Dutch Pharmacogenetics Working Group (DPWG) guideline information
for metoprolol and CYP2D6

last updated 02/07/2014

Summary

Select another drug or reduce dose of metoprolol for CYP2D6 poor and intermediate metabolizer patients. Use a dose titration of metoprolol for CYP2D6 ultra metabolizers or select an alternative drug.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for metoprolol based on CYP2D6 genotype [Article:21412232]. They recommend either selecting another drug or dose reduction for poor and intermediate metabolizer patients, with dose titration for ultra metabolizers.

Phenotype (Genotype) Therapeutic Dose Recommendation Level of Evidence Clinical Relevance
PM (2 inactive alleles) Heart failure: select alternative drug (e.g., bisoprolol, carvedilol) or reduce dose by 75%. Other indications: be alert to ADEs (e.g., bradycardia, cold extremities) or select alternative drug (e.g., atenolol, bisoprolol). Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x10^9/l; leucopenia 2.0-3.0x10^9/l; thrombocytopenia 50-75x10^9/l.
IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele) Heart failure: select alternative drug (e.g., bisoprolol, carvedilol) or reduce dose by 50%. Other indications: be alert to ADEs (e.g., bradycardia, cold extremities) or select alternative drug (e.g., atenolol, bisoprolol). Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x10^9/l; leucopenia > 3.0x10^9/l; thrombocytopenia > 75x10^9/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
UM (gene duplication in absence of inactive or decreased activity alleles) Heart failure: select alternative drug (e.g., bisoprolol, carvedilol) or titrate dose to a maximum of 250% of the normal dose in response to efficacy and ADE. Other indications: select alternative drug (e.g., atenolol, bisoprolol) or titrate dose to a maximum of 250% of the normal dose in response to efficacy and ADE. Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10^9/l; leucopenia 1.0-2.0x10^9/l; thrombocytopenia 25-50x10^9/l; severe diarrhea.
Allele Type Alleles
active *1, *2, *33, *35
decreased activity *9, *10, *17, *29, *36, *41
inactive *3-*8, *11-*16, *19-*21, *38, *40, *42

DPWG Guideline publication

Total publications: 1

Reference
1. Pharmacogenetics: From Bench to Byte- An Update of Guidelines. Clinical pharmacology and therapeutics. 2011. Swen J J, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee A H, Mulder H, Rongen G A P J M, van Schaik R H N, Schalekamp T, Touw D J, van der Weide J, Wilffert B, Deneer V H M, Guchelaar H-J. PubMed

Guideline History