Mechanism of action and PK profile

MOA

VMAT2 inhibition can help regulate dopamine function

Some vesicular monoamine transporter 2 (VMAT2) inhibitors reduce available dopamine via alpha and/or beta metabolites that block sequestration in the presynaptic vesicle.¹

Unsequestered dopamine is degraded by monoamine oxidase^2,3
Reducing dopamine levels in the presynaptic neuron results in less dopamine signaling to the postsynaptic neuron, leading to fewer abnormal involuntary movements^1-3

The precise mechanism by which AUSTEDO^® (deutetrabenazine) tablets exerts its effects in the treatment of tardive dyskinesia (TD) and chorea associated with Huntington’s disease (HD) is unknown, but it is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals.¹

The major circulating active metabolites (alpha-dihydrotetrabenazine [HTBZ] and beta-HTBZ) of deutetrabenazine are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into presynaptic vesicles and depletion of monoamine stores
VMAT2 is inhibited through both the alpha and beta metabolites to provide potent inhibition

Presynaptic neuron: AUSTEDO® (deutetrabenazine) tablets, VMAT2, vesicle. Postsynaptic neuron: monoamines (e.g. dopamine). Increased VMAT2 Inhibition leads to decreased dopamine.

See how the VMAT2 inhibition of AUSTEDO^® reduces dopamine levels

View the results of AUSTEDO^® clinical trials in patients with TD or patients with chorea associated with HD.

Flexible treatment options that effectively inhibit VMAT2 may help address the dopamine dysregulation that can lead to TD^4,5

PK PROFILE

A differentiated PK profile⁶

AUSTEDO® tablets features deuterium, resulting in stronger molecular bonds^1,7

Bonds 6 to 10 times more strongly with carbon atoms^7,8
Extends the half-life of active therapeutic metabolites to 9 to 10 hours^1,6,7

Pharmacokinetic (PK) simulations of area under the curve (AUC)–matched exposure to active metabolites based on dosing regimens of AUSTEDO^® (9 mg twice daily) and tetrabenazine (12.5 mg 3 times a day) at steady state.⁶

Plasma Concentrations of Alpha and Beta Metabolites Over 24 hours-PK Model. 3 Peaks = Tetrabenazine 3 times a day vs. 2 Peaks = AUSTEDO® (deutetrabenazine) tablets twice daily. The correlation between plasma levels and clinical efficacy has not been established. — Plasma Concentrations of Alpha and Beta Metabolites Over 24 Hours—PK Model⁶

Slower rate of rise, lower peak-to-trough fluctuations, and reduced C_max⁶
Slower metabolism allows for AUSTEDO® twice-daily dosing with AUC similar to tetrabenazine 3 times a day⁶

AUSTEDO^® allows for reduced interpatient metabolic variability and a predictable ratio of inactive to active metabolites⁶

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efficacy safety and tolerability additional resources

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AUSTEDO^® (deutetrabenazine) tablets Copay Program Terms and Conditions

Terms, Conditions and Eligibility Requirements

To the Patient:

To redeem this offer, you must have a valid prescription for AUSTEDO^®. No substitutions permitted. Commercially insured patients with coverage for AUSTEDO^® may pay no out-of-pocket costs. Commercially insured patients whose insurer requires a prior authorization for AUSTEDO^® may receive a 30 day supply of AUSTEDO^® (up to a total of three prescriptions with only one prescription per AUSTEDO^® strength or NDC) under the Program while their prior authorization is pending. If the prior authorization is approved by the commercial insurer, then the individual remains eligible for the Program. If the prior authorization is denied by the commercial insurer, then the individual is no longer eligible for this Program and may not receive any additional Program benefits. Maximum annual benefits apply and out-of-pocket expenses may vary. Patient is responsible for costs above maximum benefit amounts. If you have any questions regarding your eligibility or benefits, please call the AUSTEDO^® Copay Program at 1-800-887-8100.

You are not eligible for this offer if your prescriptions are paid for in part or full by any state or federally funded programs, including but not limited to Medicare or Medicaid, Medigap, VA, DOD, TRICARE, or by private health benefit programs which reimburse you for the entire cost of your prescription drugs. This offer is not valid for patients who are Medicare eligible and are enrolled in an employer-sponsored health plan or prescription drug benefit program for retirees (i.e., patients who are eligible for Medicare Part D but receive a prescription drug benefit through a former employer). You are not eligible for this offer if you are uninsured or a cash-paying patient. This offer is void in California if an AB-rated generic drug is available for the product. By redeeming this offer, you acknowledge that you are an eligible patient and you understand and agree to comply with the terms and if copied, transferred, purchased, altered or traded and where prohibited and restricted by law. conditions of this offer. Void if copied, transferred, purchased, altered or traded and where prohibited and restricted by law. Program managed by PSKW, LLC on behalf of Teva Pharmaceuticals. The parties reserve the right to change or discontinue this offer at any time without notice. This offer is not health insurance.

This offer is restricted to residents of the United States and Puerto Rico and valid only at participating pharmacies. This offer is limited to one per customer and may not be used with any other discount, coupon or offer. Offer expires December 31, 2019.

To the Pharmacist:

When you apply this offer, you are certifying that you have not submitted and will not submit a claim for reimbursement under any federal, state, or other governmental program for this prescription.

Pharmacist Instructions: Submit claim to Therapy First Plus. If primary coverage exists, input offer information as secondary coverage and transmit using the COB segment of the NCPDP transaction.

For questions regarding processing, please call the Help Desk 1-800-422-5604 .

AUS-41403 December 2018

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Indications and Usage

AUSTEDO^® is indicated for the treatment of chorea associated with Huntington’s disease and for the treatment of tardive dyskinesia in adults.

Important Safety Information

Depression and Suicidality in Patients with Huntington’s Disease: AUSTEDO^® can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation. AUSTEDO^® is contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.

Contraindications: AUSTEDO^® is contraindicated in patients with Huntington’s disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO^® is also contraindicated in: patients with hepatic impairment; patients taking reserpine or within 20 days of discontinuing reserpine; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; and patients taking tetrabenazine (Xenazine^®) or valbenazine (Ingrezza^®).

Clinical Worsening and Adverse Events in Patients with Huntington’s Disease: AUSTEDO^® may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO^® in their patients by assessing the effect on chorea and possible adverse effects.

QTc Prolongation: Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase in the corrected QT (QTc) interval. A clinically relevant QT prolongation may occur in some patients treated with AUSTEDO^® who are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor. Dose reduction may be necessary. The use of AUSTEDO^® in combination with other drugs known to prolong QTc may result in clinically significant QT prolongations. For patients requiring AUSTEDO^® doses greater than 24 mg per day who are using AUSTEDO^® with other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of AUSTEDO^® or the other drugs. AUSTEDO^® should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex reported in association with drugs that reduce dopaminergic transmission, has been observed in patients receiving tetrabenazine. The risk may be increased by concomitant use of dopamine antagonists or antipsychotics. The management of NMS should include immediate discontinuation of AUSTEDO^®; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.

Akathisia, Agitation, and Restlessness: AUSTEDO^® may increase the risk of akathisia, agitation, and restlessness. The risk of akathisia may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops akathisia, the AUSTEDO^® dose should be reduced; some patients may require discontinuation of therapy.

Parkinsonism: AUSTEDO^® may cause parkinsonism in patients with Huntington’s disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO^® dose should be reduced; some patients may require discontinuation of therapy.

Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO^®. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are on a maintenance dose of AUSTEDO^® and know how the drug affects them. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.

Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations in humans. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO^®.

Binding to Melanin-Containing Tissues: Deutetrabenazine or its metabolites bind to melanin-containing tissues and could accumulate in these tissues over time. Prescribers should be aware of the possibility of long-term ophthalmologic effects.

CYP2D6 Metabolism: In patients who are poor CYP2D6 metabolizers or are taking strong CYP2D6 inhibitors, the total daily dosage of AUSTEDO^® should not exceed 36 mg (maximum single dose of 18 mg).

Common Adverse Reactions: The most common adverse reactions for AUSTEDO^® (>8% and greater than placebo) in a controlled clinical study in patients with Huntington’s disease were somnolence, diarrhea, dry mouth, and fatigue. The most common adverse reactions for AUSTEDO^® (4% and greater than placebo) in controlled clinical studies in patients with tardive dyskinesia were nasopharyngitis and insomnia.

Please see accompanying full Prescribing Information, including Boxed Warning.

References: 1. AUSTEDO^® (deutetrabenazine) tablets current Prescribing Information. Teva Pharmaceuticals USA, Inc. 2. Reimer R, Zaia K, Tani H. Neurotransmitter reuptake and synaptic vesicle refilling. In: Wang ZW, ed. Molecular Mechanisms of Neurotransmitter Release. New York, NY: Humana Press; 2008:263-296. 3. Faingold C. Drugs affecting the peripheral nervous system and the skeletal and smooth muscle. In: Wecker L, Crespo LM, Dunaway G, Faingold C, Watts S, eds. Brody’s Human Pharmacology: Molecular to Clinical. 5th ed. Philadelphia, PA: Mosby Elsevier; 2010;91-162. 4. Zai CC, Tiwari AK, Mazzoco M, et al. Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia. J Psychiatr Res. 2013;47(11):1760-1765. 5. Aquino CC, Lang AE. Tardive dyskinesia syndromes: current concepts. Parkinsonism Relat Disord. 2014;20(Suppl 1):S113-S117. 6. Data on file. Teva Neuroscience, Inc. 7. Tung R. The development of deuterium-containing drugs. Innovations in Pharmaceutical Technology. 2010;32(32):24-28. 8. Huntington Study Group, Frank S, Testa CM, et al. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. JAMA. 2016;316(1):40-50.

Plasma Concentrations of Alpha and Beta Metabolites Over 24 Hours—PK Model6

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Important Safety Information

Plasma Concentrations of Alpha and Beta Metabolites Over 24 Hours—PK Model⁶