INGREZZA

Monoamine Depletor

May administer valbenazine capsules with or without food.

suicidal ideation / Delayed / 7.2-7.2
angioedema / Rapid / Incidence not known
neuroleptic malignant syndrome / Delayed / Incidence not known

hyperprolactinemia / Delayed / 1.0-10.0
akathisia / Delayed / 2.7-6.3
blurred vision / Early / 0-5.4
constipation / Delayed / 0-5.4
urinary retention / Early / 0-5.4
pseudoparkinsonism / Delayed / 3.0-4.7
depression / Delayed / 4.7-4.7
hyperglycemia / Delayed / 0-1.0
dyskinesia / Delayed / 1.0
cholestasis / Delayed / Incidence not known
QT prolongation / Rapid / Incidence not known

drowsiness / Early / 10.9-18.8
fatigue / Early / 10.9-14.1
urticaria / Rapid / 9.4-9.4
rash / Early / 7.8-7.8
insomnia / Early / 1.0-6.3
xerostomia / Early / 0-5.4
nausea / Early / 2.3-4.7
diarrhea / Early / 4.7-4.7
back pain / Delayed / 4.7-4.7
dizziness / Early / 4.1-4.1
headache / Early / 3.4-3.4
restlessness / Early / 2.7-2.7
vomiting / Early / 2.6-2.6
arthralgia / Delayed / 2.3-2.3
hypersalivation / Early / 1.0
anxiety / Delayed / 1.0
weight gain / Delayed / 1.0
infection / Delayed / 1.0
tremor / Early / Incidence not known
pruritus / Rapid / Incidence not known

Patients with Huntington's disease are at increased risk for depression and suicidal ideation or behaviors. Vesicular monoamine transporter-2 (VMAT2) inhibitors, including valbenazine, can further increase the risk for depression as well as suicidal ideation and behaviors in patients with Huntington's disease. Anyone considering the use of valbenazine must balance the risks of depression and suicidal ideation and behavior with the clinical need for treatment of chorea. Use caution in treating patients with Huntington's disease who have a pre-existing history of depression or prior suicide attempts or ideation. Closely monitor valbenazine treated patients for the emergence or worsening of depression, suicidal ideation, or unusual changes in behavior. Patients, caregivers, and families should be informed of the risk of depression and suicidal ideation and behavior and instructed to report any behaviors of concern promptly to the treating provider.

INGREZZA

Rx

Oral pre-synaptic human vesicular monoamine transporter type 2 (VMAT2) inhibitor that inhibits dopamine release
First drug approved to treat tardive dyskinesia (TD) in adults; also approved for treatment of chorea associated with Huntington's disease in adults
May cause clinically significant QT prolongation during coadministration of a strong CYP2D6 or CYP3A4 inhibitor or in those who are CYP2D6 poor metabolizers

40 mg PO once daily, initially. After 1 week, increase to the recommended dose of 80 mg PO once daily. May consider 40 mg or 60 mg PO once daily based on clinical response and tolerability. Max: 80 mg/day. ADJUSTMENTS: Valbenazine may cause an increase in the QTc interval in patients who are CYP2D6 poor metabolizers (CYP2D6 PMs); therefore, the recommended dose in CYP2D6 PMs is 40 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.

40 mg PO once daily, initially. Increase dose in 20 mg increments every 2 weeks to the recommended dose of 80 mg PO once daily. May consider 40 mg or 60 mg PO once daily based on clinical response and tolerability. Max: 80 mg/day. ADJUSTMENTS: Valbenazine may cause an increase in the QTc interval in patients who are CYP2D6 poor metabolizers (CYP2D6 PMs); therefore, the recommended dose in CYP2D6 PMs is 40 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.

Mild hepatic impairment (Child-Pugh score 5 to 6, Class A): No dosage adjustment needed.
Moderate to severe hepatic impairment (Child-Pugh score 7 to 15, Class B or C): The recommended dose is 40 mg/day PO.

Dosage adjustments are not necessary for patients with mild, moderate, or severe renal impairment.

Adagrasib: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with adagrasib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Amobarbital: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Amoxicillin; Clarithromycin; Omeprazole: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as clarithromycin. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Apalutamide: (Major) Coadministration of valbenazine with apalutamide is not recommended as plasma concentrations of valbenazine and its active metabolite may be decreased. Reduced exposure of valbenazine and its active metabolite may reduce efficacy. Valbenazine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to valbenazine and NBI-98782 by 70% and 80%, respectively.
Artemether; Lumefantrine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as lumefantrine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
Aspirin, ASA; Butalbital; Caffeine: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Atazanavir; Cobicistat: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with cobicistat is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor, and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Barbiturates: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with valbenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with valbenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking valbenazine, reduce initial dosage and titrate to clinical response. If valbenazine is initiated in a patient taking an opioid agonist, use a lower initial dose of valbenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Butalbital; Acetaminophen: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Butalbital; Acetaminophen; Caffeine: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Cabergoline: (Moderate) Cabergoline should not be coadministered with valbenazine, if possible. The prolactin-lowering effect of cabergoline may be diminished by medications that increase prolactin levels such as valbenazine.
Carbamazepine: (Major) Co-administration of strong CYP3A4 inducers, such as carbamazepine, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Ceritinib: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with ceritinib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Chloramphenicol: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as chloramphenicol. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Clarithromycin: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as clarithromycin. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Cobicistat: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with cobicistat is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor, and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Dacomitinib: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as dacomitinib. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
Darunavir: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as darunavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Darunavir; Cobicistat: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with cobicistat is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor, and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold. (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as darunavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with cobicistat is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor, and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold. (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as darunavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Degarelix: (Major) Avoid concurrent use of degarelix with valbenazine due to the risk of reduced efficacy of degarelix. Valbenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; degarelix is a GnRH analog.
Delavirdine: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as delavirdine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Deutetrabenazine: (Contraindicated) Concurrent use of deutetrabenazine and valbenazine is contraindicated. Both drugs are inhibitors of vesicular monoamine transporter 2 (VMAT2) and deplete monoamine stores.
Dextromethorphan; Quinidine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as quinidine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
Digoxin: (Major) Digoxin concentrations should be monitored during concurrent use of valbenazine. During co-administration of valbenazine and digoxin, the Cmax of digoxin increased nearly 2-fold and the AUC increased over 1-fold due to inhibition of intestinal P-glycoprotein (P-gp) by valbenazine. An increase in digoxin exposure may result in digoxin toxicity (e.g., cardiac arrhythmias, nausea and vomiting, and visual disturbances), A dosage adjustment of digoxin may be necessary.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with cobicistat is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor, and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with cobicistat is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor, and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Encorafenib: (Major) Coadministration of valbenazine with encorafenib is not recommended as plasma concentrations of valbenazine and its active metabolite may be decreased. Reduced exposure of valbenazine and its active metabolite may reduce efficacy. Valbenazine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased exposure to valbenazine and NBI-98782 by 70% and 80%, respectively.
Enzalutamide: (Major) Coadministration of valbenazine with enzalutamide is not recommended as plasma concentrations of valbenazine and its active metabolite may be decreased. Reduced exposure of valbenazine and its active metabolite may reduce efficacy. Valbenazine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to valbenazine and NBI-98782 by 70% and 80%, respectively.
Fluoxetine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as fluoxetine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant. Additionally, cases of QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP), have been reported during post-marketing use of fluoxetine.
Fosphenytoin: (Major) Co-administration of strong CYP3A4 inducers, such as Fosphenytoin, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Goserelin: (Major) Avoid coadministration of goserelin with valbenazine due to the risk of reduced efficacy of goserelin. Valbenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; goserelin is a GnRH analog.
Histrelin: (Major) Avoid concurrent use of histrelin with valbenazine due to the risk of reduced efficacy of histrelin. Valbenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
Idelalisib: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as idelalisib. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Indinavir: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as indinavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Isocarboxazid: (Major) Avoid the use of valbenazine with monoamine oxidase inhibitors (MAOIs). Concomitant use of valbenazine with MAOIs may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to an increased risk of adverse reactions such as serotonin syndrome, or an attenuated treatment effect of valbenazine.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Co-administration of strong CYP3A4 inducers, such as Rifampin, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Isoniazid, INH; Rifampin: (Major) Co-administration of strong CYP3A4 inducers, such as Rifampin, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Itraconazole: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as itraconazole. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Ketoconazole: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with ketoconazole is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as clarithromycin. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Letermovir: (Moderate) Caution is advised when administering valbenazine with letermovir, as taking these drugs together may increase valbenazine concentration and risk for adverse events, such as QT prolongation. Reduce the valbenazine dose to 40 mg once per day in patients who are also receiving cyclosporine, because the magnitude of this interaction may be increased. Valbenazine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Avoid concurrent use of leuprolide with valbenazine due to the risk of reduced efficacy of leuprolide. Valbenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog.
Leuprolide; Norethindrone: (Major) Avoid concurrent use of leuprolide with valbenazine due to the risk of reduced efficacy of leuprolide. Valbenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog.
Levoketoconazole: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with ketoconazole is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and valbenazine. Lofexidine can potentiate the effects of CNS depressants.
Lonafarnib: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with lonafarnib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Lopinavir; Ritonavir: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as ritonavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Methohexital: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Mitotane: (Major) Co-administration of strong CYP3A4 inducers, such as mitotane, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Monoamine oxidase inhibitors: (Major) Avoid the use of valbenazine with monoamine oxidase inhibitors (MAOIs). Concomitant use of valbenazine with MAOIs may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to an increased risk of adverse reactions such as serotonin syndrome, or an attenuated treatment effect of valbenazine.
Nefazodone: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as nefazodone. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Nelfinavir: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as nelfinavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Nirmatrelvir; Ritonavir: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as ritonavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Olanzapine; Fluoxetine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as fluoxetine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant. Additionally, cases of QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP), have been reported during post-marketing use of fluoxetine.
Paroxetine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as paroxetine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
Pentobarbital: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Phenelzine: (Major) Avoid the use of valbenazine with monoamine oxidase inhibitors (MAOIs). Concomitant use of valbenazine with MAOIs may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to an increased risk of adverse reactions such as serotonin syndrome, or an attenuated treatment effect of valbenazine.
Phenobarbital: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Phenytoin: (Major) Co-administration of strong CYP3A4 inducers, such as Phenytoin, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Posaconazole: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as posaconazole. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. The prescribing information for posaconazole states that posaconazole should not be administered with drugs that are known to prolong the QT interval and are metabolized by CYP3A4.
Primidone: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Quinidine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as quinidine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
Rasagiline: (Major) Avoid the use of valbenazine with rasagiline if possible. Rasagiline is a selective inhibitor of MAO type B (MAO-B), which results in an increased bioavailability of dopamine in the brain, while the therapeutic effect of valbenazine is thought to occur through inhibition of dopamine release. Concomitant use of valbenazine and rasagiline may result in an attenuated treatment effect of valbenazine or rasagiline.
Ribociclib: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with ribociclib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Ribociclib; Letrozole: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with ribociclib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Rifampin: (Major) Co-administration of strong CYP3A4 inducers, such as Rifampin, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Rifapentine: (Major) Coadministration of valbenazine with rifapentine is not recommended as plasma concentrations of valbenazine and its active metabolite may be decreased. Reduced exposure of valbenazine and its active metabolite may reduce efficacy. Valbenazine is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to valbenazine and NBI-98782 by 70% and 80%, respectively.
Ritonavir: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as ritonavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Safinamide: (Major) Avoid the use of valbenazine with safinamide if possible. Safinamide is a selective inhibitor of MAO type B (MAO-B), which results in an increased bioavailability of dopamine in the brain, while the therapeutic effect of valbenazine is thought to occur through inhibition of dopamine release. Concomitant use of valbenazine and safinamide may result in an attenuated treatment effect of valbenazine or safinamide.
Secobarbital: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Selegiline: (Major) Avoid the use of valbenazine with monoamine oxidase inhibitors (MAOIs), including selegiline. Concomitant use of valbenazine with MAO inhibitors, including selegiline, may result in an increased concentration of monoamine neurotransmitters in synapses, potentially leading to an increased risk of adverse reactions such as serotonin syndrome or an attenuated treatment effect of valbenazine.
St. John's Wort, Hypericum perforatum: (Major) Co-administration of strong CYP3A4 inducers, such as St. John's Wort, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and valbenazine. CNS depressants can potentiate the effects of stiripentol.
Tetrabenazine: (Contraindicated) Concurrent use of tetrabenazine and valbenazine is contraindicated. Both drugs are inhibitors of vesicular monoamine transporter 2 (VMAT2) and deplete monoamine stores.
Tipranavir: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, and consideration of a dose reduction, based on tolerability, is recommended in patients taking a strong CYP2D6 inhibitor. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of valbenazine and its active metabolite may be higher in patients taking a strong CYP3A4 or CYP2D6 inhibitor and QT prolongation may become clinically significant. Because tipranavir is both a strong CYP3A4 and CYP2D6 inhibitor, the potential increase in effects of such a combination with valbenazine are unknown.
Tranylcypromine: (Major) Avoid the use of valbenazine with monoamine oxidase inhibitors (MAOIs). Concomitant use of valbenazine with MAOIs may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to an increased risk of adverse reactions such as serotonin syndrome, or an attenuated treatment effect of valbenazine.
Triptorelin: (Major) Avoid concurrent use of triptorelin with valbenazine due to the risk of reduced efficacy of triptorelin. Valbenazine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; triptorelin is a GnRH analog.
Tucatinib: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with tucatinib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as clarithromycin. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Voriconazole: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with voriconazole is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.

INGREZZA Oral Cap: 40mg, 60mg, 80mg, 40-80mg

80 mg/day PO.

80 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

The mechanism of action of valbenazine in the treatment of tardive dyskinesia and chorea in patients with Huntington's disease is unknown, but is thought to be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. The active metabolite of valbenazine, [+]-alpha-dihydrotetrabenazine ([+]-alpha-HTBZ), also binds with relatively high affinity to human VMAT2. The drug and its active metabolite cause an inhibition of dopamine release via this mechanism. Valbenazine has no appreciable binding affinity for VMAT1. Valbenazine and [+]-alpha-HTBZ have no appreciable binding affinity for dopaminergic (including D2), serotonergic (including 5-HT2B), adrenergic, histaminergic, or muscarinic receptors.

Valbenazine is administered orally. The mean steady state volume of distribution of valbenazine is 92 liters. The plasma protein binding of valbenazine and its active metabolite are greater than 99% and approximately 64%, respectively. Valbenazine is extensively metabolized by hydrolysis to form the active metabolite [+]-alpha-dihydrotetrabenazine ([+]-alpha-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form other minor metabolites. The active metabolite appears to be further metabolized in part by CYP2D6. Valbenazine and [+]-a-HTBZ have half-lives of 15 to 22 hours, respectively. Approximately 60% of a dose was recovered in urine and 30% of a dose was recovered in feces. Less than 2% is excreted as unchanged valbenazine or its active metabolite in either urine or feces.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP2D6, P-glycoprotein (P-gp)
Valbenazine is extensively metabolized by hydrolysis to [+]-alpha-HTBZ, an active metabolite, and by oxidative metabolism, primarily by CYP3A4/5, to form other minor metabolites. The active metabolite [+]-alpha-HTBZ appears to be further metabolized in part by CYP2D6. Strong CYP3A4 inducers or inhibitors, as well as strong CYP2D6 inhibitors, can have an affect on the concentrations of valbenazine and its active metabolite. Valbenazine appears to inhibit intestinal P-glycoprotein (P-gp), as evidenced by a drug interaction study with digoxin. In vitro data indicate that valbenazine and its active metabolite are unlikely to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 or CYP3A4/5, BCRP, OAT1, OAT3, OCT2, OATP1B1, or OATP1B3 or induce CYP1A2, CYP2B6 or CYP3A4/5 at clinically relevant concentrations.

Following oral administration, maximum valbenazine plasma concentrations are attained in 0.5 to 1 hour. Steady-state plasma concentrations are reached within 1 week. The absolute oral bioavailability of valbenazine is about 49%. The active metabolite [+]-alpha-HTBZ gradually forms and reaches maximum concentrations 4 to 8 hours after administration of the parent compound. Ingestion of a high-fat meal decreases maximum valbenazine concentrations by about 47% and the AUC by about 13%. However, the Cmax and AUC of the active metabolite are unaffected. Valbenazine can be taken with or without food.

Data regarding valbenazine use in human pregnancy are insufficient to provide information on drug-associated risks. Therefore, the pregnant patient should be advised of the potential risks to the fetus. In animal studies, no malformations were observed during use of doses above the maximum recommended human dose (MRHD). However, administration of valbenazine to pregnant rats during the time of organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses less than 1 times the MRHD.

Based on animal findings of increased perinatal mortality in exposed fetuses and pups, patients should be advised to avoid breast-feeding during treatment with valbenazine and for 5 days after the final dose of valbenazine. There is no information regarding the presence of valbenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Valbenazine and its metabolites are present in rat milk at concentrations higher than in plasma following oral administration of valbenazine. During clinical trial evaluation of valbenazine, there was a dose-related increase in prolactin (e.g., hyperprolactinemia). The clinical significance has not been established; however, interference with proper lactation is possible.