SUPRIMIDE

Amisulpride is a benzamide derivative and a dopamine receptor antagonist that selectively works on dopamine D2 and D3 receptors.

As an antipsychotic agent, amisulpride alleviates both positive and negative symptoms of schizophrenia, and it exhibits antidepressant properties in patients with psychiatric disorders, dysthymia, and major depression.

Amisulpride predominantly works in the limbic system, which explains its relatively lower risk of extrapyramidal adverse effects compared to other atypical antipsychotic agents. 2, 11 Oral tablets of amisulpride is used in European countries as a treatment for acute and chronic schizophrenic disorders, as well as secondary negative symptoms in mental health disorders such as affective disorders, depressive mood, and mental retardation.

Amisulpride is also used as an antiemetic agent.

In the

US, the intravenous formulation of amisulpride is used to treat and prevent postoperative nausea and vomiting in adults, either as monotherapy or in combination with another antiemetic agent of a different drug class.

It is marketed under the brand name Barhemsys.

Intravenous amisulpride is indicated in adults for the prevention of postoperative nausea and vomiting, either alone or in combination with an antiemetic of a different class.

It is also indicated for the treatment of postoperative nausea and vomiting in patients who have received anti-emetic prophylaxis with an agent of a different class or have not received prophylaxis.

Oral amisulpride is indicated for the treatment of acute and chronic schizophrenic disorders, characterized by positive symptoms with delusions, hallucinations, thought disorders, hostility and suspicious behavior; or primarily negative symptoms (deficit syndrome) with blunted affect, emotional and social withdrawal.

Amisulpride also controls secondary negative symptoms in productive conditions as well as affective disorders such as depressive mood or retardation.

Amisulpride is a selective dopamine

D2 and D3 receptor antagonist with no affinity towards other dopamine receptor subtypes.

Amisulpride is an atypical antipsychotic agent that works as an antagonist at dopamine receptors in the limbic system.

Since it works preferentially in the limbic system, amisulpride is less likely to be associated with extrapyramidal adverse effects than other atypical antipsychotic agents.

Amisulpride has no affinity for serotonin, alpha-adrenergic, H1-histamine, cholinergic, and sigma receptors.

In clinical trials, amisulpride improved reduced secondary negative symptoms, affective symptoms, and psychomotor retardation in patients with acute exacerbation of schizophrenia.

Notably, amisulpride has a differential target binding profile at different doses: at low doses, amisulpride selectively binds to presynaptic dopamine autoreceptors.

At high doses, it preferentially binds to post-synaptic dopamine receptors.

This explains how amisulpride reduces negative symptoms at low doses and mediates antipsychotic effects at high doses.

One study alluded that the antinociceptive effects of amisulpride are mediated through opioid receptor acvitation and D2 receptor antagonism. 3, 5 The actions of amisulpride at opioid receptors may explain its pro-convulsant properties.

Amisulpride is also an antiemetic agent that prevents and alleviates postoperative nausea and vomiting.

It primarily works by blocking dopamine signalling in the chemoreceptor trigger zone, which is a brain area that relays stimuli to the vomiting center.

In clinical trials comprising Caucasian and

Japanese subjects, amisulpride caused dose.

• and concentration-dependent prolongation of the QT interval; thus, intravenous infusion under a strict dosing regimen and close monitoring of patients with pre-existing cardiovascular conditions are recommended.

Amisulpride increases plasma prolactin levels, leading to an association with benign pituitary tumours such as prolactinoma.

5-hydroxytryptamine receptor 7 Antagonist 5-hydroxytryptamine receptor 2A Antagonist D dopamine receptor Antagonist + 1 more target.

Following oral administration, amisulpride is rapidly absorbed with absolute bioavailability of 48%.

Amisulpride has two absorption peaks, with one rapidly achieved within one hour post-dose and a second peak occurring between three to four hours post-dose.

Following oral administration of a 50 mg dose, two peak plasma concentrations were 39 ± 3 and 54 ± 4 ng/mL.

Following intravenous administration, the peak plasma concentration of amisulpride is achieved at the end of the infusion period and the plasma concentration decreases by 50% within approximately 15 minutes.

AUC(0-∞) increases dose-proportionally in the dose range from 5 mg to 40 mg, which is about four times the maximum recommended dose.

In healthy patients receiving intravenous amisulpride, the mean (SD) Cmax was 200 ng/mL at the dose of 5 mg and 451 ng/mL at the dose of 10 mg. The AUC ranged from 136-154 ng x h/mL in the dose range of 5 mg to 10 mg. In patients undergoing surgery, the mean (SD) Cmax ranged from to 161 ng/mL at the dose of 5 mg. At the dose of 10 mg, it was 285 ng/mL.

AUC ranged from 204-401 ng x h/mL.

Following oral administration, the volume of distribution is 5.8 L/kg.

Following intravenous infusion, the mean volume of distribution of amisulpride is estimated to be 127-144 L in surgical patients and 171 L in healthy subjects.

Amisulpride undergoes minimal metabolism and its metabolites in plasma are largely undetectable. and oxidation, are pharmacologically inactive and account for approximately 4% of the dose.

Metabolites remain largely uncharacterized.

Metabolism of amisulpride does not involve cytochrome P450 enzymes.

Following intravenous administration, about 74% of amisulpride is excreted in urine, where 58% of the recovered dose was excreted as unchanged amisulpride.

About 23% of the dose is excreted in feces, with 20% of the excreted dose as unchanged parent drug.

Following intravenous administration, about four metabolites were identified in urine and feces, accounting for less than 7% of the total dose administered.

About 22-25% of Oral administered amisulpride is excreted in urine, mostly as the unchanged parent drug.

Elimination is biphasic.

The elimination half-life of amisulpride is approximately 12 hours after an oral dose.

The mean elimination half-life is approximately four to five hours in both healthy subjects and patients undergoing surgery receiving intravenous amisulpride.

The plasma clearance of amisulpride is 20.6 L/h in surgical patients and 24.1 L/h in healthy subjects following intravenous administration.

Renal clearance was estimated to be 20.5 L/hr (342 mL/min) in healthy subjects.

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In mice, oral LD is 1024 mg/kg, intraperitoneal LD is 175 mg/kg, and subcutaneous LD is 224 mg/kg. The Lowest published toxic dose (TDLo) following subcutaneous administration is 0.24 mg/kg in rats.

The oral

TDLo in men is 4.3 mg/kg.

Oral doses of amisulpride above 1200 mg/day are associated with adverse effects related to dopamine-2 (D2) antagonism.

Cardiovascular adverse reactions include prolongation of the QT interval, torsades de pointes, bradycardia, and hypotension.

Neuropsychiatric adverse reactions include sedation, coma, seizures, and dystonic and extrapyramidal reactions.

As there is no specific antidote for amisulpride overdosage, management includes cardiac monitoring and treatment of severe extrapyramidal symptoms.

Drug elimination with the use of hemodialysis is effective.

Severe extrapyramidal effects may be managed with anticholinergic drugs.

is contraindicated in patients with known hypersensitivity to amisulpride.

Known hypersensitivity to amisulpride.

The recommended dosage of BARHEMSYS

Prevention of PONV, either alone or in combination with another antiemetic: 5 mg as a single intravenous dose infused over to 2 minutes at the time of induction of anesthesia.

Treatment of

PONV: 10 mg as a single intravenous dose infused over to 2 minutes in the event of nausea and/or vomiting after a surgical procedure.

See full prescribing information for preparation and administration instructions. 2.1 Recommended Dosage The recommended adult dosage of BARHEMSYS and infusion rate by indication is shown in the table below: Indication Adult Dosage Regimen Prevention of PONV 5 mg as a single intravenous injection infused over to 2 minutes at the time of induction of anesthesia.

PONV 10 mg as a single intravenous injection infused over to 2 minutes in the event of nausea and/or vomiting after a surgical procedure. 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.

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.

(amisulpride) injection is supplied as follows: NDC 71390-125-20: Package of 10 cartons.

Each carton (NDC 71390-125-21) contains one single-dose vial of clear, colorless, sterile solution of BARHEMSYS (amisulpride) injection, 5 mg in 2 mL (2.5 mg/mL).

NDC 71390-125-50: Package of 10 cartons.

Each carton (NDC 71390-125-51) contains one single-dose vial of clear, colorless, sterile solution of BARHEMSYS (amisulpride) injection, 10 mg in 4 mL (2.5 mg/mL).

Store vials at 20°C to 25°C (68°F to 77°F) .

Protect from light.

BARHEMSYS within 12 hours after the vial is removed from the protective carton.

Store vials at 20°C to 25°C (68°F to 77°F) .

Protect from light.

BARHEMSYS within 12 hours after the vial is removed from the protective carton.

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.

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 and 645 times, respectively, the exposure delivered by the highest recommended human dose.

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.

Reproduction 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 a 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 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 a 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.

Safety and effectiveness in pediatric patients have not been established.

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.