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 .