38/23. Gerirone- (EXXURA)- (Aug 2023)- to treat major depresive disorder
Drug Name:38/23. Gerirone- (EXXURA)- (Aug 2023)- to treat major depresive disorder
List Of Brands:
Indication Type Description:
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Indication:
BRIEF SUMMARY-
GERIRONE-(Aug 2023)
Indn- To treat major depressive disoreder
Comp- Extended-release tablets: 18.2 mg, 36.3 mg, 54.5 mg, and 72.6mg The recommended starting dose is 18.2 mg administered orally once daily with food at approximately the same time each day
ADR- Most common adverse reactions (incidence of =5% and at least twice incidence of placebo) were dizziness, nausea, insomnia, abdominal pain, and dyspepsia
CI- Congenital long QT syndrome • Concomitant use of strong CYP3A4 inhibitor • Severe hepatic impairment
WARNINGS AND PRECAUTIONS-
• QT Interval Prolongation: EXXUA prolongs the QTc. Correct electrolyte abnormalities. Perform ECGs prior to initiation, during dose titration, and periodically during treatment with EXXUA. Monitor ECGs more frequently when EXXUA is used concomitantly with drugs known to prolong the QT interval,
Pat Inform-
Suicidal Thoughts and Behaviors - Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially during early treatment and when the dose is adjusted up or down and instruct them to report such symptoms to their healthcare provider .
Serotonin Syndrome- Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of EXXUA with SSRIs or tricyclic antidepressants.
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U.S. APPROVED DRUGS DURING 2023
Serial No 38
Name- EXXURA
Acive Ingredient - Gerirone
Pharmacological clssificiation- To treat major depressive disoreder
Date of approval 9/22/2023
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use EXXUA safely and effectively.
See full prescribing information for EXXUA. EXXUA (gepirone) extended-release tablets, for oral use
Initial U.S. Approval: 2023
WARNING:
SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in pediatric and young adult patients taking antidepressants. Closely monitor for worsening and emergence of suicidal thoughts and behaviors .
EXXUA is not approved for use in pediatric patients
INDICATIONS AND USAGE-
EXXUA is indicated for the treatment of major depressive disorder (MDD) in adults-
Adverse Reaction:
ADVERSE REACTIONS-
Most common adverse reactions (incidence of =5% and at least twice incidence of placebo) were dizziness, nausea, insomnia, abdominal pain, and dyspepsia
Contra-Indications:
CONTRAINDICATIONS-
• Known hypersensitivity to gepirone or components of EXXUA • Prolonged QTc interval > 450 msec at baseline • Congenital long QT syndrome • Concomitant use of strong CYP3A4 inhibitors • Severe hepatic impairment • Use with an MAOI or within 14 days of stopping treatment with EXXUA. Do not use EXXUA within 14 days of discontinuing an MAOI
WARNINGS AND PRECAUTIONS-
• QT Interval Prolongation: EXXUA prolongs the QTc. Correct electrolyte abnormalities. Perform ECGs prior to initiation, during dose titration, and periodically during treatment with EXXUA.
Monitor ECGs more frequently when EXXUA is used concomitantly with drugs known to prolong the QT interval, in patients who develop QTc = 450 msec during treatment or are at significant risk of developing torsade de pointes.
Do not escalate dosage if QTc > 450 msec
• Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents. If serotonin syndrome occurs, discontinue EXXUA and initiate supportive measures
• Activation of Mania/Hypomania: Screen patients for bipolar disorder
Dosages/ Overdosage Etc:
DOSAGE AND ADMINISTRATION-
• Correct electrolyte abnormalities and perform electrocardiogram (ECG) prior to initiating treatment with EXXUA. Do not initiate EXXUA if QTc is > 450 msec
. • Perform ECGs during dosage titration and periodically during treatment
• The recommended starting dose is 18.2 mg administered orally once daily with food at approximately the same time each day
• Depending on clinical response and tolerability, the dosage may be increased to 36.3 mg once daily on Day 4. Dosage may be further titrated to 54.5 mg once daily after Day 7 and to 72.6 mg once daily after an additional week
• Geriatric patients: Recommended starting dosage is 18.2 mg once daily. Dosage may be increased to 36.3 mg after 7 days
• Renal Impairment (creatinine clearance < 50 mL/min): Recommended starting dosage is 18.2 mg once daily. Dosage may be increased to 36.3 mg once daily after 7 days
. • Moderate Hepatic Impairment (Child Pugh B): Dosage may be increased to 36.3 mg once daily after 7 days
• Adjust EXXUA dose by 50% when a moderate CYP3A4 inhibitor is administered (2.7). -
DOSAGE FORMS AND STRENGTHS
Extended-release tablets: 18.2 mg, 36.3 mg, 54.5 mg, and 72.6mg
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Suicidal Thoughts and Behaviors - Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially during early treatment and when the dose is adjusted up or down and instruct them to report such symptoms to their healthcare provider .
Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter medications because there is an increased risk for drug interactions with EXXUA
Serotonin Syndrome- Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of EXXUA with SSRIs or tricyclic antidepressants.
Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome .
Activation of Mania or Hypomania- Advise patients to observe for signs of activation of mania or hypomania and instruct them to report such symptoms to their healthcare provi
Administration Information- Advise patients to swallow EXXUA whole and not to split, chew, or crush the tablets. Advise patients to take EXXUA at the approximately the same time every day with food
Pregnancy - Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with EXXUA.
Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to EXXUA during pregnancy.
Advise patients that EXXUA use late in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN)
Lactation - Advise breastfeeding individuals using EXXUA to monitor infants for excess sedation, restlessness, agitation, poor feeding and poor weight gain and to see medical care if they notice these signs
EXXUA extended-release tablets are manufactured and packaged by Mission Pharmacal Company, San Antonio, TX 78230 1355
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1 Mechanism of Action The mechanism of the antidepressant effect of EXXUA is not fully understood but is thought to be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT1A receptors.
2. Pharmacodynamics- The pharmacological activity of gepirone is attributed to the parent drug and its major metabolites 3’-OH-gepirone and 1 PP. Gepirone and its 3’-OH metabolite bind to 5HT1A receptors (Ki = 38 nM and 58 nM, respectively), where they act as agonists, while the 1-PP metabolite binds to alpha2 receptors (Ki = 42 nM).
Effect of Food- After a high fat meal, Tmax is reached at 3 hours. A significant effect of food has been observed on the peak plasma concentration (Cmax) of EXXUA and, to a lesser extent, on the total exposure (AUC0-tlast, AUC0-8) to EXXUA. The magnitude of the food-effect was dependent of the fat content of the meal.
Distribution- The apparent volume of distribution of EXXUA is approximately 94.5L. The in vitro plasma protein binding in human is 72% and is not concentration dependent. The in vitro plasma protein binding for metabolite 3’-OH gepirone is 59% and 42% for 1-PP.
Elimination - The mean terminal half-life is approximately 5 hours.
Metabolism- EXXUA is extensively metabolized and both major metabolites 1-PP and 3’-OH-gepirone are present in plasma in higher concentrations than the parent compound.
Excretion- Following a single oral dose of [14C]-labeled gepirone, approximately 81% and 13% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. 60% of the gepirone was eliminated in the urine within the first 24 hours. The presence of hepatic or renal impairment did affect the apparent clearance of EXXUA.
Specific Populations- 1
Effects of Specific Populations on the Pharmacokinetics of Gepirone Gepirone dose: 36.3 mg in renal, 18.2 mg in hepatic; steady-state at 18.2 mg for race and 18.2-72.6 mg for age. Data are GMRs and 90% CIs, except for Age groups (arithmetic mean ratios). AUC = area under the plasma concentration-time curve; CI = confidence interval; Cmax = maximum plasma concentration; GMR = geometric mean ratio.
Drug Interactions Studies-
Effect of Co-Administered Drugs on the Pharmacokinetics of Gepirone Gepirone 36.3 mg was administered with interacting drugs at steady-state, except with verapamil (18.2 mg gepirone). Reference = gepirone alone.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Pregnancy-
Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including EXXUA, during pregnancy.
Consider if the risks outweigh the benefits of treatment with gepirone during pregnancy.
The background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
2. Lactation-
. When a drug is present in animal milk, it is likely that the drug will be present in human milk. There are reports of breastfed infants exposed to other serotonergic antidepressants experiencing irritability, restlessness, excessive somnolence, decreased feeding, and weight loss
The developmental and health benefits of breatfeeding should be considered along with the mother’s clincial need for EXXUA and any adverse effects on the breastfed infant from EXXUA or from the underlying maternal condition.
Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as irritability, restlessness, excessive somnolence, decreased feeding, and weight loss.
3.Pediatric Use-
The safety and effectiveness of EXXUA in pediatric patients have not been established for the treatment of MDD. Efficacy was not demonstrated in two 8-week, randomized, placebo-controlled trials in 426 pediatric patients 7 to 17 years of age with MDD.
4.Geriatric Use-
Of the 1,639 patients exposed to EXXUA in placebo-controlled clinical studies of MDD, 0.7% (12 patients) were 65 years of age or older and 0.2% (3 patients) were 75 years or older.
Geriatric patients (65 to 81 years of age) had higher EXXUA AUC and Cmax values than younger adult (18 to 40 years of age) patients
The maximum recommended daily dosage of EXXUA in geriatric patients is lower than in younger adult patients
5. Renal Impairment-
In patients with creatinine clearance <50 mL/min, the metabolism and excretion of EXXUA and some of its major metabolites were decreased
The maximum recommended daily dosage of EXXUA in patients with a creatinine clearance <50 mL/min is lower than in patients with normal renal function
The recommended dosage in patients with a creatinine clearance =50 mL/min is the same as in patients with normal renal function
Hepatic Impairment - In patients with mild (Child-Pugh A) hepatic impairment to moderate (Child-Pugh B) hepatic impairment, the metabolism of EXXUA and its major metabolites was decreased
The maximum recommended dosage of EXXUA in patients with moderate hepatic impairment is lower than in patients with normal hepatic function
The recommended dosage in patients with mild hepatic impairment is the same as in patients with normal hepatic function. EXXUA is contraindicated in patients with severe (Child-Pugh C) hepatic impairment
OVERDOSAGE -
In clinical studies, cases of acute ingestions up to 454 mg (6.25 times the maximum recommended dose) of EXXUA alone or in combination with other drugs, were reported.
Signs and symptoms reported with overdose of EXXUA at doses up to 454 mg included vomiting and transient incomplete bundle branch block; an unknown dose of EXXUA produced altered level of consciousness and a 60-second convulsion.