Introduction
Carvedilol (brand name Coreg) is used to treat heart failure and high blood pressure (hypertension). It is also used in patients who developed left ventricular dysfunction after having a heart attack (myocardial infarction, MI). In patients with cardiovascular disease, carvedilol is associated with improvements in quality of life, hospitalization rates, and survival.
Carvedilol is a non-selective beta blocker (beta 1 and beta 2) and an alpha 1 blocker. It reduces the energy demands on the heart by blocking cardiac beta receptors, which decreases the heart rate and the force of heart contractions. Carvedilol lowers blood pressure by blocking alpha receptors on blood vessels, which relaxes and dilates blood vessels.
CYP2D6 is one of the primary enzymes involved in activating and metabolizing carvedilol. Approximately 8% of Caucasians and 2% of most other populations have absent CYP2D6 activity and are predicted to be “CYP2D6 poor metabolizers.”
The FDA-approved drug label for carvedilol states that plasma concentrations of carvedilol may be higher in CYP2D6 poor metabolizers compared to normal metabolizers, but does not discuss altering carvedilol dosing based on a patient’s CYP2D6 genotype (1). However, the label does state the dose of carvedilol should be individualized, and the dose should be monitored as it is gradually increased (up-titrated), based on tolerability and clinical response (Table 1).
The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) recommend that no action is needed for carvedilol and CYP2D6 genotype. For CYP2D6 poor metabolizers, DPWG states that the plasma concentration of carvedilol can be elevated, but this does not result in an increase in side effects (Table 2) (2).
Table 1.
FDA (2017) Drug Label for Carvedilol. Therapeutic recommendations based on CYP2D6 Genotype.
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| Phenotype | Carvedilol |
|---|
| CYP2D6 poor metabolizers | Retrospective analysis of side effects in clinical trials showed that poor CYP2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer. |
Table 2.
DPWG (2016) Recommendations for Carvedilol and CYP2D6
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| Phenotype | Recommendations |
|---|
| CYP2D6 poor metabolizers | No action is required for this gene-drug interaction.
The plasma concentration of carvedilol can be elevated. This does not, however, result in an increase in side effects. |
| CYP2D6 intermediate metabolizers | No action is required for this gene-drug interaction.
The plasma concentration of carvedilol can be elevated. This does not, however, result in an increase in side effects. |
| CYP2D6 ultrarapid metabolizers | No action is required for this gene-drug interaction.
The plasma concentration of carvedilol can be reduced. This does not, however, result in a decrease in the effectiveness. |
Drug: Carvedilol
Carvedilol is widely considered to be the standard of care for patients with heart failure, particularly for patients who also have hypertension. Carvedilol is used to treat mild to severe congestive heart failure, as well as hypertension, and left ventricular dysfunction in patients who recently had an MI, but are otherwise stable.
Carvedilol is a non-selective beta blocker (blocks beta 1 and beta 2 receptors) and an alpha 1 blocker. By blocking beta receptors found in the heart, carvedilol reduces the heart rate and decreases the force of heart contractions. By blocking the alpha 1 receptors found on blood vessels, carvedilol relaxes and dilates the blood vessels, which lowers blood pressure.
In the treatment of heart failure, beta blockers such as carvedilol are thought to protect the heart from increased catecholamine stimulation (catecholamines include adrenaline and noradrenaline). In the short term, adrenergic activation can help the heart maintain cardiac performance, but over time, continued activation can be detrimental. Harmful effects include a persistently increased heart rate, down-regulation and impaired functioning of the beta receptors, and myocyte hypertrophy and death—which leads to adverse re-modelling of heart tissue.
Carvedilol exerts its therapeutic effects by protecting the failing heart from harmful adrenergic stimulation. Carvedilol reduces the heart rate, improves left ventricular function, and reduces vasoconstriction. Several large trials (e.g., MOCHA, PRECISE, COPERNICUS) have reported that carvedilol reduces all-cause mortality and decreases hospitalization in patients with heart failure (3-6).
The dose of carvedilol must be individualized and monitored during up-titration. Gradual up-titration should reduce the risk of syncope (fainting) or excessive hypotension (low blood pressure). The FDA drug label recommends carvedilol to be started at 6.25 mg twice daily, which can be increased after 3 to 10 days, based on tolerability, to 12.5 mg twice daily. The dose may then be increased to the target dose of 25 mg twice daily, although patients should be maintained on a lower dose if higher doses are not tolerated. In addition, a lower starting dose may be used (3.125 mg twice daily), and the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention) (1).
Carvedilol is a mixture of equal amounts of left-handed S(-) and right-handed R(+) enantiomers (a "racemic mixture"). Enantiomers are molecules that are mirror images of each other, but are not superimposable on one another. The nonselective beta-adrenoreceptor blocking activity of carvedilol is present in the S(-) enantiomer; and the α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency.
Even though carvedilol plasma levels are about 50% higher in the elderly compared with young subjects, no overall differences in the safety or effectiveness were observed between these two populations except for higher incidence of dizziness in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects) (1).
Carvedilol is contraindicated in patients with severe hepatic (liver) impairment because patients with severe liver impairment (i.e., cirrhosis) exhibit a 4- to 7-fold increase in carvedilol plasma levels when compared with healthy subjects (1).
Gene: CYP2D6
The cytochrome P450 superfamily (CYP450) is a large and diverse group of enzymes that form the major system for metabolizing lipids, hormones, toxins, and drugs. The CYP450 genes are highly polymorphic and can result in no, decreased, normal, or increased enzyme activity.
CYP2D6 and CYP2C9 are the primary enzymes involved in the activation and metabolism of carvedilol. Other enzymes involved to a lesser extent include CYP3A4, CYP2C19, CYP1A2, and CYP2E1. The pharmacokinetics of carvedilol are known to be influenced by genetic variation in CYP2D6—data do not exist for CYP2C9.
Individuals who have two non-functional copies of the CYP2D6 gene are predicted to be “CYP2D6 poor metabolizers”. Plasma concentrations of R(+)- carvedilol are 2–3 times higher in poor metabolizers, and levels of S(-)-carvedilol are increased by approximately 20% to 25%, compared to normal metabolizers with normal CYP2D6 activity (1).
Retrospective analysis of side effects in clinical trials showed that individuals who are CYP2D6 poor metabolizers had a higher rate of dizziness during up-titration. This is thought to result from vasodilating effects of the 2–3 times higher concentrations of the α-blocking R(+) enantiomer (1).
Variation in CYP2D6 does not appear to be associated with a change in the response to carvedilol therapy. This may be because other CYP450 enzymes can convert carvedilol to its active metabolite. One small study (n=93) reported that there were no significant differences of carvedilol dose as well as the number of adverse drug reactions among patients with different CYP2D6 genotypes (7). Another small study (n=110) found that there were significant CYP2D6 allele-specific differences in carvedilol pharmacokinetics, but CYP2D6 genotype had no effect on heart rate, blood pressure or adverse effects (8).
The CYP2D6 genotype may be associated with carvedilol dosage, however. Two small studies reported that higher maintenance doses of carvedilol were tolerated by carriers of non-functional CYP2D6 alleles (n=65) (9), and by CYP2D6 poor metabolizers (n=93) (10).
Genetic Testing
The NIH’s Genetic Testing Registry (GTR) displays genetic tests that are currently available for carvedilol response and the CYP2D6 gene. According to the FDA, the pharmacokinetics of carvedilol do not appear to be different in patients with decreased or absent CYP2D6 activity. Therefore, genetic testing prior to the use of carvedilol is not recommended.
Therapeutic Recommendations based on Genotype
This section contains excerpted1
information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.
2017 Statement from the US Food and Drug Administration (FDA)
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).
Please review the complete therapeutic recommendations that are located here: (1).
2016 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
CYP2D6 PM: CARVEDILOL
Pharmacist text
NO action is required for this gene-drug interaction.
The plasma concentration of carvedilol can be elevated. This does not, however, result in an increase in side effects.
Background information
Carvedilol is primarily converted by CYP2D6 to 4’-hydroxycarvedilol and 5’-hydroxycarvedilol. Data from pre-clinical studies suggest that these metabolites are active.
Carvedilol is also converted by other CYP450 enzymes to the active metabolite desmethylcarvedilol.
CYP2D6 IM: CARVEDILOL
Pharmacist text
NO action is required for this gene-drug interaction.
The plasma concentration of carvedilol can be elevated. This does not, however, result in an increase in side effects.
Background information
Carvedilol is primarily converted by CYP2D6 to 4’-hydroxycarvedilol and 5’-hydroxycarvedilol. Data from pre-clinical studies suggest that these metabolites are active.
Carvedilol is also converted by other CYP450 enzymes to the active metabolite desmethylcarvedilol.
CYP2D6 UM: CARVEDILOL
Pharmacist text
NO action is required for this gene-drug interaction.
The plasma concentration of carvedilol can be reduced. This does not, however, result in a decrease in the effectiveness.
Background information
Carvedilol is primarily converted by CYP2D6 to 4’-hydroxycarvedilol and 5’-hydroxycarvedilol. Data from pre-clinical studies suggest that these metabolites are active.
Carvedilol is also converted by other CYP450 enzymes to the active metabolite desmethylcarvedilol.
Please review the complete therapeutic recommendations that are located here: (
2
)
Acknowledgments
The author would like to thank Saeed Alzghari, MS, MBA, PharmD, BCPS Director of Clinical Pharmacy, Gulfstream Genomics; Bernard Esquivel MD, PhD, Personalized Medicine Latin American Association – President; and Inge Holsappel, Pharmacist, Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP), Netherlands, for reviewing this summary.
References
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Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines [Internet]. Netherlands. Carvedilol [Cited August 2017]. Available from:
http://kennisbank.knmp.nl [Access is restricted to KNMP membership.]
- 3.
Bristow M.R., Gilbert E.M., Abraham W.T., Adams K.F., et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators.
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Packer M., Colucci W.S., Sackner-Bernstein J.D., Liang C.S., et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise.
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Packer M., Fowler M.B., Roecker E.B., Coats A.J., et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.
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Shihmanter R., Nulman I., Goland S., Caspi A., et al. Variation in the CYP2D6 genotype is not associated with carvedilol dose changes in patients with heart failure.
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- 8.
Sehrt D., Meineke I., Tzvetkov M., Gultepe S., et al. Carvedilol pharmacokinetics and pharmacodynamics in relation to CYP2D6 and ADRB pharmacogenetics.
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Luzum J.A., Sweet K.M., Binkley P.F., Schmidlen T.J., et al. CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure.
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PubMed: 28181117]
- 10.
Baudhuin L.M., Miller W.L., Train L., Bryant S., et al. Relation of ADRB1, CYP2D6, and UGT1A1 polymorphisms with dose of, and response to, carvedilol or metoprolol therapy in patients with chronic heart failure.
Am J Cardiol. 2010 Aug 01;106(3):402–8. [
PubMed: 20643254]
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1
The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations where necessary, other author insertions are shown in square brackets.
