Carvedilol

Registered South African indications:

• Essential hypertension - mild to moderate
• Stable symptomatic congestive heart failure of ischaemic or cardiomyopathic origin - mild, moderate and severe
• Left ventricular dysfunction following uncomplicated acute myocardial infarction

Contraindications

South African recommendations

• Hypersensitivity to carvedilol or any component of the product
• Severe heart disease 
• Second and third degree atrioventricular (A-V) block
• Sick sinus syndrome (including sino-atrial block) 
• Cardiogenic shock 
• Severe bradycardia (<50bpm) 
• Asthma 
• Chronic obstructive pulmonary disease (COPD) with a bronchospastic component
• Clinically manifest liver dysfunction 
• Safety in children has not been established 
• Severe hypotension (systolic blood pressure <85mmHg) 

Recommendations in other jurisdictions

• Hypersensitivity to carvedilol or to any of the excipients 
• Heart failure belonging to NYHA Class IV of the heart failure classification with marked fluid retention or overload requiring intravenous inotropic treatment
• Chronic obstructive pulmonary disease with bronchial obstruction
• Clinically significant hepatic dysfunction
• Bronchial asthma
• AV block, degree II or III (unless a permanent pacemaker is in place)
• Severe bradycardia (<50bpm)
• Sick sinus syndrome (including sino-atrial block)
• Cardiogenic shock
• Severe hypotension (systolic blood pressure below 85mmHg)
• Prinzmetal's angina
• Untreated phaeochromocytoma
• Metabolic acidosis
• Severe peripheral arterial circulatory disturbances
• Concomitant intravenous treatment with verapamil or diltiazem

Cautions

• Pregnancy
• Breastfeeding
• Mild to moderate hepatic impairment (Recommendations in other jurisdictions)
• Chronic heart failure
• Elderly
• Thyrotoxicosis
• Diabetes mellitus
• Bradycardia
• Contact lens use
• Psoriasis
• History of serious hypersensitivity reactions
• Desensitisation therapy
• Vascular disease
• Reynaud's syndrome
• Secondary hypertension
• Orthostasis
• Acute inflammatory heart disease
• Haemodynamic relevant obstruction of heart valves or outflow tract
• 1st degree heart block
• Galactose intolerance
• Fructose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Sucrase-isomaltase insufficiency
• High doses in cardiac patients

Forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Essential hypertension - mild to moderate (Additional agent may be required)

• Oral (tab): Initial: 12.5mg, dly for first 2 days; Maintenance: 25mg, dly

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Combination with a diuretic may also give the desired response

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In hypertensive patients it is not necessary to time the dose in relation to meals. At doses higher than 25mg the incidence of side effects increases significantly with only a marginal increase in efficacy

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Stable symptomatic congestive heart failure of ischaemic or cardiomyopathic origin - mild, moderate and severe (Additional agent(s) may be required)
- As adjunct to standard therapy
- Those unable to tolerate an ACE-inhibitor
- Those who are, or are not, taking digoxin

• Oral (tab): Initial: 3.125mg, 12hrly; Treatment duration: ≥14 days; If tolerated: Titrate by doubling dosage at intervals of ≥14 days if needed; Maintenance: 6.25-25mg, 12hrly; If <85kg: Max: 25mg, 12hrly; If >85kg: Max: 50mg, 12hrly

If carvedilol has been withdrawn for >2 weeks

• Oral (tab): Initial: 3.125mg, 12hrly; Titrate gradually according to the above recommendations

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Carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects

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Dosage must be individualised and closely monitored by a medical practitioner experienced in the management of heart failure, during up-titration. For those patients receiving digoxin, diuretics and ACE-inhibitors, dosing of these medicines should be stabilised prior to initiation of carvedilol treatment

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Dosing should be increased to the highest level tolerated by the patient

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Before each dose increase, the patient should be evaluated by the medical practitioner for symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure or fluid retention should be treated with increased doses of diuretics, although occasionally it may be necessary to lower the dose of carvedilol or temporarily discontinue carvedilol treatment

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Symptoms of vasodilation such as postural hypotension, headache and dizziness may be managed initially by a reduction in the dose of diuretics

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If symptoms persist, the dose of ACE inhibitor (if used) may be reduced, followed by a reduction in the dose of carvedilol if necessary. Under these circumstances, the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised

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Left ventricular dysfunction following uncomplicated acute myocardial infarction (Additional agent(s) required)
- Long term treatment following otherwise uncomplicated myocardial infarction, but with left ventricular dysfunction (left ventricular ejection fraction (LVEF) ≤40% or wall motion index ≤1.3), in combination with ACE inhibitors and other treatments recommended in the management of patients after myocardial infarction

• Oral (tab): Initial: 6.25mg as the first dose; Patients should remain under close medical supervision for at ≥3hrs following the initial dose; If tolerant to first dose: Subsequent doses: 6.25mg, 12hrly; Treatment duration: 3-10 days; If signs of intolerance during this period: *Down-titrate to 3.125mg, 12hrly; If this dose is not tolerated, treatment should be stopped; If it is well tolerated, it should be increased again; Titrate to 6.25mg, 12hrly after an interval of 3-10 days; If well tolerated: Subsequent up-titration: Titrate by doubling dosage at intervals of 3-10 days; Maintenance dose is the max. dose tolerated by patient; Max: 25mg, 12hrly irrespective of the patient’s weight

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Dosage must be individualised and closely monitored by a medical practitioner during up-titration. Treatment may be started as an inpatient or outpatient when the patient is haemodynamically stable and fluid retention has been minimised

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Prior to initiating carvedilol: Haemodynamically stable patients should have received an ACE inhibitor for at least 48 hours, given at a stable dose during at least the preceding 24 hours. Carvedilol can then be started between day 3 and day 21 after the myocardial infarction

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Subsequent doses should be given if patient tolerated the first dose (i.e. heart rate >50 beats/minute, systemic blood pressure >80mmHg, measured with the patient seated, and absence of clinical signs of intolerance)

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*Down titration: The dose should be reduced to 3.125mg twice daily if the patient develops signs of intolerance during this period, in particular bradycardia <50 beats/minute, systolic blood pressure <80mmHg, measured with the patient seated, or fluid retention

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Indications and dosages registered in other jurisdictions

Essential hypertension (Additional agent may be required)
- As monotherapy or in combination with other antihypertensives, especially thiazide diuretics

• Oral (tab): Initial: 12.5mg, dly for first 2 days; Thereafter: 25mg/day; Titrate gradually at intervals of 2 weeks or more rarely if needed; Max: 50mg/24hrs

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Once daily dosing is recommended, however, the recommended maximum single dose is 25mg

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Chronic stable angina pectoris

• Oral (tab): Initial: 12.5mg, 12hrly for first 2 days; Thereafter: 25mg, 12hrly; Titrate gradually at intervals of 2 weeks or more rarely if needed; Max: 100mg/day, in 2 divided doses

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Stable chronic heart failure - moderate to severe (Additional agent(s) required)
- As an adjunct to conventional basic therapy with diuretics, ACE inhibitors, digitalis, and/or vasodilators

• Oral (tab): Initial: 3.125mg, 12hrly; Treatment duration: 2 weeks; If tolerated: Titrate slowly by doubling dosage at intervals of ≥14 days if needed; Increase to the highest tolerable level; If <85kg: Max: 25mg, 12hrly; If >85kg: Max: 50mg, 12hrly provided that the heart failure is not severe

If carvedilol has been withdrawn for >2 weeks

• Oral (tab): Initial: 3.125mg, 12hrly; Titrate gradually according to the above recommendations

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The patient should be clinically stable (no change in NYHA-class, no hospitalisation due to heart failure) and the basic therapy must be stabilized for at least 4 weeks prior to treatment. Additionally the patient should have a reduced left ventricular ejection fraction and heart rate should be >50bpm and systolic blood pressure >85mmHg

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A dose increase to 50mg twice daily should be performed carefully under close medical supervision of the patient

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Transient worsening of symptoms of heart failure may occur at the beginning of treatment or due to a dose increase, especially in patients with severe heart failure and/or under high dose diuretic treatment. This does usually not call for discontinuation of treatment, but dose should not be increased

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The patient should be monitored by a physician/cardiologist for 2 hours after starting treatment or increasing the dose. Before each dose increase, an examination should be performed for potential symptoms of worsening heart failure or for symptoms of excessive vasodilatation (e.g. renal function, body weight, blood pressure, heart rate and rhythm)

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Worsening of heart failure or fluid retention is treated by increasing the dose of diuretic, and the dose of carvedilol should not be increased until the patient is stabilised. If bradycardia appears or in case of lengthening of AV conduction, the level of digoxin should first be monitored. Occasionally it may be necessary to reduce the carvedilol dose or temporarily discontinue treatment altogether. Even in these cases, carvedilol dose titration can often be successfully continued

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Renal function, thrombocytes and glucose (in case of NIDDM and/or IDDM) should be monitored regularly during dose titration. However, after dose titration the frequency of monitoring can be reduced

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It is recommended that heart failure patients take their carvedilol medication with food to allow the absorption to be slower and the risk of orthostatic hypotension to be reduced

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All indications: The tablets should be taken with the adequate supply of fluid

Not established for use in children below 18 years

Pregnancy

• Caution
• There are no adequate data from the use of carvedilol in pregnant women. 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 reactions (especially hypoglycaemia, hypotension, bradycardia, respiratory depression and hypothermia) may occur in the foetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Carvedilol should not be used during pregnancy unless clearly necessary (that is if the potential benefit for the mother outweighs the potential risk for the foetus/neonate). The treatment should be stopped 2-3 days before expected birth. If this is not possible the newborn has to be monitored for the first 2-3 days of life  

Breastfeeding

• Caution; not recommended 
• Carvedilol is lipophilic and according to results from studies with lactating animals, carvedilol and its metabolites are excreted in breast milk and, therefore, mothers receiving carvedilol should not breastfeed

Renal Impairment

• No dose adjustment recommended

Hepatic Impairment

South African recommendations

• Contraindicated
• In patients with cirrhosis of the liver, the systemic availability of the medicine is increased by up to 80% because of reduction in the first-pass effect. Carvedilol is contraindicated in patients with clinical manifestations of liver dysfunction

Recommendations in other jurisdictions

• Mild: Caution; no information available
• Moderate: Caution; dose adjustment recommended
  Dose adjustment may be required
• Severe: Contraindicated
  In patients with liver cirrhosis, the systemic availability of carvedilol is increased 80% due to reduced first pass effect. Therefore, carvedilol is contraindicated in patients with clinically manifest hepatic impairment

Elderly

• Caution; dose adjustment recommended
  Consider lower initial doses and titrate to response

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Prohibited - In certain sports
  Prohibited - In  and out of competition: 
  Archery (WA)
  Shooting (ISSF) (IPC)

  Prohibited - In competition: 
  Automobile (FIA)
  Billiards (all disciplines) (WCBS)
  Darts (WDF)
  Golf (IGF)
  Skiing / Snowboarding (FIS) in ski jumping, freestyle aerials/halfpipe and snowboard halfpipe/big air
  Underwater sports (CMAS) in constant-weight apnoea with or without fins, dynamic apnoea with and without fins, free immersion apnoea, Jump Blue apnoea, spearfishing, static apnoea, target shooting and variable weight apnoea

Central Nervous System Disorders

• Depression
• Sleep disorders
• Confusion
• Dizziness
• Headache
• Presyncope
• Syncope
• Paraesthesia

Cardiovascular Disorders

• Cardiac failure
• Bradycardia
• Fluid overload
• Atrioventricular block
• Angina pectoris
• Hypotension
• Orthostatic hypotension
• Disturbances of peripheral circulation

Respiratory Disorders

• Bronchitis
• Pneumonia
• Upper respiratory tract infection
• Dyspnoea
• Pulmonary oedema
• Asthma in predisposed patients
• Nasal congestion

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Dyspepsia
• Abdominal pain
• Dry mouth

Hepatobiliary Disorders

• Alanine aminotransferase increase
• Aspartate aminotransferase increase
• Gammaglutamyltransferase increase

Genitourinary Disorders

• Urinary tract infection
• Renal failure
• Renal function abnormalities in patients with diffuse vascular disease and/or underlying renal insufficiency and micturition disorders
• Urinary incontinence
• Erectile dysfunction

Endocrine and Metabolic Disorders

• Weight gain
• Hypercholesterolaemia
• Impaired blood glucose control

Musculoskeletal Disorders

• Pain in extremeties

Skin and Subcutaneous Tissue Disorders

• Allergic exanthema
• Dermatitis
• Urticari
• Pruritus
• Psoriatic and lichen planus like skin lesions
• Alopecia

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Thrombocytopaenia
• Leukopenia
• Hypersensitivity reactions

Sensory Disorders

• Visual impairment
• Lacrimation decreased
• Eye irritation

Others

• Increased sweating
• Oedema

• Verapamil (IV treatment)
• Diltiazem (IV treatment)
• Digitalis
• Antiarrhythmic agents
• Antihypertensive agents
• Dihydropyridines
• Cimetidine
• Debrisoquine
• Alpha-1 blockers
• Alpha-2 agonists
• Beta blockers
• Nitrates
• Cardiac glycosides
• Medications with hypotension as side-effect
• Cyclosporin
• Antidiabetic agents
• Clonidine
• Inhalational anaesthetics
• CYP450 inducers
• CYP450 inhibitors
• Ergotamine
• Neuromuscular blocking agents
• Non-steroidal anti-inflammatory drugs
• Oestrogen
• Corticosteroids

None routine. Specific cases may require

• Renal function
• Platelet count
• Blood glucose

Heart Failure 

• Transient worsening of symptoms of heart failure may occur at the beginning of carvedilol treatment or due to a dose increase, especially in patients with severe heart failure and/or under high dose diuretic treatment. This does usually not call for discontinuation of treatment, but the dose should not be increased

Carvedilol is a competitive, non-selective beta-blocker, which reduces peripheral vascular resistance through vasodilation by selective alpha 1- receptor blockade. It also suppresses the renin-angiotensin system through non-selective beta-blockade. Carvedilol has no intrinsic sympathomimetic activity, but like other non-selective beta blockers, it has membrane stabilising properties.

Tablet 6.25mg

• Aspen Carvedilol (Litha)
• Carloc (Cipla Medpro)
• Carvetrend (Pharma Dynamics)
• Carvedilol-Hexal (Sandoz)
• Carvedilol Oethmaan (Oethmaan)
• Carvedilol Unicorn (Unicorn)
• Dilatrend (Roche) originator
• Rubitrend 6.25 (Ruby Pharmaceuticals)
• Vediblok (Actavis)

Tablet 12.5mg

• Aspen Carvedilol (Litha)
• Carloc (Cipla Medpro)
• Carvetrend (Pharma Dynamics)
• Carvedilol-Hexal (Sandoz)
• Carvedilol Oethmaan (Oethmaan)
• Carvedilol Unicorn (Unicorn)
• Dilatrend (Roche) originator
• Rubitrend 12.5 (Ruby Pharmaceuticals)
• Vediblok (Actavis)

Tablet 25mg

• Aspen Carvedilol (Litha)
• Carloc (Cipla Medpro)
• Carvetrend (Pharma Dynamics)
• Carvedilol-Hexal (Sandoz)
• Carvedilol Unicorn (Unicorn)
• Dilatrend (Roche) originator
• Rubitrend 25 (Ruby Pharmaceuticals)
• Vediblok (Actavis)