Valbenazine Tosylate

Approved Indication:

• Tardive Dyskinesia (TD):
  Valbenazine Tosylate is indicated for the treatment of adults with tardive dyskinesia, a hyperkinetic movement disorder characterized by involuntary, repetitive body movements, most commonly caused by long-term exposure to dopamine receptor-blocking agents (e.g., antipsychotics or metoclopramide).

Off-Label / Clinically Accepted Uses (Investigational):

• Tourette Syndrome:
  Investigated in clinical trials for the treatment of tics in Tourette syndrome; not FDA-approved for this indication.
• Other Hyperkinetic Disorders (Experimental):
  Evaluated for use in Huntington’s disease-related chorea and other dopamine-related movement disorders; not currently approved.

Route of Administration: Oral
Available Strengths: Capsules (equivalent to valbenazine base): 40 mg, 60 mg, 80 mg

Adults (Tardive Dyskinesia):

• Initial Dose: 40 mg orally once daily
• Maintenance Dose: Increase to 80 mg once daily after 1 week, based on patient response and tolerability
• Maximum Dose: 80 mg orally once daily

Geriatric Use (≥65 years):

• No routine dose adjustment required
• Increased sensitivity possible; initiate treatment cautiously

Renal Impairment:

• Moderate to severe impairment (eGFR 15–29 mL/min/1.73 m²): 40 mg once daily
• End-stage renal disease (eGFR <15 mL/min/1.73 m²): Use is not recommended

Hepatic Impairment:

• Moderate to severe hepatic impairment (Child-Pugh B/C): Use is not recommended
• Mild hepatic impairment: No dose adjustment required, but monitor carefully

Administration Notes:

• May be taken with or without food
• Swallow capsules whole; do not open, crush, or chew

Valbenazine Tosylate is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor. VMAT2 is responsible for packaging dopamine into presynaptic vesicles for regulated release into the synaptic cleft. By inhibiting VMAT2, valbenazine reduces the storage and release of dopamine into the synapse, thereby decreasing excessive dopaminergic neurotransmission in the basal ganglia. This action helps control involuntary, repetitive movements seen in tardive dyskinesia. The drug is metabolized to an active compound (NBI-98782), which is significantly more potent in VMAT2 inhibition.

• Absorption: Rapid and well absorbed orally
• Tmax: ~0.5 to 1 hour post-dose for valbenazine
• Bioavailability: Moderate; exact absolute bioavailability not fully established
• Distribution: Widely distributed; plasma protein binding ~99%
• Metabolism:
  • Extensively metabolized in the liver
  • Major enzymes: CYP3A4, CYP3A5, and carboxylesterase 1
  • Active metabolite: NBI-98782 (longer half-life and greater potency)
• Elimination Half-Life:
  • Valbenazine: ~15 to 22 hours
  • NBI-98782: ~18 to 22 hours
• Excretion:
  • ~60% in urine
  • ~30% in feces
  • Predominantly as inactive metabolites

• Pregnancy:
  • Not assigned a category under the updated FDA pregnancy labeling rule
  • Animal studies show potential fetal harm at high doses
  • No adequate human data available
  • Use only if benefits justify potential risk
• Lactation:
  • Unknown if valbenazine or metabolites are excreted in human milk
  • Potential risk to nursing infants cannot be ruled out
  • Consider discontinuing drug or breastfeeding, based on clinical need
• Recommendation:
  Use with caution in pregnancy and lactation. Avoid unless clearly necessary.

• Primary Class: Central Nervous System (CNS) Agent
• Subclass: Selective Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor
• Indication-Specific Role: First-in-class treatment for tardive dyskinesia

• Known hypersensitivity to valbenazine, its active metabolite, or excipients
• Use of monoamine oxidase inhibitors (MAOIs) concurrently or within 14 days
• Severe hepatic impairment (Child-Pugh Class C)

• QT Prolongation:
  • May prolong QT interval; caution in patients with existing QT prolongation or those on QT-prolonging drugs
  • Obtain baseline and follow-up ECG in high-risk patients
• Somnolence:
  • May cause sedation; caution with driving or operating machinery
  • Risk increased with other CNS depressants
• Parkinsonism & Extrapyramidal Symptoms (EPS):
  • May worsen motor symptoms or induce parkinsonism
  • Monitor for new or worsening movement disorders
• Suicidal Ideation & Depression:
  • Monitor for worsening mood or behavior changes
  • Especially in patients with underlying psychiatric illness
• Hepatic/Renal Impairment:
  • Not recommended in severe hepatic or end-stage renal disease

Common (≥5%):

• Neurologic: Somnolence, fatigue, dizziness
• Gastrointestinal: Dry mouth, constipation
• Psychiatric: Akathisia
• General: Sedation

Less Common but Serious:

• Cardiac: QT interval prolongation, ventricular arrhythmia (rare)
• Neurologic: Parkinsonism, tremor
• Psychiatric: Suicidal thoughts, depression, agitation
• Hypersensitivity: Rash, pruritus, anaphylactoid reactions (rare)

Onset & Severity:

• Side effects typically occur within the first 2–4 weeks of therapy
• Most are mild to moderate and dose-dependent

Major Interactions:

• MAO Inhibitors:
  • Contraindicated; risk of hypertensive crisis and serotonin syndrome
• CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin):
  • May increase plasma concentration of valbenazine → enhanced toxicity
  • Reduce dose if used together
• CYP3A4 Inducers (e.g., rifampin, carbamazepine):
  • May decrease efficacy of valbenazine
  • Avoid concurrent use if possible
• QT-Prolonging Drugs (e.g., amiodarone, quinidine):
  • Increased risk of arrhythmia; concurrent use should be avoided or monitored closely

Enzymatic Metabolism:

• Metabolized primarily via CYP3A4/5
• Not known to inhibit or induce CYP enzymes

Food/Alcohol Interaction:

• No significant interaction with food
• Alcohol may enhance sedative effects

• FDA Safety Communication (Latest Labeling):
  • QT prolongation and suicidal behavior risks emphasized in recent revisions
  • Enhanced post-marketing monitoring recommended
• Guideline Recommendations (AAN, APA):
  • Endorsed as a first-line pharmacologic treatment for tardive dyskinesia
  • Preferred due to favorable side effect profile compared to anticholinergics and benzodiazepines
• Ongoing Clinical Trials:
  • Investigating use in Tourette syndrome, Huntington’s chorea, and other movement disorders

• Storage Temperature: 20°C to 25°C (68°F to 77°F)
• Permitted Excursions: 15°C to 30°C (59°F to 86°F)
• Humidity: Store in a dry environment
• Light Protection: Protect from direct light; keep in original packaging
• Handling Instructions:
  • Do not crush, split, or chew capsules
  • No refrigeration required
  • Keep out of reach of children