DRUG INTERACTIONS

1. Dopamine Agonists-                                                                                                  Reciprocal antagonism of effects occurs between dopamine agonists (e.g., levodopa) and BARHEMSYS. Avoid using levodopa with BARHEMSYS.

2. Drugs Prolonging the QT Interval-                                                                     BARHEMSYS causes dose- and concentration-dependent QT prolongation.                       To avoid potential additive effects, avoid use of BARHEMSYS in patients taking droperidol.

ECG monitoring is recommended in patients taking other drugs known to prolong the QT interval (e.g., ondansetron)  

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  7

ADVERSE REACTIONS

Most common adverse reactions (= 2%) are:                                                                   • Prevention of PONV: increased blood prolactin concentrations, chills, hypokalemia, procedural hypotension, and abdominal distension.                                                           • Treatment of PONV: infusion site pain. 

 CONTRAINDICATIONS

­ Known hypersensitivity to amisulpride. 

WARNINGS AND PRECAUTIONS

­ QT Prolongation: Occurs in a dose- and concentration-dependent manner. Avoid use in patients with congenital long QT syndrome and in patients taking droperidol.               

ECG monitoring is recommended in patients with pre-existing arrhythmias/cardiac conduction disorders; electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia); congestive heart failure; and in patients taking other medicinal products (e.g., ondansetron) or with other medical conditions known to prolong the QT interval.

PATIENT COUNSELING INFORMATION

QT Prolongation-                                                                                                 Instruct patients to contact their healthcare provider immediately if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode 

Drug Interactions                                                                                                  Advise patients to report to their healthcare provider if they are taking drugs which prolong the QT interval 

Lactation-                                                                                                            Women may consider reducing infant exposure through pumping and discarding breastmilk for 48 hours after BARHEMSYS administration

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 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                   Amisulpride is a selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist. D2 receptors are located in the chemoreceptor trigger zone (CTZ) and respond to the dopamine released from the nerve endings. Activation of CTZ relays stimuli to the vomiting center which is involved in emesis.

2.Pharmacodynamics                                                                                                 Cardiac Electrophysiology- In 40 healthy Caucasian and Japanese subjects, the maximum mean difference (95% upper confidence bound) in QTcF from placebo after baseline-correction (??QTcF) was 5.0 (7.1) milliseconds after a 2-minute intravenous infusion of 5 mg BARHEMSYS and 23.4 (25.5) milliseconds after an 8-minute intravenous infusion of 40 mg BARHEMSYS 

The recommended infusion rate is 1 to 2 minutes for 5 mg or 10 mg of BARHEMSYS 

3. Pharmacokinetics-                                                                                               After an intravenous infusion, the peak plasma concentration of amisulpride is achieved at the end of the infusion period and the plasma concentration decreases to about 50% of the peak value within approximately 15 minutes.

The AUC(0-8) increases dose-proportionally in the dose range from 5 mg to 40 mg (4-times the maximum recommended dose).

The following mean pharmacokinetic parameters of amisulpride were observed following a single 5 or 10 mg intravenous dose in adult healthy subjects and surgical patients.

Elimination-                                                                                                                The mean elimination half-life is approximately 4 to 5 hours and similar between healthy subjects and surgical patients.

Population pharmacokinetic analysis estimated that the plasma clearance of amisulpride is 20.6 L/h in surgical patients and 24.1 L/h in healthy subjects.

Metabolism-                                                                                                                  In a mass balance study, no metabolites were detectable in plasma while four metabolites were identified in urine and feces.

Each metabolite accounts for less than 7% of the dose. In vitro amisulpride is not metabolized by major cytochrome P450 enzymes.

Excretion-                                                                                                                 After intravenous administration of amisulpride, 74% and 23% of the administered dose was recovered in urine and feces, respectively. 58% and 20% of the dose was excreted as unchanged amisulpride in urine and feces, respectively.

Renal clearance was estimated to be 20.5 L/hr (342 mL/min) in healthy subjects suggesting that amisulpride undergoes active renal secretion.

Specific Populations-                                                                                               Age, Sex, and Racial Groups-                                                                                    No clinically significant effect on the pharmacokinetics of amisulpride was observed based on age (18 to 90 years), sex, or race.

Patients with Renal Impairment-                                                                                  In surgical patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2), the Cmax of amisulpride was not significantly different and the AUC(0-8) of amisulpride increased about 1.3-fold compared to patients with normal renal function.

The pharmacokinetics of amisulpride in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) have not been adequately studied in clinical trials

Drug Interaction Studies-                                                                                           No clinical drug interaction trials have been conducted with BARHEMSYS.

In Vitro Studies Cytochrome P450-Related Metabolism In vitro, amisulpride did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4, or induce CYP1A2, CYP2C9, CYP2C19, or CYP3A4.

In vitro, amisulpride was not a substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.

Transporters-                                                                                                 Amisulpride inhibits MATE1 and MATE2-K transporters. Amisulpride does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 at therapeutic concentrations.                                                                                                       Amisulpride is a substrate for P-gp, BCRP, OCT1, MATE1 and MATE2-K, but not a substrate for OATP1B1, OATP1B3, OAT1, OAT3 and OCT2. Reference ID: 4566736 13

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                Available data with amisulpride use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

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.

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 Risk Summary-                                                                                    Based on case reports in published literature, amisulpride is present in human milk at concentrations that are 11- to 20-fold higher than human plasma in patients taking multiple oral doses of amisulpride (200 to 400 mg/day).

There are no reports of adverse effects on the breastfed child and no information on the effects of amisulpride on milk production. 

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BARHEMSYS and any potential adverse effects on the breastfed child from BARHEMSYS or from the underlying maternal condition.

3. Females and Males of Reproductive Potential Infertility-                                      In animal fertility studies, administration of repeated doses of amisulpride over a 10­ day period to female rats resulted in infertility that was reversible 

4. Pediatric Use-                                                                                                     Safety and effectiveness in pediatric patients have not been established.

5.Geriatric use-                                                                                                            Of the total number of patients enrolled in controlled clinical trials who received BARHEMSYS 5 mg for prevention of PONV or 10 mg for treatment of PONV, 235 (17%) were 65 years of age and older, while 59 (4%) were 75 years of age and older.

No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Amisulpride is known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

6. Renal Impairment-                                                                                                     Avoid BARHEMSYS in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2). The pharmacokinetics of amisulpride in patients with severe renal impairment have not been adequately studied in clinical trials.

Amisulpride is known to be substantially excreted by the kidneys and patients with severe renal impairment may have increased systemic exposure and an increased risk of adverse reactions.

No dosage adjustment is necessary in patients with mild to moderate renal impairment (eGFR 30 mL/min/1.73 m2 and above).

 OVERDOSAGE- 

Doses of oral amisulpride (BARHEMSYS is not approved for oral dosing) above 1200 mg/day have been associated with adverse reactions related to dopamine-2 (D2) antagonism, in particular:

• cardiovascular adverse reactions- (e.g., prolongation of the QT interval, torsades de pointes, bradycardia and hypotension) [see Warnings and Precautions (5.1)].

• neuropsychiatric adverse reactions- (e.g., sedation, coma, seizures, and dystonic and extrapyramidal reactions).

There is no specific antidote for amisulpride overdose.

Management includes cardiac monitoring and treatment of severe extrapyramidal symptoms.

Since amisulpride is weakly dialyzed, hemodialysis should not be used to eliminate the drug.