DPWG Recommendations
| Phenotype / Drug* | Implication | Therapeutic recommendation |
|---|---|---|
| CYP2C19 Poor Metabolizer Clopidogrel |
The risk of serious cardiovascular and cerebrovascular events is increased in patients undergoing balloon angioplasty or stent placement (percutaneous coronary intervention) and in patients with a stroke or TIA, because the genetic variation reduces the activation of clopidogrel. No negative clinical consequences have been proved in other patients. | PERCUTANEOUS CORONARY INTERVENTION, STROKE or TIA: - Avoid clopidogrel - Prasugrel, ticagrelor and acetylsalicylic acid/dipyridamole are not metabolized by CYP2C19 (or to a lesser extent) OTHER INDICATIONS: - Determine the level of inhibition of platelet aggregation by clopidogrel - Consider an alternative in poor responders - Prasugrel and ticagrelor are not metabolized by CYP2C19 (or to a lesser extent) |
| CYP2C19 Poor Metabolizer Sertraline |
The risk of side effects is increased. The gene variation leads to increased plasma concentrations of sertraline. | - Do not give doses exceeding 75 mg/day - Guide the dose by response and side effects and/or sertraline plasma concentration. |
| CYP2D6 Ultra-rapid Metabolizer Codeine |
The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough. |
DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function: - Codeine is contra-indicated - If possible, select an alternative For PAIN: - Do not select tramadol, as this is also metabolized by CYP2D6. Morphine is not metabolized by CYP2D6. Oxycodone is metabolized by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients. For COUGH: - Noscapine is not metabolized by CYP2D6. DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function: - No action required |
| CYP2D6 Ultra-rapid Metabolizer Doxepin |
The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of doxepin and the active metabolite nordoxepin and an increase in the plasma concentrations of the potentially cardiotoxic hydroxy metabolites. |
- Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin in order to set the maintenance dose. The therapeutic range is 100-250 ng/mL for the sum of doxepin and nordoxepin plasma concentrations. Values higher than 400 ng/mL are considered toxic. - If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites: avoid doxepin. Antidepressants that are not metabolized by CYP2D6, or to a lesser extent, include citalopram and sertraline. |
| CYP2D6 Ultra-rapid Metabolizer Clomipramine |
The risk of ineffectiveness and cardiotoxic side effects may be increased. The gene variation leads to reduced plasma concentrations of clomipramine and the active metabolite desmethylclomipramine and to increased concentrations of the potentially cardiotoxic hydroxy metabolites. |
- Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose. For depression, the therapeutic range is 200-400 ng/mL for the sum of the plasma concentrations of clomipramine and desmethylclomipramine. For anxiety disorders, the therapeutic plasma concentration of clomipramine is approximately 100 ng/mL, in combination with a plasma concentration of desmethylclomipramine lower than 200 ng/mL. For obsessive compulsive disorder, the therapeutic plasma concentration of clomipramine is higher than 200 ng/mL, in combination with a plasma concentration of desmethylclomipramine that is as low as possible. - If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites: avoid clomipramine. Antidepressants that are not metabolised by CYP2D6, or to a lesser extent, include citalopram and sertraline. |
| CYP2D6 Ultra-rapid Metabolizer Tramadol |
The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects. |
As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty. - Select an alternative - Do not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolized by CYP2D6. Oxycodone is metabolized by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients. - If an alternative is not possible: - Use 40% of the standard dose - Advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention). |
| CYP2D6 Ultra-rapid Metabolizer Metoprolol |
The gene variation increases the conversion of metoprolol to inactive metabolites. This can increase the dose requirement. However, with a target dose of 200 mg/day, there was no effect on the blood pressure and hardly any effect on the reduction of the heart rate. |
1. Use the maximum dose for the relevant indication as a target dose 2. If the effectiveness is still insufficient: increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative Possible alternatives include: HEART FAILURE: bisoprolol or carvedilol. Bisoprolol: advantage: not metabolized by CYP2D6; disadvantage: elimination depends on the kidney function. Carvedilol: advantage: elimination does not depend on the kidney function; disadvantage: is metabolized (to a lesser extent than metoprolol) by CYP2D6. OTHER INDICATIONS: atenolol or bisoprolol. Neither is metabolized by CYP2D6. |
| TPMT Poor Metabolizer Mercaptopurine/Azathioprine |
Grade ≥ 2 leukopaenia and intolerance occurred in 98% of these patients with standard therapy. The gene variation increases the quantities of the active metabolites of azathioprine and mercaptopurine. |
- Choose an alternative or use 10% of the standard dose. Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness. - If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur. |
* Please find the recommendation for particular drug, you are going to prescribe, from the list.