美国FDA批准Horizant缓释片治疗不宁腿综合征

FDA于2011年4月6日批准Horizant缓释片剂（其有效成份为gabapentin enacarbil，即1-[[[[1-(2-甲基-1-氧代丙氧基)乙氧基]甲酰]氨基]甲基]环己烷乙酸）治疗中重度不宁腿综合征（Restless legs syndrome, RLS），用药方法为每日1次。
不宁腿综合征是一种神经系统障碍，让人迫切地需要活动双下肢。不宁腿综合征患者描述双腿IPKH有牵扯、瘙痒、针刺、灼痛等异常感觉，频繁活动双腿可暂时缓解此类不适。这些症状常发生在人不太活跃的时间，在晚上及清晨尤其严重。
FDA相关主管官员指出，不宁腿综合征患者深受疾病困扰，Horizant的批准意义重大。
之前进行过两项为期12周的临床试验对Horizant的有效性进行了研究，参加试验的均为成年不宁腿综合征患者。结果显示，与服用安慰剂的对照组相比，服用Horizant的患者症状有所减轻。
FDA同时批准了一份用药指南对Horizant的使用方法及风险进行说明。Horizant可引起困倦及眩晕，会对人驾驶汽车及操作复杂机械的能力造成影响。
Horizant含有gabapentin enacarbil成份，gabapentin enacarbil被人体吸收后会降解成gabapentin（中译名称为加巴喷丁），而gabapentin是一种治疗癫痫的药物。所有抗癫痫药都带有警示，说明其可能会引发自杀意识和行为。Horizant同样也会有这样的警示

HORIZANT (gabapentin enacarbil) tablet
[GlaxoSmithKline LLC]

药名：Horizant (加巴喷丁恩那卡比gabapentin enacarbil)

适应症：不宁腿综合症

公司：葛兰素史克(GlaxoSmithKline)和Xenoport

HORIZANT
Manufacturer:
GlaxoSmithKline Pharmaceuticals

Active Ingredient(s):
Gabapentin enacarbil 600mg; extended-release tablets.

Indication(s):
Treatment of moderate-to-severe ­primary restless legs syndrome (RLS) in adults.

Pharmacology:
Gabapentin enacarbil is a prodrug of gabapentin and, accordingly, its therapeutic effects in RLS are attributable to gabapentin. The precise mechanism by which gabapentin is ­efficacious in RLS is unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. In vitro studies have shown that gabapentin binds with high affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the effects of gabapentin enacarbil in RLS is unknown.

Clinical Trials:
The effectiveness of Horizant in the treatment of moderate-to-severe primary RLS was demonstrated in two 12-week clinical studies in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria. Patients with RLS secondary to other conditions (eg, pregnancy, renal failure, iron deficiency anemia) were excluded. In Study 1, patients were randomized to receive Horizant 1200mg or placebo taken once daily at about 5pm with food. In Study 2, patients were randomized to receive Horizant 600mg, Horizant 1200mg, or placebo taken once daily at about 5pm with food.

Efficacy was evaluated using the IRLS Rating Scale and Clinical Global Impression of Improvement (CGI-I) scores. The IRLS Rating Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence/sedation, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The change from baseline in the IRLS Rating Scale at Week 12 and the proportion of responders on the CGI-I Scale defined as a rating of “much improved” or “very much improved” at Week 12 were co-­primary outcomes in these studies.

Statistically significant differences between the treatment groups receiving 600mg and 1200mg of Horizant and the group receiving placebo were observed at Week 12 for both the mean change from baseline in the IRLS Scale total score (Study 1: Horizant 1200mg: –13.2, placebo: –8.8; Study 2: Horizant 600mg: –13.8, Horizant 1200mg: –13, placebo: –9.8) and the proportion of responders (“much improved” or “very much improved”) on the CGI-I Scale (Study 1: Horizant 1200mg: 76%, placebo: 39%; Study 2: Horizant 600mg: 73%, Horizant 1200mg: 77%, placebo: 45%).

Legal Classification:
Rx

Adults:
Swallow whole. Take with food. 600mg once daily at about 5pm (no additional benefit seen with 1200mg dose). If dose is not taken at recommended time, next dose should be taken the following day. Renal impairment: CrCl 30–59mL/min: 600mg on Day 1, Day 3, and every day thereafter. CrCl<30mL/min or on hemodialysis: not recommended.

Children:
Not recommended.

Warnings/Precautions:
Not interchangeable with other gabapentin products. Not recommended for patients who are required to sleep during the day and remain awake at night. May cause significant driving impairment; do not drive until impairment is assessed. Epilepsy. Monitor for worsening of depression, suicidal thoughts/behavior, and unusual changes in mood/behavior. Pregnancy (Cat. C). Nursing mothers: not recommended.

Adverse Reaction(s):
Somnolence/sedation, dizziness, balance disorder, blurred vision, disorientation, feeling drunk, lethargy, vertigo.

How Supplied:
Tabs—30

Last Updated:
7/21/2011

Important Safety Information About HORIZANT

Do not drive after taking your dose of HORIZANT until you know how it affects you, including the morning after you take it. Do not operate heavy machinery or do other dangerous activities until you know how HORIZANT affects you. HORIZANT can cause sleepiness, dizziness, slow thinking and can affect your coordination. Ask your healthcare provider when it is okay to do these activities.
Do not take other medicines that make you sleepy or dizzy while taking HORIZANT without talking to your healthcare provider. Taking HORIZANT with these other medicines may make your sleepiness or dizziness worse.
HORIZANT may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts or feelings. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

thoughts or actions about suicide, self-harm or dying; attempt to commit suicide
new or worsening depression or anxiety; or feeling agitated
new or worse restlessness or panic attacks
new or worse trouble sleeping (insomnia); or irritability
acting aggressive, being angry, or violent; acting on dangerous impulses
an extreme increase in activity or talking (mania); other unusual changes in mood or behavior
Patients, their caregivers, and families should be informed that HORIZANT increases the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Do not stop taking HORIZANT without first talking to your healthcare provider because suicidal thoughts or actions can be caused by things other than medicines. If you have these thoughts or actions, your healthcare provider may check for other causes.
HORIZANT may cause a serious or life-threatening allergic reaction that may affect your skin or other parts of your body such as your liver or blood cells. You may or may not have rash with these types of reactions. Call a healthcare provider right away if you have any of the following symptoms: skin rash, hives, fever, swollen glands that do not go away, swelling of your lips or tongue, yellowing of your skin or eyes, unusual bruising or bleeding, severe fatigue or weakness, unexpected severe muscle pain, or frequent infections. These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking HORIZANT.
HORIZANT is not the same medicine as gabapentin, for example Neurontin® and Gralise™. HORIZANT should not be used in their place. Do not take these or other gabapentin products while taking HORIZANT.
Before taking HORIZANT, tell your healthcare provider

if you have or had kidney problems or are on hemodialysis
have or had depression, mood problems, or suicidal thoughts or behavior
are pregnant or plan to become pregnant. It is not known if HORIZANT will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant while taking HORIZANT. You and your healthcare provider will decide if you should take HORIZANT while you are pregnant
are breastfeeding or plan to breastfeed. Your body turns HORIZANT into another drug (gabapentin) that passes into your milk. It is not known if this can harm your baby. You and your healthcare provider should decide if you will take HORIZANT or breastfeed
The most common side effects of HORIZANT include sleepiness and dizziness. Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of HORIZANT. For more information, ask your healthcare provider.