing carvedilol in daily doses up to 100 mg (n = 765) to placebo (n = 437), 5.4% of carvedilol patients discontinued for adverse experiences versus 8.0% of placebo patients. Generally, the overall incidence of adverse experiences in US placebo controlled trials was not related to dose. However, there was an increased incidence of dizziness, abnormal vision (primarily blurry vision), and bradycardia, with increasing dose.

More common events (occurring with a frequency of > 1%).

Events occurring with a frequency ≥ 2%. Table 1 shows adverse events in US placebo controlled clinical trials of congestive heart failure patients that occurred with an incidence of 2% or more regardless of causality and were more frequent in drug treated patients than placebo treated patients. Median study medication exposure was 6.33 months for carvedilol and placebo patients.
In addition to the events in Table 1, asthenia, cardiac failure, flatulence, anorexia, dyspepsia, palpitation, extrasystoles, hyperkalaemia, arthritis, angina pectoris, insomnia, depression, anaemia, viral infection, dyspnoea, coughing, respiratory disorder, rhinitis, rash and leg cramps were also reported, but rates were equal to, or more common in, placebo treated patients.

The following adverse events were reported more frequently with carvedilol in placebo-controlled trials in patients with congestive heart failure.
Events occurring with frequency of > 1% to < 2%.

Body as a whole.

Peripheral oedema, allergy, sudden death, malaise, hypovolaemia.

Cardiovascular system.

Fluid overload, postural hypotension.

Central and peripheral nervous system.

Hyperaesthesia and vertigo.

Gastrointestinal.

Melaena, periodontitis.

Liver and biliary system.

AST and ALT increased.

Haematology.

Purpura, prothrombin decreased.

Metabolic and nutritional.

Hyperuricaemia, hypoglycaemia, hyponatraemia, increased alkaline phosphatase, glycosuria.

Psychiatric.

Somnolence.

Reproductive, male.

Impotence.

Urinary system.

Abnormal renal function, albuminuria.

Less common reactions (> 0.1% to ≤ 1%).

The following adverse events were reported as possibly or probably related in worldwide open or controlled trials with carvedilol in patients with hypertension or congestive heart failure.

Cardiovascular.

Peripheral ischaemia, tachycardia.

Central and peripheral nervous system.

Hypokinesia.

Gastrointestinal.

Hyperbilirubinaemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of congestive heart failure patients were discontinued from therapy because of increases in hepatic enzymes; see Section 4.4 Special Warnings and Precautions for Use, Hepatic injury).

General.

Substernal chest pain, oedema.

Psychiatric.

Sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paranoia, emotional lability.

Respiratory system.

Asthma (see Section 4.3 Contraindications).

Reproductive, male.

Decreased libido.

Skin and appendages.

Pruritus, rash erythematous, rash maculopapular, rash psoriasiform, photosensitivity reaction.

Special senses.

Tinnitus.

Urinary system.

Micturition frequency.

Autonomic nervous system.

Dry mouth, sweating increased.

Metabolic and nutritional.

Hypokalaemia, diabetes mellitus, hypertriglyceridaemia.

Haematology.

Anaemia, leucopoenia.
The following events were reported in ≤ 0.1% of patients (all clinical trials) and are potentially important: complete AV block, bundle branch block, myocardial ischaemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI haemorrhage, bronchospasm, pulmonary oedema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia and atypical lymphocytes.

Adverse events in severe congestive heart failure.

The overall safety and tolerability of carvedilol in the COPERNICUS study in patients with severe CHF was found to be in good agreement with the established safety profile for patients with mild and moderate CHF.
The incidence of serious adverse events was lower in the carvedilol (39.0%) than in the placebo (45.5%) group, and the rate of withdrawal from treatment due to adverse events was also lower in the carvedilol (9.5%) than in the placebo (11.3%) group.
The most frequently occurring serious adverse events were cardiovascular disorders, the incidences of which were lower in the carvedilol (26.3%) than in the placebo group (34.2%). Among cardiovascular disorders, worsening heart failure was the most commonly reported serious adverse event. During initiation of treatment, the risk of worsening heart failure was similar in the two groups, but with continued treatment the risk of worsening heart failure decreased in the carvedilol group resulting in a slightly lower overall incidence in the carvedilol group (26%) compared with the placebo group (31.5%). The risk of experiencing vasodilatory events such as dizziness, hypotension and syncope was highest during initiation of carvedilol treatment and the risk decreased with continued treatment. Within the body system 'body as a whole', the most frequently reported serious adverse event was sudden death and the incidence was lower in the carvedilol group (see Table 2).

Post-marketing experience.

The following adverse events have been identified during post-marketing use of carvedilol. As these events are reported from a population of uncertain size, it is not possible to reliably estimate their frequency and/or establish a causal relationship to drug exposure.

Cardiac disorders.

Sinus arrest in predisposed patients (e.g. elderly patients or patients with preexisting bradycardia, sinus node dysfunction or atrioventricular block).

Renal and urinary disorders.

Isolated cases of urinary incontinence in women, which resolved upon discontinuation of the medication, have been reported.

Metabolism and nutrition disorders.

Due to the β-blocking properties, it is also possible for latent diabetes mellitus to become manifest, manifest diabetes to be aggravated and blood glucose counter-regulation to be inhibited.

Skin and subcutaneous tissue disorders.

Alopecia. Severe cutaneous adverse reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome) (see Section 4.4 Special Warnings and Precautions for Use). Hyperhidrosis.

Psychiatric disorders.

Hallucination.

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

Cases of overdosage with carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 mg. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.

Signs and symptoms.

In the event of overdosage, there may be severe hypotension, bradycardia, heart failure, cardiogenic shock, sinus arrest and cardiac arrest. There may also be respiratory problems, bronchospasm, vomiting, disturbed consciousness and generalised seizures.

Treatment.

Treatment of overdose should consist of general supportive measures.
The patient should be monitored for the above mentioned signs and symptoms and managed according to the best judgement of the treating physicians and according to standard practice for patients with beta-blocker overdose (e.g. atropine, transvenous pacing, glucagon, phosphodiesterase inhibitors such as milrinone, beta-sympathomimetics).

Note.

In the event of severe intoxication with symptoms of shock, supportive treatment with antidotes must be continued for a sufficiently long period of time since prolonged elimination half-life and redistribution of carvedilol from deeper compartments can be expected. Duration of antidote therapy is dependent upon severity of overdose. Supportive measures should therefore be continued until the patient is stabilised.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Alpha (α) and Beta (β) adrenergic receptor blocking agents, ATC code: C07AG02.

Mechanism of action.

Carvedilol is a dual action cardiovascular agent; a vasodilating, non-selective beta-blocking agent with antioxidant properties. Vasodilation has been shown to be mediated primarily by selective blockade of alpha₁-adrenoreceptors.
Carvedilol is a racemic mixture. In animal models, both enantiomers have alpha-adrenergic receptor blocking properties. The beta-adrenergic receptor blocking properties are non-selective for beta₁ and beta₂-adrenoreceptors and are associated with the laevorotatory enantiomer of carvedilol. Carvedilol has no intrinsic sympathomimetic activity and, like propranolol, it has membrane stabilising properties. Carvedilol suppresses the renin-angiotensin-aldosterone system through beta-blockade.
The mechanism for the beneficial effects of carvedilol in congestive heart failure has not been established. Possible mechanisms include neurohormonal inhibition, β-blockade, balanced vasodilation (reduced preload and afterload), antioxidant activity, potent anti-ischaemic activity and inhibition of neutrophil adhesion. Antioxidant activity and inhibition of neutrophil adhesion have been demonstrated in in vitro and in vivo animal models and in in vitro human models.
Carvedilol reduces the peripheral vascular resistance by vasodilation, predominantly mediated through selective alpha₁-antagonism and beta-blockade prevents reflex tachycardia with the net result that heart rate is slightly decreased.
In hypertensive patients, a reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as observed with pure beta-blocking agents. Renal blood flow and renal function are maintained. Peripheral blood flow is maintained; therefore, cold extremities (often observed with drugs possessing beta-blocking activity) are rarely seen. Fluid retention does not occur.
In studies that compared the acute haemodynamic effects of carvedilol to baseline measurements in patients with congestive heart failure, there were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure and heart rate. Initial effects on cardiac output, stroke volume index and systemic vascular resistance were small and variable.
In terms of chronic haemodynamic effects (12 to 14 weeks) carvedilol significantly reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance and heart rate while stroke volume index was increased.
In patients with ischaemic cardiomyopathy, long-term treatment (six months) with carvedilol (6.25, 12.5 and 25 mg) reduced left ventricular dimensions measured echocardiographically.
In patients with renal impairment, the autoregulatory blood supply is preserved and the glomerular filtration is unchanged during chronic treatment with carvedilol.
A normal ratio of high-density lipoproteins to low density lipoproteins (HDL:LDL) is maintained. Serum electrolytes are also unaffected.

Clinical trials.

The use of this agent in congestive heart failure (CHF) patients has been shown to reduce cardiovascular hospitalisation, improve patient wellbeing, slow the progression of the disease and reduce the risk of death.
Four US multicentre double blind placebo controlled studies enrolled 1,094 patients (696 randomised to carvedilol) with New York Heart Association (NYHA) class II to III heart failure and ejection fraction < 0.35. The vast majority was on digitalis, diuretics and an ACE inhibitor at study entry. Patients were assigned to the studies based upon exercise ability. An Australia/ New Zealand double blind placebo controlled study randomised 415 patients (half to carvedilol) with less severe heart failure. All protocols excluded patients expected to undergo cardiac surgery during the 6 to 12 months of double blind follow-up. All randomised patients had tolerated a two week course of carvedilol 6.25 mg b.i.d. (twice daily).
In each study, there was a primary endpoint, either progression of heart failure (one US study) or exercise tolerance (two US studies meeting enrolment goals and the Australia/ New Zealand study). There were many secondary endpoints specified in these studies, including NYHA classification, patient and doctor global assessments, and cardiovascular hospitalisation. Death was not a specified endpoint in any study, but it was analysed in all studies. Other analyses not prospectively planned included the sum of deaths and total or cardiovascular hospitalisations. In situations where the primary endpoints of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously.

The results of the US and Australia/ New Zealand trials were as follows.

Slowing progression of heart failure.

One US multicentre study (366 subjects) had as its primary endpoint the sum of cardiovascular mortality, cardiovascular hospitalisation and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow-up of seven months, by 48% (p = 0.008).
In the Australia/ New Zealand study, death and total hospitalisations were reduced by about 25% over 18 to 24 months. In the three largest US studies, death and total hospitalisations were reduced by 19%, 39% and 49%, these results being nominally statistically significant in the last two studies. The Australia/ New Zealand results were statistically borderline.

Functional measures.

None of the multicentre studies had NYHA classification as a primary endpoint, but all such studies had it as a secondary endpoint. There was at least a trend toward improvement in NYHA class in all studies. Exercise tolerance was the primary endpoint in three studies; in none was a statistically significant effect found.

Subjective measures.

Quality of life, as measured with a standard questionnaire (a primary endpoint in one study), was unaffected by carvedilol. However, patients' and investigators' global assessments showed significant improvement in most studies.

Mortality.

Mortality was not a planned endpoint in any study. Overall, the results from four US studies are consistent with a beneficial effect of carvedilol on mortality due to the consistency of the results seen across different trials. However, the actual effect, size and statistical difference of this observation are difficult to define.

Severe congestive heart failure (COPERNICUS) trial.

In a large, multicentre, double blind, placebo controlled mortality trial (COPERNICUS), 2,289 patients with stable, severe CHF of ischaemic or non-ischaemic origin, on standard therapy, were randomised to either carvedilol (1,156 patients) or placebo (1,133 patients). Patients had left ventricular systolic dysfunction with a mean ejection fraction of < 20%, sitting systolic blood pressure greater than or equal to 85 mmHg, no more than trace oedema of the peripheral limbs, no new pulmonary rales or ascites, optimisation of diuretic therapy and other established therapy such as ACE inhibitors and angiotensin II antagonists, no recent unstable angina, cardiac surgery or ventricular arrhythmias and no recent use of intravenous positive inotropic or vasodilator agents (other than digitalis). The primary efficacy parameter was all cause mortality and the secondary efficacy parameters were defined as combined mortality or hospitalisations for heart failure, mortality or cardiovascular hospitalisations and mortality or all cause hospitalisations. Interim analyses were conducted to determine whether the Data Safety Monitoring Board (DSMB) could recommend the study to be terminated early due to convincing evidence of benefit or harm. Deaths were classified as either cardiovascular or noncardiovascular, and within the group of cardiovascular deaths as being due to left ventricular dysfunction or other cardiovascular causes.
Efficacy results. At the fourth interim analysis, the upper interim monitoring boundary was exceeded, indicating a statistically significant survival benefit for patients on carvedilol. As a result, the DSMB recommended early termination of the trial.

Primary efficacy parameter.

The rate of survival was significantly higher in the patients receiving carvedilol than the placebo group. The benefit of carvedilol became apparent after about 100 days of treatment. All-cause mortality was reduced by 35% from 19.7% in the placebo group to 12.8% in the carvedilol group (Cox proportional hazards, p = 0.00013). The mortality benefit of carvedilol was consistent across all subpopulations investigated. The most frequent cause of death, sudden death, was reduced by 41% in the carvedilol group (5.3% vs 8.9%). (See Figure 1.)

Secondary efficacy parameters.

Hospitalisations due to worsening heart failure, cardiovascular hospitalisations and all hospitalisations were significantly reduced under carvedilol therapy. Thus, the combined risk of death or hospitalisation due to worsening heart failure was reduced by 31% (p = 0.000004), death or cardiovascular hospitalisation by 27% (p = 0.000023) and death or all hospitalisation by 24% (p = 0.00004). (See Table 3.)

The majority of patients were hospitalised for cardiovascular reasons. Treatment with carvedilol resulted in lower rates for almost all cardiac hospitalisations (worsening heart failure, atrial and ventricular and tachyarrhythmias, myocardial infarction and unstable angina pectoris). The number of patients hospitalised for symptomatic bradycardia and symptomatic heart block was slightly higher in the carvedilol treated patients than placebo, although the total number of patients hospitalised was low (1.3 and 0.8% respectively for bradycardia and 0.3 and 0.1% respectively for heart block). The number of patients hospitalised for noncardiovascular events was similar in both groups (placebo 11.2%, carvedilol 10.6%).

Paediatric population.

Available studies regarding safety and efficacy in children and adolescents are limited in number and size, and were focused on treatment of paediatric heart failure which however differs from the disease in adults regarding characteristics and aetiology. Because of the small number of participants compared to studies in adults and a general lack of an optimal dosing scheme for children and adolescents, the available data is not sufficient to establish a paediatric safety profile for carvedilol. Use of carvedilol in paediatric patients is therefore a safety concern and not recommended as substantial information regarding benefits and risks is missing.

5.2 Pharmacokinetic Properties

Absorption.

Carvedilol is rapidly and extensively absorbed following oral administration. The absolute bioavailability of carvedilol is approximately 25%. Plasma levels peak approximately one hour after an oral dose. Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 4-fold higher than S(-)-carvedilol following oral administration in healthy subjects. Plasma levels increase in a dose proportional manner.
After administration of a single oral dose of Carvedilol Sandoz 25 mg to healthy male and female adults, the mean peak plasma concentration of R(+)-carvedilol was 67.8 nanogram/mL and the AUC was 251.9 nanogram.hr/mL, the mean peak plasma concentration of S(-)-carvedilol was 29.1 nanogram/mL and the AUC was 127.0 nanogram.hr/mL.
After administration of a single oral dose of Carvedilol Sandoz 12.5 mg (2 x Carvedilol Sandoz 6.25 mg tablets), the mean peak plasma concentration of R(+)-carvedilol was 34.7 nanogram/mL and the AUC was 130.6 nanogram.hr/mL, the mean peak plasma concentration of S(-)-carvedilol was 13.7 nanogram/mL and the AUC was 69.6 nanogram.hr/mL.
No data on the effect of food on carvedilol tablets exist. Studies carried out with the capsule formulation indicate that food does not affect the extent of bioavailability or the maximum plasma concentration, although the time to reach maximum plasma concentration is delayed.
In vitro studies have shown that carvedilol is a substrate of the efflux transporter P-glycoprotein. The role of P-glycoprotein in the disposition of carvedilol was also confirmed in vivo in healthy subjects.

Distribution.

Greater than 98% of carvedilol is bound to plasma proteins, primarily albumin. Carvedilol is highly lipophilic; the volume of distribution is approximately 2 L/kg and is increased in patients with liver disease. When used as directed, carvedilol is unlikely to accumulate during long-term treatment.

Metabolism.

In all animal species studied, and also in humans, carvedilol is extensively metabolised into a variety of metabolites which are mainly excreted in the bile. The first-pass effect after oral administration amounts to about 60 to 75%; enterohepatic circulation of carvedilol and/or its metabolites has been shown in animals.
The major P450 enzymes responsible for the metabolism of both R(+) and S(-) carvedilol in human liver microsomes were identified as CYP2D6 and CYP2C9, and to a lesser extent CYP3A4, CYP2C19 and CYP2E1. Although results from in vitro studies demonstrate that carvedilol has inhibitory potential against several P450s (CYP1A2, CYP2C9/8, CYP2C19, CYP3A and CYP2D6), it is important to note that the estimated IC₅₀ values (concentration of carvedilol required to produce 50% inhibition of the CYP450 isoenzymes) for the R(+) and S(-) enantiomers are substantially higher than their circulating peak plasma levels achieved during therapy.
Poor metabolisers of debrisoquine (a marker for CYP2D6) exhibited two to threefold higher plasma concentrations of R(+) carvedilol, compared to extensive metabolisers. In contrast, plasma levels for S(-) carvedilol were only increased by about 20 to 25% in poor metabolisers. As R(+) carvedilol is only responsible for alpha-blocking activity, it would be anticipated that, on average, poor metabolisers of debrisoquine would have greater alpha-blockade after carvedilol administration with little change in beta-blocking activity, compared to extensive metabolisers (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). However, interpatient variability in the plasma concentration of carvedilol and clinical response to the drug make it difficult to predict an individual's response to carvedilol even with prior knowledge of their debrisoquine phenotype.
The pharmacokinetics of carvedilol do not appear to be different in poor metabolisers of S-mephenytoin (patients deficient in CYP2C19).
Carvedilol is further metabolised by the liver, with glucuronidation one of the major reactions. Demethylation and hydroxylation at the phenol ring produces three active metabolites with beta-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenol metabolite is approximately 13 times more potent than carvedilol for beta-blockade. Compared to carvedilol, the three active metabolites exhibit weak vasodilating activity. In humans, their concentrations are about one-tenth that of the parent substance.

Excretion.

After oral administration, the elimination half-life of carvedilol is approximately six to ten hours. Plasma clearance ranges from 500 to 700 mL/minute. Elimination is mainly biliary, with the primary route of excretion being via the faeces. A minor portion is eliminated via the kidneys.
The pharmacokinetics of carvedilol are affected by age. Area under the curve (AUC) and T_max values are increased in the elderly. Plasma levels of carvedilol are approximately 50% higher in the elderly compared to young subjects.
Steady-state plasma concentrations of both carvedilol enantiomers increased proportionally over the 6.25 to 50 mg dose range in patients with congestive heart failure. Compared to healthy subjects, congestive heart failure patients had increased mean AUC and C_max values for both carvedilol enantiomers with up to 50 to 100% higher values observed in class IV patients. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects.

Impaired liver and renal function.

In a study in patients with impaired liver function, serum levels of carvedilol are significantly higher (approximately four to sevenfold).
In hypertensive patients with moderate (creatinine clearance 20 to 30 mL/minute) to severe (creatinine clearance < 20 mL/minute) renal impairment, an approximately 40 to 55% increase in plasma concentration of carvedilol (based on AUC) was observed compared to hypertensive patients with normal renal function. However, there was a wide variability in the data and considerable overlap with normal values. The pharmacokinetics of carvedilol are not altered by haemodialysis.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Repeat dose toxicity studies showed an increase in the incidence of bile duct hyperplasia in rats at doses greater than 34 mg/kg/day following 12 and 18 months dietary treatment with carvedilol, and in dogs receiving doses greater than 30 mg/kg/day for 12 months. Focal hepatocellular hyperplasia was noted in rats at oral doses greater than 100 mg/kg/day at three months and greater than 30 mg/kg/day at 12 months of treatment with carvedilol. Hepatocellular hyperplasia was not noted in dogs at doses up to 300 mg/kg/day. In addition, there was a small increase in the incidence of hepatic adenomas in rats receiving carvedilol at doses greater than 100 mg/kg/day in the 18-month dietary study. There was no increase in the incidence of hepatic adenomas in the rat two year dietary carcinogenicity study, in which the average dose was 75 mg/kg/day. Based on AUC, this dose showed a 9 to 15-fold higher systemic exposure when compared to a dose of 50 mg/day in humans. A carcinogenicity study in mice was negative at dietary doses up to 200 mg/kg/day. Therefore, the carcinogenic risk to humans following long-term administration of carvedilol appears to be low.

6 Pharmaceutical Particulars

6.1 List of Excipients

Carvedilol Sandoz tablets contain inactive (excipients) ingredients:
Lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, colloidal anhydrous silica, magnesium stearate, iron oxide yellow (6.25 mg and 12.5 mg), iron oxide red (12.5 mg).

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.

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 and moisture.

6.5 Nature and Contents of Container

Carvedilol Sandoz tablets are available in 60 tablet blister packs and bottles*.
* Not all presentations maybe marketed 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

Chemical structure.

It is a white crystalline powder and has low solubility in water (0.01 mg/mL). It is soluble in ethanol (22.7 mg/mL).
The chemical name of carvedilol is (±)-1-(9 H-carbazol-4-yloxy)-3-{[2-(2-methoxyphenoxy) ethyl] amino} propan-2-ol. Its molecular formula is C₂₄H₂₆N₂O₄ (MW: 406.5) and its chemical structure is:

CAS number.

72956-09-3.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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Carvedilol Sandoz Tablets 12.5 mg

Carvedilol Sandoz Tablets 25 mg

Carvedilol Sandoz Tablets 6.25 mg