2.1 Recommended Dosage

The recommended adult dosage of BARHEMSYS and infusion rate by indication is shown in the table below:

2.2 Preparation 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 Ringer's Solution (also known as Ringer's Lactate Solution, Compound Sodium Lactate Solution, and Hartmann's 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.

5.1 QT Prolongation

BARHEMSYS causes dose- and concentration-dependent prolongation of the QT interval [see Clinical Pharmacology (12.2)]. The recommended dosage is 5 or 10 mg as a single intravenous dose infused over 1 to 2 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)].

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 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 a dose of 5 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.

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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• 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

7.1 Dopamine Agonists

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

7.2 Drugs Prolonging the QT Interval

BARHEMSYS causes dose- and concentration-dependent QT prolongation [see Clinical Pharmacology (12.2)]. 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) [see Warnings and Precautions (5.1)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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 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.

12.1 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. Studies in multiple species indicate that D3 receptors in the area postrema also play a role in emesis. Studies conducted in ferrets have shown that amisulpride inhibits emesis caused by apomorphine, with an estimated ED50 of less than 1 mcg/kg, subcutaneously; and inhibits cisplatin-induced emesis at 2 mg/kg and morphine-induced emesis at 3 to 6 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

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 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies to assess the carcinogenic potential of amisulpride have not been conducted. Amisulpride was not genotoxic in the bacterial reverse mutation assay, the in vitro human peripheral blood lymphocytes assay, and the in vivo rat bone marrow micronucleus assay.

The effect of amisulpride on fertility was studied in rats at oral doses up to 160 mg/kg/day (43 times the exposure based on AUC at the highest recommended dose of 10 mg). Most female animals (90% to 95%) at each dose level remained in diestrus and failed to mate. However, this effect on mating reversed following cessation of treatment. No treatment-related effects were observed on uterine/implantation parameters or sperm counts, sperm motility or sperm morphology.

14.1 Prevention 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 1 and Study 2). In Study 1 (NCT01991860), patients received monotherapy with BARHEMSYS; while in Study 2 (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 1 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 2 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.

14.2 Treatment of Postoperative Nausea and Vomiting

The efficacy of BARHEMSYS 10 mg as a 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 3 and Study 4). Study 3 (NCT02449291) enrolled patients who had not received prior PONV prophylaxis, whereas Study 4 (NCT02646566) included patients who had received and failed PONV prophylaxis with an antiemetic of another class. Patients were excluded if they had received a D2 receptor antagonist antiemetic.

Study 3 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 4 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: a 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.

Store vials at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

Protect from light. Administer BARHEMSYS within 12 hours after the vial is removed from the protective carton [see Dosage and Administration (2.2)].

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 [see Warnings and Precautions (5.1)].

Drug Interactions

Advise patients to report to their healthcare provider if they are taking drugs which prolong the QT interval [see Warnings and Precautions (5.1)].

Lactation

Women may consider reducing infant exposure through pumping and discarding breastmilk for 48 hours after BARHEMSYS administration [see Use in Specific Populations (8.2)].