Valbenazine - Risk Factors and Side Effects

Overview:

Valbenazine is a vesicular monoamine transporter type 2 (VMAT2) inhibitor manufactured by a San Diego-based company called neurocrine biosciences. It is widely used to treat tardive dyskinesia, moderate to severe hepatic impairment, etc. It is available in capsule form and has three dosages 40 mg, 60 mg, and 80 mg. It is the first approved drug to treat tardive dyskinesia (TD).

Valbenazine received its FDA (food and drug administration) approval in April 2017. Studies have shown a considerable decrease in TD symptoms after taking Valbenazine. It is also seen that after six weeks of treatment with Valbenazine 40 % of people have shown about a 50 % decrease in their symptoms. It is currently not available in its generic form. The tablet comes in an opaque white and purple combination. The safety of this drug in children is not yet known.

How Does Valbenazine Work?

It works through reversible inhibition of VMAT2, which is responsible for the transmission and recycling of neurotransmitters along with the central nervous system.

Uses:

1.It is used in patients who suffer uncontrolled movements in body parts such as the face and tongue (dyskinesia).

2. It is used in treating tardive dystonia.

3. Also, it is used in treating moderate to severe hepatic (liver) impairment.

Dosage:

Valbenazine, which is available in capsule form, should be taken as per the doctor’s instructions.

Following are the instructions to be kept in mind while taking Valbenazine;

• Valbenazine is administered orally.

• It should be taken once daily.

• The initial dosage should be 40 mg; after a week the dose should be increased to 80 mg.

• Food does not interfere with this drug and hence there is no specific way for taking this capsule.

• Valbenazine capsules should be taken as a whole; do not break or cut open the capsule, as there is no information about adding the capsule content to the food or water and having it.

Warning:

1. Somnolence - It means feeling drowsy or sleepiness. Valbenazine has the tendency to cause somnolence. Hence, if taking Valbenazine for the first time, wait and watch for such symptoms. Also, refrain from performing activities such as riding a motorbike, operating a heavy machine, etc., until you are sure about how you respond to Valbenazine.

2. Prolongation of QT (Heart Rhythm Problems) -QT interval is a measurement in the ECG (electrocardiogram) that measures some of the electrical properties of the heart. Valbenazine tends to prolong the QT interval. Hence, patients suffering arrhythmias showing prolonged QT intervals or congenitally long QT syndrome should avoid taking Valbenazine. Assess the QT intervals before prescribing Valebenazine to susceptible patients.

For Patients:

What Do You Need to Know About Dyskinesia?

Dyskinesia is when your body experiences abnormal uncontrollable movements, ranging from mild to severe, affecting any part of the body or all body parts. The movements are usually stiff and jerky. Blinking the eyes, sticking the tongue out, or waving the hand without being aware or without even wanting to do it represents dyskinesia. These movements might be slow or can occur fast; they can be frequent or rare.

What Are the Causes of Dyskinesia?

• Dyskinesia occurs as a side effect of certain medications after their long-term use. When taken in a high dosage, in very few cases, it happens immediately after the initiation of the particular drug. The medications prescribed to treat Parkinson's disease (a brain disorder that often causes difficulties with movements and causes tremors), mental disorders, antipsychotic drugs, etc., are the most common group of drugs causing dyskinesia. Some rare causes include brain injuries and neurological disorders like Wilson’s disease (a rare inherited disorder in which copper accumulates in the vital organs of the body such as the liver, brain, etc.).

• The common medications that can cause dyskinesia when taken long-term include Levodopa, Chlorpromazine, Fluphenazine, Haloperidol, Risperidone, Amitriptyline, etc.

• The symptoms appear gradually. They can occur while taking the medications responsible or a few months or years after stopping the medication.

• Dyskinesia does not happen to everyone taking these medications, but if dyskinesia occurs sometimes, it becomes untreatable.

Why Does Dyskinesia Occur?

The occurrence of dyskinesia is interlinked to the dopamine release in the brain. Dopamine is a brain’s byproduct with many functions such as movement, memory, focus or motivation, etc. The disorders related to dopamine affect these functions. To regulate the functions and bring them back to certain normal, medications such as antidepressants, antipsychotics, etc., are prescribed. However, while trying to regulate the dopamine levels, when they are taken in high doses or taken for a longer duration, they lower the dopamine levels to the least, which results in uncontrolled body movements called dyskinesia.

Who Is MWhat Are the Risk Factors for Dyskinesia?

Dyskinesia most commonly affects the following populations;

• Individuals aged 55 years of age or more.

• Female; usually those who have reached menopause.

• People who are addicted to or have a habit of taking alcohol frequently.

• Those are suffering from diseases such as diabetes and dementia.

• African-Americans and Asian-Americans are said to suffer from dyskinesia more frequently than others.

Learn More About Valbenazine:

Before Starting Valbenazine:

When and Why to Take Valbenazine?

Valbenazine is a drug that strictly requires a prescription before taking it. It is usually prescribed after getting diagnosed with dyskinesia. It is the first medication administered to patients suffering from tardive dyskinesia. It reduces the raised dopamine levels, thereby minimizing the symptoms encountered by patients with dyskinesia.

How Effective Is Valbenazine?

It is seen to minimize or treat all the symptoms or only certain symptoms of dyskinesia. Six weeks of treatment with Valbenazine with a timely increase in dosage has shown to improve the symptoms by 50 % in around 67 % population, which is considered a much-improved response.

Things to Inform Your Doctor Before They Prescribe You Valbenazine:

Inform your doctor about the following before the doctor prescribes Valbenazine,

• Prior history of allergy or hypersensitivity reactions to any drugs.

• History of cardiac arrhythmias that show prolonged QT interval, faulty rhythms, or conditions like congenital long QT syndrome.

• Inform about the pregnancy status, planning pregnancy, breastfeeding, planning to breastfeed, etc., as this drug is said to cause harm to the baby.

• If taking any medication as this drug has interactions with certain drugs. Also, mention even if you are taking any vitamins, herbal supplements, or medications.

• If taken any medications for the suffering condition and if that medication worked.

• Habits such as alcohol and drugs, if any.

• History of any other medical conditions like diabetes, renal problems, liver disorders, etc.

• History of any cardiac problems, recent or previous history of heart attacks, heart failure, etc.

Starting Valbenazine:

How to Take Valbenazine?

Prescription is a must before taking Valbenazine. If prescribed, ask your doctor how to take the drug and what all should be considered before taking it. Valbenazine is available as a capsule and should be taken orally. It can be taken before or after having food. It should be taken once a day, and is preferable to be taken at the same time every day. The drug should not be stopped or the dosage of the drug should never be changed without consulting a doctor. If you are under any medication, confirm with your doctor both drugs can be taken simultaneously as Valbenazine reacts badly and can cause adverse effects when taken with certain drugs.

Things to Do After You Start Taking Valbenazine:

Once you start taking Valbenazine, look for the changes in symptoms.

• In case of worsening symptoms or any adverse effects inform your doctor so that they can suggest to you what needs to be done.

• Note down if all the symptoms have subsided or if only one or few of the symptoms is subsiding, and do not forget to note down when you started noticing improvement.

• Only if the effects of the drug are kept on track and informed clearly, will the doctor be able to analyze how well the drug works.

Look Out for Side Effects:

For patients who have the possibility to experience or who have experienced side effects, the drug dose should be altered or should be stopped based on the severity. Following are the few possible side effects of Valbenzine so that you will not be confused about what to look for when you start taking Valbenazine.

The common side effects include;

• Drowsiness or feeling sleepy.

• Inability to balance and perform heavy-duty jobs.

• Nausea.

• Headache.

• Blurred vision.

• Constipation can occur; if it does not get alright in three days, consult your doctor.

• Dry mouth, which can be managed at home by hydrating at regular intervals and chewing sugarless gums.

• Urinary retention.

• Joint pain.

• Less attentive behavior.

• Restlessness.

• Dry skin.

Other symptoms with a lesser percentage of incidence include;

• Increase in blood sugar levels.

• Weight gain.

• Anxiety.

• Insomnia.

• Respiratory infections and respiratory symptoms.

• If allergic to Valbenazine, hypersensitivity reactions such as skin rash, itching, swollen lips, tongue or face, etc., can occur.

Also, symptoms that are not on this list might occur as well; several other symptoms that are not present in the list can occur as well. If any difference is felt more negatively than usual, consult your doctor, explain the symptoms and get it checked.

Dietary Alterations:

There are no specific diet alterations required when taking Valbenazine. Continue to take the diet that you normally consume unless your doctor requests some diet changes. Make sure to take a healthy diet rich in all the necessary minerals and vitamins for the body's functioning.

What Should Be Done When You Miss a Dose?

It is okay to take the missed dose when you remember it unless it is already time for the next dose. If it is time for your dose, skip the dose that you missed; do not take two capsules just to cover for the missed dose; only one capsule should be taken at a time. If more than one capsule is taken at a time, it can lead to an overdose.

What Should Be Done to Treat Valbenazine Overdose?

There is no antidote for overdose of this drug. Call for an ambulance and seek emergency medical care immediately. A combination of various medications along with supportive care is given to patients suffering from an overdose.

How to Store Valbenazine?

Valbenazine should be stored at a temperature of less than 30 ℃, ideally 20 ℃ to 25 ℃. The capsule should be taken out just before having it. Do not leave the bottle open as it is easy to get contaminated. Keep it away from the reach of children. Check the expiration date before purchasing the drug, if the expiration date has passed, dispose of it; do not use it.

Avoid Self-Medication:

As mentioned earlier, this is a prescription drug. Having Valbenazine without a prescription could go wrong in many ways. The doctor does evaluate the condition and customizes the medication and the dosage to be taken. So, do not take this medication without getting prescribed and do not suggest it to anyone else or take it after somebody else’s recommendation. Medications do not react uniformly in different individuals and some can even react worse. It is important to note all the medications taken and should be taken to the doctor every time you visit. In case of emergencies, the list should be carried with you.

Staying On Valbenazine:

Tips to Stay On Track:

• Valbenazine has to be taken as prescribed by the doctor. The designated time to take the medication should be maintained regularly. It is not advisable to stop the medication abruptly or lower the dose of the drug without consulting a doctor.

• Usually, Valbenazine has shown results in six weeks of treatment but the healing cycle is not the same for everyone, it varies with individuals.

• So, if the results show up earlier than anticipated or if there is a delay in response to the medication, do not panic.

• Do not miss a dose; take it regularly without fail as the doctor recommends.

• Note down the results of the medicine.

• Keep your doctor posted on your condition, if the symptoms have subsided and if there are any side effects. Do not miss the follow-up consultations.

For Doctors:

Indication:

Valbenazine is indicated in patients suffering from dyskinesia as a side effect of certain drugs, dystonia, etc.

Pharmacology:

Mechanism of Action:

Though the mechanism of action of Valbenazine in treating dyskinesia is still unclear, it is assumed that the mechanism is performed through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), which is responsible for the transmission and recycling of neurotransmitters across the synapses in the central nervous system. The inhibition of VMAT2 causes neurotransmitter degradation resulting in presynaptic neurotransmitter depletion, particularly of the neurotransmitter that the drug aims at, dopamine. Dopamine plays a major role in the motor functions of the body; any dysregulation or problems associated with its release can cause hyperkinetic disorders.

Pharmacodynamics:

Following are the pharmacological changes that take place in the body after intake of Valbenazine;

• Inhibition of VMAT2.

• There is no marked binding affinity for VMAT1.

• Valbenazine is converted into an active metabolite [+]-ɑ-HTBZ.

• The selective affinity of the drug to VMAT2 may be responsible for the efficiency of the drug in treating dyskinesia.

Chemical Taxonomy:

Ingredients:

Active Ingredient:

The only active ingredient present is Valbenazine tosylate.

Inactive Ingredients:

The inactive ingredients present are;

• Mannitol.

• Partially pregelatinized starch.

• Fumed silica.

• Magnesium stearate.

Absorption:

• The absorption of Valbenazine is moderate.

• The oral bioavailability is approximately found to be 49 %.

• It takes around 30 minutes to 60 minutes for the drug to reach its utmost concentration.

• It reaches a steady plasma concentration within one week.

• If Valbenazine is taken along with meals rich in fat then the maximum concentrations drop to around 47 %.

Distribution:

• Valbenazine has a higher binding efficiency to protein which is around 99 %.

• Valbenazine’s mean steady-state volume of distribution is 92 L.

Metabolism:

• After an oral intake, this drug is primarily metabolized by hydrolysis of valine ester into [+]-ɑ-HTBZ and by oxidative metabolism to form an oxidized variant of the drug and various other metabolites.

Elimination:

• Total plasma systemic clearance is 7.2 L per hour.

• The half-lives of Valbenazine and [+]-ɑ-HTBZ are 15 to 22 hours.

• 60 % of oral ingested Valbenazine is excreted in the urine and about 30 % in the feces.

• Unaltered excretion of Valbenazine is around 2 % in the urine and feces.

Toxicity:

No cases of mutagenicity, no incidence of infertility, and no carcinogenicity were observed. No proper or sufficient information about overdose is observed yet. These conclusions have been made after performing studies on rats by administering the drug.

Warning and Precaution:

• The most common adverse effects associated are somnolence and prolonging of the QT interval. Care must be taken before patients with prolonged QT levels, otherwise are prescribed this drug. Patients who ought to perform activities like riding a vehicle or managing a heavier motor or a machine, those requiring mental alertness, should put off such work till they observe how they respond to the drug.

• Certain other conditions, such as low potassium and magnesium levels in the blood, can also prolong the QT intervals. If you suffer from such conditions, do mention your doctor about it.

• As this drug carries a side effect of making you dizzy and drowsy, taking alcohol when under this medication can make your symptoms worse. Inform your doctor about any drug or alcohol abuse. Alcohol and drugs should definitely be avoided when under this drug.

• If you suffer from any liver diseases, kidney problems, or any medical condition, let your doctor know before you are prescribed.

• In case of any surgeries or dental extractions, it is important to mention the drug history.

Dosage and Forms:

• Valbenazine is an orally administered drug.

• It is available in capsules.

• For 40 mg of Valbenazine, the color of the capsule is an opaque white body and a purple cap combination with VBZ printed on it along with the dosage (40 mg) in black ink. 60 mg capsules come in a combination of a purple cap and a red body, whereas 80 mg capsules are entirely purple with VBZ and 80 mg printed in black on the capsule.

Administration of the Drug:

• Valbenazine should be taken once daily.

• The initial dosage should be 40 mg; after a week, the dose should be increased to 80 mg.

• Taking it before or after food does not make a difference, so taking it anytime is fine.

• The capsule should be taken as a whole; there is no information on whether it can be taken by opening up the capsule or adding the capsule content to the food and having it.

Considerations for Administration:

• Evaluate how well the patient responds before letting them perform heavy-duty activities and jobs.

• Evaluate the QT intervals in patients with congenital prolonged QT.

• Look for the patient’s general health by performing blood tests.

Contraindications:

Valbenazine is contraindicated in patients who have,

• Hypersensitivity reactions to the drug.

• Have a history of prolonged QT intervals.

• History of arrhythmias.

• In patients with severe renal disorders.

• In patients with liver-related problems ranging from moderate to severe.

• It is also contraindicated in feeding mothers.

Clinical Studies for Valbenazine:

• Placebo-controlled randomized controlled trials were conducted in selected patients who were diagnosed with moderate to severe tardive dyskinesia. The patients who were suffering from schizophrenia, schizoaffective disorder, and mood disorders were selected. Also, those patients with unstable moods who had suicidal thoughts and psychiatric problems were excluded.

• The abnormal involuntary movement scale (AIMS) was considered the base of assessment for these studies. The AIMS score assessed the severity of dyskinesia.

• AIMS has 12 components in which only the first seven were used in the severity assessment of dyskinesia.

• The components one to seven were graded from zero to four based on the severity of the symptoms; the grading was based on the following conditions;

1. Grade zero - No dyskinesia.

2. Grade one - Low amplitude, which is present only during some but not during most parts of the exam.

3. Grade two - Low amplitude, present during most of the exam, or moderate amplitude, present during only some parts of the exam.

4. Grade three - moderate amplitude, present during most of the exam.

5. Grade four - maximal amplitude, present during most of the exam.

The score of dyskinesia could range from anywhere between (0 to 28) considering grades one, two four among the seven components.

In the KINECT 2 study, which involved around 120 patients, it was observed that there was a reduction in the AIMS score by 2.4 units in patients taking Valbenazine for around six weeks. In randomization of 1:1, Valbenazine and placebo reduction of 3.6 units was observed for Valbenazine and 1.1 for placebo.

The KINECT 3 study was conducted involving 225 participants, 1:1:1 fixed ratio to placebo once a day, 40 mg Valbenazine and 80 mg Valbenazine. At the end of six weeks, the mean reduction of 3.2 units was observed with 80 mg of Valbenazine.

Results From Clinical Trials:

• The safety and adverse effects of using this drug were analyzed by placebo-controlled randomized trials; Each trial was conducted for a period of six weeks using 445 patients in total. The patients involved in the study belonged to the age group of 26 to roughly 84 years.

• 3 % of the patients treated with Valbenazine and 2 % of patients who were placebo-treated had to discontinue the drug as they experienced adverse reactions to the drug.

• Also, an increase in prolactin, alkaline phosphatase, and bilirubin was seen which were dose-related, which suggested that there might be a possibility of cholestasis.

• The most common adverse effects encountered were somnolence and anticholinergic effects.

Drug Interactions:

• In some cases, taking two drugs together can cause harmful effects. As they react in a bad way when they interact with each other than when taken separately.

• The drugs that definitely have to be avoided when taking Valbenazine include; Tetrabenazine and Deutetrabenazine.

• Valbenazine may also react with the following medications; Alcohol, Ketoconazole, Itraconazole, Carbamazepine, Phenytoin, Clarithromycin, Rifampin, etc. So caution must be taken before taking any medication along with Valbenazine.

• St. John’s wort is a herbal product suggested for mental and psychiatric disorders which should not be taken along with Valbenazine as they have a proven record of causing adverse effects when taken together.

Other Specifications:

Valbenazine in Pregnant and Lactating Women:

Though the effects of this drug in pregnant women have not been studied clearly yet, there is a possibility that this drug could cause harm to the baby. In breastfeeding mothers, it is strictly not advisable to feed while taking Valbenazine drug. Also, after stopping the drug, a gap of five days should be left before resuming to feed.

Valbenazine in Pediatric Patients:

The drug's adverse effects on children have not been studied and verified. Therefore, the use of Valbenazine is still a query in children.

Valbenazine in Geriatric Patients:

There are no dose adjustments required in geriatric patients. The dose can be the same as any other young patient.

Valbenazine in Renal Impairment Patients:

As Valbenazine does not undergo any primary metabolism in the kidney no drug alteration is required in patients with mild to moderate kidney impairment. However, in patients with severe renal impairment, Valbenazine is not advised.

Valbenazine in Hepatic Impairment Patients:

Dose reduction is indicated in patients suffering moderate to severe hepatic impairment.

The recommended dose of Valbenazine in patients with moderate to severe liver abnormalities is 40 mg once per day.