RAVICTI (glycerol phenylbutyrate) liquid
[Hyperion Therapeutics, Inc.]
2013年2月1日，美国食品药品管理局(FDA)和Hyperion Therapeutics公司宣布，Ravicti (苯丁酸甘油酯)已获准用于部分2岁或以上尿素循环障碍(UCD)患者的长期治疗。Ravicti是一种氮结合剂。
氮是蛋白质代谢所产生的废弃产物，尿素循环可将其从血液中清除并转化为尿素，后者通过尿液排出体外。UCD患者体内氮蓄积，并以氨的形式存留在体内。
据Hyperion公司和FDA称，UCD属于遗传性代谢疾病，患者全身氨水平较高，而氨是一种潜在神经毒素。在UCD患者一生中，一旦氨水平升高，患者可反复出现高氨血症危象。并发症包括恶心、呕吐、头痛、昏迷和死亡。
Ravicti为液体制剂，每日3次，随餐服用，用于不能单纯通过蛋白限制饮食或氨基酸补充剂控制的UCD患者。Ravicti必须与蛋白限制饮食以及在某些情况下与膳食补充剂同时应用。
FDA批准Ravicti是基于10项临床试验数据，其中包括6项纳入UCD患者的研究。一项支持Ravicti安全性和有效性的主要研究纳入了44例服用Buphenyl(另一获批用于UCD控制的药物)的成人患者。患者随机服用Buphenyl或Ravicti 2周后交叉转换用药，再治疗2周。血液检查显示，Ravicti在控制氨水平方面与Buphenyl效果相当。另外针对儿童和成人的3项研究证实了Ravicti用于≥2岁患者的长期安全性和有效性。
Ravicti治疗患者最常见不良反应包括腹泻、腹胀和头痛。



HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RAVICTI safely and effectively. See full prescribing information for
RAVICTI.
RAVICTI™ (glycerol phenylbutyrate) oral liquid
Initial U.S. Approval: 1996
 
INDICATIONS AND USAGE
RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). (1)

Limitations of Use:
RAVICTI is not indicated for treatment of acute hyperammonemia in patients with UCDs. (1)
Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established. (1)
The use of RAVICTI in patients <2 months of age is contraindicated (4)
DOSAGE AND ADMINISTRATION
RAVICTI should be prescribed by a physician experienced in management of UCDs. (2.1)

Instruct patients to take with food and to administer directly into mouth via oral syringe or dosing cup. (2.1)
Total daily dosage is given in 3 equally divided dosages, rounded up to nearest 0.5 mL. (2.1)
Maximum daily dosage is 17.5 mL (19 g). (2.1)
Must be used with dietary protein restriction. (2.1)
Switching From Sodium Phenylbutyrate to RAVICTI:

Daily dosage of RAVICTI (mL) = daily dosage of sodium phenylbutyrate (g) x 0.86. (2.2)
Initial Dosage in Phenylbutyrate-Naïve Patients:
Recommended dosage range is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). (2.3)
For patients with some residual enzyme activity who are not adequately controlled with dietary restriction, recommended starting dose is 4.5 mL/m2/day. (2.3)
Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence. (2.3)
Dosage Modifications in Patients With Hepatic Impairment:

Start dosage at lower end of range. (2.5, 8.6)

DOSAGE FORMS AND STRENGTHS
Oral liquid: 1.1 g/mL of glycerol phenylbutyrate. (3)

CONTRAINDICATIONS
Patients <2 months of age. (4)
Known hypersensitivity to phenylbutyrate. (4)
WARNINGS AND PRECAUTIONS
Neurotoxicity (phenylacetate [PAA], the active moiety of RAVICTI, may be toxic): Reduce dosage for symptoms of neurotoxicity. (5.1)
Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia levels closely. (5.2)

ADVERSE REACTIONS
Most common adverse reactions in ≥10% of patients are diarrhea, flatulence, and headache. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hyperion Therapeutics at 1-855-823-7878 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Corticosteroids, valproic acid, or haloperidol: May increase plasma ammonia level. Monitor ammonia levels closely. (7.1)
Probenecid: May affect renal excretion of metabolites of RAVICTI, including PAGN and PAA. (7.2)
 
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
Nursing Mothers: Discontinue nursing or discontinue the drug. (8.3)
 
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 02/2013
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