CoregTM (carvedilol) is indicated for treatment of stable symptomatic congestive heart failure (CHF) in patients with NYHA Class II and III, heart failure currently managed on diuretics and ACE inhibitors, with or without digoxin.
Data are limited in NYHA Class IV patients and therefore CoregTM is not recommended in these patients.
Efficacy
In clinical trials conducted on the use of CoregTM in the treatment of CHF, CoregTM has been demonstrated to reduce the relative risk of death in patients by 65 % and to reduce relative risk of hospitalization by 36 %.
The reduction in risk of death was observed across patient groups regardless of severity or cause of CHF. Considering the observed reduction in mortality of 65%, if 22 patients are treated for 6.5 months with CoregTM the equivalent of one life is saved.
In February 1995, an independent monitoring board of medical and statistical experts informed SmithKline Beecham of the marked reduction in mortality in the U.S. Carvedilol Heart Failure Program in patients treated with CoregTM plus conventional therapy versus those receiving placebo plus conventional therapy (conventional therapy consisted of diuretics, ACE inhibitors with or without digoxin). The board advised that to continue giving patients placebo plus conventional therapy, as the trial design dictated, would be unethical in view of the stronger-than-expected reduction in mortality among patients administered CoregTM.
Over 1900 patients have participated in carvedilol CHF clinical trial programs worldwide, the largest patient experience of any drug with beta-blocking properties in the treatment of heart failure. Of these patients, 1300 participated in U.S. Carvedilol Heart Failure Program. Approximately 54% of the CoregTM ttreated population patients received CoregTM for at least 6 months and 20% received CoregTM for at least 12 months.
CoregTM is the only agent with beta-blocking properties to demonstrate a significant survival benefit for patients with CHF when used as an adjunctive to conventional therapy of diuretics, ACE inhibitors with or without digoxin.
Pharmacologic Action
CoregTM (carvedilol) is a unique agent for the treatment of Congestive Heart Failure (CHF) in that it combines three pharmacologic actions:
Beta-blockade, which prevents excessive sympathetic stimulation and protects the heart from overstimulation by noradrenaline.
Alpha-blockade, eases initiation of therapy by reducing peripheral vascular resistance, helping to offset the initial effects of beta-blockade.
Antioxidant effect, which is believed to prevent myocardial cell damage and death in response to oxidative stress, by preventing the formation and scavenging of oxygen free radicals.
These combined unique actions of carvedilol are not shared by any other drugs currently used in the management of congestive heart failure, or by any other drugs with beta-blocking properties. While the mechanism for the beneficial effects of carvedilol in congestive heart failure has not been established, the multiple actions of carvedilol provide the underlying pharmacologic rationale for its use in the treatment of congestive heart failure.
Titration of Dosage
It is very important that physicians experienced in the treatment of CHF should individualize dosage and closely monitor patients on CoregTM during initiation and up-titration process. Information on how to initiate and up-titrate CoregTM is provided in detail in the Dosage in Congestive Heart Failure.
Tolerability
CoregTM is well-tolerated when used with careful titration and close clinical monitoring. The most common adverse experiences reported with the CoregTM treated patients in the US clinical trial during the double-blind phase was dizziness, fatigue, dyspnea, upper respiratory infection, cardiac failure and chest pain. Upper respiratory infection and cardiac failure were reported more often in the placebo group. Chest pain was similar in both groups.
Of the 1202 patients who received randomized treatment in these trials, 5.4% of CoregTM patients withdrew because of adverse experiences compared with 8% of placebo patients. Bradycardia, fatigue, hypotension, dizziness and dyspnea were the most commonly reported adverse experiences leading to discontinuation in CoregTM treated patients.
Dosage In Congestive Heart Failure
While dramatic benefits have been demonstrated with the use of CoregTM in CHF patients, care must be taken when initiating and up-titrating any drug with beta-blocking properties in heart failure patients, since worsening heart failure has been observed during this phase of treatment. It should be noted however, that worsening heart failure was more prevalent in the placebo control group as compared to CoregTM in the recent US carvedilol heart failure trial. During initiation and up-titration, patients may have occasional or intermittent symptoms of dizziness, headaches, or fatigue. These symptoms are generally transient and subside when the titration process is complete. Adjustments to concomitant medications may be required. In order to minimize the risk of these events, it is critical to carefully follow the recommended dosing for CoregTM in patients with congestive heart failure.
Before Implementing CoregTM Therapy
All patients in whom CoregTM therapy is to be considered must be clinically stable for 4 weeks prior to initiation of CoregTM.
Prior to initiation of CoregTM therapy, patients should be on stable doses of diuretics and angiotensin converting enzyme inhibitors, with or without digitalis. In clinical trials, all patients shown to have benefit were on the above regimen unless they were intolerant to an ACE inhibitor.
Dosage must be individualized and patients closely monitored during initiation and up-titration by a physician experienced in the treatment of heart failure.
Initiating CoregTM Therapy
All patients with heart failure should start CoregTM therapy at a dose of 3.125 mg twice daily for two weeks.
Take CoregTM with Food
CoregTM should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects, especially during up-titration.
Up-Titrating CoregTM Therapy
If the initial dose is tolerated (see Assessing Tolerability below), titrate slowly to the maximum tolerated (up to 25 mg twice daily) by doubling the dose every 2 weeks as listed in the following chart.
Week 1 & 2 3.125 mg twice daily (starting dose)
Week 3 & 4 6.25 mg twice daily
Week 5 & 6 12.5 mg twice daily
Week 7 & 8 25 mg twice daily (maximum dose)
Assessing Tolerability
After each dosage increase
· Patients should be monitored for symptoms of excessive vasodilatation (e.g. dizziness, lightheadedness, symptomatic hypotension) for 1-2 hours.
· If the dose is tolerated, the patient should continue on that dose for the next 2 weeks.
At each patient visit, before increasing dose
· Patients should be assessed for their ability to tolerate CoregTM during the previous week.
· Signs of intolerance may include: worsening CHF, excessive vasodilatation, bradycardia.
During initiation and up-titration of CoregTM, occasional or intermittent symptoms of dizziness, headache and tiredness are not unusual. These symptoms are generally transient.
Transient worsening of heart failure may be treated with increased doses of diuretics, lowering the dose of CoregTM or, if necessary, discontinuation of CoregTM. Symptoms of vasodilation such as dizziness, lightheadedness or decreasing blood pressure may respond to a reduction in the dose of diuretics. If these changes do not relieve symptoms, the dose of CoregTM should be decreased. If the dose of CoregTM was decreased, it should not be increased again until symptoms of worsening heart failure or vasodilatation have been stabilized for 2 weeks. Initial difficulty with titration may not preclude later attempts to reintroduce or resume titration of CoregTM. However, caution is required in these circumstances. If congestive heart failure patients experience bradycardia (pulse rate below 55 beats/min.), the dose of CoregTM should be reduced, or may require discontinuation.
Adjustment of Concomitant Medications
During the up-titration phase, dosage adjustments of concomitant medications may be required based on symptoms as follows:
| Step 1 | Step 2 | Step 3 | |
| Symptoms of excessive vasodilatation | Decrease diuretic | Decrease Coreg | |
| Symptoms of fluid retention, worsening heart failure* | Increase diuretic | Decrease Coreg | Discontinue Coreg |
| Bradycardia, (if CHF patients experience pulse rate <55 beats.min) | Decrease Coreg | Discontinue Coreg |
*Symptoms of worsening heart failure include: increasing dyspnea, fatigue, a new or louder S3 sound, increased rales or weight gain(>2 kg.)
If the CoregTM dose is decreased, it should not be increased again until symptoms of worsening heart failure or excessive vasodilatation have been stabilized for 2 weeks.
Initial difficulty with titration, may not preclude later attempts to re-introduce or resume titration of CoregTM, however caution is required in these circumstances.
If heart failure patients experience bradycardia (pulse rate below 55 beats/min.), the dose of CoregTM should be reduced, or may require discontinuation.
If Discontinuing CoregTM Therapy is Required
Should it be necessary to discontinue CoregTM, it should be gradually reduced over a period of about 2 weeks, if possible, and the patient should be carefully observed.
Patients with ischemic heart disease should be warned against abrupt discontinuation of beta-adrenergic blocking agents. There have been reports of severe exacerbation of angina, and of myocardial infarction or ventricular arrythmias occurring in patients with angina pectoris, following abrupt discontinuation of beta-blocker therapy. The same frequency of administration should be maintained.
In situations of greater urgency, CoregTM should be discontinued stepwise and under conditions of closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with the drug be re-instituted promptly, at least temporarily.
Further information on the dosage of CoregTM is provided in the study by Packer et in CHF patients.
References:
1. Product Monograph
2. Packer M. et al: The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure. N. Eng. J. Med. 334:1349- 1355(May 23),1996
How Does Coreg Work?
Coreg is a new medicine that has been given to you by your doctor. Coreg is a medication for the treatment of congestive heart failure. Coreg does a number of things. It protects your heart muscle from having to do too much work and becoming overtired. Coreg does this by relaxing your heart and slowing your heart rate. This gives vour weak heart a chance to rest and recover.
You may feel more tired at the beginning. As your heart begins to adjust and get stronger, you will have more energy and will begin to feel better. Your doctor has given Coreg to you because it helps to reduce the workload on your heart. Studies show that Coreg helped people with heart failure live longer, spend less time in hospital and made them feel better.
What Dose of Coreg Is Best For Me?
As everyone is different, the dose of Coreg will be adjusted to the dose that is best for you. It may take several weeks to build up to the right dose of medicine that is best for you.. Coreg will be started at a low dose. The dose will be raised slowly by your doctor. This is normal. Just because the dose is increasing, does not mean you are getting sicker. It just means that the dose has to be tailored to you. It often takes time for your body to adjust to a new drug. Your doctor will monitor your progress closely.
How Do I Take Coreg?
It is very important that you take Coreg exactly as your doctor has instructed. The doctor will decide how many tablets you need to take each day, at what time of day you should take them, and for how long. If your doctor changes your dose of Coreg, be careful to take the tablets just as you have been told. Please do not forget:
Swallow your tablets whole with a drink of water. It is best to take the tablets with food.
Do not chew or break your tablet.
Take your tablets at the same time each day.
Do not stop taking Coreg, even if you are feeling better, except on your doctor's advice.
If you have been taking Coreg for a while and your doctor has told you to stop, make sure you follow your doctor's instructions on how to stop.
What If I Miss A Dose?
Please remember:
If you forget to take a tablet, take it as soon as you remember.
If possible, take your next dose at the normal time, but do not take two doses within 6 hours of each other.
If you miss more than two doses of Coreg, contact your doctor for instructions.
Do not re-start Coreg until you have spoken to your doctor.
Do not stop taking Coreg without talking to your doctor first.
How Will I Feel When I Take Coreg?
At first, your body may feel a little bit different when you are taking Coreg. You need to know that:
Your heart takes time to adjust to Coreg. Your heart is relaxing and recovering.
It takes approximately 3-10 weeks for the heart to adjust to Coreg; each person is different.
Feelings of being short of breath, dizzy or tired may become worse at first.
When your heart adjusts, you should feel better.
You should keep track of how you feel and tell your doctor how you are doing.
When Should I Not Take Coreg?
You should not take Coreg if you are pregnant or if you plan on becoming pregnant, unless the doctor tells you to. You should also not use Coreg if you are allergic to it or any of its ingredients. If you become unwell while taking Coreg, tell your doctor at once.
What Are Some Of The
Side Effects Of Coreg?
All medicines have possible side effects. This is also true of Coreg. The most common side effects of Coreg are dizziness, headache and tiredness. These side effects often occur when Coreg is started or the dose is changed. These symptoms often go away. If they do not go away or become more severe, tell your doctor. There are other symptoms that can occur. These do not happen very often. They probably will not happen to you. Let your doctor know if you are feeling any unusual discomfort.
When Should I Be Cautious
About Using Coreg?
If you suffer from Raynaud's phenomenon, an increase in coldness/spasms in the hands may be seen.
Psoriasis may occur. If you already have psoriasis, it may become worse.
If vou are diabetic, you could become less aware of symptoms of hypoglycemia (low blood sugar). You should monitor your blood sugar more carefully. Tell your doctor if you see any noticeable changes.
If vou wear contact lenses, you may suffer from dryness of the eyes while taking your tablets.
If you develop any unusual discomfort, tell the doctor as soon as possible. When your dose is being increased, your doctor needs to know if you have unusual dizziness, ankle swelling, tiredness or loss of breath.
If you are dizzy or tired, do not drive or operate machinery.
Be especially careful when you are starting or changing the dose of Coreg.
Coreg should not be taken with alcohol.
It is very important to tell your doctor:
About all your medical conditions, including a history of heart, kidney or liver problems, asthma or breathing difficulties.
About any medicines (prescription or nonprescription) that you are taking. Other drugs can affect and be affected by Coreg. Some of these may be of particular concern to your doctor.
If you change the amount of any other medicine you are taking.
If you are pregnant or thinking about becoming pregnant, or if you are breast feeding.
What To Do If I Have Taken More
Tablets Than I Should Have?
If you take more tablets than the dose your doctor prescribed for you, tell your doctor or the nearest hospital emergency department right away. Show the doctor your bottle of tablets and any other drugs you have taken.
What Does Coreg Contain?
Carvedilol is the active ingredient in Coreg. The other ingredients are: sucrose, lactose, povidone, colloidal silicone dioxide, crospovidone, magnesium stearate, Opadry white and Opadry clear. There is no tartrazine or any other azo dyes.
How Should Coreg Be Stored?
Coreg tablets should be stored at room temperature (15o-30o C) in a dry place. Protect your pills from high humidity and light. Keep tablets in the original container. Keep the container tightly closed. Do not use Coreg after the expiry date that is printed on the label. Keep out of reach of children.
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