法国里昂--（MarketWired-2016年5月2日）-弗拉梅尔科技公司（Nasdaq:FLML）今天宣布，美国食品和药物管理局（FDA）已批准该公司针对Akovaz™（硫酸麻黄碱）的新药申请（NDA）。作为一种加压剂在肠外给药以治疗外科环境中临床上重要的低血压。弗拉梅尔于4月29日如期获得了阿科瓦兹的保密协议批准，也是第一个获得FDA批准的硫酸麻黄碱。弗拉梅尔预计将在2016年第三季度推出阿科瓦兹，强度为50毫克/毫升。

“我们非常高兴能获得FDA对Akovaz的批准，这是我们产品组合中的第三种产品，符合PDUFA的日期预期。与本产品相关的收入预期包括在我们之前发布的2016年收入指导值1.1亿至1.3亿美元中。我们的E.CLAT产品组合，包括BrxVelz®和Vaululp®，已经产生了显著的现金流为弗拉梅尔，让我们独立运作的合作伙伴，基金战略收购，并继续发展我们的专有管道产品，说：“Mike Anderson，首席执行官弗拉梅尔。

目前，Akorn Pharmaceuticals销售的50毫克/毫升硫酸麻黄碱注射液有一种“未经批准上市”的配方，据IMS Health称，市场规模每年超过500万瓶。

关于阿科瓦兹

Akovaz是该公司硫酸麻黄碱注射液、USP、α和β肾上腺素能激动剂和去甲肾上腺素释放剂的品牌，用于治疗麻醉环境中出现的临床重要低血压。阿科瓦兹注射液，50毫克/毫升（相当于38毫克麻黄碱）必须在给药前稀释，并作为一个丸静脉注射。

Akovaz (ephedrine sulfate) Injection

Date of Approval: April 29, 2016
Company: Flamel Technologies
Treatment for: Hypotension

Akovaz (ephedrine sulfate) is a pressor agent administered parenterally to address clinically important hypotension in surgical settings.

Indications and Usage for Akovaz

Akovaz (ephedrine sulfate injection) is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia.

Akovaz Dosage and Administration

General Dosage and Administration Instructions

Akovaz (ephedrine sulfate injection) must be diluted before administration as an intravenous bolus to achieve the desired concentration. Dilute with normal saline or 5% dextrose in water.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dosing for the Treatment of Clinically Important Hypotension in the Setting of Anesthesia

The recommended dosages for the treatment of clinically important hypotension in the setting of anesthesia is an initial dose of 5 to 10 mg administered by intravenous bolus. Administer additional boluses as needed, not to exceed a total dosage of 50 mg.

•

Adjust dosage according to the blood pressure goal (i.e., titrate to effect).

Prepare a 5 mg/mL Solution for Bolus Intravenous Administration

For bolus intravenous administration, prepare a solution containing a final concentration of 5 mg/mL of Akovaz (ephedrine sulfate injection):

•

Withdraw 50 mg (1 mL of 50 mg/mL) of Akovaz (ephedrine sulfate injection) and dilute with 9 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.

•

Withdraw an appropriate dose of the 5 mg/mL solution prior to bolus intravenous administration.

Dosage Forms and Strengths

Akovaz (ephedrine sulfate injection) is available as a single-dose 1 mL vial that contains 50 mg/mL ephedrine sulfate, equivalent to 38 mg ephedrine base.

Contraindications

None

Warnings and Precautions

Pressor Effect with Concomitant Oxytocic Drugs

Serious postpartum hypertension has been described in patients who received both a vasopressor (i.e., methoxamine, phenylephrine, ephedrine) and an oxytocic (i.e., methylergonovine, ergonovine) [see Drug Interactions (7)]. Some of these patients experienced a stroke. Carefully monitor the blood pressure of individuals who have received both ephedrine and an oxytocic.

Tolerance and Tachyphylaxis

Data indicate that repeated administration of ephedrine can result in tachyphylaxis. Clinicians treating anesthesia-induced hypotension with Akovaz (ephedrine sulfate injection) should be aware of the possibility of tachyphylaxis and should be prepared with an alternative pressor to mitigate unacceptable responsiveness.

Risk of Hypertension When Used Prophylactically

When used to prevent hypotension, ephedrine has been associated with an increased incidence of hypertension compared with when ephedrine is used to treat hypotension.

Adverse Reactions

The following adverse reactions associated with the use of ephedrine sulfate were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Gastrointestinal disorders: Nausea, vomiting

Cardiac disorders: Tachycardia, palpitations (thumping heart), reactive hypertension, bradycardia, ventricular ectopics, R-R variability

Nervous system disorders: Dizziness

Psychiatric disorders: Restlessness

Drug Interactions

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Limited published data on the use of ephedrine sulfate are insufficient to determine a drug associated risk of major birth defects or miscarriage. However, there are clinical considerations [see Clinical Considerations]. Animal reproduction studies have not been conducted with ephedrine sulfate.

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.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Cases of potential metabolic acidosis in newborns at delivery with maternal ephedrine exposure have been reported in the literature. These reports describe umbilical artery pH of ≤7.2 at the time of delivery [see Clinical Pharmacology 12.3]. Monitoring of the newborn for signs and symptoms of metabolic acidosis may be required. Monitoring of infant’s acid-base status is warranted to ensure that an episode of acidosis is acute and reversible.

Lactation

Risk Summary

Limited published literature reports that ephedrine is present in human milk. However, no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Akovaz (ephedrine sulfate injection) and any potential adverse effects on the breastfed child from Akovaz (ephedrine sulfate injection) or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of ephedrine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal Impairment

Ephedrine and its metabolite are excreted in urine. In patients with renal impairment, excretion of ephedrine is likely to be affected with a corresponding increase in elimination half-life, which will lead to slow elimination of ephedrine and consequently prolonged pharmacological effect and potentially adverse reactions. Monitor patients with renal impairment carefully after the initial bolus dose for adverse events.

Overdosage

Overdose of ephedrine can cause a rapid rise in blood pressure. In the case of an overdose, careful monitoring of blood pressure is recommended. If blood pressure continues to rise to an unacceptable level, parenteral antihypertensive agents can be administered at the discretion of the clinician.

Akovaz Description

Ephedrine is an alpha- and beta-adrenergic agonist and a norepinephrine-releasing agent. Akovaz (ephedrine sulfate injection) is a clear, colorless, sterile solution for intravenous injection. It must be diluted before intravenous administration. The chemical name of ephedrine sulfate is (1R,2S)-(-)-2-methylamine-1-phenylpropan-1-ol sulfate, and the molecular weight is 428.5 g/mol. Its structural formula is depicted below:

Ephedrine sulfate is freely soluble in water and ethanol, very slighly soluble in chloroform, and practically insoluble in ether. Each mL contains ephedrine sulfate 50 mg (equivalent to 38 mg ephedrine base) in water for injection. The pH is adjusted with sodium hydroxide and/or glacial acetic acid if necesssary. The pH range is 4.5 to 7.0.

Akovaz - Clinical Pharmacology

Mechanism of Action

Ephedrine sulfate is a sympathomimetic amine that directly acts as an agonist at α- and β-adrenergic receptors and indirectly causes the release of norepinephrine from sympathetic neurons. Pressor effects by direct alpha- and beta-adrenergic receptor activation are mediated by increases in arterial pressures, cardiac output, and peripheral resistance. Indirect adrenergic stimulation is caused by norepinephrine release from sympathetic nerves.

Pharmacodynamics

Ephedrine stimulates heart rate and cardiac output and variably increases peripheral resistance; as a result, ephedrine usually increases blood pressure. Stimulation of the α-adrenergic receptors of smooth muscle cells in the bladder base may increase the resistance to the outflow of urine. Activation of β-adrenergic receptors in the lungs promotes bronchodilation.

The overall cardiovascular effect from ephedrine is the result of a balance among α-1 adrenoceptor-mediated vasoconstriction, β-2 adrenoceptor-mediated vasoconstriction, and β-2 adrenoceptor-mediated vasodilatation. Stimulation of the β-1 adrenoceptors results in positive inotrope and chronotrope action.

Tachyphylaxis to the pressor effects of ephedrine may occur with repeated administration [see Warnings and Precautions 5.2].

Pharmacokinetics

Publications studying pharmacokinetics of oral administration of (-)-ephedrine support that (-)-ephedrine is metabolized into norephedrine. However, the metabolism pathway is unknown. Both the parent drug and the metabolite are excreted in urine. Limited data after IV administration of ephedrine support similar observations of urinary excretion of drug and metabolite. The plasma elimination half-life of ephedrine following oral administration was about 6 hours.

Ephedrine crosses the placental barrier [see Use in Specific Populations 8.1].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Two-year feeding studies in rats and mice conducted under the National Toxicology Program (NTP) demonstrated no evidence of carcinogenic potential with ephedrine sulfate at doses up to 10 mg/kg/day and 27 mg/kg/day (approximately 2 times and 3 times the maximum human recommended dose on a mg/m2 basis, respectively).

Mutagenesis: Ephedrine sulfate tested negative in the in vitro bacterial reverse mutation assay, the in vitro mouse lymphoma assay, the in vitro sister chromatid exchange, the in vitro chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.

Impairment of Fertility: Studies to evaluate the effect of ephedrine on fertility have not been conducted.

Clinical Studies

The evidence for the efficacy of ephedrine injection is derived from the published literature. Increases in blood pressure following administration of ephedrine were observed in 14 studies, including 9 where ephedrine was used in pregnant women undergoing neuraxial anesthesia during Cesarean delivery, 1 study in non-obstetric surgery under neuraxial anesthesia, and 4 studies in patients undergoing surgery under general anesthesia. Ephedrine has been shown to raise systolic and mean blood pressure when administered as a bolus dose following the development of hypotension during anesthesia.

How Supplied/Storage and Handling

Akovaz (ephedrine sulfate injection), 50 mg/mL, is supplied as follows:

Vial stoppers are not manufactured with natural rubber latex. Store Akovaz (ephedrine sulfate injection), 50 mg/mL, at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in carton until time of use. For single use only. Discard unused portion.

Manufactured for:

Avadel Legacy Pharmaceuticals, LLC

Chesterfield, MO 63005

For BluePoint Laboratories

Rev. 08/2018

PRINCIPAL DISPLAY PANEL - NDC: 68001-330-59 - 1 mL Vial Label

PRINCIPAL DISPLAY PANEL - NDC: 68001-330-60 - 25-count Carton Label

BluePoint Laboratories