Ingrezza

Mechanism of Action

The mechanism of action of valbenazine in the treatment of tardive dyskinesia is unknown, but is thought to be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release

Absorption

Bioavailability: ~49%

Peak plasma time: 0.5-1 hr (parent); 4-8 hr (active metabolite)

Steady-state: 1 week

Distribution

Protein bound: >99% (parent); ~64% (active metabolite)

Vd: 92 L

Metabolism

Extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-alpha-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites

[+]-alpha-HTBZ appears to be further metabolized in part by CYP2D6

Elimination

Half-life: 15-22 hr (parent drug and active metabolite)

Total plasma clearance: 7.2 L/hr

Excretion: 60% urine; 30% feces; <2% excreted as unchanged valbenazine or [+]-alpha-HTBZ

Pharmacogenomics

CYP2D6 poor metabolizers

• Consider reducing valbenazine dose based on tolerability for known CYP2D6 poor metabolizers
• Increased exposure (Cmax and AUC) to the active metabolite is anticipated in CYP2D6 poor metabolizers, which may increase risk for exposure-related adverse effects

This medicine may impair your thinking or reactions. Avoid driving or operating machinery until you know how this medicine will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

Contraindications

None.1

Warnings/Precautions

Somnolence

Valbenazine tosylate 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 valbenazine tosylate.1

QT Prolongation

Valbenazine tosylate may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. In patients taking a strong CYP2D6 or CYP3A4 inhibitor, or who are CYP2D6 poor metabolizers, valbenazine tosylate concentrations may be higher and QT prolongation clinically significant. For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary. For patients taking a strong CYP3A4 inhibitor, reduce the dose of valbenazine to 40 mg once daily. Valbenazine tosylate 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.1

Specific Populations

The limited available data on valbenazine tosylate use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m2 . Advise a pregnant woman of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognized pregnancies, respectively.1

Valbenazine was administered orally to pregnant rats during the period of organogenesis at 1, 5, and 15 mg/kg/day, which are approximately 0.1, 0.6, and 2 times the MRHD of 80 mg/day based on mg/m2 body surface area. Valbenazine produced a significant decrease in maternal body weight gain at 0.6 and 2 times the MRHD of 80 mg/day based on mg/m2. No adverse embryo fetal effects were produced when valbenazine was administered at doses up to 2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine was administered orally to pregnant rabbits during the period of organogenesis at 20, 50, and 100 mg/kg/day, which are approximately 5, 12, and 24 times the MRHD of 80 mg/day based on mg/m2. No malformations were observed at doses up to 24 times the MRHD of 80 mg/day based on mg/m2. However, valbenazine produced a delay in fetal development (decreased fetal weights and delayed ossification) at 24 times the MRHD of 80 mg/day based on mg/m2, likely secondary to maternal toxicity (decreased food intake and loss in body weight). Valbenazine was administered orally to pregnant rats during the period of organogenesis through lactation (day 7 of gestation through day 20 postpartum) at 1, 3, and 10 mg/kg/day, which are approximately 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine produced an increase in the incidence of stillbirths and postnatal pup mortality at 0.4 and 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine did not affect neurobehavioral function including learning and memory and had no effect on sexual maturation at doses <1 times the MRHD of 80 mg/day based on mg/m2 (because of death in the majority of the high dose group [1.2 times the MRHD], these parameters were not assessed in this group).1

There is no information regarding the presence of valbenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Valbenazine and its metabolites have been detected in rat milk at concentrations higher than in plasma following oral administration of valbenazine at doses 0.1 to 1.2 times the MRHD based on mg/m2. Based on animal findings of increased perinatal mortality in exposed fetuses and pups, advise a woman not to breastfeed during treatment with valbenazine tosylate and for 5 days after the final dose. 1

Safety and effectiveness of valbenazine tosylate have not been established in pediatric patients. 1

No dose adjustment is required for elderly patients. In 3 randomized, placebo-controlled studies of valbenazine tosylate, 16% were 65 years and older. The safety and effectiveness were similar in patients older than 65 years compared to younger patients. 1

Consider reducing valbenazine tosylate dose based on tolerability for known CYP2D6 poor metabolizers. Increased exposure (Cmax and AUC) to valbenazine’s active metabolite is anticipated in CYP2D6 poor metabolizers. Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions.1

Dosage reduction of valbenazine tosylate is recommended for patients with moderate or severe hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function. 1

Dosage adjustment is not necessary for patients with mild to moderate renal impairment (creatinine clearance 30 to 90 mL/min). Valbenazine tosylate does not undergo primary renal clearance. Valbenazine tosylate is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min).1

Common Adverse Effects

Most common adverse reaction (≥5% and twice the rate of placebo): somnolence.1

Take this medicine only as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with patient information leaflet Read and follow the instructions carefully. Ask your doctor if you have any questions.

You may take this medicine with or without food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For tardive dyskinesia:
    • Adults—At first, 40 milligrams (mg) once a day. After 1 week, your doctor may increase your dose to 80 mg once a day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

This medicine may cause some people to become sleepy or drowsy. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that requires you to be alert.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem such as QT prolongation.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Dizziness
• inability to sit still
• need to keep moving
• restlessness
• trouble walking

• Fainting
• irregular heartbeat recurrent

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blurred vision
• decrease in the frequency of urination
• decrease in urine volume
• difficulty having a bowel movement (stool)
• difficulty in passing urine (dribbling)
• dry mouth
• painful urination
• sleepiness or unusual drowsiness

• Difficulty in moving
• fear or nervousness
• headache
• muscle pain or stiffness
• nausea
• pain in the joints
• trouble sleeping
• vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

2.1 Dosing and Administration Information

The initial dose for Ingrezza is 40 mg once daily. After one week, increase the dose to the recommended dose of 80 mg once daily. Continuation of 40 mg once daily may be considered for some patients.

Administer Ingrezza orally with or without food [see Clinical Pharmacology (12.3)].

2.2 Dosage Recommendations for Patients with Hepatic Impairment

The recommended dose for patients with moderate or severe hepatic impairment (Child-Pugh score 7 to 15) is Ingrezza 40 mg once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.3 Dosage Recommendations for Known CYP2D6 Poor Metabolizers

Consider reducing Ingrezza dose based on tolerability for known CYP2D6 poor metabolizers [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.4 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inducers and Strong CYP3A4 or CYP2D6 Inhibitors

Coadministration with Strong CYP3A4 Inducers

Concomitant use of strong CYP3A4 inducers with Ingrezza is not recommended [see Drug Interactions (7.1)].

Coadministration with Strong CYP3A4 Inhibitors

Reduce Ingrezza dose to 40 mg once daily when Ingrezza is coadministered with a strong CYP3A4 inhibitor [see Drug Interactions (7.1)].

Coadministration with Strong CYP2D6 Inhibitors

Consider reducing Ingrezza dose based on tolerability when Ingrezza is coadministered with a strong CYP2D6 inhibitor [see Drug Interactions (7.1)].

7.1 Drugs Having Clinically Important Interactions with Ingrezza

1. The induction potency of St. John’s wort may vary widely based on preparation.

7.2 Drugs Having No Clinically Important Interactions with Ingrezza   

Dosage adjustment for Ingrezza is not necessary when used in combination with substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 based on in vitro study results.

Ingrezza (valbenazine) blocks certain chemicals in the body that may be involved with involuntary muscle movement.

Ingrezza is used to treat symptoms of tardive dyskinesia, a nervous system disorder. Tardive dyskinesia causes repetitive uncontrolled muscle movements, usually in the face (chewing, lip smacking, frowning, tongue movement, blinking or eye movement).

Ingrezza is not a permanent cure for this condition.

You should not use Ingrezza if you are allergic to valbenazine.

To make sure this medicine is safe for you, tell your doctor if you have ever had:

• heart disease;

• long QT syndrome or other heart rhythm disorder;

• congestive heart failure;

• a heart attack;

• liver disease; or

• kidney disease.

It is not known whether Ingrezza will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Do not breast-feed while using this medicine and for at least 5 days after your last dose.

Ingrezza is not approved for use by anyone younger than 18 years old.

Other drugs may interact with valbenazine, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Valbenazine may impair your thinking or reactions. Avoid driving or operating machinery until you know how this medicine will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

Applies to valbenazine: oral capsule

General

-The most common adverse reaction (5% or more and twice the rate of placebo) was somnolence.
-A total of 3% of patients discontinued treatment because of adverse reactions.[Ref]

Nervous system

Very common (10% or more): Somnolence/fatigue/sedation (10.9%)
Common (1% to 10%): Anticholinergic effects (dry mouth, constipation, attention disturbance, blurred vision, urinary retention), balance disorders/fall/gait disturbance/dizziness, headache, akathisia/restlessness, drooling, dyskinesia,
non-akathisia extrapyramidal symptoms[Ref]

Gastrointestinal

Common (1% to 10%): Vomiting, nausea[Ref]

Hepatic

Common (1% to 10%): Increased alkaline phosphatase and bilirubin[Ref]

Metabolic

Common (1% to 10%): Increased blood glucose, increased weight, increased prolactin[Ref]

Musculoskeletal

Common (1% to 10%): Arthralgia[Ref]

Psychiatric

Common (1% to 10%): Anxiety, insomnia[Ref]

Respiratory

Common (1% to 10%): Respiratory infections[Ref]

Some side effects of Ingrezza may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.