Deutetrabenazine - Indications, Dosage, Precautions, and Mechanism of Action

Overview:

Deutetrabenazine is a vesicular monoamine transporter-2 (VMAT-2) inhibitor used to treat chorea related to Huntington's disease and tardive dyskinesia. Deutetrabenazine tablets have been approved by the US Food and Drug Administration (FDA) for treating chorea associated with Huntington's disease (HD). Huntington's disease is a rare and fatal neurodegenerative condition that affects around 35,000 Americans.

Chorea, defined as uncontrollable, unpredictable, and sudden twisting and writhing movements, is one of the most noticeable physical signs of this disease, affecting approximately 90 percent of patients. Chorea is a common sign of Huntington's disease in many people. It influences patients' functionality and daily activities, and therapeutic choices for these patients have been restricted.

How Does the Drug Work?

Deutetrabenazine's precise mode of action in regulating its anti-chorea properties is unknown. Deutetrabenazine's active metabolites reversibly reduce the amounts of monoamines such as dopamine, serotonin, norepinephrine, and histamine in nerve terminals. The primary circulating metabolites are alpha-dihydro tetrabenazine [HTBZ] and beta-HTBZ, reversible VMAT-2 inhibitors. Inhibiting VMAT-2 reduces monoamine uptake into synaptic terminals and depletes monoamine reserves from nerve terminals.

Indications:

Deutetrabenazine is used for treating the following conditions:

• Chorea related to Huntington's disease.

• Adult tardive dyskinesia.

Contraindications:

Deutetrabenazine is not recommended for the following patients:

• Patients with Huntington's disease who are at risk for suicide or have untreated or insufficiently treated depression.

• Patients with hepatic impairment.

• In patients using Reserpine, Deutetrabenazine is recommended to be started at least 20 days after quitting Reserpine.

• In patients using MAOIs (monoamine oxidase inhibitors), Deutetrabenazine should not be taken in conjunction with an MAOI or within 14 days after stopping MAOI therapy.

• Patients taking Valbenazine or Tetrabenazine.

Dosage:

• The Deutetrabenazine dose is determined separately for each patient depending on chorea reduction and tolerability.

• The recommended beginning dose of Deutetrabenazine for individuals with Huntington's disease who are not being transitioned from Tetrabenazine (a similar VMAT-2 inhibitor) is six milligrams (mg) delivered orally once a day.

• Deutetrabenazine dosage can be raised in six mg increments at weekly intervals up to a maximum suggested daily intake of 48 mg.

• Deutetrabenazine should be taken with food.

• Deutetrabenazine should be taken wholly as tablets, not chewed, crushed, or broken.

• Evaluate the QT interval before and after increasing the overall Deutetrabenazine dose above 24 mg daily for patients susceptible to QT prolongation.

Dosage Forms and Strengths:

Deutetrabenazine is available as a tablet. The dosage strengths for Deutetrabenazine are 6 mg, 9 mg, and 12 mg.

Adverse Reactions:

Adverse effects in patients with Huntington's disease occur in more than 8 percent, such as

• Somnolence.

• Diarrhea.

• Dry mouth.

• Fatigue.

For Patients

What Is Huntingtons Disease?

Huntington's disease (HD) is hereditary, in which nerve cells (neurons) in various brain areas gradually degrade and die. The condition affects parts of the brain that assist in controlling voluntary (deliberate) movement and other regions.

Why Is Deutetrabenazine Prescribed?

Deutetrabenazine is a drug used to treat chorea (uncontrollable movements) caused by Huntington's disease (an inherited condition that causes the progressive disintegration of nerve cells in the brain). It is also used to treat tardive dyskinesia, defined as uncontrollable movement of the face, tongue, or other body parts. Deutetrabenazine belongs to a class of drugs known as vesicular monoamine transporter-2 (VMAT-2) inhibitors. It works by altering the action of certain natural brain chemicals that impact nerves and muscles.

How Should Deutetrabenazine Be Used?

• Deutetrabenazine is available as a tablet or extended-release tablet for oral use.

• The tablet is usually consumed with food twice a day. The prolonged-release tablet is typically taken once a day, either with or without food.

• Every day, consume Deutetrabenazine at the same time.

• Follow the recommendations on the prescription label strictly, and see a doctor or pharmacist if any doubt arises. Deutetrabenazine should be taken exactly as prescribed.

• Do not split, chew, or crush the tablets; instead, swallow the tablet whole.

• The doctor will most likely start the patient on a low dose of Deutetrabenazine and progressively increase it, no more than once a week.

• Request a copy of the manufacturer's information for the patient from a pharmacist or doctor.

What Special Precautions Should Be Taken?

• If patients are allergic to Deutetrabenazine, other medications, or substances in Deutetrabenazine tablets or extended-release tablets, they should notify their doctor and pharmacist.

• Some drugs should not be taken in conjunction with Deutetrabenazine. Before beginning Deutetrabenazine, ensure the patient has discussed any previously taken drugs, is currently taking, or plans to take with their doctor and pharmacist. Kindly follow the physician’s or pharmacist's advice before starting, stopping, or changing any medications while taking Deutetrabenazine. The doctor may need to adjust the dose of the medication or closely monitor for side effects.

• If the patient has a liver illness, breast cancer, or a family history of breast cancer, inform the doctor.

• Inform the doctor if the patient has or has ever had long QT syndrome (a condition that raises the chance of having an abnormal heartbeat that can lead to fainting or sudden death) or any other sort of irregular heartbeat or heart rhythm problem. Inform the doctor if the patient has low magnesium or potassium levels in the blood and breast cancer.

• Inform the doctor whether the patient is pregnant, intends to become pregnant, or is breastfeeding. Inform the doctor if the patient gets pregnant while using Deutetrabenazine.

• The patient should be aware that Deutetrabenazine can make them drowsy or tired. Do not use machinery or drive a car.

• The patient should be aware that drinking alcohol can worsen the drowsiness caused by this drug. Deutetrabenazine should not be taken in conjunction with alcohol.

What Are the Side Effects of Deutetrabenazine?

Side effects of Deutetrabenazine include:

• Diarrhea.

• Constipation.

• Dry mouth.

• Fatigue.

• Sleep issues.

• Discomfort and a burning sensation upon urination.

• Bruising.

• Upper respiratory infections.

Some serious side effects include:

• Fever.

• Sweating.

• Disorientation.

• Muscle stiffness.

• Shaking.

• Difficulty moving.

• Falls.

• Irregular heartbeat.

• Fainting.

If patients encounter any odd side effects while taking Deutetrabenazine, immediately contact the doctor.

Storage of Deutetrabenazine:

Keep this medication in its packaging, tightly closed, and away from children. It should be stored at room temperature, away from direct sunlight, high temperatures, and moisture.

What Can Be Done in the Event of an Overdose?

In the case of an overdose, call emergency services or the poison control center immediately if the patient experiences any of the overdose symptoms.

The symptoms of an overdose might consist of the following:

• Jerking or twisting movements.

• Quick eye movement.

• Nausea.

• Vomiting.

• Sedation.

• Sweating.

• Confusion.

• Diarrhea.

• Hallucinations (the perception of seeing or hearing things or sounds that do not exist).

• Skin redness.

• Uncontrollable trembling.

For Doctors:

What Is the Clinical Pharmacology of Deutetrabenazine?

Pharmacodynamics:

A single dose of 24 mg Deutetrabenazine results in a 4.5 msec mean increase in QTc in a randomized, double-blind, placebo-controlled crossover study in healthy male and female volunteers. The effects of greater doses of Deutetrabenazine or its metabolites have yet to be studied. In pigmented rats, Deutetrabenazine and its metabolites were found to bind to melanin-containing tissues such as the eyes, skin, and hair. At 35 days after a single oral dose of radiolabeled Deutetrabenazine, radioactivity was still detectable in the eye and fur.

Mechanism of Action:

VMAT-2 regulates dopamine and other monoamines organization into neuronal synaptic vesicles. Deutetrabenazine inhibits VMAT-2 by regulating dopamine translocation into presynaptic vesicles, lowering dopamine release, and inhibiting postsynaptic dopamine receptor stimulation. The frequency and severity of hyperkinetic disorders such as chorea, tardive dyskinesia, tics, and ballism are reduced.

Deuteterabenazine is a molecule in which the hydrogen atoms have been substituted by a heavier isotope, deuterium, which has an eight-fold stronger connection than carbon-hydrogen bonds. This resistance to degradation slows its metabolism, decreasing fluctuations in peak plasma concentrations and maintaining a constant area under the curve for total drug exposure. This could be the mechanism underlying better tolerance and fewer medication interactions.

Pharmacokinetics:

Absorption: Oral Deutetrabenazine has an absorption rate of 80 percent. As Deutetrabenazine is extensively metabolized to its primary active metabolites after administration, linear dose dependence of peak plasma concentrations (Cmax) and area under the curve (AUC) for the metabolites was observed after single or multiple Deutetrabenazine doses (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). The Cmax of deuterated alpha-HTBZ and beta-HTBZ is attained three to four hours after the dose. Food may increase the Cmax of alpha-HTBZ or beta-HTBZ by about fifty percent, but it is unlikely to affect the AUC.

Half-Life in Adults: 9 to 12 hours.

Distribution: The median volume of distribution (Vc/F) of Deutetrabenazine alpha-HTBZ and the beta-HTBZ metabolites is around 500 L and 730 L, respectively. Tetrabenazine PET scans in humans show fast distribution to the brain, with the highest affinity in the striatum and the lowest affinity in the cortex. Deutetrabenazine is predicted to have an identical distribution pattern.

Metabolism: Deutetrabenazine is extensively biotransformed in the liver by carbonyl reductase to produce its primary active metabolites, alpha-HTBZ and beta­-HTBZ. Such metabolites can then be metabolized into a number of lesser metabolites, with CYP2D6 playing a key role and CYP1A2 and CYP3A4/5 serving lesser ones.

Excretion: Deutetrabenazine metabolites are primarily eliminated in the urine. In healthy participants, the urine eliminated 75 percent to 86 percent of the Deutetrabenazine dose, while fecal clearance constituted 8 percent to 11 percent. The bulk of metabolites in the urine were sulfate and glucuronide conjugates of the alpha-HTBZ and beta-HTBZ and other products of oxidative metabolism. In the urine, alpha-HTBZ and beta-HTBZ metabolites comprised less than 10 percent of the given dose.

Warnings and Precautions:

• QT Prolongation: An increase in the QT interval may occur if Deutetrabenazine is used in patients with congenital long QT syndrome or arrhythmias.

• Neuroleptic Malignant Syndrome (NMS): If patients develop Neuroleptic Malignant Syndrome (NMS), stop taking the medication.

• Akathisia, Agitation, Restlessness, or Parkinsonism: If akathisia, agitation, restlessness, or parkinsonism occur, reduce or cease the medication.

• Sedation or Somnolence: This condition may impede the patient's ability to drive or operate sophisticated apparatus.

• Binding to Melanin-Containing Tissues: As Deutetrabenazine or its metabolites attach to melanin-containing tissues, it is likely to accumulate in these tissues over time. This raises the chance of Deutetrabenazine toxicity in these tissues following prolonged usage. Although no precise guidelines exist for periodic ophthalmologic monitoring, doctors should be conscious of the risk of long-term ophthalmologic effects.

• Depression and Suicidality in Huntington's Disease Patients: In people with Huntington's disease, it increases the likelihood of depression and suicidal thoughts and behaviors (suicidality).

Drug Interactions:

• Strong CYP2D6 Inhibitors: In patients on a stable dose of Deutetrabenazine, a dose reduction may be required when introducing a strong CYP2D6 inhibitor. Concurrent use of powerful CYP2D6 inhibitors (e.g., Paroxetine, Fluoxetine, Quinidine, and Bupropion) has been demonstrated to increase systemic intake of Deutetrabenazine active dihydrometabolites by about threefold. In patients taking strong CYP2D6 inhibitors, the daily dose of Deutetrabenazine should not exceed 36 mg, and the maximum single dose of Deutetrabenazine should not exceed 18 mg.

• Drugs That Cause QTc Prolongation: Tetrabenazine, a VMAT2 inhibitor that is closely related, may induce an increase in the corrected QT (QTc) interval. Deutetrabenazine may cause clinically significant QT prolongation. Evaluate the QTc interval before and after increasing the dose of Deutetrabenazine or other medications that are thought to extend QTc in patients who require Deutetrabenazine doses of more than 24 mg per day and are using Deutetrabenazine in combination with other treatments known to prolong QTc. Antipsychotic drugs (e.g., Chlorpromazine, Haloperidol, Thioridazine, Ziprasidone), antibiotics (e.g., Moxifloxacin), Class 1A (e.g., Quinidine, Procainamide), and Class III (e.g., Amiodarone, Sotalol) antiarrhythmic drugs are all known to extend QTc.

• Reserpine: Reserpine links irreversibly to VMAT2 and has a several-day course of action. To avoid the danger of overdosage and substantial serotonin and norepinephrine depletion in the central nervous system, doctors should wait for chorea or dyskinesia to reappear before providing Deutetrabenazine. Before commencing Deutetrabenazine, patients should wait at least 20 days after quitting reserpine. Deutetrabenazine and reserpine should not be taken together.

• Monoamine Oxidase Inhibitors (MAOIs): Deutetrabenazine is not recommended for patients using MAOIs. Deutetrabenazine should not be used in conjunction with an MAOI or within 14 days after stopping MAOI therapy.

• Dopamine Antagonists or Antipsychotics: Concurrent usage of Deutetrabenazine with dopamine antagonists or antipsychotics may raise the risk of Parkinsonism, NMS, and akathisia.

• Alcohol or Other Sedating Medicines: Using alcohol or other sedating medicines concurrently may have cumulative effects, worsening sedation and somnolence.

• Tetrabenazine or Valbenazine: Deutetrabenazine is not recommended for patients presently taking Tetrabenazine or Valbenazine. Deutetrabenazine can be started the day after Tetrabenazine is stopped.

Clinical Trials

A randomized, 12-week, placebo-controlled study was done in patients with Huntington's disease who had chorea. Deutetrabenazine was given to 45 patients, whereas placebo was given to 45 other patients. The patients' ages ranged from 23 to 74 years (mean 54 years); 56 percent were male, and 92 percent were Caucasian.

The most prevalent adverse events in individuals receiving Deutetrabenazine were somnolence, diarrhea, dry mouth, and weariness. Somnolence, diarrhea, dry mouth, fatigue, urinary tract infection, insomnia, anxiety, constipation, and contusion occurs in more than four percent of patients treated with Deutetrabenazine, and at a higher rate than in placebo patients. In seven percent of participants, one or more adverse events reduced the study medication dose. Dizziness (four percent of patients receiving Deutetrabenazine) was the most common adverse response resulting in dose reduction. In two percent of Deutetrabenazine-treated patients, agitation led to withdrawal.

Conclusion:

Chorea management can be controlled and enhanced in patients with Huntington's disease, including those who formerly responded to tetrabenazine, through long-term administration of twice-daily Deutetrabenazine, with excellent safety and tolerability.