Ingrezza Drug Information
Generic name: VALBENAZINE
Uses of Ingrezza
- and INGREZZA SPRINKLE are indicated for the treatment of adults with: - tardive dyskinesia . - chorea associated with Huntington’s disease . INGREZZA and INGREZZA SPRINKLE are vesicular monoamine transporter 2 (VMAT2) inhibitors indicated for the treatment of adults with: - tardive dyskinesia. - chorea associated with Huntington’s disease.
Dosage & Administration of Ingrezza
- Tardive dyskinesia: The initial dosage is 40 mg once daily. After one week, increase the dose to the recommended dosage of 80 mg once daily. ( 2.1 ) Chorea associated with Huntington’s disease: The initial dosage is 40 mg once daily. Increase the dose in 20 mg increments every two weeks to the recommended dosage of 80 mg once daily. ( 2.1 ) 40 mg or 60 mg once daily may be considered depending on response and tolerability. ( 2.1 ) Can be taken with or without food. ( 2.2 ) INGREZZA SPRINKLE may be opened and sprinkled over soft food (do not use milk or drinking water). INGREZZA SPRINKLE may be swallowed whole with water. Do not crush or chew. ( 2.2 ) The recommended dosage for patients with moderate or severe hepatic impairment is 40 mg once daily. ( 2.3 ) The recommended dosage for known CYP2D6 poor metabolizers is 40 mg once daily. ( 2.4 ) 2.1 Recommended Dosage Tardive Dyskinesia The initial dosage for INGREZZA and INGREZZA SPRINKLE is 40 mg once daily. After one week, increase the dose to the recommended dosage of 80 mg once daily. A dosage of 40 mg or 60 mg once daily may be considered depending on response and tolerability. Chorea Associated with Huntington ’s Disease The initial dosage for INGREZZA and INGREZZA SPRINKLE is 40 mg once daily. Increase the dose in 20 mg increments every two weeks to the recommended dosage of 80 mg once daily. A dosage of 40 mg or 60 mg once daily may be considered depending on response and tolerability. 2.2 Administrative Information Administer INGREZZA and INGREZZA SPRINKLE orally with or without food [see Clinical Pharmacology ( 12.3 )] . Administration Information for INGREZZA SPRINKLE
- Open INGREZZA SPRINKLE and sprinkle the entire contents of the capsule over a bowl containing a small amount (1 tablespoonful) of soft food such as applesauce, yogurt, or pudding. Do not sprinkle the contents of the capsule into milk or drinking water. Stir the contents of the capsule into the soft food with the tablespoon and swallow the drug/food mixture immediately. If necessary, the mixture can be stored for up to 2 hours at room temperature. Discard of any unused portion after 2 hours. Following administration of the drug/food mixture, drink a glass (e.g., 240 mL) of water. Do not administer INGREZZA SPRINKLE via nasogastric, gastrostomy, or other enteral tubes because it may cause obstruction of enteral tubes.
- INGREZZA SPRINKLE may be swallowed whole with water. Do not crush or chew INGREZZA SPRINKLE. 2. 3 Dosage Recommendations for Patients with Hepatic Impairment The recommended dosage for patients with moderate or severe hepatic impairment (Child-Pugh score 7 to 15) is INGREZZA or INGREZZA SPRINKLE 40 mg once daily [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. 2. 4 Dosage Recommendations for Known CYP2D6 Poor Metabolizers The recommended dosage for known CYP2D6 poor metabolizers is INGREZZA or INGREZZA SPRINKLE 40 mg once daily [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 , 12.5 )]. 2. 5 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 or INGREZZA SPRINKLE is not recommended [ see Drug Interactions ( 7.1 ) ] . Coadministration with Strong CYP3A4 Inhibitors The recommended dosage for patients receiving strong CYP3A4 inhibitors is INGREZZA or INGREZZA SPRINKLE 40 mg once daily [see Drug Interactions ( 7.1 )]. Coadministration with Strong CYP2D6 Inhibitors The recommended dosage for patients receiving strong CYP2D6 inhibitors is INGREZZA or INGREZZA SPRINKLE 40 mg once daily [see Drug Interactions ( 7.1 )].
Side Effects of Ingrezza
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of INGREZZA SPRINKLE has been established from adequate and well-controlled studies of INGREZZA . Below is a display of the adverse reactions of INGREZZA in these adequate and well-controlled studies. Tardive Dyskinesia Variable and Fixed Dose Placebo-Controlled Trial Experience The safety of INGREZZA was evaluated in 3 placebo-controlled studies, each 6 weeks in duration (fixed dose, dose escalation, dose reduction), including 445 patients.
Patients were 26 to 84 years of age with moderate to severe tardive dyskinesia and had concurrent diagnoses of mood disorder (27%) or schizophrenia/ schizoaffective disorder (72%). The mean age was 56 years. Patients were 57% Caucasian, 39% African-American, and 4% other. With respect to ethnicity, 28% were Hispanic or Latino.
All subjects continued previous stable regimens of antipsychotics; 85% and 27% of subjects, respectively, were taking atypical and typical antipsychotic medications at study entry. Adverse Reactions Leading to Discontinuation of Treatment A total of 3% of INGREZZA-treated patients and 2% of placebo-treated patients discontinued because of adverse reactions. Common Adverse Reactions Adverse reactions that occurred in the 3 placebo-controlled studies at an incidence of ≥2% and greater than placebo are presented in Table 1. Table 1: Adverse Reactions in 3 Placebo-Controlled Studies of 6-week Treatment Duration Reported at ≥2% and >Placebo – Tardive Dyskinesia Adverse Reaction 1 INGREZZA (n=262) % Placebo (n=183) % General Disorders Somnolence (somnolence, fatigue, sedation) 10.9
Nervous System Disorders Anticholinergic effects 5.4 4.9 (dry mouth, constipation, disturbance in
attention, vision blurred, urinary retention) Balance disorders/fall (fall, gait disturbance, dizziness, balance disorder) 4.1
Nausea 2.3 2.1 Musculoskeletal Disorders Arthralgia 2.3 0.5 1 Within each adverse
reaction category, the observed adverse reactions are listed in order of decreasing frequency. Other Adverse Reactions Observed During the Premarketing Evaluation of INGREZZA Other adverse reactions of ≥1% incidence and greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo.
Endocrine Disorders: blood glucose increased General Disorders: weight increased Infectious Disorders: respiratory infections Neurologic Disorders: drooling, dyskinesia, extrapyramidal symptoms (non-akathisia) Psychiatric Disorders: anxiety, insomnia During the tardive dyskinesia controlled trials, there was a dose-related increase in prolactin. Additionally, in these trials there was a dose-related increase in alkaline phosphatase and bilirubin, suggesting a potential risk for cholestasis. Chorea Associated with Huntington ’s Disease The safety of INGREZZA was evaluated in a 14-week placebo-controlled study including 127 patients with chorea associated with Huntington’s disease.
Patients were 25 to 75 years of age. The mean age was 54 years. Patients were 96% Caucasian, 1% African-American, 1% Asian, and 2% Other.
With respect to ethnicity, 6% were Hispanic or Latino. Adverse Reactions Leading to Discontinuation of Treatment A total of 8% of INGREZZA-treated patients and 6% of placebo-treated patients discontinued because of adverse reactions. Common Adverse Reactions Adverse reactions that occurred in the placebo-controlled study at an incidence of ≥4% and greater than placebo are presented in Table 2. Table 2: Adverse Reactions in the Placebo-Controlled Study of 12-week Treatment Duration Reported at ≥4% and >Placebo – Chorea Associated with Huntington’s Disease Adverse Reaction INGREZZA (n=64) % Placebo (n=63) % Nervous System Disorders Somnolence, lethargy, sedation 18.8
Akathisia 6.3 4.8 General Disorders and
Administration Site Conditions Fatigue 14.1
Skin and Subcutaneous Tissue Disorders Urticaria 9.4 0 Rash 7.8 0 Gastrointestinal
Disorders Diarrhea 4.7
Nausea 4.7 0 Psychiatric Disorders Insomnia, middle insomnia 6.3 1.6 Depression, depressed
mood 4.7
Musculoskeletal D isorders Back pain 4.7 0 6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of INGREZZA that are not included in other sections of labeling. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: hypersensitivity reactions (including allergic dermatitis and pruritis)
Warnings & Cautions for Ingrezza
Depression and Suicidal Ideation and Behavior in Patients with Huntington’s Disease Patients
with Huntington’s disease are at increased risk for depression, and suicidal ideation or behaviors. VMAT2 inhibitors, including INGREZZA and INGREZZA SPRINKLE, can increase the risk for suicidal ideation and behaviors in patients with Huntington’s disease. In a 14-week, double-blind, placebo-controlled trial , depression or depressed mood was reported in 4.7% of patients taking INGREZZA compared to 1.6% of patients who received placebo, and no patients taking INGREZZA reported suicidal ideation or behavior compared to 1 patient (1.6%) who received placebo.
Patients with significant risk for suicidal behavior or with unstable psychiatric symptoms were excluded from this trial. Suicidal ideation (9 subjects; 7.2%) and suicide attempts (3 subjects; 2.4%) were reported in the longer open-label extension trial (N=125). When considering the use of INGREZZA or INGREZZA SPRINKLE, the risk of suicidal ideation and behaviors must be balanced against the need for treatment of chorea. All patients treated with INGREZZA and INGREZZA SPRINKLE should be observed for new or worsening depression, suicidal ideation or behaviors.
If any of these reactions occur and do not resolve, consider discontinuing treatment with INGREZZA or INGREZZA SPRINKLE.
Hypersensitivity Reactions Hypersensitivity reactions, including cases of angioedema involving the larynx, glottis
lips, and eyelids, have been reported in the postmarketing setting in patients after taking the first or subsequent doses of INGREZZA . A case of angioedema involving the lips and face, with rash and shortness of breath was reported in a patient with Huntington’s disease taking INGREZZA during a clinical study. Urticaria and rash were also reported during a clinical study in patients with Huntington’s disease. Angioedema associated with laryngeal edema can be fatal.
If any of these reactions occur, discontinue INGREZZA or INGREZZA SPRINKLE. 5. 3 Somnolence and Sedation INGREZZA and INGREZZA SPRINKLE can cause somnolence and sedation, which was the most common adverse reaction in placebo-controlled trials with INGREZZA . 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 or INGREZZA SPRINKLE. 5. 4 QT Prolongation INGREZZA and INGREZZA SPRINKLE 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, INGREZZA and INGREZZA SPRINKLE 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 INGREZZA or INGREZZA SPRINKLE to 40 mg once daily.
INGREZZA and INGREZZA SPRINKLE 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.
Neuroleptic Malignant Syndrome (NMS )
A potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with drugs that reduce dopaminergic transmission. In the postmarketing setting, NMS has been reported in patients taking VMAT2 inhibitors, including INGREZZA. Clinicians should be alerted to the signs and symptoms associated with NMS. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms.
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include immediate discontinuation of INGREZZA or INGREZZA SPRINKLE; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. Recurrence of NMS has been reported with resumption of drug therapy.
If treatment with INGREZZA or INGREZZA SPRINKLE is needed after recovery from NMS, patients should be monitored for signs of recurrence. 5. 6 Parkinsonism INGREZZA and INGREZZA SPRINKLE may cause parkinsonism. Parkinsonism has also been observed with other VMAT2 inhibitors. In the 3 placebo-controlled clinical studies in patients with tardive dyskinesia, the incidence of parkinson-like adverse events was 3% of patients treated with INGREZZA and <1% of placebo-treated patients.
In a placebo-controlled clinical study in patients with chorea associated with Huntington’s disease, the incidence of parkinson-like adverse events was 4.7% in patients treated with INGREZZA and 0% in placebo-treated patients. Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it may be difficult to distinguish between potential drug-induced parkinsonism and progression of underlying Huntington’s disease. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease.
Postmarketing safety reports have described parkinson-like symptoms in patients taking INGREZZA for tardive dyskinesia, some of which were severe and required hospitalization. In most cases, severe parkinsonism occurred within the first two weeks after starting or increasing the dose of INGREZZA. Associated symptoms have included falls, gait disturbances, tremor, drooling and hypokinesia. In cases in which follow-up clinical information was available, parkinson-like symptoms were reported to resolve following discontinuation of INGREZZA therapy.
Reduce the dose or discontinue INGREZZA or INGREZZA SPRINKLE treatment in patients who develop clinically significant parkinson-like signs or symptoms.
Drug Interactions with Ingrezza
Drugs Having Clinically Important Interactions with
INGREZZA and INGREZZA SPRINKLE Table 3: Clinically Significant Drug Interactions with INGREZZA and INGREZZA SPRINKLE Monoamine Oxidase Inhibitors (MAOIs) Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with MAOIs may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to increased risk of adverse reactions such as serotonin syndrome, or attenuated treatment effect of INGREZZA or INGREZZA SPRINKLE. Prevention or Management: Avoid concomitant use of INGREZZA or INGREZZA SPRINKLE with MAOIs, or within 14 days of discontinuing therapy with an MAOI. Strong CYP3A4 Inhibitors Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with strong CYP3A4 inhibitors increased the exposure (C max and AUC) to valbenazine and its active metabolite compared with the use of INGREZZA or INGREZZA SPRINKLE alone. Increased exposure of valbenazine and its active metabolite may increase the risk of exposure-related adverse reactions. Prevention or Management: Reduce INGREZZA or INGREZZA SPRINKLE dose when INGREZZA or INGREZZA SPRINKLE is coadministered with a strong CYP3A4 inhibitor.
Strong CYP2D6 Inhibitors Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with strong CYP2D6 inhibitors increased the exposure (C max and AUC) to valbenazine’s active metabolite compared with the use of INGREZZA or INGREZZA SPRINKLE alone . Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions. Prevention or Management: Reduce INGREZZA or INGREZZA SPRINKLE dose when INGREZZA or INGREZZA SPRINKLE is coadministered with a strong CYP2D6 inhibitor. Strong CYP3A4 Inducers Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with a strong CYP3A4 inducer decreased the exposure of valbenazine and its active metabolite compared to the use of INGREZZA or INGREZZA SPRINKLE alone.
Reduced exposure of valbenazine and its active metabolite may reduce efficacy. Prevention or Management: Concomitant use of strong CYP3A4 inducers with INGREZZA or INGREZZA SPRINKLE is not recommended. Digoxin Clinical Implication: Concomitant use of INGREZZA or INGREZZA SPRINKLE with digoxin increased digoxin levels because of inhibition of intestinal P-glycoprotein (P-gp) . Prevention or Management: Digoxin concentrations should be monitored when co-administering INGREZZA or INGREZZA SPRINKLE with digoxin.
Increased digoxin exposure may increase the risk of exposure-related adverse reactions. Dosage adjustment of digoxin may be necessary.
Pregnancy Safety for Ingrezza
Pregnancy Risk Summary The limited available data on INGREZZA or INGREZZA SPRINKLE 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/m 2 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/m 2. 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 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.
Data Animal Data 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/m 2 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/m 2. 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/m 2. 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/m 2. No malformations were observed at doses up to 24 times the MRHD of 80 mg/day based on mg/m 2. 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/m 2, 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/m 2. 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/m 2. 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/m 2 (because of death in the majority of the high dose group (1.2 times the MRHD), these parameters were not assessed in this group).
Pediatric Use of Ingrezza
Pediatric Use Safety and effectiveness of INGREZZA and INGREZZA SPRINKLE have not been established in pediatric patients.
Contraindications for Ingrezza
and INGREZZA SPRINKLE are contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA or INGREZZA SPRINKLE. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported with use of INGREZZA. Known hypersensitivity to valbenazine or any components of INGREZZA or INGREZZA SPRINKLE.
Overdosage Information for Ingrezza
Human Experience The pre-marketing clinical trials involving INGREZZA in approximately 850 subjects do not provide information regarding symptoms with overdose. Management of Overdosage No specific antidotes for INGREZZA or INGREZZA SPRINKLE are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement.
Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
Clinical Studies of Ingrezza
Tardive Dyskinesia
INGREZZA SPRINKLE The effectiveness of INGREZZA SPRINKLE has been established from adequate and well-controlled studies of INGREZZA for the treatment of tardive dyskinesia. Presented below is a display of the efficacy results of the adequate and well-controlled studies of INGREZZA in patients with tardive dyskinesia. INGREZZA A randomized, double-blind, placebo-controlled trial of INGREZZA was conducted in patients with moderate to severe tardive dyskinesia as determined by clinical observation.
Patients had underlying schizophrenia, schizoaffective disorder, or a mood disorder. Individuals at significant risk for suicidal or violent behavior and individuals with unstable psychiatric symptoms were excluded. The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity.
The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=no dyskinesia; 1=low amplitude, present during some but not most of the exam; 2=low amplitude and present during most of the exam (or moderate amplitude and present during some of the exam); 3=moderate amplitude and present during most of exam; or 4=maximal amplitude and present during most of exam. The AIMS dyskinesia total score (sum of items 1 to 7) could thus range from 0 to 28, with a decrease in score indicating improvement.
The AIMS was scored by central raters who interpreted the videos blinded to subject identification, treatment assignment, and visit number. The primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia total score at the end of Week 6. The change from baseline for two fixed doses of INGREZZA (40 mg or 80 mg) was compared to placebo. At the end of Week 6, subjects initially assigned to placebo were re-randomized to receive INGREZZA 40 mg or 80 mg.
Subjects originally randomized to INGREZZA continued INGREZZA at their randomized dose. Follow-up was continued through Week 48 on the assigned drug, followed by a 4-week period off-drug (subjects were not blind to withdrawal). A total of 234 subjects were enrolled, with 29 (12%) discontinuing prior to completion of the placebo-controlled period. Mean age was 56 (range 26 to 84). Patients were 54% male and 46% female.
Patients were 57% Caucasian, 38% African-American, and 5% other. Concurrent diagnoses included schizophrenia/schizoaffective disorder (66%) and mood disorder (34%). With respect to concurrent antipsychotic use, 70% of subjects were receiving atypical antipsychotics, 14% were receiving typical or combination antipsychotics, and 16% were not receiving antipsychotics. Results are presented in Table 4, with the distribution of responses shown in Figure 4. The change from baseline in the AIMS total dyskinesia score in the 80 mg INGREZZA group was statistically significantly different from the change in the placebo group.
Subgroup analyses by gender, age, racial subgroup, underlying psychiatric diagnostic category, and concomitant antipsychotic medication did not suggest any clear evidence of differential responsiveness. The mean changes in the AIMS dyskinesia total score by visit are shown in Figure 5. Among subjects remaining in the study at the end of the 48-week treatment (N=123 ), following discontinuation of INGREZZA, the mean AIMS dyskinesia total score appeared to return toward baseline (there was no formal hypothesis testing for the change following discontinuation). Table 4: Primary Efficacy Endpoint – Severity of Tardive Dyskinesia at Baseline and the End of Week 6 Endpoint Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SEM) ** Placebo-subtracted Difference (95% CI) AIMS Dyskinesia Total Score INGREZZA 40 mg 9.8 -1.9 -1.8 (-3.0, -0.7) INGREZZA 80 mg* 10.4 -3.2 -3.1 (-4.2, -2.0) Placebo 9.9 -
LS Mean=least-squares mean; SD=standard deviation;
SEM=standard error of the mean; CI=2-sided 95% confidence interval *Dose that was statistically significantly different from placebo after adjusting for multiplicity. ** A negative change from baseline indicates improvement. Figure 4: Percent of Patients with Specified Magnitude of AIMS Total Score Improvement at the End of Week 6 ITT=Intent to Treat; This analysis set includes all randomized patients who had a baseline and at least one post-baseline AIMS dyskinesia total score value reported. Figure 5: AIMS Dyskinesia Total Score Mean Change from Baseline – Entire Study Duration (Arithmetic Mean) DB=Double-Blind; After Week 6, subjects initially receiving placebo were re-randomized to receive INGREZZA 40 mg or 80 mg until the end of Week 48. Error bars represent ±1 Standard Error of the Mean (SEM). Efficacy of INGREZZA 60 mg Based on modeling and simulation, the predicted mean change from baseline in the AIMS dyskinesia total score at Week 6 for INGREZZA 60 mg once daily in subjects with TD is -2.69 (95% CI: -3.30, -2.13), which is within the efficacy range for INGREZZA 40 mg and 80 mg once daily.
Chorea Associated with Huntington ’s Disease
INGREZZA SPRINKLE The effectiveness of INGREZZA SPRINKLE has been established from adequate and well-controlled studies of INGREZZA for the treatment of chorea associated with Huntington’s disease. Presented below is a display of the efficacy results of the adequate and well-controlled studies of INGREZZA in patients with chorea associated with Huntington’s disease. INGREZZA A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and tolerability of INGREZZA in patients with chorea associated with Huntington’s disease (NCT04102579). Treatment duration was 12 weeks followed by a 2-week period off drug.
INGREZZA was started at 40 mg per day and the dose could be increased every 2 weeks in 20 mg increments up to a maximum dosage of 80 mg per day. The primary efficacy endpoint was the change from baseline to the end of the treatment period (average of Week 10 and Week 12) in the Total Maximal Chorea score of the Unified Huntington’s Disease Rating Scale (UHDRS). The Total Maximal Chorea score is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body, with a total score ranging from 0 to 28. A total of 128 patients were randomized into the study, and 125 patients were included in the analysis of efficacy. In these patients, the mean age was 54 years (range 25 to 74 years), 46% were male and 96% were White.
Greater than 80% of patients were taking the 80 mg daily dosage at the end of the 12-week treatment period. Table 5 and Figure 6 summarize the effects of INGREZZA on chorea based on the Total Maximal Chorea score. The mean change in Total Maximal Chorea scores for patients receiving INGREZZA improved by 4.6 units (LS mean) from baseline to the end of the treatment period (average of Week 10 and Week 12), compared to 1.4 units in the placebo group.
The treatment effect of -3.2 units was statistically significant (p<0.0001) ( Figure 6 ). At the Week 14 follow-up visit (2 weeks after discontinuation of the study medication), the Total Maximal Chorea scores of patients who had received INGREZZA returned to baseline. Table 5: Primary Efficacy Endpoint - Mean Change from Baseline to End of Treatment in Total Maximal Chorea Score in Patients with Huntington’s Disease Treated with INGREZZA Primary Endpoint Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SEM) b Placebo-subtracted Difference (95% CI) TMC Score a INGREZZA N=64 12.2 -4.6 -3.2 (-4.4, -2.0) p <0.0001 Placebo N=61 12.1 -1.4 a TMC, Total Maximal Chorea is a subscale of the Unified Huntington’s Disease Rating Scale (UHDRS) b LS Mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean; CI=2-sided 95% confidence interval Figure 6: Mean Change in Total Maximal Chorea Score Over Time LSMD=least-squares mean difference (SEM) CI=confidence interval SEM=standard error of the mean Figure 7: Distribution of the Change in Total Maximal Chorea Score (Average of Week 10 and 12) Figure 7 shows the distribution of values for the change in Total Maximal Chorea Score. Negative values indicate a reduction in chorea and positive values indicate an increase in chorea.
In a clinician-rated global impression of change (CGI-C), clinicians rated 43% of patients treated with INGREZZA as “Much Improved” or “Very Much Improved” at the end of treatment, compared to 13% of patients who received placebo (p<0.001). A patient-rated global impression of change (PGI-C) assessed how patients rated their overall chorea symptoms. Of the patients treated with INGREZZA, 53% rated their symptoms as “Much Improved” or “Very Much Improved” at the end of treatment, compared to 26% of patients who received placebo (p <0.01).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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