Valbenazine (Ingrezza)

Valbenazine (ingrezza) acts as a monoamine transporter inhibitor that has been FDA approved for the treatment of tardive dyskinesia. Tardive dyskinesias are involuntary movements of the face, neck, jaw, and other body parts that usually occur following the use of antipsychotic medications.

Ingrezza (valbenazine) dose in Adults

Ingrezza (valbenazine) dose in the treatment of Tardive dyskinesia:

- 40 mg orally once a day
- after one week, increase to 80 mg once a day.
- Continuation of 40 mg once a day can be considered for some patients based on response and tolerability.
Dosage adjustment for concomitant CYP3A4 and CYP2D6 inhibitors/inducers:
- Concomitant administration with a strong CYP3A4 inducer (eg, carbamazepine, phenytoin, rifampin, St John's wort) is not recommended.
- Concomitant administration with a strong CYP3A4 inhibitor (eg, clarithromycin, itraconazole, ketoconazole):
  - The maximum dose of ingrezza (valbenazine) is 40 mg daily.
- Concomitant administration with a strong CYP2D6 inhibitor (eg, fluoxetine, paroxetine, quinidine):
  - Dosage adjustment is not given in the manufacturer's labeling, however, a dose reduction might be necessary based on tolerability.

Ingrezza (valbenazine) dose in Childrens

Safety and efficacy in children not established.

Ingrezza (valbenazine) pregnancy Risk Factor: C

In some studies on animal reproduction, adverse events were observed

Use of valbenazine while breastfeeding

It is unknown if valbenazine can be found in breast milk.
According to animal studies, the manufacturer doesn't recommend breastfeeding during therapy or for more than 5 days following the last dose.

Ingrezza (valbenazine) dose in renal disease:

Mild to moderate impairment (CrCl 30 - 90 mL/minute).
- There is no need to adjust the dosage.
Severe impairment (CrCl >30 mL/minute).
- It is not recommended.

Ingrezza (valbenazine) dose in liver disease:

Mild impairment (Child Puugh class A)
- The manufacturer's labeling does not include any dosage adjustments.
Moderate to severe impairment (Child Puugh class B orC):
- 40 mg daily

Common Side Effects of Ingrezza (Valbenazine) Include:

Central nervous system:
- Drowsiness
- Fatigue
- Sedation

Less Common Side Effects of Ingrezza (Valbenazine) Include:

Central Nervous System:
- Abnormal gait
- Dizziness
- Equilibrium Disturbance
- Falling
- Akathisia
- Restlessness
- Anxiety
- Drooling
- Extrapyramidal Reaction
- Insomnia
Endocrine & Metabolic:
- Increased Serum Glucose
- Weight Gain
Gastrointestinal:
- Vomiting
Neuromuscular & Skeletal:
- Arthralgia
- Dyskinesia
Respiratory:
- Respiratory tract infection

valbenazine side effects (rare)

Endocrine & metabolic:
- Increased serum prolactin
Hepatic:
- Increased serum alkaline phosphatase
- Increased serum bilirubin

Contraindication to Ingrezza (Valbenazine) Include:

Hypersensitivity to valbenazine and any part of this formulation

Warnings and precautions

Depression in the CNS:
- It can cause CNS depression that may lead to mental or physical impairments.
- Patients who perform tasks that require mental alertness, such as driving or operating machinery, should be warned about the dangers of taking this drug.
Depression and suicidal ideation
- VMAT inhibitors are also associated with depression, suicidal thoughts, and behavior.
Extension of QT
- It could prolong the QT interval
- Use caution when taking CYP2D6 inhibitors or CYP3A4 metabolizers. Dose reduction may be required.
- Patients with congenital long-QT syndrome, arrhythmias or prolonged QT intervals should not use this product.
- Patients at high risk for prolonged QT interval should have an EKG performed before increasing dosage.
Hepatic impairment:
- Patients with severe or moderate hepatic impairment should be cautious; they may need to take a lower dose.
Renal impairment
- Patients with severe renal impairment should not use this medication.

Valbenazine: Drug Interaction

Risk Factor C (Monitor therapy)
Aprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP2D6 Inhibitors (Strong)	May increase serum concentrations of the active metabolite(s) of Valbenazine.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Digoxin	Valbenazine may increase the serum concentration of Digoxin.
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Simeprevir	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Risk Factor D (Consider therapy modification)
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Valbenazine. Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
MiFEPRIStone	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus.
Pitolisant	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
Risk Factor X (Avoid combination)
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Valbenazine.
Deutetrabenazine	May enhance the adverse/toxic effect of Valbenazine.
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Monoamine Oxidase Inhibitors	Valbenazine may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors.
St John's Wort	May decrease the serum concentration of Valbenazine.
Tetrabenazine	May enhance the adverse/toxic effect of Valbenazine.

Monitor:

Abnormal Involuntary movement Scale (AIMS), or Dyskinesia Identification Systems Condensed User Scales (DISCUS).
EKG (for patients at high risk of QT prolongation).

How to administer Valbenazine?

Administer with or without food.

Valbenazine Mechanism of action (Ingrezza MOA):

Although its mechanism of action remains unknown, it is believed to reverse the effects of the vesicular monamine transporter 2, (VMAT2)
VMAT2 is a monoamine transporter that regulates monoamine storage and release from the cytoplasm.
Valbenazine or its active metabolite do not have a significant binding affinity to VMAT1 or any dopaminergic, serotonergic or muscarinic or dopaminergic receptors.

Absorption:

High-fat meals decrease C by 47% and AUC by 13%.

Distribution: V :

92 L

Protein binding:

Valbenazine: >99%; Active metabolite: ~64%

Metabolism:

It is mainly metabolized by hydrolysis to form active metabolite ([+]-α-HTBZ) (and by oxidative metabolism, primarily by CYP3A4/5, to form monooxidized valbenazine and other minor metabolites).
The active metabolite is further metabolized in part by CYP2D6.

Bioavailability: