HIGHLIGHTS OF PRESCRIBING INFORMATION INGREZZA. INGREZZA
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to useINGREZZA safely and effectively. See full prescribing information forINGREZZA. Parkinsonism: Cases of parkinson-like symptoms, some of which weresevere, have been reported in the postmarketing period. Reduce the dose ordiscontinue INGREZZA treatment in patients who develop clinicallysignificant Parkinson-like signs or symptoms. (5.3)INGREZZA (valbenazine) capsules, for oral useInitial U.S. Approval: 2017-------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reaction ( 5% and twice the rate of placebo):somnolence. (6.1)----------------------------RECENT MAJOR CHANGES------------------------ Contraindications (4)08/2018Warnings and Precautions (5.3)XX/2019To report SUSPECTED ADVERSE REACTIONS, contact NeurocrineBiosciences, Inc. at 877-641-3461 or FDA at 1-800-FDA-1088 --INDICATIONS AND USAGE------------------------- INGREZZA is a vesicular monoamine transporter 2 (VMAT2) inhibitorindicated for the treatment of adults with tardive dyskinesia. (1)------------------------------DRUG INTERACTIONS------------------------------ Dose adjustments due to drug interactions (2.4, 7.1):FactorsDose Adjustments forINGREZZAUse of MAOIs with INGREZZAAvoid concomitant use withMAOIs.Use of strong CYP3A4 inducersConcomitant use is notwith INGREZZArecommended.Use of strong CYP3A4 inhibitorsReduce dose to 40 mg.with INGREZZAUse of strong CYP2D6 inhibitorsConsider dose reduction based onwith E AND ADMINISTRATION--------------------- The initial dose is 40 mg once daily. After one week, increase the dose tothe recommended dose of 80 mg once daily. (2.1) Can be taken with or without food. (2.1) The recommended dose for patients with moderate or severe hepaticimpairment is 40 mg once daily. (2.2) Consider dose reduction based on tolerability in known CYP2D6 poormetabolizers. (2.3)---------------------DOSAGE FORMS AND STRENGTHS--------------------- Capsules: 40 mg and 80 mg. (3)--------------------------USE IN SPECIFIC POPULATIONS-------------------- Pregnancy: May cause fetal harm. (8.1) Lactation: Advise not to breastfeed. (8.2) Renal Impairment: No dosage adjustment is necessary for patients withmild to moderate renal impairment. Use is not recommended in patientswith severe renal impairment. ONS----------------------------- Known hypersensitivity to valbenazine or any components of INGREZZA. (4)----------------------WARNINGS AND PRECAUTIONS--------------------- Somnolence: May impair patient’s ability to drive or operate hazardousmachinery. (5.1) QT Prolongation: May cause an increase in QT interval. Avoid use inpatients with congenital long QT syndrome or with arrhythmias associatedwith a prolonged QT interval. (5.2)See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling.Revised: 07/2019FULL PRESCRIBING INFORMATION: CONTENTS*12345678INDICATIONS AND USAGEDOSAGE AND ADMINISTRATION2.1 Dosing and Administration Information2.2 Dosage Recommendations for Patients with Hepatic Impairment2.3 Dosage Recommendations for Known CYP2D6 Poor Metabolizers2.4 Dosage Recommendations for Concomitant Use with StrongCYP3A4 Inducers and Strong CYP3A4 or CYP2D6 InhibitorsDOSAGE FORMS AND STRENGTHSCONTRAINDICATIONSWARNINGS AND PRECAUTIONS5.1 Somnolence5.2 QT Prolongation5.3 ParkinsonismADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Postmarketing ExperienceDRUG INTERACTIONS7.1 Drugs Having Clinically Important Interactions with INGREZZA7.2 Drugs Having No Clinically Important Interactions withINGREZZAUSE IN SPECIFIC POPULATIONS8.1 Pregnancy8.2 Lactation8.4 Pediatric Use10111213141617* Sections or subsections omitted from the full prescribing information are notlisted.1Reference ID: 44606768.5 Geriatric Use8.6 CYP2D6 Poor Metabolizers8.7 Hepatic Impairment8.8 Renal ImpairmentOVERDOSAGE10.1 Human Experience10.2 Management of OverdosageDESCRIPTIONCLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 PharmacokineticsNONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCLINICAL STUDIESHOW SUPPLIED/STORAGE AND HANDLINGPATIENT COUNSELING INFORMATION
FULL PRESCRIBING INFORMATION1INDICATIONS AND USAGEINGREZZA is indicated for the treatment of adults with tardive dyskinesia [see Clinical Studies (14)].2DOSAGE AND ADMINISTRATION2.1Dosing and Administration InformationThe initial dose for INGREZZA is 40 mg once daily. After one week, increase the dose to the recommendeddose 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)].2.2Dosage Recommendations for Patients with Hepatic ImpairmentThe recommended dose for patients with moderate or severe hepatic impairment (Child-Pugh score 7 to 15) isINGREZZA 40 mg once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].2.3Dosage Recommendations for Known CYP2D6 Poor MetabolizersConsider reducing INGREZZA dose based on tolerability for known CYP2D6 poor metabolizers [see Use inSpecific Populations (8.6), Clinical Pharmacology (12.3)].2.4Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inducersand Strong CYP3A4 or CYP2D6 InhibitorsCoadministration with Strong CYP3A4 InducersConcomitant use of strong CYP3A4 inducers with INGREZZA is not recommended [see Drug Interactions(7.1)].Coadministration with Strong CYP3A4 InhibitorsReduce INGREZZA dose to 40 mg once daily when INGREZZA is coadministered with a strong CYP3A4inhibitor [see Drug Interactions (7.1)].Coadministration with Strong CYP2D6 InhibitorsConsider reducing INGREZZA dose based on tolerability when INGREZZA is coadministered with a strongCYP2D6 inhibitor [see Drug Interactions (7.1)].3DOSAGE FORMS AND STRENGTHSINGREZZA capsules are available in the following strengths: 40 mg capsules with a white opaque body and purple cap, printed with ‘VBZ’ and ‘40’ in black ink. 80 mg capsules with a purple opaque body and cap, printed with ‘VBZ’ and ‘80’ in black ink.2Reference ID: 4460676
4CONTRAINDICATIONSINGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any componentsof INGREZZA. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, andmouth) have been reported [see Adverse Reactions (6.2)].5WARNINGS AND PRECAUTIONS5.1SomnolenceINGREZZA can cause somnolence. Patients should not perform activities requiring mental alertness such asoperating a motor vehicle or operating hazardous machinery until they know how they will be affected byINGREZZA [see Adverse Reactions (6.1)].5.2QT ProlongationINGREZZA may prolong the QT interval, although the degree of QT prolongation is not clinically significant atconcentrations expected with recommended dosing. In patients taking a strong CYP2D6 or CYP3A4 inhibitor,or who are CYP2D6 poor metabolizers, INGREZZA concentrations may be higher and QT prolongationclinically significant [see Clinical Pharmacology (12.2)]. For patients who are CYP2D6 poor metabolizers orare taking a strong CYP2D6 inhibitor, dose reduction may be necessary. For patients taking a strong CYP3A4inhibitor, reduce the dose of INGREZZA to 40 mg once daily [see Dosage and Administration (2.3, 2.4)].INGREZZA should be avoided in patients with congenital long QT syndrome or with arrhythmias associatedwith a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT intervalbefore increasing the dosage.5.3ParkinsonismINGREZZA may cause parkinsonism in patients with tardive dyskinesia. Parkinsonism has also been observedwith 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% ofplacebo-treated patients. Postmarketing safety reports have described parkinson-like symptoms, some of whichwere severe and required hospitalization. In most cases, severe parkinsonism occurred within the first twoweeks after starting or increasing the dose of INGREZZA. Associated symptoms have included falls, gaitdisturbances, 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. Reducethe dose or discontinue INGREZZA treatment in patients who develop clinically significant parkinson-likesigns or symptoms.6ADVERSE REACTIONSThe following adverse reactions are discussed in more detail in other sections of the labeling: Hypersensitivity [see Contraindications (4)] Somnolence [see Warnings and Precautions (5.1)] QT Prolongation [see Warnings and Precautions (5.2)] Parkinsonism [see Warnings and Precautions (5.3)]3Reference ID: 4460676
6.1Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.Variable and Fixed Dose Placebo-Controlled Trial ExperienceThe 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 tosevere 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% AfricanAmerican, and 4% other. With respect to ethnicity, 28% were Hispanic or Latino. All subjects continuedprevious stable regimens of antipsychotics; 85% and 27% of subjects, respectively, were taking atypical andtypical antipsychotic medications at study entry.Adverse Reactions Leading to Discontinuation of TreatmentA total of 3% of INGREZZA treated patients and 2% of placebo-treated patients discontinued because ofadverse reactions.Common Adverse ReactionsAdverse reactions that occurred in the 3 placebo-controlled studies at an incidence of 2% and greater thanplacebo are presented in Table 1.Table 1:Adverse Reactions in 3 Placebo-Controlled Studies of 6-week Treatment DurationReported at 2% and PlaceboAdverse Reaction1INGREZZA(n 262) (%)Placebo(n 183) (%)Somnolence(somnolence, fatigue, sedation)Nervous System Disorders10.9%4.2%Anticholinergic effects(dry mouth, constipation, disturbance in attention, visionblurred, urinary retention)Balance disorders/fall(fall, gait disturbance, dizziness, balance (akathisia, restlessness)Gastrointestinal %0.5%General DisordersMusculoskeletal DisordersArthralgia1Within each adverse reaction category, the observed adverse reactions are listed in order of decreasing frequency.Other Adverse Reactions Observed During the Premarketing Evaluation of INGREZZA4Reference ID: 4460676
Other adverse reactions of 1% incidence and greater than placebo are shown below. The following list doesnot include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which adrug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to haveclinically significant implications, or 5) which occurred at a rate equal to or less than placebo.Endocrine Disorders: blood glucose increasedGeneral Disorders: weight increasedInfectious Disorders: respiratory infectionsNeurologic Disorders: drooling, dyskinesia, extrapyramidal symptoms (non-akathisia)Psychiatric Disorders: anxiety, insomniaDuring controlled trials, there was a dose-related increase in prolactin. Additionally, there was a dose-relatedincrease in alkaline phosphatase and bilirubin, suggesting a potential risk for cholestasis.6.2Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of INGREZZA that are notincluded in other sections of labeling. Because these reactions are reported voluntarily from a population ofuncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship todrug exposure.Immune System Disorders: hypersensitivity reactions (including allergic dermatitis, angioedema, pruritis, andurticaria)Skin and Subcutaneous Tissue Disorders: rash7DRUG INTERACTIONS7.1Drugs Having Clinically Important Interactions with INGREZZATable 2:Clinically Significant Drug Interactions with INGREZZAMonoamine Oxidase Inhibitors (MAOIs)Clinical Implication:Concomitant use of INGREZZA with MAOIs may increase theconcentration of monoamine neurotransmitters in synapses, potentiallyleading to increased risk of adverse reactions such as serotonin syndrome,or attenuated treatment effect of INGREZZA.Prevention or Management:Avoid concomitant use of INGREZZA with MAOIs.Examples:isocarboxazid, phenelzine, selegilineStrong CYP3A4 InhibitorsClinical Implication:Concomitant use of INGREZZA with strong CYP3A4 inhibitors increasedthe exposure (Cmax and AUC) to valbenazine and its active metabolitecompared with the use of INGREZZA alone [see Clinical Pharmacology(12.3)]. Increased exposure of valbenazine and its active metabolite mayincrease the risk of exposure-related adverse reactions [see Warnings andPrecautions (5.2)].Prevention or Management:Reduce INGREZZA dose when INGREZZA is coadministered with astrong CYP3A4 inhibitor [see Dosage and Administration (2.3)].Examples:itraconazole, ketoconazole, clarithromycinStrong CYP2D6 InhibitorsClinical Implication:Concomitant use of INGREZZA with strong CYP2D6 inhibitors mayincrease the exposure (Cmax and AUC) to valbenazine’s active metabolitecompared with the use of INGREZZA alone [see Clinical Pharmacology5Reference ID: 4460676
Prevention or Management:Examples:Strong CYP3A4 InducersClinical Implication:Prevention or Management:Examples:DigoxinClinical Implication:Prevention or Management:17.2(12.3)]. Increased exposure of active metabolite may increase the risk ofexposure-related adverse reactions [see Warnings and Precautions (5.2)].Consider reducing INGREZZA dose based on tolerability whenINGREZZA is coadministered with a strong CYP2D6 inhibitor [seeDosage and Administration (2.3)].paroxetine, fluoxetine, quinidineConcomitant use of INGREZZA with a strong CYP3A4 inducer decreasedthe exposure of valbenazine and its active metabolite compared to the useof INGREZZA alone. Reduced exposure of valbenazine and its activemetabolite may reduce efficacy [see Clinical Pharmacology (12.3)].Concomitant use of strong CYP3A4 inducers with INGREZZA is notrecommended [see Dosage and Administration (2.3)].rifampin, carbamazepine, phenytoin, St. John’s wort1Concomitant use of INGREZZA with digoxin increased digoxin levelsbecause of inhibition of intestinal P-glycoprotein (P-gp) [see ClinicalPharmacology (12.3)].Digoxin concentrations should be monitored when co-administeringINGREZZA with digoxin. Increased digoxin exposure may increase therisk of exposure-related adverse reactions. Dosage adjustment of digoxinmay be necessary.The induction potency of St. John’s wort may vary widely based on preparation.Drugs Having No Clinically Important Interactions with INGREZZADosage 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.8USE IN SPECIFIC POPULATIONS8.1PregnancyRisk SummaryThe limited available data on INGREZZA use in pregnant women are insufficient to inform a drug-associatedrisk. In animal reproductive studies, no malformations were observed when valbenazine was administeredorally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, themaximum 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 inthe number of stillborn pups and postnatal pup mortalities at doses 1 times the MRHD based on mg/m2 [seeData]. 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 ofmajor birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognizedpregnancies, respectively.DataAnimal Data6Reference ID: 4460676
Valbenazine was administered orally to pregnant rats during the period of organogenesis at 1, 5, and15 mg/kg/day, which are approximately 0.1, 0.6, and 2 times the MRHD of 80 mg/day based on mg/m2 bodysurface area. Valbenazine produced a significant decrease in maternal body weight gain at 0.6 and 2 times theMRHD of 80 mg/day based on mg/m2. No adverse embryo fetal effects were produced when valbenazine wasadministered 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 100mg/kg/day, which are approximately 5, 12, and 24 times the MRHD of 80 mg/day based on mg/m2. Nomalformations 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 24times the MRHD of 80 mg/day based on mg/m2, likely secondary to maternal toxicity (decreased food intakeand loss in body weight).Valbenazine was administered orally to pregnant rats during the period of organogenesis through lactation (day7 of gestation through day 20 postpartum) at 1, 3, and 10 mg/kg/day, which are approximately 0.1, 0.4, and 1.2times the MRHD of 80 mg/day based on mg/m2. Valbenazine produced an increase in the incidence ofstillbirths 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 sexualmaturation at doses 1 times the MRHD of 80 mg/day based on mg/m2 (because of death in the majority of thehigh dose group (1.2 times the MRHD), these parameters were not assessed in this group).8.2LactationRisk SummaryThere is no information regarding the presence of valbenazine or its metabolites in human milk, the effects onthe breastfed infant, or the effects on milk production. Valbenazine and its metabolites have been detected inrat milk at concentrations higher than in plasma following oral administration of valbenazine at doses 0.1 to 1.2times the MRHD based on mg/m2. Based on animal findings of increased perinatal mortality in exposed fetusesand pups, advise a woman not to breastfeed during treatment with INGREZZA and for 5 days after the finaldose.8.4Pediatric UseSafety and effectiveness of INGREZZA have not been established in pediatric patients.8.5Geriatric UseNo dose adjustment is required for elderly patients. In 3 randomized, placebo-controlled studies ofINGREZZA, 16% were 65 years and older. The safety and effectiveness were similar in patients older than 65years compared to younger patients.8.6CYP2D6 Poor MetabolizersConsider reducing INGREZZA dose based on tolerability for known CYP2D6 poor metabolizers [see Dosageand Administration (2.2)]. Increased exposure (Cmax and AUC) to valbenazine’s active metabolite is anticipatedin CYP2D6 poor metabolizers. Increased exposure of active metabolite may increase the risk ofexposure-related adverse reactions [see Clinical Pharmacology (12.3)].8.7Hepatic ImpairmentDosage reduction of INGREZZA is recommended for patients with moder
6.1 . 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
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling . Revised: 4/2021 . FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE . 2 DOSAGE AND ADMINISTRATION . 2.1 Dosing and Administration Information . 2.2 Dosage
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ESBRIET safely and effectively. See full prescribing information for ESBRIET. ESBRIET. ESBRIET (pirfenidone) capsules and film-coated tablets, for oral use Initial U.S. Approval: 2014 discontinuations may be required.
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Practical Botany 314 Practical Zoology 334. Now a days we find contributions of Aristotle, Socrates, Theophrastus and many other scholars of the past age in different fields of knowledge. This is not possible for the scholars of the present time. A question may arise in your mind as to why it is not possible today. The reason is that in ages long past the extent of knowledge was limited .
