Valbenazine

Introduction Overview

Generic Name

valbenazine

Brand Name

Ingrezza

Dosage Form

capsule (40 mg, 60 mg, 80 mg), sprinkle capsules (40 mg, 60 mg, 80 mg)

Drug Class

VMAT2 inhibitors

Pharmacokinetics

Absorption: Valbenazine is administered orally and exhibits good bioavailability, with peak plasma concentrations typically achieved within a few hours post-dose. The drug can be taken with or without food, and food does not significantly affect its absorption, facilitating flexible dosing in clinical practice. Sprinkle capsules may be opened and sprinkled onto soft food to aid administration in patients with swallowing difficulties, without compromising pharmacokinetic properties. Distribution: Following absorption, valbenazine displays moderate plasma protein binding, which supports its distribution into the central nervous system where it exerts its pharmacologic effect. Its lipophilic nature facilitates penetration of the blood-brain barrier, a critical characteristic for drugs targeting neurological receptors and transporters such as VMAT2. Metabolism: Valbenazine is extensively metabolized in the liver. The primary metabolic pathway involves hydrolysis to an active metabolite, which is believed to contribute significantly to the drug's pharmacological activity. Cytochrome P450 enzymes, notably CYP3A4 and CYP2D6, are involved in further metabolism, with CYP2D6 poor metabolizers requiring dosage adjustments due to altered pharmacokinetics. The half-life of the active metabolite supports once-daily dosing in adults. Elimination: The drug and its metabolites are predominantly eliminated via the feces, with a smaller proportion excreted in urine. The elimination half-life of the active metabolite ranges from approximately 15 to 22 hours, supporting sustained therapeutic levels with once-daily dosing. In patients with moderate or severe hepatic impairment, clearance may be reduced, necessitating dose adjustments. Renal impairment has less impact on elimination, but caution is advised in severe renal dysfunction. Overall, the pharmacokinetic profile of valbenazine supports convenient once-daily oral administration with predictable plasma concentrations and minimal accumulation in most patient populations.

Dosage Forms

Available Dosage Forms: Ingrezza is available as capsules and sprinkle capsules in strengths of 40 mg, 60 mg, and 80 mg. The capsules are designed to be swallowed whole with water. The sprinkle capsules offer an alternative route, whereby the capsule can be opened and its contents sprinkled over soft foods such as applesauce, yogurt, or pudding for easier administration, particularly in patients with difficulty swallowing pills. It is crucial that the granules are not chewed and that milk or drinking water is not used for sprinkling due to potential stability concerns. Dosages for Adults and Adolescents: The usual adult dose for tardive dyskinesia treatment begins at 40 mg once daily. After one week, if tolerated and clinically indicated, the dose is increased to 80 mg once daily. For chorea associated with Huntington's disease, treatment starts at 40 mg once daily with titration in 20 mg increments every two weeks to a target dose of 80 mg once daily. Treatment is sustained once the maintenance dose is achieved. Specific Patient Populations: For patients with moderate to severe hepatic impairment, the recommended dose is reduced to 40 mg once daily to avoid potential toxicity due to impaired metabolism and clearance. Similarly, individuals identified as CYP2D6 poor metabolizers should receive 40 mg once daily to accommodate altered enzyme activity affecting drug metabolism. No specific dosing recommendations are required for renal impairment, but clinical discretion is advised. Pediatric and adolescent use is not currently indicated. In summary, the dosage forms and regimen are designed to optimize flexibility and patient compliance, with considerations for special populations to maintain safety and efficacy.

Mechanism Of Action

Valbenazine, the active pharmaceutical ingredient in Ingrezza, functions primarily through selective inhibition of the vesicular monoamine transporter 2 (VMAT2), a vital protein responsible for the transport of monoamines, such as dopamine, into synaptic vesicles within presynaptic neurons. By inhibiting VMAT2, valbenazine reduces the uptake and storage of dopamine in synaptic vesicles, leading to decreased dopamine release into the synaptic cleft. This mechanism is significant because aberrant dopamine signaling is implicated in movement disorders such as tardive dyskinesia (TD) and chorea associated with Huntington's disease. The dysregulation and hypersensitivity of dopamine receptors contribute to the involuntary movements observed in these conditions. At the cellular level, valbenazine’s inhibition of VMAT2 decreases the cytosolic and extracellular dopamine concentrations, thereby mitigating excessive dopaminergic neurotransmission that underlies the pathophysiology of hyperkinetic movement disorders. Unlike dopamine receptor antagonists, which block receptors directly and risk exacerbating parkinsonism, VMAT2 inhibition provides a more targeted approach by modulating presynaptic dopamine availability. Research from clinical trials supports this mechanism, demonstrated by significant reductions in involuntary movements as measured by standardized scales such as the Abnormal Involuntary Movement Scale (AIMS) for TD and Total Maximal Chorea scores in Huntington’s disease chorea. Comparative to other treatments, valbenazine’s unique VMAT2 inhibition confers a favorable safety profile with fewer central nervous system adverse effects and no significant blockade of postsynaptic dopamine receptors. Additionally, the drug’s high selectivity for VMAT2 minimizes off-target effects and enables once-daily dosing due to its metabolite’s pharmacokinetic properties. Taken together, valbenazine’s mechanism of VMAT2 inhibition disrupts the pathogenic dopaminergic overactivity involved in hyperkinetic movement disorders, offering symptomatic relief without compromising motor function.

Pharmacological Actions

Selective inhibition of vesicular monoamine transporter 2 (VMAT2) leading to decreased presynaptic dopamine release.
Reduction of abnormal dopaminergic neurotransmission implicated in tardive dyskinesia and chorea.
Modulation of dopamine storage within synaptic vesicles to mitigate involuntary movements.
Improvement of hyperkinetic motor symptoms without causing significant extrapyramidal side effects.
Once-daily dosing enabled by sustained release and active metabolite pharmacokinetics.
Minimal interaction with postsynaptic dopamine receptors, reducing risk of parkinsonism.
Neuroprotective potential by regulating excessive dopamine release in basal ganglia circuits.
Specific targeting of presynaptic mechanisms, providing clinical advantage over dopamine antagonists.
Dose-dependent modulation of movement disorder severity in adults.
Well-tolerated profile with manageable central nervous system side effects.
Demonstrated efficacy in Phase III trials with significant improvements in AIMS and chorea scores.
Adjustment for CYP2D6 poor metabolizers to optimize therapy.
Reduction of dopamine-related neurotransmitter imbalances underlying movement disorder pathophysiology.
No known direct effects on serotonergic, noradrenergic, or cholinergic neurotransmission.
Ability to be administered with or without food enhances patient compliance.

Therapeutic Or Clinical Uses

Treatment of tardive dyskinesia (TD) in adults, particularly TD induced by long-term neuroleptic use.
Management of chorea associated with Huntington's disease in adult patients.
Reduction of involuntary, repetitive muscle movements, especially in the face, lips, tongue, and limbs.
Improvement of motor control and reduction of symptom severity in hyperkinetic movement disorders.
Utilized as a selective VMAT2 inhibition therapy in neurological movement disorders.
Adjunctive therapy for movement disorders unresponsive to other treatments.
Symptomatic control to enhance quality of life and functional ability in TD and Huntington’s chorea.
FDA-approved as a once-daily oral treatment providing long-term symptom management.
Alternative option for patients intolerant to dopamine receptor antagonists due to better safety profile.
Treatment to reduce the burden of neuroleptic-induced movement abnormalities.
Potential off-label use in other hyperkinetic movement disorders, pending clinical investigation.
Monotherapy for chorea reduction without worsening parkinsonian symptoms.
Application in patients with hepatic impairment with adjusted dosing.
Treatment indicated for adults, with no current pediatric approval.
Use in patients who require flexibility in dosing form, including sprinkle capsules for swallowing difficulties.

Side Or Adverse Effects

Common headache, dizziness, and drowsiness impacting patient alertness.
Impairment of balance or coordination, potentially increasing fall risk.
Dry mouth reported in many patients, affecting oral comfort.
Restlessness or akathisia-like sensation observed in some cases.
Constipation as a gastrointestinal side effect requiring monitoring.
Blurred vision reported, necessitating caution in activities requiring visual acuity.
Serious hypersensitivity reactions including angioedema and anaphylaxis.
QT interval prolongation posing arrhythmia risk, especially in susceptible individuals.
Neuroleptic malignant syndrome (NMS) reported rarely, requiring immediate cessation if suspected.
Development of Parkinson-like symptoms, such as tremor, rigidity, and bradykinesia.
Potential for sedation and somnolence affecting daily activities and safety.
Possible cardiac adverse events including palpitations and irregular heartbeat.
Weight gain reported infrequently but notable in some clinical studies.
Rare reports of severe drowsiness necessitating medical attention.
Allergic reactions including hives and facial swelling requiring emergency care.

Precautions

Use cautiously in patients with existing heart disease or arrhythmias, especially long QT syndrome.
Monitor hepatic function closely; adjust dose in moderate to severe hepatic impairment.
Avoid abrupt discontinuation to prevent worsening of movement symptoms or withdrawal effects.
Assess patient history for depression or suicidal ideation prior to initiation.
Advise patients regarding potential sedation and impairment in activities requiring alertness.
Use with caution in patients with a history of parkinsonism or extrapyramidal symptoms.
Screen for CYP2D6 metabolizer status to tailor dosing and reduce adverse effects.
Monitor for signs of hypersensitivity reactions during therapy.
Avoid in pregnancy or use only if clearly needed due to potential fetal harm.
Breastfeeding is contraindicated during and for at least five days following treatment.
Patients should be informed about the risk of dizziness and advised on fall prevention.
Periodic ECG monitoring may be necessary to evaluate QT prolongation risk.
Educate patients on identifying symptoms of neuroleptic malignant syndrome.
Avoid concomitant use with strong CYP3A4 and CYP2D6 inhibitors or inducers without medical supervision.
Evaluate hepatic and renal function prior to and during treatment.

Warnings

Risk of depression and suicidal ideation, particularly in patients with Huntington's disease.
Potential for hypersensitivity reactions including angioedema; discontinue immediately if occurs.
Somnolence and sedation can impair ability to drive or operate machinery.
QT interval prolongation observed; contraindicated in congenital long QT syndrome or known QT prolongation.
Neuroleptic malignant syndrome (NMS) may occur; discontinue drug if symptoms present.
Development of Parkinsonism-like symptoms reported postmarketing; dose reduction or discontinuation may be required.
Avoid use in patients with known hypersensitivity to valbenazine or formulation components.
Patients with cardiac disease require cautious use due to risk of arrhythmias.
Avoid abrupt cessation to prevent symptom exacerbation.
Use caution in elderly patients who may be more sensitive to sedative effects.
Monitor for potential interactions that may increase drug plasma concentration and toxicity.
Pregnancy category indicates potential fetal harm; use only if benefits outweigh risks.
Breastfeeding is contraindicated during and shortly after treatment.
Patients should be warned about risks of falls due to dizziness or sedation.
Regular medical evaluation is recommended to monitor for signs of adverse neurological effects.

Contraindication

Known hypersensitivity to valbenazine or any component of the formulation.
Patients with congenital long QT syndrome or known risk factors for QT prolongation.
Concurrent use with monoamine oxidase inhibitors (MAOIs) due to risk of adverse interactions.
Patients with active neuroleptic malignant syndrome.
Pregnancy unless benefits clearly outweigh potential fetal risks.
Breastfeeding mothers during drug therapy and for at least five days after last dose.
Severe hepatic impairment without the ability to monitor and adjust dosing carefully.
Patients with history of severe cardiac conduction abnormalities without cardiac monitoring.
Known intolerance or allergy to capsule components including gelatin and coloring agents.
Use contraindicated in patients with severe hypersensitivity or anaphylactic reactions to related compounds.
Patients with arrhythmias related to drugs that prolong QT interval.
Concomitant use with strong CYP3A4 or CYP2D6 inhibitors without dosage adjustments.
Individuals with Parkinsonism exacerbated by VMAT2 inhibitors unless specifically evaluated.
Children and adolescents under approved age indications.
Use in combination with other VMAT2 inhibitors.

Drug Interactions

Monoamine oxidase inhibitors (MAOIs): Concurrent use may lead to severe hypertensive reactions or serotonin syndrome.
Strong CYP3A4 inducers (e.g., rifampin, carbamazepine) may reduce valbenazine plasma concentrations and efficacy.
Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) can increase plasma levels, requiring dosing adjustments.
Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) may increase exposure and risk of adverse effects.
Other CNS depressants may potentiate sedation and dizziness when co-administered.
Drugs that prolong QT interval (e.g., certain antiarrhythmics, antipsychotics) increase risk of cardiac arrhythmias.
Concomitant medications affecting dopamine levels should be used cautiously to avoid additive effects.
Use with other VMAT2 inhibitors (e.g., deutetrabenazine) may increase risk of adverse reactions.
Avoid co-administration with drugs metabolized by CYP2D6 where valbenazine is a substrate.
Potential pharmacodynamic interactions with antihypertensives causing hypotension and dizziness.
Combination with anticholinergic agents may exacerbate dry mouth and constipation.
Avoid grapefruit juice with valbenazine due to CYP3A4 inhibition and increased drug plasma levels.
Caution with alcohol as it may amplify CNS depressive effects.
Medications influencing hepatic metabolism may require valbenazine dose adjustments.
Monitoring is required when valbenazine is used with medications that affect cardiac conduction.

Preparations Of The Drug

Ingrezza capsules available in strengths of 40 mg, 60 mg, and 80 mg for oral administration.
Ingrezza sprinkle capsules manufactured with coated granules designed for dispersion over soft foods.
Capsule shells contain excipients such as hypromellose, isomalt, magnesium stearate, pregelatinized starch, and silicified microcrystalline cellulose.
Colorants in capsule shells include candurin silver fine, FD&C Blue #1, and FD&C Red #40 in the capsule formulation.
Sprinkle capsules contain active ingredient granules with excipients including pregelatinized maize starch, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.
Both capsule and sprinkle formulations use gelatin in the capsule shell.
Drug formulations are supplied in bottles that protect contents from moisture; sprinkle capsules require tight closure to maintain stability.
Granules from sprinkle capsules can be stored on soft food up to 2 hours at room temperature before consumption.
Capsules and sprinkle capsules are designed for once-daily dosing.
Storage requirements include keeping capsules at 59°F to 86°F (15°C to 30°C) and sprinkle capsules between 68°F to 77°F (20°C to 25°C).
Manufactured and distributed by Neurocrine Biosciences, Inc., San Diego, CA.
Each formulation undergoes rigorous quality control to ensure consistent dosing and bioavailability.
Packaging includes patient information leaflets detailing administration instructions and safety warnings.
No generic equivalents yet; Ingrezza is available as brand-name drug with specific prescribing information.
The sprinkle formulation aids in swallowing difficulties without altering drug pharmacokinetics.