Guidelines regarding the use of pharmacogenomic tests in dosing for codeine have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
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Excerpt from the codeine dosing guidelines:
[The table below] summarizes the therapeutic recommendations for codeine based on CYP2D6 phenotype. A standard starting dose of codeine, as recommended in the product label, is warranted in patients with an extensive metabolizer phenotype (i.e., a CYP2D6 activity score of 1.0 to 2.0). Likewise, a standard starting dose of codeine is warranted in patients with an intermediate metabolizer phenotype (i.e., a CYP2D6 activity score of 0.5); these patients should be monitored closely for less than optimal response and should be offered an alternative analgesic if required. If the CYP2D6 substrate tramadol is selected as alternative therapy in intermediate metabolizers, close monitoring should be carried out because of the possibility of low response.
If clinical genotyping identifies a patient as a CYP2D6 poor metabolizer (i.e., a CYP2D6 activity score of 0), current evidence suggests that the use of codeine be avoided because of the possibility of lack of effect, and that an alternative analgesic should be used. That is, it may be preferable to use an analgesic other than the CYP2D6 substrate tramadol in poor metabolizers. There is insufficient evidence in the literature to recommend a higher dose of codeine in poor metabolizers, especially given that adverse effects do not differ between poor metabolizers and extensive metabolizers.
In a patient identified as a CYP2D6 ultrarapid metabolizer (i.e., a CYP2D6 activity score of >2.0), the choice of an alternative analgesic should be made to avoid the risk of severe toxicity associated with a "normal" dose of codeine. That is, it may be preferable to use an analgesic other than the CYP2D6 substrate tramadol in ultrarapid metabolizers.
| Likely phenotype* | Activity score | Genotypes | Examples of diplotypes | Implications for codeine metabolism | Recommendations for codeine therapy | Classification of recommendation for codeine therapy |
|---|---|---|---|---|---|---|
| Ultrarapid metabolizer (~1-2% of patients) | >2.0 | An individual carrying more than two copies of functional alleles | *1/*1xN, *1/*2xN | Increased formation of morphine following codeine administration, leading to higher risk of toxicity | Avoid codeine use due to potential for toxicity. Consider alternative analgesics such as morphine or a nonopiod. Consider avoiding tramadol. | Strong |
| Extensive metabolizer (~77-92% of patients) | 1.0-2.0** | An individual carrying two alleles encoding full or reduced function or one full function allele together with either one nonfunctional or one reduced-function allele | *1/*1, *1/*2, *2/*2, *1/*41, *1/*4, *2/*5, *10/*10 | Normal morphine formation | 15-50 mg every 4h as needed for pain (label recommendation) | Strong |
| Intermediate metabolizer (~2-11% of patients) | 0.5** | An individual carrying one reduced and one nonfunctional allele | *4/*10, *5/*41 | Reduced morphine formation | Begin with 15-60 mg every 4h as needed for pain. If no response, consider alternative analgesics such as morphine or a nonopiod. Monitor tramadol use for response. | Moderate |
| Poor metabolizer (~5-10% of patients) | 0 | An individual carrying no functional alleles | *4/*4, *4/*5, *5/*5, *4/*6 | Greatly reduced morphine formation following codeine administration, leading to insufficient pain relief | Avoid codeine use due to lack of efficacy. Consider alternative analgesics such as morphine or a nonopiod. Consider avoiding tramadol. | Strong |
*Frequency estimates are based on data from Caucasians and may differ substantially for other ethnicities. See Supplementary Data for estimates of phenotype frequencies among different ethnic/geographic groups.
**Note that some investigators define patients with an activity score of 0.5 and 1.0 as intermediate metabolizers and define patients with an activity score of 1.5 and 2.0 as extensive metabolizers. Classifying patients with an activity score of 1.0 as extensive metabolizers in this guideline is based on data specific for formation of morphine from codeine in these patients.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for amitriptyline based on CYP2D6 genotypes (PMID:21412232). They recommend selecting an alternative drug or reducing the initial dose for patients carrying intermediate metabolizer alleles and selecting alternative drugs or monitor amitypityline and nortriptyline plasma concentration for patients carrying the poor metabolizer or ultrarapid metabolizer alleles.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline) or monitor amitriptyline and nortriptyline plasma concentration. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S) |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Reduce dose by 25% and monitor plasma concentration or select alternative drug (e.g., citalopram, sertraline). | 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram,sertraline) or monitor (E-10-hydroxy)amitriptyline plasma concentration. | Published controlled studies of moderate 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
- *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Amitriptyline CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for aripiprazole based on CYP2D6 genotypes (PMID:21412232). They recommend reducing maximum dose for patients carrying poor metabolizer alleles of CYP2D6.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Reduce maximum dose to 10 mg/day (67% of the maximum recommended daily dose). | 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | No recommendations. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S) |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | No recommendations. | -- | -- |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Aripiprazole CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for atomoxetine based on CYP2D6 genotypes (PMID:21412232).
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Standard dose. Dose increase probably not necessary; be alert to ADEs. | Published controlled studies of moderate 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 > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | No recommendations. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S). |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Insufficient data to allow calculation of dose adjustment. Be alert to reduced efficacy or select alternative drug (e.g., methylphenidate, clonidine). | -- | -- |
- *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Atomoxetine CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for carvedilol based on CYP2D6 genotypes (PMID:21412232). They conclude that there are no recommendations at this time.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | No recommendations. | 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 > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | No recommendations. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S). |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | No recommendations. | -- | -- |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Carvedilol CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clomipramine based on CYP2D6 genotypes (PMID:21412232). They recommend lower dose for patients carrying the poor metabolizer (PM) alleles and alternative drug for patients carrying the ultrarapid metabolizer (UM) allleles.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Reduce dose by 50% and monitor (desmethyl) clomipramine plasma concentration. | 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Insufficient data to allow calculation of dose adjustment. Monitor (desmethyl)clomipramine plasma concentration | 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Select alternative drug (e.g., citalopram, sertralin) or monitor (desmethyl)clomipramine plasma concentration. | Published case reports, well documented, and having relevant pharmacokinetic or clinical endpoints. Well documented case series. | 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Clomipramine CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clozapine based on CYP2D6 genotypes (PMID:21412232). They conclude that there are no recommendations at this time.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | No recommendations. | 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 (not statistically significant difference). |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | No recommendations. | 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 (not statistically significant difference). |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | No recommendations. | 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 (not statistically significant difference). |
- *See Methods or PMID: 18253145 for definition of "good quality."
- Please see attached PDF for detailed information about the evaluated studies: Clozapine CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for codeine based on CYP2D6 genotypes (PMID:21412232). They recommend alternative drug for analgesia for patients carrying the poor metabolizer (PM) alleles, intermediate metabolizer alleles and the ultrarapid metabolizer (UM) allleles.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief. Cough: no. | 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 > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief. Cough: no | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S). |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to ADE. Cough: be extra alert to ADEs due to increased morphine plasma concentration. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression. |
- *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Codeine CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for doxepin based on CYP2D6 genotypes (PMID:21412232). They recommend lower dose for patients carrying the poor metabolizer (PM) alleles and intermediate metabolizer alleles and alternative drug for patients carrying the ultrarapid metabolizer (UM) allleles.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Reduce dose by 60%. Adjust maintenance dose in response to (nor)doxepin plasma concentration | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Reduce dose by 20%. Adjust maintenance dose in response to (nor)doxepin plasma concentration. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5 Kinetic effect (S) |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Select alternative drug (citalopram, sertraline) or increase dose by 100%. Adjust maintenance dose in response to (nor)doxepin plasma concentration. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5 Kinetic effect (S). |
- *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for duloxetine based on CYP2D6 genotypes (PMID:21412232). They conclude that there are no recommendations at this time.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | No recommendation. | Data on file. | Clinical effect (not statistically significant difference). |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | No recommendation. | No evidence. | -- |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | No recommendation. | No evidence. | -- |
- Please see attached PDF for detailed information about the evaluated studies: Duloxetine CYP2D6
- See Methods or PMID: 18253145 for more background information about the project.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for flecainide based on CYP2D6 genotypes (PMID:21412232). They recommend lower dose for patients carrying the poor metabolizer (PM) alleles and intermediate metabolizer alleles.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Reduce dose by 50%, record ECG, monitor plasma concentration. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S) |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Reduce dose by 25%, record ECG, monitor plasma concentration. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S) |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Record ECG and monitor plasma concentration or select alternative drug (e.g., sotalol, disopyramide, quinidine, amiodarone). | no evidence. | -- |
- *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for flupenthixol based on CYP2D6 genotype (PMID:21412232). They did not find evidence for a gene-drug interaction and therefore provide no dosing recommendations at this time.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles) | None. | None. | None. |
| IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele) | None. | None. | None. |
| UM (gene duplication in absence of inactive or decreased activity alleles) | None. | None. | None. |
| 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 |
- See Methods or PMID: 18253145 for more background information about the project.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for haloperidol based on CYP2D6 genotype (PMID:21412232). They recommend dose reduction for poor metabolizer patients.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles) | Reduce dose by 50% or select alternative drug (e.g., pimozide, flupenthixol, fluphenazine, quetiapine, olanzapine, clozapine). | 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) | None. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms women, <470 ms men); INR increase < 4.5 Kinetic effect (S). |
| UM (gene duplication in absence of inactive or decreased activity alleles) | Insufficient data to allow calculation of dose adjustent. Be alert to decreased haloperidol plasma concentration and adjust maintenance dose in response to haloperidol plasma concentration or select alternative drug (e.g., pimozide, flupenthixol, fluphenazine, quetiapine, olanzapine, clozapine). | 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. |
| 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 |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for imipramine based on CYP2D6 genotype (PMID:21412232). They recommend reducing the dose for poor and intermediate metabolizer patients, and selecting an alternative drug for ultra metabolizers.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles) | Reduce dose by 70% and monitor imipramine and desipramine plasma concentrations. | 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) | Reduce dose by 30% and monitor imipramine and desipramine plasma concentrations. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S). |
| UM (gene duplication in absence of inactive or decreased activity alleles) | Select alternative drug (e.g., citalopram, sertraline) or increase dose by 70% and monitor imipramine and desipramine plasma concentrations. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S). |
| 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 |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Imipramine CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for metoprolol based on CYP2D6 genotype (PMID: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 |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for mirtazapine based on CYP2D6 genotype (PMID:21412232). They do not provide dosing recommendations at this time.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles) | None. | Published controlled studies of moderate 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. |
| IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele) | None. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S). |
| UM (gene duplication in absence of inactive or decreased activity alleles) | None. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S). |
| 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 |
- *See Methods or PMID: 18253145 for definition of "moderate" quality.
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for nortriptyline based on CYP2D6 genotype (PMID:21412232). They recommend reducing the dose for poor and intermediate metabolizer patients and selecting an alternative drug or increasing the dose for ultra metabolizers.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles) | Reduce dose by 60% and monitor nortriptyline + 10-hydroxynortriptyline plasma concentrations. | Published controlled studies of moderate 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) | Reduce dose by 40% and monitor nortriptyline + 10-hydroxynortriptyline plasma concentrations. | 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. |
| UM (gene duplication in absence of inactive or decreased activity alleles) | Select alternative drug (e.g., citalopram, sertraline) or increase dose by 60% and monitor nortriptyline + 10-hydroxynortriptyline plasma concentrations. | Published controlled studies of moderate 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. |
| 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 |
- *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Nortriptyline CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for olanzapine based on CYP2D6 genotype (PMID:21412232). They do not provide dosing recommendations at this time.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles) | None. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS). Kinetic effect (NS). |
| IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele) | None. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS). Kinetic effect (NS). |
| UM (gene duplication in absence of inactive or decreased activity alleles) | None. | None. | None. |
| 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 |
- *See Methods or PMID: 18253145 for definition of "moderate" quality.
- NS: not statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for oxycodone based on CYP2D6 genotype (PMID:21412232). They recommend using an alternate drug for poor, intermediate and ultra metabolizer patients.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles) | Insufficient data to allow calculation of dose adjustment. Select alternate drug - not tramadol or codeine - or be alert to symptoms of insufficient pain relief. | Published controlled studies of moderate 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. |
| IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele) | Insufficient data to allow calculation of dose adjustment. Select alternate drug - not tramadol or codeine - or be alert to symptoms of insufficient pain relief. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS). Kinetic effect (NS). |
| UM (gene duplication in absence of inactive or decreased activity alleles) | Insufficient data to allow calculation of dose adjustment. Select alternate drug (NOT tramadol or codeine) or be alert to ADEs (e.g., nausea, vomiting, constipation, respiratory depression, confusion, urinary retention). | Published incomplete case reports. Product information. | Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S). |
| 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 |
- *See Methods or PMID: 18253145 for definition of "moderate" quality.
- S: statistically significant difference.
- NS: not statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for paroxetine based on CYP2D6 genotype (PMID:21412232). They suggest using an alternative drug for ultra metabolizers.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles) | None. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S). |
| IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele) | None. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms men, <470 ms women); INR increase < 4.5. Kinetic effect (S). |
| UM (gene duplication in absence of inactive or decreased activity alleles) | Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline). | 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. |
| 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 |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for propafenone based on CYP2D6 genotype (PMID:21412232). They suggest a reduced dose for poor metabolizers, and adjusting dose according to plasma concentrations or using an alternative drug for intermediate and ultrarapid metabolizers.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles) | Reduce dose by 70%, record ECG, monitor plasma concentration | 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) | Insufficient data to allow calculation of dose adjustment. Adjust dose in response to plasma concentration and record ECG or select alternative drug (e.g., sotalol, disopyramide, quinidine, amiodarone) | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms male, <470 ms female); INR increase < 4.5, Kinetic effect (S) |
| UM (gene duplication in absence of inactive or decreased activity alleles) | Insufficient data to allow calculation of dose adjustment. Adjust dose in response to plasma concentration and record ECG or select alternative drug (e.g., sotalol, disopyramide, quinidine, amiodarone) | Published controlled studies of moderate 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 |
- *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for risperidone based on CYP2D6 genotypes (PMID:21412232). For all genotypes, they recommend selecting an alternative drug or being extra alert to Adverse Drug Events and adjusting dose to clinical response.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., quetiapine,olanzapine, clozapine) or be extra alert to ADEs and adjust dose to clinical response. | 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 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., quetiapine, olanzapine, clozapine) or be extra alert to ADEs and adjust dose to clinical response. | 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., quetiapine, olanzapine, clozapine) or be extra alert to ADEs and adjust dose to clinical response. | 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tamoxifen based on CYP2D6 genotypes (PMID:21412232). For PM and IM genotypes, they recommend considering using aromatase inhibitors for postmenopausal women due to increased risk for relapse of breast cancer with tamoxifen. For IM genotypes, they recommend avoiding concomitant CYP2D6 inhibitor use.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Increased risk for relapse of breast cancer. Consider aromatase inhibitor for postmenopausal women. | 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): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening complications from diarrhea. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Increased risk for relapse of breast cancer. Avoid concomitant use of CYP2D6 inhibitors. Consider aromatase inhibitor for postmenopausal women. | 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): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening complications from diarrhea. |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | No. | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (S). |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tramadol based on CYP2D6 genotypes (PMID:21412232). For PM and IM genotypes, they recommend selecting an alternative drug (not oxycodone or codeine) and/or being extra alert to symptoms of insufficient pain relief. For UM genotypes, they recommend using a 30% decreased dose and being alert for ADEs, or using an alternative drug (not oxycodone or codeine).
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Select alternative drug-not oxycodone or codeine- or be alert to symptoms of insufficient pain relief. | 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 > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Be alert to decreased efficacy. Consider dose increase. If response is still inadequate, select alternative drug- not oxycodone or codeine-or be alert to symptoms of insufficient pain relief. | 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 > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test. |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Reduce dose by 30% and be alert to ADEs (e.g., nausea, vomiting, constipation, respiratory depression, confusion, urinary retention) or select alternative drug (e.g., acetaminophen, NSAID, morphine-not oxycodone or codeine). | Published controlled studies of moderate 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
- *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for venlafaxine based on CYP2D6 genotypes (PMID:21412232). For PM and IM genotypes, they state that there are not sufficient data to allow calculation of dose adjustment, and they recommend selecting an alternative drug or adjusting dose to clinical response and monitoring (O-desmethyl)venlafaxine plasma concentration. For UM genotypes, they recommend titrating dose to a maximum of 150% of the normal dose(based on venlafaxine and (O-desmethyl)venlafaxine plasma concentration or selecting an alternative drug.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline) or adjust dose to clinical response and monitor (O-desmethyl)venlafaxine plasma concentration. | 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Insufficient data to allow calculation of dose adjustment. Select alternative drug (e.g., citalopram, sertraline) or adjust dose to clinical response and monitor (O-desmethyl)venlafaxine plasma concentration. | 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 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l. |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Be alert to decreased venlafaxine and increased (O-desmethyl)venlafaxine plasma concentration. Titrate dose to a maximum of 150% of the normal dose or select alternative drug (e.g., citalopram, sertraline). | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (S). |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Venlafaxine CYP2D6
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for zuclopenthixol based on CYP2D6 genotypes (PMID:21412232). For PM genotypes, they recommend reducing dose by 50% or selecting an alternative drug. For IM genotypes, they recommend reducing dose by 25% or selecting an alternative drug. For UM genotypes, they state that there are insufficient data to allow calculation of dose adjustment, and to be alert to low zuclopenthixol plasma concentrations or to select an alternative drug.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) | Reduce dose by 50% or select alternative drug (e.g., flupenthixol, quetiapine, olanzapine, clozapine). | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms , <470 ms ); INR increase < 4.5. Kinetic effect (S). |
| IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) | Reduce dose by 25% or select alternative drug (flupenthixol, quetiapine, olanzapine, clozapine). | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5. Kinetic effect (S). |
| UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) | Insufficient data to allow calculation of dose adjustment. Be alert to low zuclopenthixol plasma concentrations or select alternative drug (flupenthixol, quetiapine, olanzapine, clozapine). | not given. | not given. |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Zuclopenthixol CYP2D6
Information regarding PGx on FDA drug labels is derived from the FDA's Table of Pharmacogenomic Biomarkers in Drug Labels. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Chlordiazepoxide and Amitriptyline.
Excerpt from the Chlordiazepoxide and Amitriptyline drug label:
"Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small or quite large (8-fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy.
The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the type 1c antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Chlordiazepoxide and Amitriptyline drug label PDF.
Aripiprazole is an atypical antipsychotic medication mainly used for the treatment of schizophrenia. It is also indicated for the acute and maintenance treatment of manic and mixed episodes associated with bipolar I disorder and for an adjunctive therapy treatment to antidepressants for the treatment of major depressive disorder. The mechanism of action is unknown, but aripiprazole shows partial agonist activity at DRD2 and HTR1A receptors and antagonist activity at HTR2A receptors. Aripiprazole undergoes hepatic metabolization, primarily by the cytochrome P450 enzymes CYP3A4 and CYP2D6.
Excerpts from the Aripiprazole drug label:
"Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Coadministration of ABILIFY with known inhibitors of CYP2D6, such as quinidine or fluoxetine in EMs, approximately doubles aripiprazole plasma exposure, and dose adjustment is needed (see DRUG INTERACTIONS (7.1)). The mean elimination half-lives are about 75 hours and 146 hours for aripiprazole in EMs and PMs, respectively."
"Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg. quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause increased blood levels. Aripiprazole dose should be reduced to one-half of its normal dose when quinidine is given concomitantly with aripiprazole. Other significant inhibitors of CYP2D6, such as fluoxetine or paroxetine, would be expected to have similar effects and should lead to similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased. "
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Aripiprazole drug label.
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Atomoxetine is a selective noradrenaline reuptake inhibitor. It is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder. The exact mechanism of action is unknown, but atomoxetine selectively inhibits the pre-synaptic noradrenaline transporter (SLC6A2), as determined in ex vivo studies. Atomoxetine is eliminated primarily through oxidative metabolism by CYP2D6 and subsequent glucuronidation.
Excerpts from the Atomoxetine drug label:
"Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. Laboratory tests are available to identify CYP2D6 PMs. Coadministration of STRATTERA with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary."
"A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity (extensive metabolizers (EMs)). Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure."
"In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css,max is about 3- to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. "
"Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. Dosage adjustment of STRATTERA may be necessary when coadministered with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) or when administered to CYP2D6 PMs."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Atomoxetine drug label.
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Carvedilol is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, to reduce cardiovascular mortality in clinically stable patients with left ventricular dysfunction following myocardial infarction, and for the management of essential hypertension. It is a nonselective beta-adrenergic blocking agent with a1-blocking activity.
Carvedilol is a racemic mixture and undergoes stereoselective first-pass metabolism. Cytochrome 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, CYP2C19, CYP1A2, and CYP2E1.
Excerpts from the Carvedilol drug label:
"Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the a-blocking R(+) enantiomer."
"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 to 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)."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Carvedilol drug label.
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Cevimeline is a muscarinic agonist which binds to muscarinic receptors. Cevimeline is indicated for the treatment of symptoms of dry mouth in patients with Sjögrens Syndrome. Cytochrome P450 enzymes CYP2D6 and CYP3A3/4 are responsible for the metabolism of cevimeline.
Excerpts from the Cevimeline drug label:
"Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevimeline. Cevimeline should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at a higher risk of adverse events."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Cevimeline drug label.
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Clozapine is an atypical antipsychotic drug. It is approved for the treatment of severely ill patients with schizophrenia who fail to show an acceptable response to standard antipsychotic drug treatment. Clozapine is a substrate for many CYP450 isozymes, in particular 1A2, 2D6, and 3A4.
Excerpts from the Clozapine drug label:
"A subset (3%-10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme P450 2D6. Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, the tricyclic antidepressants, and clozapine. These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. In addition, certain drugs that are metabolized by this isozyme, including many antidepressants (clozapine, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isozyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interaction.
Concomitant use of clozapine with other drugs metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug. Therefore, coadministration of clozapine with other drugs that are metabolized by this isozyme, including antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Clozapine drug label.
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Doxepin hydrochloride is a tricyclic psychotherapeutic agent (TCA). It is recommended for the treatment of psychoneurotic patients with depression and/or anxiety. Doxepin is primarily metabolized by CYP2D6.
Excerpts from the Doxepin drug label:
"The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA)."
"In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide)...Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 and CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors (SSRIs)) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Doxepin drug label PDF.
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Combined fluoxetine and olanzapine is a drug mixture used for the treatment of bipolar disorder and major depressive disorder. Fluoxetine is a selective serotonin reuptake inhibitor and metabolized by several cytochrome P450 enzymes with CYP2D6 being a major contributor (see Fluoxetine Pathway and CYP2D6 VIP for more details). Olanzepine is an atypical antipsychotic. Olanzepine is metabolized via CYP1A2 and clearance is influences by smoking (see CYP1A2 VIP for additional information).
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Fluoxetine and Olanzapine.
Excerpt from the Fluoxetine and Olanzapine (Symbyax) drug label:
"A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme CYP2D6. Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower."
"Fluoxetine inhibits the activity of CYP2D6 and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6 ... should be approached with caution."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Fluoxetine and Olanzapine drug label.
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Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). Fluoxetine is indicated for the treatment of major depressive disorder, obsessive compulsive disorder, bulimia nervosa, and panic disorder. Fluoxetine is metabolized by several cytochrome P450 enzymes with CYP2D6 being a major contributor. At the same time, fluoxetine is an inhibitor of CYP2D6 mediated reactions.
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Fluoxetine.
Excerpts from the Fluoxetine drug label:
"Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.9)"
"Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued."
"Because fluoxetine's metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Fluoxetine drug label.
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Metoprolol is a selective beta1-adrenoreceptor blocking agent used for the treatment of hypertension, angina pectoris, and acute myocardial infarction. Metoprolol is metabolized by the cytochrome P450 enzymes in the liver with a major contribution of CYP2D6.
Excerpts from the Metoprolol drug label:
"The oxidative metabolism of Lopressor is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers. Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of Lopressor than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of Lopressor seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of Lopressor contribute significantly to its beta-blocking effect."
"Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of Lopressor. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer (see Pharmacokinetics section). Caution should therefore be exercised when coadministering potent CYP2D6 inhibitors with Lopressor. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Metoprolol drug label.
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Propafenone is used to treat cardiac arrhythmia, but should be used only if the condition is thought to be life-threatening.
Its metabolism is by CYP2D6,CYP3A4 and CYP1A2. The combination of propafenone, CYP3A4 inhibition and CYP2D6 inhibition or CYP2D6 genetic deficiency could be hazardous.
Excerpt from the propafenone drug label:
"Propafenone is metabolized by CYP2D6,CYP3A4,and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the U.S. population are naturally deficient in CYP2D6 activity and to a somewhat lesser extent in other demographic groups. Drugs that inhibit these CYP pathways(such as desipramine,paroxetine,ritonavir,sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone."
"There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from 2-10 hours. These patients metabolize propafenone into two active metabolites: 5-hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone (norpropafenone) which is formed by both CYP3A4 and CYP1A2. In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Propafenone drug label.
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Propanolol is a beta-blocker which is used for treatment of various conditions including hypertension, angina pectoris and migraine.
Excerpt from the propanolol drug label:
"In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance of 4-hydroxy propranolol was significantly higher and naphthyloxyactic acid was significantly lower in EMs than PMs."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Propanolol drug label.
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Protriptyline hydrochloride is an antidepressant agent, while its mechanism of action in man is not known. Protriptyline belongs to the class of tricyclic antidepressants.
Excerpts from the Protriptyline drug label:
"The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquine hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers")."
" Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses."
"In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics, propafenone and flecainide)."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Protriptyline drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Quinidine is a Class I antiarrhythmic medication which inhibits CYP2D6.
Excerpt from the quinidine drug label:
"Quinidine is not metabolized by cytochrome P450IID6, but therapeutic serum levels of quinidine inhibit the action of cytochrome P450IID6, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450IID6."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Quinidine drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Risperidone is an atypical antipsychotic used in the treatment of schizophrenia, bipolar I disorder, and autism. CYP2D6 is important in its metabolism.
Excerpts from the risperidone drug label:
"Risperidone is metabolized to 9-hydroxyrisperidone by CYP2D6, an enzyme that is polymorphic in the population and that
can be inhibited by a variety of psychotropic and other drugs (see Clinical Pharmacology (12.3)). Drug interactions that reduce
the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the
concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n#70) does not
suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups
has been made."
"CYP2D6 is subject to genetic polymorphism (about 6% to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9- hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Risperidone drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Terbinafine is an antifungal drug used for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium). It is an inhibitor of CYP2D6.
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Terbinafine.
Excerpts from the Terbinafine (Lamisil) drug label:
"Terbinafine is an inhibitor of CYP4502D6 isozyme and has an effect on metabolism of desipramine, cimetidine, fluconazole, cyclosporine, rifampin, and caffeine."
"There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between Lamisil Tablets and these changes has not been established."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Terbinafine (Lamisil) drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Tetrabenazine is used to treat Huntington's Disease chorea. Its primary metabolites are metabolized mainly by CYP2D6, and people with CYP2D6 poor metabolizer genotypes should be treated with lower doses.
Excerpts from the tetrabenazine drug label:
"DOSAGE AND ADMINISTRATION). Patients should be genotyped for CYP2D6 prior to treatment with daily doses of tetrabenazine
over 50 mg (see WARNINGS - Laboratory Tests). Patients who are PMs should not be given daily doses greater than 50 mg."
"Before patients are given a daily dose of greater than 50 mg, they should be tested for the CYP2D6 gene to determine whether they
are poor metabolizers (PMs) or extensive or intermediate metabolizers (EMs or IMs). When a dose of tetrabenazine is given to PMs,
exposure will be substantially higher (about 3-fold for a-HTBZ and 9-fold for b-HTBZ) than it would be in EMs. The dosage should
therefore be adjusted according to a patient's CYP2D6 metabolizer status by limiting the dose to 50 mg in patients who are CYP2D6
poor metabolizers."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tetrabenazine drug label.
The FDA recommends, but does not require, genetic testing prior to initiating treatment with tetrabenazine.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Thioridazine is used to treat schizophrenic patients. It has potentially fatal effects on heart rythm and should only be used if other antipsychotic drugs are not effective or cause intolerable side effects. Its use is warned against in people with reduced CYP2D6 activity and hence, reduced clearance of the drug, as that increases the likelihood of the potential fatal effects.
Excerpts from the thioridazine drug label:
"Therefore, thioridazine is contraindicated with these drugs as well as in patients, comprising about 7% of the normal population, who
are known to have a genetic defect leading to reduced levels of activity of P450 2D6."
"Certain circumstances may increase the risk of Torsades de pointes and/or sudden death in association with the use of drugs that
prolong the QTc interval, including 1) bradycardia, 2) hypokalemia, 3) concomitant use of other drugs that prolong the QTc interval,
4) presence of congenital prolongation of the QT interval, and 5) for thioridazine in particular, its use in patients with reduced activity
of P450 2D6 or its coadministration with drugs that may inhibit P450 2D6 or by some other mechanism interfere with the clearance of
thioridazine."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Thioridazine drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Timolol is a non-selective beta adrenergic agonist applied to the eye to reduce intraocular pressure. It is metabolized via CYP2D6.
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Timolol (Istalol).
Excerpt from the Timolol (Istalol) drug label:
"Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Timolol (Istalol) drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Tiotropium is an inhaled long-acting, antimuscarinic agent for the treatment of chronic obstructive pulmonary disease (COPD). It inhibits the M3-receptors of the airway smooth muscle leading to bronchodilation. Although mostly excreted unchanged it may in some part be metabolized by CYP2D6 and CYP3A4.
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Tiotropium.
Excerpt from the Tiotropium (Spiriva) drug label:
"In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tiotropium (Spiriva) drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Tolterodine, is a competitive muscarinic receptor antagonist used for the treatment of overactive bladder. It is primarily metabolized by CYP2D6.
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Tolterodine.
Excerpts from the Tolterodine (Detrol) drug label:
"The primary metabolic route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a pharmacologically active 5-hydroxymethyl metabolite."
"Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers; this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite."
"In a study of the effect of tolterodine immediate release tablets on the QT interval (SeeCLINICAL PHARMACOLOGY, Cardiac Electrophysiology), the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs). The effect of tolterodine 8mg/day was not as large as that observed after four days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped. These observations should be considered in clinical decisions to prescribe DETROL for patients with a known history of QT prolongation or patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications (see PRECAUTIONS, Drug Interactions). There has been no association of Torsade de Pointes in the international post-marketing experience with DETROL or DETROL LA."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tolterodine (Detrol) drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Tramadol and Acetaminophen is a mixture of two analgesic drugs used to treat pain. Tramadol is an opioid and metabolized mainly via CYP2D6. Acetaminophen is mainly metabolized via glucuronidation.
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Tramadol and Acetaminophen.
Excerpt from the Tramadol and Acetaminophen drug label:
"Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers", while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicates that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure (see WARNINGS) and serotonin syndrome."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tramadol and Acetaminophen drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Trimipramine.
Excerpt from the Trimipramine (Surmontil) drug label:
"Drugs Metabolized by P450 2D6
The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10% of caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of the isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Trimipramine drug label PDF.
Venlafaxine (Effexor) is an inhibitor of neuronal serotonin and norepinephrine reuptake and weak inhibitor of dopamine reuptake used in the treatment of depression.
The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Venlafaxine.
Excerpt from the Venlafaxine (Effexor) drug label:
"Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine ... was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups."
"CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Venlafaxine (Effexor) drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
PharmGKB contains no Clinical Variants that meet the highest level of criteria.
To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.
| Position ? | Drug ? | Relevance ? |
Strength of Evidence ? |
||
|---|---|---|---|---|---|
Download a summary of all Clinical Annotations available.
Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.
The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.
A non-comprehensive list of genetic tests for specific variants, including descriptions of and links to individual tests; manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.
| PGx Test | Variants Assayed | Related Drugs? |
|---|---|---|
| Roche AmpliChip CYP450 Test and Affymetrix GeneChip System 3000Dx | rs1135840, CYP2D6*1, CYP2D6*2ABD, CYP2D6*3, CYP2D6*4ABDJK, CYP2D6*5, CYP2D6*6ABC, CYP2D6*7, CYP2D6*8, CYP2D6*9, CYP2D6*10AB, CYP2D6*11, CYP2D6*15, CYP2D6*17, CYP2D6*19, CYP2D6*20, CYP2D6*29, CYP2D6*35, CYP2D6*36, CYP2D6*40, CYP2D6*41, CYP2D6*1XN, CYP2D6*2XN, CYP2D6*4XN, CYP2D6*10XN, CYP2D6*17XN, CYP2D6*35XN, CYP2D6*41XN, [HAP : CYP2D6*7][HAP : CYP2D6*8][HAP : CYP2D6*9][HAP : CYP2D6*11][HAP : CYP2D6*15][HAP : CYP2D6*19][HAP : CYP2D6*20][HAP : CYP2D6*29][HAP : CYP2D6*35][HAP : CYP2D6*36][HAP : CYP2D6*40] |
The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.
The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.
Links in the "Drugs" column lead to PharmGKB Drug Pages.
|
Variant?
(build 132) |
Alternate Names ? | Drugs ? | Alleles ? | Function ? |
Amino Acid?
Translation |
|
|---|---|---|---|---|---|---|
| rs1065852 | CYP2D6:100C>T, c.100C>T, g.21917263G>A, g.24825C>T, g.40856638G>A, g.5190C>T, p.Pro34Ser, part of CYP2D6*4 and CYP2D6*10 | G > A | Missense | Pro34Ser | ||
| rs1135840 | CYP2D6: S486T, CYP2D6:4180G>C, c.1304C>G, c.1457C>G, g.21913182G>C, g.28906C>G, g.40852557G>C, g.4327C>G, g.9271C>G, p.Thr435Ser, p.Thr486Ser, part of CYP2D6*2A an extensive metabolizer haplotype. | G > C | Missense | Thr486Ser | ||
| rs16947 | CYP2D6:2850C>T, c.733T>C, c.886T>C, g.21914512A>C, g.21914512A>G, g.21914512A>T, g.27576T>C, g.40853887A>G, g.7941T>C, p.Cys245Arg, p.Cys296Arg | T > C | Missense | Cys296Arg | ||
| rs28371706 | CYP2D6:1023 C>T, c.320C>T, g.21916341G>A, g.25747C>T, g.6112C>T, p.Thr107Ile | G > A | Missense | Thr107Ile | ||
| rs28371725 | CYP2D6*41, CYP2D6:2988G>A, c.832+39G>A, c.985+39G>A, g.21914374C>T, g.27714G>A, g.8079G>A, part of CYP2D6*41 | T/C | Not Available | |||
| rs35742686 | c.622delA, c.775delA, g.21914813delT, g.2708delA, g.27275delA, g.7640delA, p.Arg208fx, p.Arg259fx | T | Not Available | Arg | ||
| rs3892097 | CYP2D6*4, CYP2D6:1846G>A, c.353-1G>A, c.506-1G>A, g.2012G>A, g.21915516C>T, g.26572G>A, g.6937G>A, part of CYP2D6*4 | T/C | Not Available | |||
| rs5030655 | CYP2D6*6, CYP2D6:1707 del T, c.353-140delT, c.454delT, g.1873delT, g.21915655delA, g.26433delT, g.6798delT, p.Trp152fx, part of CYP2D6*6 | A | Not Available | Trp | ||
| rs5030656 | c.688_690del3, c.841_843del3, g.21914745_21914747del3, g.27341_27343del3, g.2774_2776del3, g.7706_7708del3 | TTC | Not Available | LysAla230Ala | ||
| rs5030865 | G > T | Not Available | Gly169Xaa | |||
| rs59421388 | 3271G>A, CYP2D6: 3183G>A, c.1012G>A, c.859G>A, g.21914179C>T, g.27909G>A, g.3330G>A, g.8274G>A, p.Val287Met, p.Val338Met | G > A | Missense | Val338Met | ||
| rs61736512 | 1747G>A, CYP2D6: 1659G>A, c.353-188G>A, c.406G>A, g.1825G>A, g.21915703C>A, g.21915703C>T, g.26385G>A, g.6750G>A, p.Val136Ile | G > A | Not Available | Val136Ile |
Overview
| Alternate Names: | cytochrome P450 2D6; cytochrome P450, family 2, subfamily D, polypeptide 7 pseudogene 2; cytochrome P450, family 2, subfamily D, polypeptide 8 pseudogene 2; cytochrome P450, subfamily II (debrisoquine, sparteine, etc., -metabolising), polypeptide 7 pseudogene 2; cytochrome P450, subfamily IID (debrisoquine, sparteine, etc., -metabolising), polypeptide 8 pseudogene 2; cytochrome P450, subfamily IID (debrisoquine, sparteine, etc., -metabolizing), polypeptide 6; cytochrome P450, subfamily IID (debrisoquine, sparteine, etc., -metabolizing)-like 1; cytochrome P450-DB1; debrisoquine 4-hydroxylase; flavoprotein-linked monooxygenase; microsomal monooxygenase; xenobiotic monooxygenase |
|---|---|
| Alternate Symbols: | CPD6; CYP2D; CYP2D7AP; CYP2D7BP; CYP2D7P2; CYP2D8P2; CYP2D@; CYP2DL1; CYPIID6; MGC120389; MGC120390; P450-DB1; P450C2D; P450DB1 |
| Haplotypes: | CYP2D6*1; CYP2D6*2; CYP2D6*3; CYP2D6*4; CYP2D6*5; CYP2D6*5 [gene deletion]; CYP2D6*6; CYP2D6*9; CYP2D6*10; CYP2D6*17; CYP2D6*29; CYP2D6*41 |
| PharmGKB Accession Id: | PA128 |
Details
| Cytogenetic Location: | chr22 : q13.2 - q13.2 |
|---|---|
| GP mRNA Boundary†: | chr22 : 42522501 - 42526883 |
| GP Gene Boundary†: | chr22 : 42519501 - 42536883 |
| Strand: | minus |
| Product Name: | cytochrome P450 2D6, cytochrome P450, family 2, subfamily D, polypeptide 6, cytochrome P450, family 2, subfamily D, polypeptide 6 isoform 1, cytochrome P450, family 2, subfamily D, polypeptide 6 isoform 2, cytochrome P450, subfamily IID (debrisoquine, sparteine, etc., -metabolizing), polypeptide 6, cytochrome P450, subfamily IID (debrisoquine, sparteine, etc., -metabolizing)-like 1, cytochrome P450, subfamily IID, polypeptide 6, debrisoquine 4-hydroxylase, flavoprotein-linked monooxygenase, microsomal monooxygenase, xenobiotic monooxygenase |
All alleles are displayed on the positive chromosomal strand.
| Haplotype | rs1065852 | rs16947 | rs28371706 | rs28371725 | rs35742686 | rs3892097 | rs4986774 | rs5030655 | rs5030656 | rs59421388 | rs61736512 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| CYP2D6*1 | G | G | G | C | T | C | A | TTC | C | C | |
| CYP2D6*2 | G | A | G | C | T | C | A | TTC | C | C | |
| CYP2D6*3 | G | G | G | C | del | C | A | TTC | C | C | |
| CYP2D6*4 | A | G | G | C | T | T | A | TTC | C | C | |
| CYP2D6*5 [gene deletion] | del | del | del | del | del | del | del | ||||
| CYP2D6*5 [gene deletion] | del | del | del | del | del | del | del | del | del | del | |
| CYP2D6*6 | G | G | G | C | T | C | del | TTC | C | C | |
| CYP2D6*9 | G | G | G | C | T | C | A | del | C | C | |
| CYP2D6*10 | A | G | G | C | T | C | A | TTC | C | C | |
| CYP2D6*17 | G | A | A | C | T | C | A | TTC | C | C | |
| CYP2D6*29 | G | A | G | C | T | C | A | TTC | T | T | |
| CYP2D6*41 | G | A | G | T | T | C | A | TTC | C | C |
PharmGKB Curated Pathways
Pathways created internally by PharmGKB based primarily on literature evidence.
-
Atorvastatin/Lovastatin/Simvastatin Pathway, Pharmacokinetics
Drug-specific representation of the candidate genes involved in transport, metabolism and clearance.
-
Citalopram Pathway, Pharmacokinetics
Pharmacokinetics of the selective serotonin reuptake inhibitor citalopram.
-
Codeine and Morphine Pathway, Pharmacokinetics
Representation of the candidate genes involved in metabolism of codeine and morphine.
-
Fluoxetine Pathway, Pharmacokinetics
Representation of the candidate genes involved in the metabolism of fluoxetine.
-
Fluvastatin Pathway, Pharmacokinetics
Drug-specific representation of the candidate genes involved in transport, metabolism and clearance.
-
Gefitinib Pathway (PK)
Representation of the candidate genes involved in the transportation and metabolism of gefitinib
-
Imipramine/Desipramine Pathway, Pharmacokinetics
Representation of the candidate genes involved in the metabolism of the tricyclic antidepressants imipramine and desipramine.
-
Phenytoin Pathway, Pharmacokinetics
Genes involved in the metabolism of phenytoin in the human liver cell.
-
Statin Pathway - Generalized, Pharmacokinetics
Representation of the superset of all genes involved in the transport, metabolism and clearance of statin class drugs.
-
Tamoxifen Pathway, Pharmacokinetics
Tamoxifen metabolism in the liver.
External Pathways
Links to non-PharmGKB pathways.
Datasets
- Bone mineral density in tamoxifen patients
- Hot flashes in tamoxifen patients
- Lipid measurements in tamoxifen study
- Lipid measurements in tamoxifen study - set 2
- Meperidine N-demethylation by human CYP450 isoforms
- Metabolism of yohimbine by human CYP450 isoforms
- Patient responses to tamoxifen
- Pharmacokinetics of Tamoxifen at 4 months
- Thyroid binding globulin in tamoxifen patients
- Genetic Variants in Selective Serotonin Reuptake Inhibitors (SSRIs) associated Adverse Events
- Genetic Variants in Tricyclic Antidepressant associated Adverse Events
- P450s involved in Efavirenz Metabolism
Downloads
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LinkOuts
- Entrez Gene:
- 1565
- OMIM:
- 124030
- 608902
- UCSC Genome Browser:
- NM_000106
- RefSeq RNA:
- NM_000106
- NM_001025161
- RefSeq Protein:
- NP_000097
- NP_001020332
- RefSeq DNA:
- AC_000065
- AC_000154
- NC_000022
- NG_003180
- NG_008376
- NT_011520
- NW_001838745
- NW_927628
- Web Resource:
- http://www.imm.ki.se/CYPalleles/cyp2d6.htm
- UniProtKB:
- Q6NWU0_HUMAN (Q6NWU0)
- Q6NXU8_HUMAN (Q6NXU8)
- Ensembl:
- ENSG00000100197
- GenAtlas:
- CYP2D6
- GeneCard:
- GC22M042522 (1565)
- SOURCE:
- CYP2D6
- MutDB:
- CYP2D6
- PromoLign:
- ortho_8019
Common Searches
Non-Curated Publications
A list of non-curated publications that mention this gene is available.