Side effects of carvedilol

Contents

Severe carvedilol toxicity without overdose – caution in cirrhosis

Pharmacokinetic considerations

Pharmacologically, carvedilol is a unique beta blocker. The formulation is a racemic mixture that forms S(−) and R(+) enantiomers which enable the drug to possess both non-selective β-adrenoreceptor antagonist and also α1-andrenoreceptor antagonist activity, respectively. Its vasodilating effect is theorized to contribute to its potency in reducing mortality and morbidity in the settings of ischemic heart disease and portal hypertension . Compared to the pure β-adrenoreceptor antagonists, carvedilol’s α1-andrenoreceptor-antagonist activity may be both its strength and weakness. The vasodilating effect makes it more potent, but also presents a theoretical risk for additional hypotension in cases of overdose or supratherapeutic levels. In healthy individuals, after oral dosing, carvedilol is rapidly absorbed and undergoes extensive first-pass metabolism in the liver with a peak concentration 1 to 2 h after and subsequent hepatic metabolism .

Safety and optimal dosing of carvedilol in patients with cirrhosis

As a therapeutic class the beta blockers have a good safety profile. Carvedilol has been widely used for decades, and at a dose of 25 mg daily, postmarketing surveillance has shown that it is generally well tolerated . To the best of our knowledge, cardiogenic shock has not been reported with carvedilol use in therapeutic doses. Several clinical studies have investigated carvedilol in cirrhotic patients at varying doses. A summary of several studies is shown in Table 1 . Hypotensive events were noted both acutely and delayed and varied in incidence from 2.6% to 17.6%. These results imply that hemodynamic compromise can be a significant adverse effect of carvedilol at standard doses in cirrhosis.

Table 1 Hypotensive events in several studies investigating carvedilol in cirrhosis

Due to its extensive hepatic metabolism, carvedilol is contraindicated in severe hepatic impairment. However, there are no dosage adjustments in the manufacturer’s labelling for mild to moderate hepatic impairment. The pharmacokinetics of carvedilol are greatly altered in cirrhosis at both hepatic and systemic levels. Hepatic blood flow and drug extraction are reduced, leading to impaired metabolism and elimination of the drug. To add to this, carvedilol is a highly protein bound drug and hypoalbuminemia in cirrhosis affects the unbound serum concentrations.

Despite its widespread use in these patients, there is limited data on pharmacokinetics outside of healthy volunteers or patients with heart failure. Rasool et al. performed physiologically based pharmacokinetic modelling to simulate use in cirrhotic patients. They suggested that in these patients, to maintain drug exposure equivalent to 25 mg carvedilol in healthy individuals, the administered doses should be reduced to 12.5 mg, 6.25 mg, and 3.125 mg stratified by Child-Pugh class A, B, and C. Additionally, in liver cirrhosis the unbound systemic concentration of carvedilol increases much more in comparison to that of total systemic concentration of carvedilol .

Carvedilol decreases portal pressure after acute and long-term administration. Some authors have suggested that the clinical benefit of carvedilol, as reflected by reduction in HVPG, is directly proportional to dosage. In the studies examined (Table 1), investigators tended to initiate therapy at daily doses of either 6.25 mg (7–9,11) or 25 mg (2,10,12–15). Studies with a protocol that initially administered 25 mg daily dosing recorded a higher incidence of bradycardia and hypotension. From these studies as well as the case presented, we can suggest that a starting dose of 25 mg daily is too large a dose in patients with cirrhosis. We recommend initiating carvedilol at low dose, 3.125 mg twice daily, with close monitoring of heart rate and blood pressure that would require home monitoring and clinic visits. Slow uptitration at regular follow up visits can then be done as the patient tolerates.

Carvedilol toxidrome and treatment with glucagon

Despite its widespread use, from our review of PubMed, ToxLine and International Pharmaceutical Abstracts, there are only two published case reports (English) of carvedilol toxicity and both of these were in the setting of overdose . The typical threshold for carvedilol toxicity in overdose is 50 mg but in patients with cirrhosis this is not applicable. Especially in the absence of overdose, clinical recognition of the toxidrome is the key to early diagnosis leading to treatment. As in this case, the classic hallmarks of beta blocker toxidrome are hypotension and bradycardia, that can progress to cardiogenic shock and less frequently be accompanied by change in mental status, hypoglycemia or hypothermia. We were limited in this case because serum testing for carvedilol level was not available. However, the recognition of classic signs of beta blocker toxidrome and exclusion of alternative diagnoses allowed a clinical diagnosis. In practice, clinicians are unlikely to have access to carvedilol levels and prompt recognition of the toxidrome is essential to enable rapid treatment.

Carvedilol is a highly lipophilic drug and mental status should be monitored closely. In carvedilol toxicity, the signs of hypoglycemia are masked and a high index of suspicion is needed. With normal mental status and a stable airway, the focus of management should be on hemodynamic stabilization. We successfully used crystalloids and albumin followed by glucagon as a high dose intravenous bolus and infusion. Atropine has been recommended by some as first line treatment but has poor results in severe beta blocker toxicity . In carvedilol toxicity, it is possible to use inotropes to maintain hemodynamic support. Bouchard et al. reported a case of overdose where the patient was responsive to glucagon boluses, 2-3 mg, but this was not followed by glucagon infusion . Instead a dopamine infusion was started. Despite the dopamine infusion, however, the patient had occasional hypotension and bradycardia, and glucagon boluses were still used adjunctively with good response. If inotropes are used, it is suggested to select an agent based upon specific hemodynamic and cardiodynamic monitoring. There is no one catecholamine that is superior for cardiovascular drug toxicity but catecholamines such as isoproterenol and dobutamine, that possess predominant beta receptor activity and little alpha agonist activity may decrease peripheral resistance and worsen hypotension .

The treatment of beta blocker toxicity continues to be an area of active investigation. In beta blocker poisoning with bradycardia and hypotension, high-dose glucagon is considered the first-line antidote . Glucagon has positive inotropic and chronotropic effects. Mechanistically, glucagon activates adenyl cyclase and exerts inotropic and chronotropic effects via a pathway not mediated by the adrenergic system. As Kerns points out, this property makes glucagon particularly attractive as an antidote for beta blocker toxicity by providing cAMP necessary for myocardial cell performance in the face of beta blockade.

There are no studies on glucagon use in humans and current therapy is guided by animal studies and case reports. It would be unethical to undertake a randomized clinical trial investigating treatment of beta blocker toxicity. In the five studies of animal models of beta-blocker overdose in systematic review by Bailey, glucagon increased the heart rate (at least transiently) but appeared to have no effect on mean arterial pressure . In this case we observed glucagon restoring the blood pressure (Fig. 1). When glucagon is used as an antidote, an “appropriate dose” should be administered. We agree that an appropriate dose represents a bolus of 5–10 mg followed by an infusion of 1–5 mg/h, titrated based on clinical response.

Article Highlights

  • Coreg is a medication used for the treatment of high blood pressure and heart failure.
  • By blocking the effect of adrenaline, Coreg slows the heart’s pumping action and lowers blood pressure.
  • Coreg, usually taken twice daily and with food, comes in tablets from 3.125 to 25 mg, and capsules from 10 to 80 mg.
  • Common side effects include dizziness, nausea, headache, and vision changes.

Overview

Carvedilol is a beta blocker, a type of medication that lowers blood pressure by reducing arterial tension and slowing heart rate, thus improving the flow of blood.

Coreg, the brand name for the generic Carvedilol drug, was approved by the Food and Drug Administration (FDA) in 1995 for the treatment of:

  1. Hypertension: High blood pressure that occurs when the blood’s pressure against the arterial walls is higher than normal
  2. Heart failure: Occurs when the heart’s pumping action isn’t getting a normal amount of blood to the various parts of the body
  3. Post-heart attack: Prescribed to patients after they’ve had a heart attack to improve their chance of survival when their heart is not pumping adequately

Carvedilol, available in tablets and extended-release capsules, is frequently prescribed in conjunction with other medications.

How Coreg and Beta Blocker Drugs Work

Coreg belongs to a class of medicines known as beta blockers. These drugs work by obstructing the impact of the hormone adrenaline (or epinephrine), which causes the heart to beat faster and blood pressure to rise. By causing the heart to beat more slowly and with reduced strength, blood pressure is decreased.

Hypertension is a very common condition, in both industrialized nations as well as developing countries. The American Heart Association estimates that there are some 76 million U.S. citizens age 20 and above, i.e. one in 3 adults, who have high blood pressure.

Beta blocker drugs, commonly prescribed in combination with other medications, are used for the treatment of the following conditions:

  • High blood pressure
  • Irregular heartbeat (arrhythmia, i.e. when the heart beats too fast or too slow or irregularly, feeling like palpitations or fluttering)
  • Chest pain (possibly a tight, squeezing, or crushing sensation, or sharp, dull, burning, stabbing sensation)
  • Congestive heart failure (which occurs when there’s a reduction in blood flow to the body and a clogging of blood into the lungs and other parts of the body)
  • Heart attack (Heart attacks happen when blood flow to the heart is blocked)
  • Hyperthyroidism (overactive thyroid)
  • Glaucoma (considerable high pressure in one or both eyes that can injure the optic nerve)
  • Migraines (intense headache)
  • Tremors
  • Anxiety disorders (severe and persistent stress)

If left untreated, high blood pressure can lead to stroke, heart failure, kidney failure, arterial disease and retinal problems.

Carvedilol Dosage Information

Carvedilol comes in the following forms and dosage:

Tablet

  • 3.125mg
  • 6.25mg
  • 12.5mg
  • 25mg

Capsule, extended release

  • 10mg
  • 20mg
  • 40mg
  • 80mg

Coreg is not recommended for children under the age of 18. For adults, the drug is usually started at 3.125mg twice a day, with the potential of increasing the dose every two weeks (when it is well tolerated) to the higher dosages up to 25mg twice daily. Patients weighing over 187 lbs. can be given the maximum dosage of 50mg twice daily for mild to moderate heart failure. Dizziness may preclude such patients undertaking hazardous tasks including driving and using industrial machinery, until the dizziness dissipates and they feel back to their normal state of alertness.

Carvedilol should be taken with food to slow the rate of the drug’s absorption and reduce the incidence of orthostatic or postural hypotension, which is a form of low blood pressure that occurs when standing from a sitting position.

Dosage must be prescribed individually, depending on each patient’s overall health condition, medical history, and other determinants, and it should be closely monitored by the patient’s health care professional, particularly during up-titration (the gradual increase of a drug until it reaches the desired longer-term dosage).

Furthermore, when Coreg treatment is started, or when there are drug dosage increases, patients may experience temporary feelings of dizziness within an hour or so of administering the medication.

Potential Coreg Side Effects

Many people using this drug do not experience serious side effects. If your health care professional prescribes this medication for you, they likely feel that its benefits outweigh its risks of side effects. However, if you experience discomfort or any concerning symptoms after starting this drug, talk to your doctor.

Common Side Effects of Carvedilol Can Include:

  • Vision changes
  • Changes in sex drive
  • Dizziness, nausea, diarrhea
  • Weakness
  • Headache

Serious Side Effects of Carvedilol Can Include:

  • Rapid weight gain
  • Chest tightness and pain, wheezing
  • Low or uneven heartbeats
  • Difficulty breathing, shortness of breath
  • Loss of bladder control, difficulty urinating
  • Swelling

More Concerning Side Effects (see a physician promptly):

  • Symptoms of allergic reaction (swelling of the face, lips, and tongue, or hives and difficulty breathing)
  • Skin rash that spreads, especially on the face or upper body
  • Skin blistering, peeling, and pain
  • Sudden and unexplained shortness of breath
  • Rapid heart beat
  • Numbness or feeling cold in extremities
  • Pale and dry skin, dry mouth
  • Lightheadedness, drowsiness, and trouble focusing
  • Severe skin reaction
  • Fever
  • Sore throat
  • Burning eyes, blurred vision
  • Increased thirst
  • Hunger and changes in weight (mostly weight loss)
  • Fruity breath odor

Carvedilol Interactions with Other Drugs

The following list includes only a few of the many drugs that interact with carvedilol:

  • Antidepressant medications, such as Elavil, Prozac, Zoloft, Cymbalta, and various other drugs
  • Heart or blood pressure medications, such as Norvasc, Catapres, Cartia, and many other drugs
  • Medicines to treat nausea and vomiting, such as Reglan or Phenergan or others
  • Skin testing drugs for allergies
  • Tagamet (cimetidine)
  • Gengraf, Neoral, and other drugs (cyclosporine)
  • Fluconazole (Diflucan)
  • Insulin or oral diabetes medication
  • Rifampin (Rifadin, Rifater, Rifamate)
  • Heart rhythm drugs, such as Cordarone, Pacerone, digitalis, and others
  • HIV or AIDS drugs, such as Rescriptor, Norvir, or Kaletra
  • Medications that treat psychiatric disorders, such as Thorazin, Haldol, Mellaril, and others

Check with your doctor or pharmacist to determine if there can be negative interactions between any other medications you are taking and carvedilol.

Carvedilol Warnings

Get emergency help if you feel unusual and persistent sweating, difficulty breathing, irregular or fast heartbeat, shortness of breath, pain or tightness, or pain that spreads to your jaw, neck, or arm.

Avoid taking carvedilol if you have severe liver complications or various types of heart conditions that your health care professional will advise you against. Let your doctor know before taking carvedilol if you have:

  • Low blood pressure
  • A feeling that you might pass out
  • Allergies, particularly an allergy to the elements in carvedilol
  • Heart rhythm problems, such as a slow or irregular heartbeat
  • Sick sinus syndrome (SSS), which is a group of abnormal heart rhythms (arrhythmias) resulting from a malfunction of the heart’s primary pacemaker known as the sinus node
  • Asthma, emphysema, chronic bronchitis (OCPD)
  • Liver or kidney disease
  • A certain type of tumor known as pheochromocytoma
  • A certain muscle disease known as myasthenia gravis
  • Certain eye problems such as cataracts or glaucoma
  • Ongoing or have a history of blood flow problems in your legs and feet
  • Diabetes or other low blood sugar issues (Coreg may make it more difficult to control or manage your blood sugar levels)
  • Excessive thyroid hormone in your system (hyperthyroidism)
  • Sudden and unexplained chest pain when you are in a resting position
  • Pending surgery or dental surgery

Pregnancy and Carvedilol:

Studies regarding Coreg and pregnancy and breastfeeding have not been conclusive. It is not clear whether this medication would harm the offspring through breastfeeding. In the absence of such evidence, the best course of action is to allow your health care professional to counsel you as to the best medication for your condition.

Once you are on carvedilol, you should not stop taking it or change the dosage that was prescribed for you without first consulting with your health care professional. If your doctor decides to lower your dosage of Coreg, it would be good for you if you abstained from arduous physical activity to reduce the stress on your heart.

Risk Factors for High Blood Pressure

The following risk factors can raise your odds of developing hypertension:

Aging:

As you age, your chances of developing high blood pressure increase. This increased risk applies in particular to men age 45 or older High blood pressure is more common in men who are 45 years of age and older, and women who are 65 years of age or older.

Race:

African-American adults are more likely to have high blood pressure than Caucasian or Hispanic-American groups. In African-Americans, high blood pressure is also likely to be more severe and acquired at an earlier age.

Genetics:

Hypertension has a pattern of running in families, and having a family history of high blood pressure can put you at greater risk as well.

Birth control:

Women who take birth control pills are at greater risk of developing high blood pressure.

Obesity:

The greater your weight, the more your body tissues will need oxygen and nutrients, the higher the circulation of blood in your veins, and the higher the blood pressure against your arterial walls. Abdominal obesity also increases arterial tension, causing high blood pressure.

Lack of exercise:

A sedentary lifestyle is often associated with increased heart rate and type 2 diabetes, and the higher your heart rate, the more pressure your heart has to exert.

Tobacco use:

Every time you smoke tobacco products (or any other stimulating substances such as coffee or cocaine), you increase the flow of the adrenaline hormone, a powerful stimulant, causing your blood pressure to rise, even if only temporarily. Besides, certain chemicals in tobacco cause your arterial walls to constrict, thus also increasing your blood pressure.

Alcohol consumption:

Men drinking more than two alcohol drinks per day, and women consuming more than one drink a day, are at greater risk for hypertension.

High blood pressure in children:

Children in their teens are becoming more prone to high blood pressure difficulties. Africa-American and Mexican-American children are more likely to be affected by hypertension than their Caucasian counterparts. In addition, boys are at greater risk than girls. Obesity in children and other lifestyle patterns are the main culprits for this worrisome pattern.

Dietary habits:

Remember the old adage, “You are what you eat?” Well, what you ingest is directly linked to your chances for developing high blood pressure. Be aware of the following unhealthy items, particularly when consumed regularly and in excessive quantities:

  • Too much sodium (salt) causes your body to retain fluid, which increases blood pressure.
  • Since potassium helps balance the amount of sodium in your cells, not getting enough potassium can lead to too much sodium in your blood.
  • Low levels of vitamin D; this vitamin impacts an enzyme created by the kidney that affects blood pressure, thus having decreased levels of vitamin D can be harmful.

Stress:

Stress:
Stress causes the release of the powerful stimulant hormones cortisol and adrenaline, which increase heart rate and blood pressure. Furthermore, when these hormones are allowed to linger and persist in the system, as a result of chronic stress, they cause increased injury to various body systems. In addition, to alleviate the preponderance of stress, many people resort to alcohol, smoking or over-eating, all of which are harmful.

Helena’s story of heart failure

Helena, a 49-year old telephone company assistant manager in Michigan, knew everything there was to know about her family history of obesity, type 2 diabetes, and high blood pressure. In fact, she blamed her physical failings, including her unseemly and lumbering overweight, squarely on precisely that, saying to whomever would listen, “Hey, all that was inevitable knowing what my mother, uncles and aunts handed me down.”

To the casual observer, Helena seemed entirely resigned, though not unduly unhappy, to her so-called predestined, etched-in-stone, and unmovable predicament. Although her weight issue bothered her endlessly, as did her troubled breathing, neither that nor her diabetes or hypertension worried her much. She thought of them as long-term issues, stuff to worry about “later”. Within herself though, and at times of inner crisis and turmoil, Helena was scared stiff that her heart condition would have her one day wake up stone dead.

On one particular day, Helena’s nonchalant attitude changed drastically, and it changed for good. She’d been watching a health program on television when suddenly the program showed a heart pumping away furiously, obviously malfunctioning, followed by a 3D animation of the heart troubled by blood congestion in the lungs and again pumping at a terrifying fast rate. The animation showed colored parts of the chest displaying the affected areas -with dark and menacing crimson red all around the heart. For some reason, it was this animation, rather than the real thing, that made her own heart pump with a sudden rush of adrenaline. She even experienced extreme shortness of breath at that moment, and although she’d had such difficulty breathing often enough in the past, it was more pronounced this time and shook her to the core as she panted for breath.

Her life changed significantly from that point on. She went back to her doctor, the same doctor who’d diagnosed her with heart failure three years earlier, and shared her determination to start looking after herself. He printed on his computer a copy of the Dash Diet and gave it her, advising her that it was the best diet for weight control, and for lowering her blood pressure. In the one month that followed, she managed to lose 17 lbs. and another 15 lbs. in the subsequent month, and she started taking short walks at first, and then up to a daily mile after that. What was almost instantly rewarding was that her breathing issues seemed to have dissipated noticeably, and her wheezing had nearly gone altogether.

At the time of her resolve, her doctor also increased her maintenance dose of the beta blocker drug Coreg from 20mg twice daily to 40mg twice daily. He advised her she might experience some resulting dizziness, and that she should not drive until she got accustomed to and tolerated her new dose.

Helena took to the Dash diet like a mouse to nuts. She continued with it, preparing herself daily meals with very little or no sodium at all and, together with her increased dosage of Coreg and regular exercise, the results were more than simply gratifying. She had undergone a 180-degree change in attitude, greatly relishing what years she had left in her.

Over the months that followed, Helena lost more than 60 lbs., and her heart rate dropped to a more reasonable level. She also started breathing almost normally again. These results compounded her resolve, giving her daily reinforcement for the new lifestyle she’d carved for herself. She seemed on the way to recovery from her heart issues as well, although her cardiologist kept pressing her to continue with her healthy regimen and to keep taking her Coreg. He told her that she would probably have to take this beta blocker for the rest of her life.

Final Thoughts

.As with many diseases and health outcomes, the most effective strategy is prevention. While it is comforting to know that there are medications such as Coreg that can help, there are also many lifestyle changes people can make to lower or control blood pressure. Losing weight is typically one of the most effective things you can do to lower blood pressure. Other things you can do are exercise regularly, maintain a healthy diet (such as the DASH diet), limit the amount of sodium and alcohol you consume, stop smoking, cut back on caffeine intake, and try to manage and reduce your stress. There is evidence that behavioral changes like taking up meditation can help reduce blood pressure in stressed individuals. Finally, social support is also linked to lower blood pressure and better health all around. Therefore, in addition to being healthy and active, make sure you keep up your social activity as well, surrounding yourself with people who are supportive.

Carvedilol for heart failure

This leaflet is about the use of carvedilol for the treatment of heart failure in children.

This leaflet is for parents and carers about how to use this medicine in children. Our information sometimes differs from that provided by the manufacturers, because their information is usually aimed at adults. Please read this leaflet carefully. Keep it somewhere safeso that you can read it again.

Name of medicine

Carvedilol
Brand name: Eucardic®

Why is it important for my child to take this medicine?

In heart failure, the heart does not pump as well as it might. Carvedilol relaxes the blood vessels, which makes it easier for the heart to pump blood around the body.

What is carvedilol available as?

Tablets: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg; these contain a small amount of lactose

When should I give carvedilol?

Carvedilol is usually given twice each day, once in the morning and once in the evening. Ideally, these times are 10–12 hours apart, for example sometime between 7 am and 8 am, and between 7 pm and 8 pm.

Give the medicine at about the same times each day so that this becomes part of your child’s daily routine, which will help you to remember.

How much should I give?

Your doctor will work out the amount of carvedilol (the dose) that is right for your child. The dose will be shown on the medicine label.
Your doctor may suggest that your child has a low dose to start with. They may then increase the dose as your child gets used to the medicine and depending on how they respond to it.

It is important that you follow your doctor’s instructions about how much to give.

How should I give carvidolol?

Carvedilol should be taken with some food.

Tablets should be swallowed with a glass of water, milk or juice. Your child should not chew the tablet.

  • You can crush the tablet and mix it with a small amount of cold or room temperature soft food such as yogurt, mashed potato or jam. Make sure your child swallows it straight away without chewing.
  • Occasionally, the only way to provide the correct dose of carvedilol is to give part of a tablet or to disperse a tablet in a small amount of water and give some of the mixture.
  • Your doctor or pharmacist will let you know if this is necessary and explain what to do. This method should only be used when you have been told to do it.
  • Any unused mixture should be poured into a paper towel and put in the bin. Do not pour it down the sink.

When should the medicine start working?

Your child’s symptoms of heart failure should start to get better once your doctor has worked out the best dose. You may notice that your child is less short of breath, has a better appetite and their skin is less puffy.

What if my child is sick (vomits)?

  • If your child is sick less than 30 minutes after having a dose of carvedilol, give them the same dose again.
  • If your child is sick more than 30 minutes after having a dose of carvedilol, you do not need to give them another dose. Wait until the next normal dose.

If your child is sick again, seek advice from your family doctor, pharmacist or hospital.

What if I forget to give it?

If you remember up to 4 hours after you should have given a dose, give your child the missed dose. For example, if you usually give a dose at about 7 am, you can give the missed dose at any time up to 11 am. If you remember after that time, do not give the missed dose. Give the next dose as usual.

Never give a double dose of carvedilol.

What if I give too much?

It can be dangerous to give too much carvedilol because it may make your child’s blood pressure fall.

If you think you may have given your child too much carvedilol, contact your doctor or local NHS services (details at the end of leaflet) or take your child to hospital. Take the medicine or packaging with you, even if it is empty. This will be useful to the doctor. Have the medicine or packaging with you if you telephone for advice.

If your child feels very faint or dizzy, cold and sweaty, or has a weak or rapid heart rate (they may feel as though their heart is racing or fluttering), or they begin to breathe quickly, contact your doctor or take your child to hospital straight away.

Are there any possible side-effects?

We use medicines to make our children better, but sometimes they have other effects that we don’t want (side-effects).

Side effects you must do something about

If your child gets a rash in the first 2 weeks of taking carvedilol, contact your doctor straight away, as they may be allergic to carvedilol. Do not give any more medicine until you have spoken to your doctor.

Side-effects you need to know about
  • Your child may feel dizzy or light-headed when they stand up, or they may faint. Encourage them to stand up slowly, and to sit or lie down if they feel dizzy. This occurs most often after starting treatment or increasing the dose and should get better after a little time. If it happens often, contact your doctor, as your child’s blood pressure may be too low.
  • Your child may get flu-like symptoms (high temperature, aches and pains, headache), blocked nose, headache or wheeziness.
  • They may get nausea, vomiting or diarrhoea.
  • They may get a dry mouth. Eating citrus fruits (e.g. oranges) and taking sips of water may help.
  • Your child’s eyes may feel dry or irritated (red and itchy) and their eyesight may become blurred.
  • Children sometimes feel depressed when taking this medicine, and may have difficulty sleeping or have nightmares.

There may, sometimes, be other side-effects that are not listed above. If you notice anything unusual and are concerned, contact your doctor. You can report any suspected side-effects to a UK safety scheme at www.mhra.gov.uk/yellowcard

Can other medicines be given at the same time as carvedilol?

  • You can give your child medicines that contain paracetamol or ibuprofen, unless your doctor has told you not to.
  • Carvedilol should not be taken with some other medicines that you get on prescription. Tell your doctor and pharmacist about any other medicines that your child is taking before giving carvedilol.
  • You must also tell your doctor and pharmacist that your child is taking carvedilol before giving any other medicines to your child. This includes herbal and complementary medicines.

Is there anything else I need to know about this medicine?

  • Treatment with carvidolol is usually started in hospital, so that the effect on your child can be monitored carefully and the right dose can be worked out.
  • Your doctor will do blood tests to make sure that your child’s kidneys are working well. They will also check your child’s blood pressure regularly.

General advice about medicines

  • Try to give medicines at about the same times each day, to help you remember.
  • Only give this medicine to your child. Never give it to anyone else, even if their condition appears to be the same, as this could do harm.
  • If you are not sure a medicine is working, contact your doctor but continue to give the medicine as usual in the meantime. Do not give extra doses, as you may do harm.

If you think someone else may have taken the medicine by accident, contact your doctor straight away.

  • Make sure that you always have enough medicine. Order a new prescription at least 2 weeks before you will run out.
  • Make sure that the medicine you have at home has not reached the ‘use by’ date on the packaging. Give old medicines to your pharmacist to dispose of.

Where I should keep this medicine?

  • Keep the medicines in a cupboard, away from heat and direct sunlight. It does not need to be kept in the fridge.
  • Make sure that children cannot see or reach the medicine.
  • Keep the medicine in the container it came in.

Who to contact for more information

Your doctor, pharmacist or nurse will be able to give you more information about carvedilol and about other medicines used to treat heart failure.

Blood pressure drugs feeding the obesity epidemic?

NEW YORK (Reuters Health) – Blood pressure drugs known as beta-blockers could be helping to fuel the obesity epidemic, by dampening the body’s ability to burn calories and fat over the long term, researchers say in a new report.

Weight gain is a known side effect of beta blockers, particularly older ones such as atenolol (Tenormin) and metoprolol (Lopressor, Toprol-XL). Newer versions, like carvedilol (Coreg), appear to carry less risk of added pounds.

Beta-blockers are not the only medications that promote weight gain. Antidepressants, corticosteroids and some diabetes medications are among the other culprits.

But with the growing problem of obesity worldwide, researchers are starting to look into the role that medications could be playing — along with the usual suspects of poor diet and sedentary lifestyle.

In the new study, Australian researchers found that among more than 11,400 adults with high blood pressure and/or diabetes, those on beta-blockers weighed more, on average, and had larger waistlines.

And in a separate look at 30 patients with high blood pressure, they found that people on beta-blockers generally burned fewer calories and fat after a meal — measured by a device called a calorimeter.

The patients on beta blockers also reported lower physical activity levels in their day-to-day lives. (Beta blockers are suspected of curbing people’s physical activity because the drugs slow the heart rate and may cause people to tire more easily.)

Together, the findings suggest that beta blockers lead to weight gain by curbing people’s calorie expenditure, according to the researchers, led by Dr. Paul Lee of St. Vincent’s Hospital in Sydney.

In today’s society, where obesity is a general public-health issue, that weight gain is particularly concerning, according to Lee.

“Our hypothesis is that widespread use of beta blockers may fuel the modern-day obesity epidemic,” he told Reuters Health in an email.

So what should you do if you’re on a beta blocker?

Just what people not on the drugs should do, Lee said. “Lifestyle modification is always the first step: a good balanced diet and regular exercise,” he noted.

That said, exercise and calorie burning may be more difficult for people on a beta blocker. So beta blocker users who are worried about weight gain may want to ask their doctor if they could use a different type of blood-pressure medication — or one of the newer beta blockers that seem to have less risk of weight gain, Lee said.

He stressed, though, that beta-blockers are often an important drug for people with heart disease, and patients should not simply stop using them because of weight worries.

Instead, Lee said, they may need to be “extra mindful” of their weight, and get additional help — like referral to a dietitian — if needed.

The findings are based on data from 11,438 adults; most were patients in a clinical trial looking at the effects of blood pressure lowering among people with diabetes. The rest were patients being treated for diabetes or high blood pressure at St. Vincent’s.

On average, Lee’s team found, patients on beta blockers were anywhere from 11 to 37 pounds heavier, depending on the study group.

In the smaller study of patients with high blood pressure, the researchers compared calorie- and fat-burning in 11 people on beta blockers and 19 adults the same age and weight who were not on the drugs.

They found that after a meal, the beta blockers users burned roughly 30 to 50 percent fewer calories and fat.

The findings do not prove that beta blockers were the reason for the excess weight or lower calorie-burning. But they are in line with what’s known about the medications’ effects on the nervous system and weight.

Lee noted that beta blockers are no longer the first choice drugs for high blood pressure. So for people who do not need the drugs to manage heart disease, another blood pressure medication might be more appropriate anyway.

Other types of blood pressure drugs include ACE inhibitors, calcium channel blockers and diuretics (water pills). Many of these, as well as the beta blockers, are available in generic forms for as low as $20 per month or less.

SOURCE: bit.ly/gF5RuW International Journal of Obesity, online February 8, 2011.

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Coreg

SIDE EFFECTS

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

COREG has been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these patient populations are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks).

Heart Failure

COREG has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received COREG for at least 6 months and 30% received COREG for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with COREG for up to 5.9 years (mean: 4.8 years). Both in U.S. clinical trials in mild-to-moderate heart failure that compared COREG in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared COREG in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo-controlled clinical trials, the only cause of discontinuation greater than 1% and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).

Table 1 shows adverse events reported in subjects with mild-to-moderate heart failure enrolled in U.S. placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated subjects than placebo-treated subjects with an incidence of greater than 3% in subjects treated with carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both carvedilol and placebo subjects in the trials of mild-to-moderate heart failure and 10.4 months in the trial of subjects with severe heart failure. The adverse event profile of COREG observed in the long-term COMET trial was generally similar to that observed in the U.S. Heart Failure Trials.

Table 1. Adverse Events (%) Occurring More Frequently with COREG than with Placebo in Subjects with Mild-to-Moderate Heart Failure (HF) Enrolled in U.S. Heart Failure Trials or in Subjects with Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Subjects Treated with Carvedilol, Regardless of Causality)

Body System/ Adverse Event Mild-to-Moderate HF Severe HF
COREG
(n = 765)
Placebo
(n = 437)
COREG
(n = 1,156)
Placebo
(n = 1,133)
Body as a Whole
Asthenia 7 7 11 9
Fatigue 24 22
Digoxin level increased 5 4 2 1
Edema generalized 5 3 6 5
Edema dependent 4 2
Cardiovascular
Bradycardia 9 1 10 3
Hypotension 9 3 14 8
Syncope 3 3 8 5
Angina pectoris 2 3 6 4
Central Nervous System
Dizziness 32 19 24 17
Headache 8 7 5 3
Gastrointestinal
Diarrhea 12 6 5 3
Nausea 9 5 4 3
Vomiting 6 4 1 2
Metabolic
Hyperglycemia 12 8 5 3
Weight increase 10 7 12 11
BUN increased 6 5
NPN increased 6 5
Hypercholesterolemia 4 3 1 1
Edema peripheral 2 1 7 6
Musculoskeletal
Arthralgia 6 5 1 1
Respiratory
Cough increased 8 9 5 4
Rales 4 4 4 2
Vision
Vision abnormal 5 2

Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo.

The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with COREG in either the U.S. placebo-controlled trials in subjects with mild-to-moderate heart failure or in subjects with severe heart failure in the COPERNICUS trial.

Incidence Greater Than 1% To Less Than Or Equal To 3%

Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.

Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension.

Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.

Gastrointestinal: Melena, periodontitis.

Liver and Biliary System: SGPT increased, SGOT increased.

Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased.

Musculoskeletal: Muscle cramps.

Platelet, Bleeding, and Clotting: Prothrombin decreased, purpura, thrombocytopenia.

Psychiatric: Somnolence.

Reproductive, male: Impotence.

Special Senses: Blurred vision.

Urinary System: Renal insufficiency, albuminuria, hematuria.

Left Ventricular Dysfunction Following Myocardial Infarction

COREG has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received COREG and 980 who received placebo. Approximately 75% of the subjects received COREG for at least 6 months and 53% received COREG for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with COREG and placebo, respectively.

The most common adverse events reported with COREG in the CAPRICORN trial were consistent with the profile of the drug in the U.S. heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in greater than 3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with COREG: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation greater than 1% and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo).

Hypertension

COREG has been evaluated for safety in hypertension in more than 2,193 subjects in U.S. clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received COREG for at least 6 months. Most adverse events reported during therapy with COREG were of mild to moderate severity. In U.S. controlled clinical trials directly comparing COREG in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of subjects receiving COREG discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in U.S. placebo-controlled trials increased with increasing dose of COREG. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg.

Table 2 shows adverse events in U.S. placebo-controlled clinical trials for hypertension that occurred with an incidence of greater than or equal to 1% regardless of causality and that were more frequent in drug-treated subjects than placebo-treated subjects.

Table 2. Adverse Events (%) Occurring in U.S. Placebo-Controlled Hypertension Trials (Incidence ≥1%, Regardless of Causality)a

Body System/ Adverse Event COREG
(n = 1,142)
Placebo
(n = 462)
Cardiovascular
Bradycardia 2
Postural hypotension 2
Peripheral edema 1
Central Nervous System
Dizziness 6 5
Insomnia 2 1
Gastrointestinal
Diarrhea 2 1
Hematologic
Thrombocytopenia 1
Metabolic
Hypertriglyceridemia 1
a Shown are events with rate >1% rounded to nearest integer.

Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo.

The following adverse events not described above were reported as possibly or probably related to COREG in worldwide open or controlled trials with COREG in subjects with hypertension or heart failure.

Incidence Greater Than 0.1% To Less Than Or Equal To 1%

Cardiovascular: Peripheral ischemia, tachycardia.

Central and Peripheral Nervous System: Hypokinesia.

Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) .

Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.

Respiratory System: Asthma .

Reproductive, male: Decreased libido.

Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.

Special Senses: Tinnitus.

Urinary System: Micturition frequency increased.

Autonomic Nervous System: Dry mouth, sweating increased.

Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.

Hematologic: Anemia, leukopenia.

The following events were reported in less than or equal to 0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.

Laboratory Abnormalities

Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with COREG. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between subjects treated with COREG and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with COREG. In a long-term, placebo-controlled trial in severe heart failure, subjects treated with COREG had lower values for hepatic transaminases than subjects treated with placebo, possibly because improvements in cardiac function induced by COREG led to less hepatic congestion and/or improved hepatic blood flow.

COREG has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients; fasting serum glucose was not evaluated in the heart failure clinical trials.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of COREG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood And Lymphatic System Disorders

Aplastic anemia.

Immune System Disorders

Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).

Renal And Urinary Disorders

Urinary incontinence.

Respiratory, Thoracic, And Mediastinal Disorders

Interstitial pneumonitis.

Skin And Subcutaneous Tissue Disorders

Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Read the entire FDA prescribing information for Coreg (Carvedilol)

CLINICAL PHARMACOLOGY

Mechanism Of Action

COREG is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. COREG has no intrinsic sympathomimetic activity.

Pharmacodynamics

The basis for the beneficial effects of COREG in heart failure is not established.

Two placebo-controlled trials compared the acute hemodynamic effects of COREG with baseline measurements in 59 and 49 subjects with NYHA class II-IV heart failure receiving diuretics, ACE inhibitors, and digitalis. 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.

These trials measured hemodynamic effects again at 12 to 14 weeks. COREG significantly reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate, while stroke volume index was increased.

Among 839 subjects with NYHA class II-III heart failure treated for 26 to 52 weeks in 4 U.S. placebo-controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving COREG and by 2 EF units in placebo subjects at a target dose of 25 to 50 mg twice daily. The effects of carvedilol on ejection fraction were related to dose. Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily were associated with placebo-corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.

The basis for the beneficial effects of COREG in patients with left ventricular dysfunction following an acute myocardial infarction is not established.

The mechanism by which β-blockade produces an antihypertensive effect has not been established.

β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects, (2) reduces exercise-and/or isoproterenol-induced tachycardia, and (3) reduces reflex orthostatic tachycardia. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.

α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of phenylephrine, (2) causes vasodilation, and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.

Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when COREG is administered with food at the recommended starting dose and titration increments are closely followed .

In hypertensive patients with normal renal function, therapeutic doses of COREG decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after COREG and placebo.

COREG has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.

Pharmacokinetics

COREG is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking COREG with food should minimize the risk of orthostatic hypotension.

Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation.

The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4’-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.

Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.

Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.

The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4′-and 5′-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.

Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2-to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).

Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.

Specific Populations

Steady-state plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25-to 50-mg dose range in subjects with heart failure. Compared with healthy subjects, subjects with heart failure had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects.

Geriatric

Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects. Hepatic Impairment Compared with healthy subjects, patients with severe liver impairment (cirrhosis) exhibit a 4-to 7-fold increase in carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment.

Renal Impairment

Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in subjects with hypertension and moderate to severe renal impairment compared with a control group of subjects with hypertension and normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.

Consistent with its high degree of plasma protein-binding, carvedilol does not appear to be cleared significantly by hemodialysis.

Drug-Drug Interactions

Since carvedilol undergoes substantial oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes.

Amiodarone

In a pharmacokinetic trial conducted in 106 Japanese subjects with heart failure, coadministration of small loading and maintenance doses of amiodarone with carvedilol resulted in at least a 2-fold increase in the steady-state trough concentrations of S(-)-carvedilol .

Cimetidine

In a pharmacokinetic trial conducted in 10 healthy male subjects, cimetidine (1,000 mg per day) increased the steady-state AUC of carvedilol by 30% with no change in Cmax .

Digoxin

Following concomitant administration of carvedilol (25 mg once daily) and digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin were increased by 14% and 16%, respectively, in 12 subjects with hypertension .

Glyburide

In 12 healthy subjects, combined administration of carvedilol (25 mg once daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic interaction for either compound.

Hydrochlorothiazide

A single oral dose of carvedilol 25 mg did not alter the pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 subjects with hypertension. Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.

Rifampin

In a pharmacokinetic trial conducted in 8 healthy male subjects, rifampin (600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by about 70% .

Torsemide

In a trial of 12 healthy subjects, combined oral administration of carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant differences in their pharmacokinetics compared with administration of the drugs alone.

Warfarin

Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state prothrombin time ratios and did not alter the pharmacokinetics of R(+)-and S(-)-warfarin following concomitant administration with warfarin in 9 healthy volunteers.

Clinical Studies

A total of 6,975 subjects with mild-to-severe heart failure were evaluated in placebo-controlled trials of carvedilol.

Mild-To-Moderate Heart Failure

Carvedilol was studied in 5 multicenter, placebo-controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.

Four U.S. multicenter, double-blind, placebo-controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction less than or equal to 0.35. The vast majority were on digitalis, diuretics, and an ACE inhibitor at trial entry. Patients were assigned to the trials based upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled trial enrolled 415 subjects (half randomized to carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double-blind follow-up. All randomized subjects had tolerated a 2-week course on carvedilol 6.25 mg twice daily.

In each trial, there was a primary end point, either progression of heart failure (1 U.S. trial) or exercise tolerance (2 U.S. trials meeting enrollment goals and the Australia-New Zealand trial). There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points 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 U.S. and Australia-New Zealand trials were as follows:

Slowing Progression of Heart Failure

One U.S. multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow-up of 7 months, by 48% (P = 0.008).

In the Australia-New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the 3 largest U.S. trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia-New Zealand results were statistically borderline.

Functional Measures

None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in 3 trials; in none was a statistically significant effect found.

Subjective Measures

Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trial), was unaffected by carvedilol. However, patients’ and investigators’ global assessments showed significant improvement in most trials.

Mortality

Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in these 4 U.S. trials, mortality was reduced, nominally significantly so in 2 trials.

The COMET Trial

In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction less than or equal to 35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and “statin” lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42 mg per day.

The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. The results of COMET are presented in Table 3 below. All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95% CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.

Table 3. Results of COMET

It is not known whether this formulation of metoprolol at any dose or this low dose of metoprolol in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL) with benefits in heart failure.

Severe Heart Failure (COPERNICUS)

In a double-blind trial (COPERNICUS), 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular ejection fraction less than 25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%), were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.

The primary end point of the trial was all-cause mortality, but cause-specific mortality and the risk of death or hospitalization (total, cardiovascular , or heart failure ) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow-up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol; hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 4.

Table 4. Results of COPERNICUS Trial in Subjects with Severe Heart Failure

Figure 1. Survival Analysis for COPERNICUS (Intent-to-Treat)


The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure.

Patients’ global assessments, in which carvedilol-treated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening, or no change compared with baseline. Subjects treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.

The protocol also specified that hospitalizations would be assessed. Fewer subjects on COREG than on placebo were hospitalized for any reason (372 versus 432, P = 0.0029), for cardiovascular reasons (246 versus 314, P = 0.0003), or for worsening heart failure (198 versus 268, P = 0.0001).

COREG had a consistent and beneficial effect on all-cause mortality as well as the combined end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial population and in all subgroups examined, including men and women, elderly and non-elderly, blacks and non-blacks, and diabetics and non-diabetics (see Figure 2).

Figure 2. Effects on Mortality for Subgroups in COPERNICUS


CAPRICORN was a double-blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of less than or equal to 40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a systolic blood pressure greater than 90 mm Hg, a sitting heart rate greater than 60 beats per minute, and no contraindication to β-blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensinreceptor blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow-up was 15 months.

All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%, P = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol). Another trial end point, total mortality and all-cause hospitalization, did not show a significant improvement.

There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.

Figure 3. Survival Analysis for CAPRICORN (Intent-to-Treat)


Figure 4. Effects on Mortality for Subgroups in CAPRICORN

COREG was studied in 2 placebo-controlled trials that utilized twice-daily dosing at total daily doses of 12.5 to 50 mg. In these and other trials, the starting dose did not exceed 12.5 mg. At 50 mg per day, COREG reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at 25 mg per day the effect was about 7.5/3.5 mm Hg. Comparisons of trough-to-peak blood pressure showed a trough-to-peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats per minute at 50 mg per day. In general, as is true for other β-blockers, responses were smaller in black than non-black subjects. There were no age-or gender-related differences in response.

The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related blood pressure response was accompanied by a dose-related increase in adverse effects .

Hypertension With Type 2 Diabetes Mellitus

In a double-blind trial (GEMINI), COREG, added to an ACE inhibitor or angiotensin-receptor blocker, was evaluated in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: -0.06 to 0.10, P = NS) .

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