6. Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines [Internet]. Netherlands. CYP2D6 : clozapine [Cited 01 May 2020]. Available from:
http://kennisbank.knmp.nlThis section contains excerpted
1
information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.
2020 Statement from the US Food and Drug Administration (FDA)
Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers
Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering clozapine tablets concomitantly with drugs that are inducers or inhibitors of these enzymes.
[…]
Dose adjustments may be necessary in patients with concomitant use of:
- strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin);
- moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine);
- CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline);
- CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin);
- or CYP1A2 inducers (e.g., tobacco smoking)
[…]
Concomitant use of Strong CYP1A2 Inhibitors: Reduce clozapine tablets dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin).
Concomitant use of Strong CYP3A4 Inducers is not recommended.
Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing clozapine tablets dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued.
Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity.
[…]
Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted.
[…]
A subset (3%–10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses.
Please review the complete therapeutic recommendations that are located here:
(1).
Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) (2016, 2020)
CYP2D6 Poor, Intermediate or Ultrarapid Metabolizer-Clozapine [December 2020]
NO action is required for this gene-drug interaction.
The genetic variation results in a slightly elevated plasma concentration of clozapine, but there are no clinical consequences.
CYP1A2 [2016]
This is NOT a drug-gene interaction.
Please review the complete therapeutic recommendations that are located here: (
6
).
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The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance with nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.