Iloperidone

The label says iloperidone's mechanism is unknown but may involve blocking dopamine D2 and serotonin 5-HT2 receptors. It forms an active metabolite, P88, that binds receptors much like the parent drug, and a second major metabolite, P95 [1].

The liver breaks iloperidone down three ways: carbonyl reduction, hydroxylation by CYP2D6, and O-demethylation by CYP3A4. Steady levels are reached in 3 to 4 days. To avoid a drop in blood pressure on standing, the dose is raised over about a week, from 1 mg twice a day to a target of 6 to 12 mg twice a day for schizophrenia, or 12 mg twice a day for bipolar mania [1].

Iloperidone prolongs the QT interval, a measure of how long the heart takes to recharge between beats. In the label's study, 12 mg twice a day lengthened the QTc by about 9 milliseconds; with paroxetine (a CYP2D6 inhibitor) and ketoconazole (a CYP3A4 inhibitor) added, the increase was about 19 milliseconds. No cases of torsade de pointes were seen before approval [1].

CYP2D6 is a liver enzyme with many inherited variants. People with two non-working copies are poor metabolizers. CPIC estimates that about 6.5% of people of European ancestry are poor metabolizers, compared with about 2% to 3% in most other groups and under 1% of people of East Asian or Oceanian ancestry [2].

Without CYP2D6, the balance of metabolites shifts: in poor metabolizers P88 makes up 34% of total exposure instead of 19.5%, and P95 25% instead of 47.9%. The label also reports that 8 poor metabolizers had 47% more iloperidone and 85% more P88 than 18 normal metabolizers, and 85% less P95. Half-lives were longer too: 33 hours for iloperidone and 37 hours for P88 in poor metabolizers, compared with 18 and 26 hours in normal (extensive) metabolizers [1].

Because both the parent drug and P88 are active, the label treats the higher combined exposure as a QT concern. Its warning advises caution in people with reduced CYP2D6 activity [1]. A QTc study in 188 adults found larger QTc increases when CYP2D6 and CYP3A4 were blocked by other drugs, and also in people with certain CYP2D6 variants; no participant reached a QTc of 500 milliseconds or more [3].

The label and the FDA table give no advice for intermediate metabolizers.

The FDA label says to reduce the iloperidone dose by half for CYP2D6 poor metabolizers and gives a separate titration (section 2.2) [1]:

The same halving applies to people taking a strong CYP2D6 inhibitor such as fluoxetine or paroxetine, or a strong CYP3A4 inhibitor such as ketoconazole or clarithromycin. When the inhibitor is stopped, the dose goes back to where it was [1].

The FDA's Table of Pharmacogenetic Associations lists iloperidone and CYP2D6 in its first section, where the data support therapeutic management recommendations [4]. A Gene2Rx report shows that FDA statement for your CYP2D6 result.

CPIC has not published an iloperidone guideline; its gene-drug list gives the pair a provisional level of B/C [5]. The DPWG's antipsychotic guideline does not cover iloperidone [6].

Bring the report to your prescriber or pharmacist with a full list of your medicines. A poor metabolizer result matters most when iloperidone is started, because the label's poor metabolizer schedule is shorter and ends at a lower dose.

Other medicines can make CYP2D6 behave as if your genes were different, an effect called phenoconversion. The FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [7]. The label also says to avoid iloperidone with other drugs that prolong the QT interval, including class 1A and class III antiarrhythmics, some other antipsychotics such as chlorpromazine and thioridazine, and some antibiotics. It recommends checking potassium and magnesium in people at risk of low levels, because low levels raise the risk [1].

Do not start, stop or change iloperidone or any other medicine because of a genetic result without talking to your prescriber.

Consumer arrays (23andMe, AncestryDNA, MyHeritage) are not clinical-grade tests, and their raw data is labeled not for medical use. They read fixed positions, and Gene2Rx uses imputation to infer some variants that were not measured directly. A normal result means none of the assessed variants was found among the positions your data covers; it cannot rule out a variant at a position the data does not cover. Because the label ties the dose to poor metabolizer status and the concern is heart rhythm, a clinical CYP2D6 test is reasonable before relying on the result. If a clinical test (GeneSight, Genomind or another lab) has already reported your CYP2D6 genotype, those results can be entered for a Panel Report.

A genotype says nothing about other QT risks, such as an inherited long QT syndrome, a slow heart rate or other medicines. An ECG measures the QT interval directly.

Why does a slower metabolism matter for the heart?

Iloperidone prolongs the QT interval, and the label links greater prolongation to higher drug exposure, as when CYP2D6 and CYP3A4 are blocked (see How iloperidone works).

I am a poor metabolizer. Can I still take iloperidone?

The label does not rule it out. It halves the dose and uses a shorter titration (see What the FDA label recommends).

1. Fanapt (iloperidone) tablets: prescribing information (Vanda). DailyMed. Indications, titration, poor metabolizer dosing, QT data, pharmacokinetics and pharmacogenomics.
2. CPIC. CYP2D6 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographic group.
3. Potkin SG et al. A thorough QTc study of 3 doses of iloperidone including metabolic inhibition via CYP2D6 and/or CYP3A4 and a comparison to quetiapine and ziprasidone. J Clin Psychopharmacol (2013). QTc changes with iloperidone, metabolic inhibitors and CYP2D6 variants.
4. US Food and Drug Administration. Table of Pharmacogenetic Associations. The FDA statement for iloperidone and CYP2D6 poor metabolizers.
5. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Provisional level B/C for CYP2D6 and iloperidone.
6. Beunk L et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. Eur J Hum Genet (2024). The drugs the DPWG antipsychotic guideline covers.
7. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2D6 inhibitors.