BARHEMSYS® (amisulpride) injection

BARHEMSYS® (amisulpride) injection

BARHEMSYS® (amisulpride) injection

The active ingredient of BARHEMSYS is amisulpride, a dopamine-2 (D2) receptor antagonist. Its chemical name is 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5­(ethylsulfonyl)-o-anisamide.

The empirical formula is C17H27N3O4S representing a molecular weight of 369.48.

Amisulpride is a white or almost white crystalline powder. It is practically insoluble in water, sparingly soluble in ethanol and freely soluble in methylene chloride, and has a melting point of around 126°C. 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 a clear, colorless, nonpyrogenic, sterile solution formulation of amisulpride 5 mg/2 mL (2.5 mg/mL) or 10 mg/4 mL  (2.5 mg/mL) for intravenous infusion presented in a single-dose vial. It has a pH of approximately 5.0 and the osmolality of the product is between 250 and 330 mOsmol/kg.

Each 2 mL vial of BARHEMSYS contains 5 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 4 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.

INDICATIONS AND USAGE

BARHEMSYS® is indicated in adults for:

  • prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class.
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  • treatment of PONV in patients who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.

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.

DOSAGE AND ADMINISTRATION

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

IndicationAdult Dosage Regimen
Prevention of PONV5 mg as a single intravenous injection infused over 1 to 2 minutes at the time of induction of anesthesia.
Treatment of PONV10 mg as a single intravenous injection infused over 1 to 2 minutes in the event of nausea and/or vomiting after a surgical procedure.

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.

CONTRAINDICATIONS

BARHEMSYS is contraindicated in patients with known hypersensitivity to amisulpride.

WARNINGS AND PRECAUTIONS

QT Prolongation

BARHEMSYS causes dose-and concentration-dependent prolongation of the QT interval. The recommended dosage is 5 or 10 mg as a single intravenous dose infused over 1 to 2 minutes.

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.

ADVERSE REACTIONS

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

DRUG INTERACTIONS

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

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).

USE IN SPECIFIC POPULATIONS

Pregnancy: 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 43 and 645 times, respectively, the exposure delivered by the highest recommended human dose.

Lactation: 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). The estimated infant daily dose ranged from 5% to 11% of the maternal dose. There are ways to minimize drug exposure to a breastfed infant. 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, a dopamine-2 (D2) receptor antagonist, may result in an increase in serum prolactin levels, which may lead to a reversible increase in maternal 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.

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A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 48 hours after BARHEMSYS administration to minimize drug exposure to a breastfed infant.

Females and Males of Reproductive Potential

In animal fertility studies, administration of repeated doses of amisulpride over a 10­day period to female rats resulted in infertility that was reversible.

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

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).
  • 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.

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