Antipsychotics and antiepileptics
Several antipsychotics may interact with ART. First-generation antipsychotics such as chlorpromazine, levomepromazine, fluphenazine, and haloperidol are not anticipated to have pharmacokinetic interaction with LAI cabotegravir and rilpivirine . However, since these antipsychotics have potential to cause QTc prolongation and given the potential rilpivirine has potential to cause QTc prolongation at supratherapeutic doses, there is need to monitor for this potential pharmacodynamic interaction. This is also applicable to second-generation antipsychotics, which include olanzapine, aripiprazole, clozapine, paliperidone, quetiapine, risperidone, and are not anticipated to have any significant pharmacokinetic interaction with LAI cabotegravir and rilpivirine, though the potential for overlapping QTc prolongation effect exists . Both first- and second-generation antipsychotics are mainly metabolised by CYP enzymes (3A4 and 2D6) and also by glucuronidation. Both cabotegravir and rilpivirine have no clinically relevant impact on these pathways .
No studies have been conducted for the selective serotonin reuptake inhibitors (SSRIs) sertraline, fluvoxamine, fluoxetine, and paroxetine. These are mostly metabolised by CYP enzymes, predominantly CYP2D6. Clinically relevant drug interactions with cabotegravir and rilpivirine are not anticipated . Citalopram and its therapeutically active isomer escitalopram are SSRIs predominantly metabolised by CYP2C19 and while no clinically relevant interactions are anticipated, caution is advised due to the risk of QT prolongation with both citalopram and escitalopram . The tricyclic antidepressants amitriptyline, clomipramine and imipramine have similar metabolic pathways to SSRIs and are anticipated to have no significant interactions, but imipramine has a potential for QTc prolongation . Lithium carbonate is commonly used as a mood stabiliser. It is anticipated to have no significant pharmacokinetic interaction as it is mainly eliminated by renal filtration. However, caution is advised due to a risk for QT prolongation .
The antiepileptics carbamazepine, oxcarbazepine, phenobarbitone and phenytoin are potent inducers of CYP enzymes . Based on clinically significant interactions between rifampicin which is also a potent inducer and rilpivirine as described above, significant reduction of both oral and LAI rilpivirine are anticipated, and co-administration is therefore contraindicated. Lamotrigine undergoes glucuronidation while sodium valproate undergoes both glucuronidation and metabolism by CYP-2C9 and 2C19. No clinically significant interactions are anticipated. Levetiracetam does not undergo CYP metabolism, however due to its potential for QT prolongation there is risk for pharmacodynamic interaction.
Non-oral formulations of benzodiazepines are indicated for status epilepticus and include diazepam, midazolam, and lorazepam. Coadministration of midazolam (3 mg) and oral cabotegravir (30 mg once daily) was studied in 12 subjects. Midazolam Cmax and AUC increased by 9% and 10%, however this was not clinically relevant. A similar effect is expected between parenteral midazolam and the LAI formulations. Neither lorazepam nor diazepam are anticipated to have significant interactions .