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Once-daily INGREZZA® (valbenazine) capsules

Tardive dyskinesia and INGREZZA mechanism of action (MOA)

INGREZZA is a selective VMAT2 inhibitor with once-daily dosing1,2

1

Selective VMAT2 inhibition

Key showing a vesicle, VMAT2, Dopamine, D2 receptor, Ingrezza

While the MOA of INGREZZA® (valbenazine) capsules is not fully understood, it is believed that it may be mediated through selective inhibition of VMAT2 in presynaptic neurons, with no appreciable binding affinity for VMAT1, dopaminergic receptors, or serotonergic receptors2

VMAT1, vesicular monoamine transporter 1; VMAT2, vesicular monoamine transporter 2.

2

Reduction of dopamine release

INGREZZA® (valbenazine) capsules is believed to provide reversible reductions of dopamine release into the synaptic cleft2

VMAT1, vesicular monoamine transporter 1; VMAT2, vesicular monoamine transporter 2.

3

Less dopamine available to receptors

INGREZZA® (valbenazine) capsules is believed to reduce the amount of dopamine available to hypersensitive postsynaptic dopamine D2 receptors1,2

VMAT1, vesicular monoamine transporter 1; VMAT2, vesicular monoamine transporter 2.

Tardive dyskinesia (TD)—an often persistent movement disorder
induced by prolonged DRBA exposure3

1

VMAT2 packages dopamine

INGREZZA

VMAT2 plays a key role in dopamine signaling2

  • VMAT2 is a transporter protein found in presynaptic neurons of the CNS
  • VMAT2 packages monoamines (eg, dopamine) for release into the synaptic cleft

CNS, central nervous system; DRBA, dopamine receptor blocking agent; VMAT2, vesicular monoamine transporter 2.

2

DRBA exposure causes hypersensitivity

TD is associated with prolonged exposure to DRBAs, including antipsychotics3

CNS, central nervous system; DRBA, dopamine receptor blocking agent; VMAT2, vesicular monoamine transporter 2.

3

Hypersensitive dopamine receptors may trigger uncontrolled movements

Prolonged exposure to DRBAs is believed to cause hypersensitivity in postsynaptic dopamine D2 receptors in one of the areas of the brain that controls motor function2

CNS, central nervous system; DRBA, dopamine receptor blocking agent; VMAT2, vesicular monoamine transporter 2.

Watch the INGREZZA MOA video

See how INGREZZA® (valbenazine) capsules is thought to work.

View full transcript
Video thumbnail of INGREZZA MOA

THE ONLY ONCE-DAILY
VMAT2 INHIBITOR

One-capsule, once-daily dosing with three effective dosing options sets INGREZZA apart from other VMAT2 inhibitors1

EXPLORE DOSING

TREAT FIRST LINE WITH
VMAT2 INHIBITORS

VMAT2 inhibitors, like INGREZZA, are recommended as first-line treatment for TD4-6

TD GUIDELINES

REFERENCES:

  1. INGREZZA [package insert]. San Diego, CA: Neurocrine Biosciences, Inc
  2. Harriott ND, Williams JP, Smith EB, Bozigian HP, Grigoriadis DE. VMAT2 inhibitors and the path to INGREZZA (valbenazine). Prog Med Chem. 2018;57(1):87-111
  3. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476-484
  4. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. American Psychiatric Association Publishing, 2020
  5. Bhidayasiri R, Jitkritsadakul O, Friedman JH, Fahn S. Updating the recommendations for treatment of tardive syndromes: a systematic review of new evidence and practical treatment algorithm. J Neurol Sci. 2018;389:67-75
  6. Caroff SN, Citrome L, Meyer J, et al. A modified Delphi consensus study of the screening, diagnosis, and treatment of tardive dyskinesia. J Clin Psychiatry. 2020;81(2):19cs12983

Important Information

INDICATION & USAGE

INGREZZA® (valbenazine) capsules is indicated for the treatment of adults with tardive dyskinesia.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported.

WARNINGS & PRECAUTIONS

Somnolence

INGREZZA can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by INGREZZA.

QT Prolongation

INGREZZA may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. INGREZZA should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage.

Parkinsonism

INGREZZA may cause parkinsonism in patients with tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. Reduce the dose or discontinue INGREZZA treatment in patients who develop clinically significant parkinson-like signs or symptoms.

ADVERSE REACTIONS

The most common adverse reaction (≥5% and twice the rate of placebo) is somnolence. Other adverse reactions (≥2% and >Placebo) include: anticholinergic effects, balance disorders/falls, headache, akathisia, vomiting, nausea, and arthralgia.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see INGREZZA full Prescribing Information

Indication and Important Safety Information

INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA.

+Expand-Collapse

Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported.

INDICATION & USAGE

INGREZZA® (valbenazine) capsules is indicated for the treatment of adults with tardive dyskinesia.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported.

Important Information

INDICATION & USAGE

INGREZZA® (valbenazine) capsules is indicated for the treatment of adults with tardive dyskinesia.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported.

WARNINGS & PRECAUTIONS

Somnolence

INGREZZA can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by INGREZZA.

QT Prolongation

INGREZZA may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. INGREZZA should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage.

Parkinsonism

INGREZZA may cause parkinsonism in patients with tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. Reduce the dose or discontinue INGREZZA treatment in patients who develop clinically significant parkinson-like signs or symptoms.

ADVERSE REACTIONS

The most common adverse reaction (≥5% and twice the rate of placebo) is somnolence. Other adverse reactions (≥2% and >Placebo) include: anticholinergic effects, balance disorders/falls, headache, akathisia, vomiting, nausea, and arthralgia.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see INGREZZA full Prescribing Information

EXPAND FOR
GUIDELINES

INGREZZA is a recommended first-line TD treatment option.

See guidelines and recommendations
+

How INGREZZA® (valbenazine) capsules is thought to work

Tardive dyskinesia, or TD, is a condition of involuntary movements of the face, trunk, and/or extremities, and may affect multiple regions.

[A man faces camera. His eyes blink excessively, and he has abnormal lateral movements in his jaw. Text behind him reads, “Tardive dyskinesia,” “Face,” “Trunk,” “Extremities.”]

TD is associated with prolonged exposure to dopamine receptor blocking agents, such as antipsychotics.

[Camera slowly zooms in on man’s head, which darkens to a silhouette, then transitions to an image of a brain.]

These agents are referred to as DRBAs.

[Camera continues to zoom into the brain anatomy through a field of neurons.]

Monoamines, such as dopamine, play a key role in neurotransmission.

[Camera stops at a close-up view of the synapse. Synapse fires, as dopamine molecules (labeled “Dopamine”) are released from vesicles in the presynaptic bouton into the synaptic cleft.]

Dopamine helps to control emotional and motor function by binding receptors on postsynaptic neurons.

[Vesicles once again transport dopamine molecules within the presynaptic bouton, then release dopamine into the synaptic cleft. When dopamine binds to D2 receptor (labeled “D2 Receptor”), the receptor glows to signify normal postsynaptic signaling.]

Dopamine is then recycled by dopamine transporters and packaged in presynaptic vesicles by the vesicular monoamine transporter, or VMAT2.

[After the postsynaptic signaling, dopamine is released from D2 receptor and ascends to cycle back into the presynaptic bouton. Camera follows a dopamine molecule as it enters the presynaptic bouton through the dopamine transporter. Once inside, dopamine enters a vesicle through VMAT2, where it is packaged and transported for future release.]

[An arrow points to a spherical structure, labeled “Vesicle,” and to a channel-like protein attached to the vesicle, labeled “VMAT2.”]

Although not fully understood, aberrant dopamine signaling in pathways responsible for perception or mood may contribute to psychiatric conditions.

[Long shot of the synaptic cleft where vesicles again descend toward bottom of presynaptic bouton and release a large amount of dopamine into the synaptic cleft.]

[Dopamine binds to many D2 receptors, which glow erratically to signify aberrant postsynaptic signaling. Excess dopamine remains in the synaptic cleft.]

[Camera cuts to a long shot of neuron, which shows abnormal neuronal firing with an erratic, intense glowing from the cell body down the axon.]

[Camera returns to show the synaptic cleft, which also radiates an intense glow from the large amounts of dopamine binding to D2 receptors.]

One of the ways antipsychotics are thought to impact psychiatric symptoms is by helping balance dopamine signaling.

[Dopamine receptor blocking agents enter the synapse and bind to the D2 receptors. When they bind to D2 receptors, they flash quickly to signal inactivation. Excess dopamine is left in the synaptic cleft.]

However, chronic DRBA use may cause a response in the postsynaptic neuron, leading to D2 receptor upregulation and hypersensitivity to dopamine.

[A large amount of dopamine is again released into the synaptic cleft. This time, dopamine is unable to bind to D2 receptors, as they are blocked by the dopamine receptor blocking agents. The limited number of activated D2 receptors causes the corresponding postsynaptic signal to be normal.]

[New D2 receptors began to emerge from the postsynaptic floor.]

This hypersensitivity in the nigrostriatal pathway is thought to manifest in the signs and symptoms of TD.

[A large amount of dopamine is again released by vesicles into the synaptic cleft. The new D2 receptors are uninhibited by dopamine receptor blocking agents and allow the dopamine to bind. The bound D2 receptors are activated, shown by a glow. The resulting postsynaptic signal is once again abnormally intense, flashing for emphasis.]

INGREZZA® (valbenazine) capsules is indicated for the treatment of adults with tardive dyskinesia.

[Screen swipes left, bringing a new synaptic cleft into focus.]

[An INGREZZA molecule (labeled “INGREZZA® (valbenazine) capsules”) enters the synapse. On-screen text reads, “INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported. Please see accompanying Important Safety Information.”]

The mechanism of action of INGREZZA in the treatment of TD is unknown, but it is thought to be mediated through reversible inhibition of VMAT2.

[INGREZZA molecule continues to spin and float in place, then enters the presynaptic bouton. On-screen text reads, “Depiction is for illustrative purposes only—actual molecule has not been visualized.”]

[Camera follows INGREZZA molecule into the presynaptic bouton where it binds to VMAT2, limiting the amount of dopamine that can enter the vesicles.]

By inhibiting dopamine uptake from the cytoplasm to the synaptic vesicles by VMAT2, the amount of dopamine available for release into the synapse to interact with hypersensitive D2 receptors is reduced.

[Camera zooms out to show vesicles within the presynaptic bouton descend and release a limited amount of dopamine into the synaptic cleft. Dopamine binds to a small number of unblocked D2 receptors with a glow. Normal postsynaptic signaling is shown, indicated by a flash.]

INGREZZA is selective, exhibiting high affinity for VMAT2, and no appreciable binding affinity for VMAT1, dopaminergic, serotonergic, or other receptors.

[On-screen text reads, “INGREZZA: Selective VMAT2 inhibitor designed for TD.” “INGREZZA has no appreciable binding affinity for: VMAT1, Dopaminergic receptors, Serotonergic receptors, Adrenergic receptors, Histaminergic receptors, Muscarinic receptors.” Scene fades.]

Important Information

INDICATION & USAGE: INGREZZA® (valbenazine) capsules is indicated for the treatment of adults with tardive dyskinesia.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS: INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported.

WARNINGS & PRECAUTIONS

Somnolence: INGREZZA can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by INGREZZA.

QT Prolongation: INGREZZA may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. INGREZZA should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage.

Parkinsonism: INGREZZA may cause parkinsonism in patients with tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. Reduce the dose or discontinue INGREZZA treatment in patients who develop clinically significant parkinson-like signs or symptoms.

ADVERSE REACTIONS: The most common adverse reaction (≥5% and twice the rate of placebo) is somnolence. Other adverse reactions (≥2% and >Placebo) include: anticholinergic effects, balance disorders/falls, headache, akathisia, vomiting, nausea, and arthralgia.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see INGREZZA full Prescribing Information

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