2014 年3月11日,新型托吡酯缓释胶囊获FDA批准上市，与2013年上市的缓释胶囊（Qudexy XR）不同，本品的胶囊能够打开，内容物为一勺的量，便于定量配药，使它成为唯一获得批准用于那些吞咽整个胶囊获片剂患者的缓释托吡酯产品。
Qudexy XR不仅可用于10及以上伴有癫痫部分发作或原发性强直-阵挛性发作患者的单一治疗，也批准用于2岁及以上伴有癫痫部分性发作，癫痫原发全身性强直-阵挛性发作，以及与Lennox-Gastaut 综合征（又称儿童期弥漫性慢棘-慢波（小发作变异型）癫痫性脑病）相关癫痫患者的辅助治疗。
QUDEXY XR (topiramate) capsule, extended release
[Upsher-Smith Laboratories, Inc.]
General Information

Action Date	Supplement Number	Approval Type	Letters, Reviews, Labels, Patient Package Insert	Note
03/11/2014	000	Approval	Label (PDF)12 Letter (PDF)13

Qudexy XR is an extended release formulation of topiramate, an anticonvulsant.
Qudexy XR is specifically indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures and adjunctive therapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures and as adjunctive therapy in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.
Qudexy XR is supplied as a capsule for oral administration. The recommended dose is as follows:
Monotherapy
Adults and Pediatric Patients 10 Years and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures
400 mg orally once daily. Titrate according to the following schedule:
Week 1 50 mg once daily
Week 2 100 mg once daily
Week 3 150 mg once daily
Week 4 200 mg once daily
Week 5 300 mg once daily
Week 6 400 mg once daily
Adjunctive Therapy
Adults (17 Years of Age and Older) - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
The recommended total daily dose of Quedexy XR as adjunctive therapy in adults with partial onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily. The recommended total dose for adults with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week.
Pediatric Patients (Ages 2 Years to 16 Years) - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
Approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1 or 2 week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome.
Clinical Results
FDA Approval
The FDA approval of Qudexy XR was based on previously conducted studies using immediate-release topiramate and the demonstration of the pharmacokinetic equivalence of Quedexy XR to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points.
QUDEXY XR (topiramate) capsule, 中文药名：托吡酯缓释胶囊
Pharmacological Class:
Sulfamate.

Active Ingredient(s):
Topiramate 25mg, 50mg, 100mg, 150mg, 200mg; ext-rel caps.

Company
Upsher-Smith Laboratories, Inc.
Indication(s):
Initial monotherapy and adjunct in partial onset or primary generalized tonic-clonic seizures. Adjunct in Lennox-Gastaut Syndrome.

Pharmacology:
The precise mechanisms by which topiramate exerts it anticonvulsant effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate’s efficacy for epilepsy. Evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

Clinical Trials:
The efficacy of Qudexy XR as an adjunctive treatment for adults (18–75 years old) was evaluated in a randomized, international, multi-center, double-blind, parallel group, placebo-controlled trial (Study 11) in patients with a history of partial onset seizures, with or without secondary generalization.

Patients with partial onset seizures on a stable dose of 1–3 antiepileptic drugs (AEDs) entered into an 8-week baseline period. Patients who experienced at least 8 partial onset seizures, with or without secondary generalization, and no more than 21 consecutive seizure free days during the baseline phase were randomized to placebo or Qudexy XR once daily in addition to their concomitant AEDs.

After randomization, patients (n=249) entered into a 3-week initial titration period followed by an 8 week maintenance period. During the titration period, patients received placebo or Qudexy XR initially at 50mg once daily, and then increased by 50mg once daily in weekly intervals to reach a final dose of 200mg once daily. Patients then entered the maintenance period at the assigned dose of 200mg once daily or its placebo equivalent.

The primary endpoint was the percent reduction in the frequency of partial-onset seizure from baseline compared to the treatment phase. There was a statistically significant difference in the median percent reduction in seizure rate with 39.5% in the Qudexy XR group and 21.7% in the placebo group.

For more clinical trial data, see full labeling.

Legal Classification:
Rx

Adults:
Swallow whole or may open caps and sprinkle contents on a teaspoonful of soft food. Monotherapy: initially 50mg once daily, increase at 1-week intervals by increments of 50mg/week for the first 4 weeks, then increase by 100mg/week for Weeks 5–6 to target dose of 400mg once daily. Adjunctive therapy: ≥17yrs: initially 25–50mg once daily, increase at 1-week intervals by increments of 25–50mg/week to target dose of 200–400mg once daily (partial onset seizures or Lennox-Gastaut) or 400mg (primary generalized tonic-clonic seizures); usual max 1.6g/day. Renal impairment (CrCl <70mL/min): reduce dose by ½. Hemodialysis: may need extra dose. Other dose modifications: see full labeling.

Children:
Swallow whole or may open caps and sprinkle contents on a teaspoonful of soft food. Monotherapy: <10yrs: not recommended. ≥10yrs: initially 50mg once daily, increase at 1-week intervals by increments of 50mg/week for the first 4 weeks, then increase by increments of 100mg/week for Weeks 5–6 to target dose of 400mg once daily. Adjunctive therapy: <2yrs: not recommended. 2–16yrs: initially 25mg once daily (based on range: 1–3mg/kg/day) given nightly for the 1st week, increase at 1- or 2-week intervals by increments of 1–3mg/kg to target range of 5–9mg/kg once daily or until optimal clinical response. Renal impairment (CrCl <70mL/min): reduce dose by ½. Hemodialysis: may need extra dose. Other dose modifications: see full labeling.

Contraindication(s):
Concomitant metformin during metabolic acidosis.

Warnings/Precautions:
Discontinue if acute myopia and secondary angle-closure glaucoma occur. Consider discontinuing if other visual problems occur. Obtain baseline and periodic serum bicarbonate during therapy; consider reducing dose or discontinuing if acidosis occurs. Hepatic or renal impairment; obtain CrCl prior to dosing in high-risk patients (eg, older age, diabetes mellitus, hypertension, autoimmune disease). Monitor closely for oligohydrosis and hyperthermia (esp. children). Suicidal tendencies (monitor). Inborn errors of metabolism, reduced hepatic mitochondrial activity: increased risk of hyperammonemia; measure ammonia levels if encephalopathic symptoms occur. Kidney stones. Maintain adequate hydration; avoid ketogenic diets. Avoid abrupt cessation. Fetal toxicity. Labor & delivery. Pregnancy (Cat. D). Nursing mothers.

Interaction(s)
See Contraindications. Avoid concomitant other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide). Phenytoin, carbamazepine, valproic acid, lamotrigine reduce topiramate levels. May increase phenytoin levels. May antagonize oral contraceptives, valproic acid, glyburide, diltiazem. CNS depression potentiated with alcohol, other CNS depressants. Hyperammonemia (w/ and w/o encephalopathy) and/or hypothermia possible with valproic acid. Caution with other drugs that interfere with temperature regulation (eg, anticholinergics, carbonic anhydrase inhibitors). Monitor lithium levels with high-dose topiramate. Potentiated by HCTZ; may need to adjust dose. Caution with concomitant pioglitazone; monitor for adequate glycemic control.

Adverse Reaction(s)
Paresthesia, anorexia, weight decrease, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with memory, difficulty with concentration/attention, cognitive problem, confusion, mood problems, fever, infection, flushing; metabolic acidosis, kidney stones, hyperammonemia, visual disorders, hypothermia.

How Supplied:
XR caps—30, 90, 500

LAST UPDATED:
8/11/2014
FDA批准治疗癫痫的另一种缓释托吡酯
Upsher-Smith研发公司宣告，美国食品药品监督管理局（FDA）已经批准了另一种缓释托吡酯（Qudexy XR），该药每天用药一次。
该药物可用于10岁及以上伴有癫痫部分性发作或原发性强直-阵挛性发作患者的单一治疗，也批准用于2岁及以上伴有癫痫部分性发作，癫痫原发全身性强直-阵挛性发作，以及与Lennox-Gastaut综合征相关癫痫患者的辅助治疗。
该声明称，新剂型有25-、50-、100-、150-、及200-mg的缓释胶囊。胶囊能够打开，内容物为一勺（盛软食）的量，便于定量配药。这使它成为唯一获得批准用于那些难以吞咽整个胶囊或片剂患者的缓释托吡酯产品。
另一种每日一次用药的缓释托吡酯口服产品（Trokendi XR，Supernus制药公司）于2013年8月被批准。该药物用于10岁及以上伴有部分性发作或癫痫原发全身性强直-阵挛性发作患者的单一治疗，也用于6岁及以上伴有部分性发作或原发性强直-阵挛性发作的辅助治疗，以及6岁及以上伴有与Lennox-Gastaut综合征相关癫痫患者的辅助治疗。
Qudexy XR的批准基于PREVAIL 3期研究数据，该研究于2013年12月第67届美国癫痫学会年会上发表。
PREVAIL研究纳入了249名伴有癫痫部分性发作的患者，在8周的基线阶段患者癫痫发作天数为8天或更长且无发作天数为21天或更短。那些服用1至3种其他抗癫痫药物（AEDs）的患者被随机分配至接受有效药物组或安慰剂组。
结果显示，相比于安慰剂组，积极治疗组在11周时（3周滴定+8周维护）癫痫发作频率下降的中位百分比更显著(39.5% vs 21.7%；P<0.001.)。50%的应答率也显著更高(37.9% vs 23.2%；P=0.013)。
亚组分析显示该药物对于那些服用许多AEDs的伴有各种类型癫痫部分性发作的患者以及那些最难治癫痫患者的治疗有效。
该试验的研究者，凤凰城巴罗神经学研究所的神经学教授Steve Chung博士说：“PREVAIL研究表明，Qudexy XR是有效的，且普遍耐受性好，尤其对于认知副作用的发生率方面。作为医生，我认为Qudexy XR将成为众多患者可用的治疗选择。”