PHARMACOKINETICS SECTION.

12.3 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-) increases dose-proportionally in the dose range from mg to 40 mg (4-times the maximum recommended dose).The following mean pharmacokinetic parameters of amisulpride were observed following single or 10 mg intravenous dose in adult healthy subjects and surgical patients.Table 2. Summary of Key Pharmacokinetic Parameters of Amisulpride from Clinical StudiesSingle DoseInfusion Duration (minutes)Number of SubjectsMean (SD)Peak Plasma Concentration(ng/mL)AUC(0-) (ngh/mL)Healthy Subjects5 mg239200 (139)154 (30)Healthy Subjects10 mg129451 (230)136 (28)AUC(0-2 hr) Patients5 mg1 to 226Patients in clinical trial for prophylaxis of PONV 161 (58)260 (65)27Patients in clinical trials for treatment of PONV 127 (64)204 (94)Patients10 mg1 to 231 285 (446)401 (149). DistributionFollowing intravenous infusion, the mean volume of distribution of amisulpride is estimated to be 127 to 144 in surgical patients and 171 in healthy subjects.Amisulpride distributes into erythrocytes. Plasma protein binding is 25% to 30% in the concentration range from 37 to 1850 ng/mL.. EliminationThe mean elimination half-life is approximately to 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.. MetabolismIn 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.. ExcretionAfter 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 GroupsNo clinically significant effect on the pharmacokinetics of amisulpride was observed based on age (18 to 90 years), sex, or race.. Patients with Renal ImpairmentIn 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-) 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 [see Use in Specific Populations (8.6)].. Drug Interaction StudiesNo clinical drug interaction trials have been conducted with BARHEMSYS.. In Vitro Studies. Cytochrome P450-Related MetabolismIn 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 substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.. TransportersAmisulpride inhibits MATE1 and MATE2-K transporters.Amisulpride does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 at therapeutic concentrations.Amisulpride is substrate for P-gp, BCRP, OCT1, MATE1 and MATE2-K, but not substrate for OATP1B1, OATP1B3, OAT1, OAT3 and OCT2.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (>= 2%) are:Prevention of PONV: increased blood prolactin concentrations, chills, hypokalemia, procedural hypotension, and abdominal distension. (6.1)Treatment of PONV: infusion site pain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Acacia Pharma at 1-877-357-9237 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Prevention of PONV: increased blood prolactin concentrations, chills, hypokalemia, procedural hypotension, and abdominal distension. (6.1). Treatment of PONV: infusion site pain. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described below reflect exposure to BARHEMSYS in 1,166 patients treated in placebo-controlled trials. 748 of these patients received dose of mg for prevention of PONV (of whom 572 received another antiemetic concomitantly) and 418 patients received 10 mg for treatment of PONV [see Clinical Studies (14.1, 14.2)]. The mean age of the population was 49 years (range 18 to 91 years), 87% female, 80% White/Caucasian, 9% Black, and 1% Asian.. Prevention of PONVCommon adverse reactions reported in at least 2% of adult patients who received BARHEMSYS mg and at higher rate than placebo in Studies and for the prevention of PONV are shown in Table 1.Table 1. Common Adverse ReactionsReported in at least 2% of patients treated with BARHEMSYS and at higher rate than placebo in Adult Patients in Studies and of BARHEMSYS for Prevention of PONVBARHEMSYS mgPlaceboN=748N=741Chills4%3%Hypokalemia4%2%Procedural hypotension3%2%Abdominal distension2%1%Serum prolactin concentrations were measured in Study where 5% (9/176) of BARHEMSYS-treated patients vs 1% (1/166) of placebo-treated patients had increased blood prolactin reported as an adverse reaction. Serum prolactin concentrations increased from mean of 10 ng/mL at baseline to 32 ng/mL after BARHEMSYS treatment in 112 females (upper limit of normal 29 ng/mL) and from 10 ng/mL to 19 ng/mL in 61 males (upper limit of normal 18 ng/mL). No clinical consequences due to elevated prolactin levels were reported.. Treatment of PONVThe most common adverse reaction, reported in at least 2% of adult patients who received BARHEMSYS 10 mg (N=418) and at higher rate than placebo (N=416), in clinical trials for the treatment of PONV (Studies and 4) was infusion site pain (BARHEMSYS 6%; placebo 4%).. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval chronic oral use of amisulpride outside of the United States (BARHEMSYS is not approved for oral dosing or chronic use). Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and lymphatic system disorders: agranulocytosisCardiac disorders: bradycardia, torsades de pointes, ventricular tachycardia, prolonged QT by electrocardiogramGeneral disorders: neuroleptic malignant syndromeImmune system disorders: angioedema, hypersensitivity, urticariaHepatic disorders: increased hepatic enzymes Nervous system disorders: agitation, anxiety, dystonia, extrapyramidal disorder, seizurePsychiatric disorders: confusional state, insomnia, somnolenceVascular disorders: hypotension. Blood and lymphatic system disorders: agranulocytosis. Cardiac disorders: bradycardia, torsades de pointes, ventricular tachycardia, prolonged QT by electrocardiogram. General disorders: neuroleptic malignant syndrome. Immune system disorders: angioedema, hypersensitivity, urticaria. Hepatic disorders: increased hepatic enzymes Nervous system disorders: agitation, anxiety, dystonia, extrapyramidal disorder, seizure. Psychiatric disorders: confusional state, insomnia, somnolence. Vascular disorders: hypotension.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Amisulpride is 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. Studies in multiple species indicate that D3 receptors in the area postrema also play role in emesis. Studies conducted in ferrets have shown that amisulpride inhibits emesis caused by apomorphine, with an estimated ED50 of less than mcg/kg, subcutaneously; and inhibits cisplatin-induced emesis at mg/kg and morphine-induced emesis at to mg/kg, when given intravenously.Amisulpride has no appreciable affinity for any other receptor types apart from low affinities for 5-HT2B and 5-HT7 receptors.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyA significant exposure-response relationship was identified between amisulpride concentration and QTcF. 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 2-minute intravenous infusion of mg BARHEMSYS and 23.4 (25.5) milliseconds after an 8-minute intravenous infusion of 40 mg BARHEMSYS [see Warnings and Precautions (5.1)].The recommended infusion rate is to minutes for mg or 10 mg of BARHEMSYS [see Dosage and Administration (2.1)]. 12.3 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-) increases dose-proportionally in the dose range from mg to 40 mg (4-times the maximum recommended dose).The following mean pharmacokinetic parameters of amisulpride were observed following single or 10 mg intravenous dose in adult healthy subjects and surgical patients.Table 2. Summary of Key Pharmacokinetic Parameters of Amisulpride from Clinical StudiesSingle DoseInfusion Duration (minutes)Number of SubjectsMean (SD)Peak Plasma Concentration(ng/mL)AUC(0-) (ngh/mL)Healthy Subjects5 mg239200 (139)154 (30)Healthy Subjects10 mg129451 (230)136 (28)AUC(0-2 hr) Patients5 mg1 to 226Patients in clinical trial for prophylaxis of PONV 161 (58)260 (65)27Patients in clinical trials for treatment of PONV 127 (64)204 (94)Patients10 mg1 to 231 285 (446)401 (149). DistributionFollowing intravenous infusion, the mean volume of distribution of amisulpride is estimated to be 127 to 144 in surgical patients and 171 in healthy subjects.Amisulpride distributes into erythrocytes. Plasma protein binding is 25% to 30% in the concentration range from 37 to 1850 ng/mL.. EliminationThe mean elimination half-life is approximately to 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.. MetabolismIn 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.. ExcretionAfter 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 GroupsNo clinically significant effect on the pharmacokinetics of amisulpride was observed based on age (18 to 90 years), sex, or race.. Patients with Renal ImpairmentIn 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-) 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 [see Use in Specific Populations (8.6)].. Drug Interaction StudiesNo clinical drug interaction trials have been conducted with BARHEMSYS.. In Vitro Studies. Cytochrome P450-Related MetabolismIn 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 substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.. TransportersAmisulpride inhibits MATE1 and MATE2-K transporters.Amisulpride does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 at therapeutic concentrations.Amisulpride is substrate for P-gp, BCRP, OCT1, MATE1 and MATE2-K, but not substrate for OATP1B1, OATP1B3, OAT1, OAT3 and OCT2.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Prevention of Postoperative Nausea and Vomiting. The efficacy of BARHEMSYS for the prevention of PONV was evaluated in two randomized, double-blind, placebo-controlled, multi-center trials in patients undergoing general anesthesia and elective surgery (Study and Study 2). In Study (NCT01991860), patients received monotherapy with BARHEMSYS; while in Study (NCT02337062), patients received BARHEMSYS in combination with one other intravenously administered, non-dopaminergic antiemetic (ondansetron, dexamethasone or betamethasone). In both trials, patients were administered BARHEMSYS at the induction of anesthesia.Study was conducted in the United States in 342 patients. The mean age was 54 years (range 21 to 88 years); 65% female; 87% White/Caucasian, 12% Black, and 1% Asian race. The treatment groups were similarly matched in terms of risk for PONV with 30% of patients having two risk factors, 47% of patients having three risk factors and 23% of patients having four risk factors.Study was conducted in the United States and Europe in 1,147 patients. The mean age was 49 years (range 18 to 91 years); 97% female; 75% White/Caucasian, 9% Black, 1% Asian, and 14% of unreported race. The treatment groups were similarly matched in terms of risk for PONV with 56% of patients having three risk factors and 43% of patients having four risk factors.The primary efficacy endpoint in both trials was Complete Response, defined as absence of any episode of emesis or use of rescue medication within the first 24 hours postoperatively. Results for both trials are shown in Table 3.Table 3. Complete Response Rates in Adult Patients for the Prevention of PONV Within 24 Hours After End of Surgery in Studies and 2Study 1Study 2BARHEMSYS mg (n=176)Placebo (n=166)BARHEMSYS mg with Another Antiemetic (n=572)Placebo with Another Antiemetic (n=575)Complete Response78 (44%)54 (33%)330 (58%)268 (47%)Difference (95% CI)Unadjusted, nominal 95% confidence interval 12% (2%, 22%)11% (5%, 17%). 14.2Treatment of Postoperative Nausea and Vomiting. The efficacy of BARHEMSYS 10 mg as single dose was evaluated in two randomized, double-blind, placebo-controlled, multi-center trials in patients experiencing PONV after general anesthesia and elective surgery (Study and Study 4). Study (NCT02449291) enrolled patients who had not received prior PONV prophylaxis, whereas Study (NCT02646566) included patients who had received and failed PONV prophylaxis with an antiemetic of another class. Patients were excluded if they had received D2 receptor antagonist antiemetic.Study was conducted in 369 patients (mean age 47 years, range 19 to 82 years; 76% female; 82% White/Caucasian, 8% Black, 2% Asian, and 8% of unreported race). Most of the patients had either two risk factors (36%) or three risk factors (53%) for PONV and these percentages were similar between treatment groups.Study was conducted in 465 patients (mean age 46 years, range 18 to 85 years; 90% female; 82% White/Caucasian, 9% Black, 3% Asian, and 6% of unreported race). Patients had received prior PONV prophylaxis with one or more non-dopaminergic antiemetics: 5-HT3-antagonist in 77%, dexamethasone in 65% and another antiemetic class in 10%. Most of the patients had either three risk factors (43%) or four risk factors (51%) for PONV and these percentages were similar between treatment groups.For both trials, the primary efficacy endpoint was Complete Response defined as absence of any episode of emesis or use of rescue medication within the first 24 hours after treatment (excluding emesis within the first 30 minutes).BARHEMSYS Complete Response in both studies is shown in Table 4.Table 4. Complete Response Rates in Adult Patients for the Treatment of PONV Within 24 Hours After TreatmentExcluding emesis within the first 30 minutes in Studies and 4Study (no prophylaxis)Study (prior prophylaxis)Received prior PONV prophylaxis with one or more non-dopaminergic antiemetics: 5-HT3-antagonist in 77%, dexamethasone in 65% and another antiemetic class in 10% BARHEMSYS 10 mg (n=188)Placebo (n=181)BARHEMSYS 10 mg (n=230)Placebo (n=235)Complete Response59 (31%)39 (22%)96 (42%)67 (29%)Difference (95% CI)Unadjusted, nominal 95% confidence interval 10% (1%, 19%)13% (5%, 22%).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described below reflect exposure to BARHEMSYS in 1,166 patients treated in placebo-controlled trials. 748 of these patients received dose of mg for prevention of PONV (of whom 572 received another antiemetic concomitantly) and 418 patients received 10 mg for treatment of PONV [see Clinical Studies (14.1, 14.2)]. The mean age of the population was 49 years (range 18 to 91 years), 87% female, 80% White/Caucasian, 9% Black, and 1% Asian.. Prevention of PONVCommon adverse reactions reported in at least 2% of adult patients who received BARHEMSYS mg and at higher rate than placebo in Studies and for the prevention of PONV are shown in Table 1.Table 1. Common Adverse ReactionsReported in at least 2% of patients treated with BARHEMSYS and at higher rate than placebo in Adult Patients in Studies and of BARHEMSYS for Prevention of PONVBARHEMSYS mgPlaceboN=748N=741Chills4%3%Hypokalemia4%2%Procedural hypotension3%2%Abdominal distension2%1%Serum prolactin concentrations were measured in Study where 5% (9/176) of BARHEMSYS-treated patients vs 1% (1/166) of placebo-treated patients had increased blood prolactin reported as an adverse reaction. Serum prolactin concentrations increased from mean of 10 ng/mL at baseline to 32 ng/mL after BARHEMSYS treatment in 112 females (upper limit of normal 29 ng/mL) and from 10 ng/mL to 19 ng/mL in 61 males (upper limit of normal 18 ng/mL). No clinical consequences due to elevated prolactin levels were reported.. Treatment of PONVThe most common adverse reaction, reported in at least 2% of adult patients who received BARHEMSYS 10 mg (N=418) and at higher rate than placebo (N=416), in clinical trials for the treatment of PONV (Studies and 4) was infusion site pain (BARHEMSYS 6%; placebo 4%).

DESCRIPTION SECTION.

11 DESCRIPTION. The active ingredient of BARHEMSYS is amisulpride, dopamine-2 (D2) receptor antagonist. Its chemical name is 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-o-anisamide. It has the following chemical structure:(racemic)The empirical formula is C17H27N3O4S representing molecular weight of 369.48.Amisulpride is white or almost white crystalline powder. It is practically insoluble in water, sparingly soluble in ethanol and freely soluble in methylene chloride, and has melting point of around 126C. The compound is racemic and shows no optical rotation and is not hygroscopic. No other polymorphs of amisulpride have been reported.BARHEMSYS (amisulpride) injection is clear, colorless, nonpyrogenic, sterile solution formulation of amisulpride mg/2 mL (2.5 mg/mL) or 10 mg/4 mL (2.5 mg/mL) for intravenous infusion presented in single-dose vial. It has pH of approximately 5.0 and the osmolality of the product is between 250 and 330 mOsmol/kg.Each mL vial of BARHEMSYS contains mg of amisulpride; 18.7 mg of citric acid monohydrate USP; 3.6 mg of sodium chloride USP; 32.64 mg of trisodium citrate dihydrate; hydrochloric acid NF and sodium hydroxide NF as needed to adjust the pH (4.75 to 5.25); and Water for Injection USP to make up to volume.Each mL vial of BARHEMSYS contains 10 mg of amisulpride; 37.4 mg of citric acid monohydrate USP; 7.2 mg of sodium chloride USP; 65.3 mg of trisodium citrate dihydrate; hydrochloric acid NF and sodium hydroxide NF as needed to adjust the pH (4.75 to 5.25); and Water for Injection USP to make up to volume.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of BARHEMSYS:Prevention of PONV, either alone or in combination with another antiemetic: mg as single intravenous dose infused over to minutes at the time of induction of anesthesia. (2.1)Treatment of PONV: 10 mg as single intravenous dose infused over to minutes in the event of nausea and/or vomiting after surgical procedure. (2.1)See full prescribing information for preparation and administration instructions. (2.2). Prevention of PONV, either alone or in combination with another antiemetic: mg as single intravenous dose infused over to minutes at the time of induction of anesthesia. (2.1). Treatment of PONV: 10 mg as single intravenous dose infused over to minutes in the event of nausea and/or vomiting after surgical procedure. (2.1). See full prescribing information for preparation and administration instructions. (2.2). 2.1Recommended Dosage. The recommended adult dosage of BARHEMSYS and infusion rate by indication is shown in the table below:IndicationAdult Dosage RegimenPrevention of PONV5 mg as single intravenous injection infused over to minutes at the time of induction of anesthesia [see Dosage and Administration (2.2)].Treatment of PONV10 mg as single intravenous injection infused over to minutes in the event of nausea and/or vomiting after surgical procedure [see Dosage and Administration (2.2)].. 2.2Preparation and Administration. Dilution of BARHEMSYS is not required before administration. BARHEMSYS is chemically and physically compatible with Water for Injection, 5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringers Solution (also known as Ringers Lactate Solution, Compound Sodium Lactate Solution, and Hartmanns Solution), any of which may be used to flush an intravenous line before or after administration of BARHEMSYS.Protect from light. BARHEMSYS is subject to photodegradation. Administer BARHEMSYS within 12 hours of removal of the vial from the protective carton.Prior to administration, inspect the BARHEMSYS solution visually for particulate matter and discoloration. Discard if particulate matter or discoloration is observed.. Dilution of BARHEMSYS is not required before administration. BARHEMSYS is chemically and physically compatible with Water for Injection, 5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringers Solution (also known as Ringers Lactate Solution, Compound Sodium Lactate Solution, and Hartmanns Solution), any of which may be used to flush an intravenous line before or after administration of BARHEMSYS.. Protect from light. BARHEMSYS is subject to photodegradation. Administer BARHEMSYS within 12 hours of removal of the vial from the protective carton.. Prior to administration, inspect the BARHEMSYS solution visually for particulate matter and discoloration. Discard if particulate matter or discoloration is observed.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. BARHEMSYS(R) is indicated in adults for:prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of different class.treatment of PONV in patients who have received antiemetic prophylaxis with an agent of different class or have not received prophylaxis.. prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of different class.. treatment of PONV in patients who have received antiemetic prophylaxis with an agent of different class or have not received prophylaxis.. BARHEMSYS is dopamine-2 (D2) antagonist indicated in adults for:Prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of different class. (1)Treatment of PONV in patients who have received antiemetic prophylaxis with an agent of different class or have not received prophylaxis. (1). Prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of different class. (1). Treatment of PONV in patients who have received antiemetic prophylaxis with an agent of different class or have not received prophylaxis. (1).

LACTATION SECTION.

8.2 Lactation. Risk SummaryBased 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). The estimated infant daily dose ranged from 5% to 11% of the maternal dose. There are ways to minimize drug exposure to breastfed infant (see Clinical Considerations). There are no reports of adverse effects on the breastfed child and no information on the effects of amisulpride on milk production. The pharmacological action of amisulpride, dopamine-2 (D2) receptor antagonist, may result in an increase in serum prolactin levels, which may lead to reversible increase in maternal milk production [see Adverse Reactions (6.1)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BARHEMSYS and any potential adverse effects on the breastfed child from BARHEMSYS or from the underlying maternal condition.. Clinical ConsiderationsA lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 48 hours after BARHEMSYS administration to minimize drug exposure to breastfed infant.

OVERDOSAGE SECTION.

10 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.. 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).

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval chronic oral use of amisulpride outside of the United States (BARHEMSYS is not approved for oral dosing or chronic use). Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and lymphatic system disorders: agranulocytosisCardiac disorders: bradycardia, torsades de pointes, ventricular tachycardia, prolonged QT by electrocardiogramGeneral disorders: neuroleptic malignant syndromeImmune system disorders: angioedema, hypersensitivity, urticariaHepatic disorders: increased hepatic enzymes Nervous system disorders: agitation, anxiety, dystonia, extrapyramidal disorder, seizurePsychiatric disorders: confusional state, insomnia, somnolenceVascular disorders: hypotension. Blood and lymphatic system disorders: agranulocytosis. Cardiac disorders: bradycardia, torsades de pointes, ventricular tachycardia, prolonged QT by electrocardiogram. General disorders: neuroleptic malignant syndrome. Immune system disorders: angioedema, hypersensitivity, urticaria. Hepatic disorders: increased hepatic enzymes Nervous system disorders: agitation, anxiety, dystonia, extrapyramidal disorder, seizure. Psychiatric disorders: confusional state, insomnia, somnolence. Vascular disorders: hypotension.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data with amisulpride use in pregnant women are insufficient to establish drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, there were no adverse developmental effects observed with oral administration of amisulpride in rats and rabbits during the period of organogenesis at exposures about 43 and 645 times, respectively, the exposure delivered by the highest recommended human dose (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.. Data. Animal DataReproduction studies of amisulpride were conducted in pregnant rats administered oral doses up to 160 mg/kg/day (43 times the exposure based on area under the curve (AUC) at the highest recommended dose of 10 mg) throughout the period of organogenesis. No adverse embryo-fetal developmental effects were observed at any dose level. Maternal animals exhibited dose-related decrease in overall mean body weight gain. In rabbits administered amisulpride throughout the period of organogenesis, oral doses up to 210 mg/kg/day (645 times the exposure based on AUC at the highest recommended dose of 10 mg) had no adverse developmental effects on the fetus. Maternal animals exhibited reduced mean body weight gain at doses of 100 and 210 mg/kg/day and reduced food intake was observed at 210 mg/kg/day.The pre- and post-natal developmental effects of amisulpride were assessed in rats administered oral doses of 60, 100 or 160 mg/kg/day during the periods of organogenesis and lactation. At 160 mg/kg/day (43 times the exposure based on AUC at the highest recommended dose of 10 mg), maternal animals exhibited reduction in mean body weight gain and decrease in food intake during lactation. Amisulpride had no effect on maternal pregnancy parameters, litter survival or pup growth, development or maturation at any dose tested.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: lactating woman may pump and discard breast milk for 48 hours after BARHEMSYS administration. (8.2). 8.1 Pregnancy. Risk SummaryAvailable data with amisulpride use in pregnant women are insufficient to establish drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, there were no adverse developmental effects observed with oral administration of amisulpride in rats and rabbits during the period of organogenesis at exposures about 43 and 645 times, respectively, the exposure delivered by the highest recommended human dose (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.. Data. Animal DataReproduction studies of amisulpride were conducted in pregnant rats administered oral doses up to 160 mg/kg/day (43 times the exposure based on area under the curve (AUC) at the highest recommended dose of 10 mg) throughout the period of organogenesis. No adverse embryo-fetal developmental effects were observed at any dose level. Maternal animals exhibited dose-related decrease in overall mean body weight gain. In rabbits administered amisulpride throughout the period of organogenesis, oral doses up to 210 mg/kg/day (645 times the exposure based on AUC at the highest recommended dose of 10 mg) had no adverse developmental effects on the fetus. Maternal animals exhibited reduced mean body weight gain at doses of 100 and 210 mg/kg/day and reduced food intake was observed at 210 mg/kg/day.The pre- and post-natal developmental effects of amisulpride were assessed in rats administered oral doses of 60, 100 or 160 mg/kg/day during the periods of organogenesis and lactation. At 160 mg/kg/day (43 times the exposure based on AUC at the highest recommended dose of 10 mg), maternal animals exhibited reduction in mean body weight gain and decrease in food intake during lactation. Amisulpride had no effect on maternal pregnancy parameters, litter survival or pup growth, development or maturation at any dose tested.. 8.2 Lactation. Risk SummaryBased 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). The estimated infant daily dose ranged from 5% to 11% of the maternal dose. There are ways to minimize drug exposure to breastfed infant (see Clinical Considerations). There are no reports of adverse effects on the breastfed child and no information on the effects of amisulpride on milk production. The pharmacological action of amisulpride, dopamine-2 (D2) receptor antagonist, may result in an increase in serum prolactin levels, which may lead to reversible increase in maternal milk production [see Adverse Reactions (6.1)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BARHEMSYS and any potential adverse effects on the breastfed child from BARHEMSYS or from the underlying maternal condition.. Clinical ConsiderationsA lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 48 hours after BARHEMSYS administration to minimize drug exposure to breastfed infant.. 8.3 Females and Males of Reproductive Potential. InfertilityIn animal fertility studies, administration of repeated doses of amisulpride over 10-day period to female rats resulted in infertility that was reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number of patients enrolled in controlled clinical trials who received BARHEMSYS 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 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].. 8.6 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 [see Clinical Pharmacology (12.3)]. 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).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. QT Prolongation: Occurs in 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. (5.1, 7.2). 5.1QT Prolongation. BARHEMSYS causes dose- and concentration-dependent prolongation of the QT interval [see Clinical Pharmacology (12.2)]. The recommended dosage is or 10 mg as single intravenous dose infused over to minutes [see Dosage and Administration (2.1)].Avoid use in patients with congenital long QT syndrome and in patients taking droperidol.Electrocardiogram (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 [see Drug Interactions (7.2)].