Drug Name: Silenor (doxepin)
Company: Somaxon Pharma
Approval Status: Approved March 2010
Treatment Area: insomnia
General Information
Silenor (doxepin) binds with high affinity to the histamine H1 receptor where it functions as an antagonist. The exact mechanism by which doxepin exerts its sleep maintenance effect is unknown but is believed due to its antagonism of the H1 receptor.
Silenor is specifically indicated for the treatment of insomnia characterized by difficulty with sleep maintenance.
Silenor is supplied as an immediate release tablet for oral administration. The recommended dose of Silenor for adults is 6 mg once daily. The recommended starting dose of Silenor in elderly patients (>65 years old) is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically indicated. Silenor should be taken within 30 minutes of bedtime.The total Silenor dose should not exceed 6 mg per day.
Clinical Results
FDA Approval
The efficacy of Silenor for improving sleep maintenance was supported by six randomized, double-blind studies in a total of 1,423 subjects, 18 to 93 years of age, with chronic or transient insomnia. Silenor was evaluated at doses of 1 mg, 3 mg, and 6 mg relative to placebo. The primary efficacy measures for assessment of sleep maintenance were the objective and subjective time spent awake after sleep onset (respectively, objective Wake After Sleep Onset [WASO] and subjective WASO).
Chronic Insomnia: Adults
A randomized, double-blind, parallel-group study was conducted in 221 adults with chronic insomnia. Silenor 3 mg and 6 mg was compared to placebo out to 30 days. Silenor 3 mg and 6 mg were superior to placebo on objective WASO. Silenor 3 mg was superior to placebo on subjective WASO at night 1 only. Silenor 6 mg was superior to placebo on subjective WASO at night 1, and nominally superior at some later time points out to Day 30.
Chronic Insomia: Elderly
Elderly subjects with chronic insomnia were assessed in two parallel-group studies. The first randomized, double-blind study assessed Silenor 1 mg and 3 mg relative to placebo for 3 months in inpatient and outpatient settings in elderly subjects (N=240) with chronic insomnia. Silenor 3 mg was superior to placebo on objective WASO. The second randomized, double-blind study assessed Silenor 6 mg relative to placebo for 4 weeks in an outpatient setting in elderly subjects (N=254) with chronic insomnia. On subjective WASO, Silenor 6 mg was superior to placebo.

Transient Insomnia
A randomized, double-blind, parallel-group, single-dose study enrolled 565 healthy adults who were experiencing transient insomnia during the first night in a sleep laboratory. Silenor 6 mg was superior to placebo on objective WASO and subjective WASO.

Withdrawal Effects
Potential withdrawal effects were assessed in a 35-day double blind study of adults with chronic insomnia who were randomized to placebo, Silenor 3 mg, or Silenor 6 mg. There was no indication of a withdrawal syndrome after discontinuation of Silenor treatment (3 mg or 6 mg), as measured by the Tyrer’s Symptom Checklist. Discontinuation-period emergent nausea and vomiting occurred in 5% of subjects treated with 6 mg Silenor, versus 0% in 3 mg and placebo subjects.

Rebound Insomnia Effects
Rebound insomnia, defined as a worsening in WASO compared with baseline following discontinuation of treatment, was assessed in a double-blind, 35-day study in adults with chronic insomnia. Silenor 3 mg and 6 mg showed no evidence of rebound insomnia.

Side Effects
Adverse events associated with the use of Silenor may include, but are not limited to, the following:
somnolence
sedation
nausea
upper respiratory tract infection

Mechanism of Action
Silenor (doxepin) binds with high affinity to the histamine H1 receptor where it functions as an antagonist. The exact mechanism by which doxepin exerts its sleep maintenance effect is unknown but is believed due to its antagonism of the H1 receptor.

2010年3月18日，Somaxon制药公司(Somaxon Pharmaceuticals)宣布，美国食品药品管理局(FDA)已批准Silenor用于治疗以睡眠维持困难为特征的失眠症。Silenor是一种低剂量(3 mg、6 mg)多塞平片剂，现已获准用于治疗成人(包括老年人)暂时性和慢性失眠症。

睡眠维持困难定义为夜间经常觉醒和(或)觉醒过早而无法再次入睡。据Somaxon公司称，该症状是最常报道的夜间失眠症状。临床试验证实，Silenor可使夜间睡眠达到7-8 h且次日无明显的后遗效应表现。

FDA批准Silenor是依据相关的临床试验数据，这些临床试验共纳入受试者逾1,000例。临床试验表明，Silenor有着极优的安全性和耐受性。Silenor治疗组不良反应的总发生率与安慰剂对照组相当，患者无停药反应、耐受、遗忘或复杂的睡眠行为(如梦游驾驶症、梦游饮食症)等表现。

鉴于Silenor经证实不具备滥用可能，美国缉毒局(US Drug Enforcement Administration)一直未将其列为受管制药品。另外，在Silenor的临床研发项目中，未观察到显示躯体依赖的停药反应或其他不良反应。

Silenor与组胺受体具有较高的亲和力。研究认为，该药通过与组胺受体结合这一机制促进睡眠的维持。

医护人员应知道，睡眠紊乱可能由潜在的躯体疾病和(或)精神失常所致，应在对患者进行仔细评估后，方开始失眠症对症治疗。治疗失眠7-10天后无效可能意味着存在原发性精神和(或)医学疾病，应对这类疾病进行评估。

患者应仅在准备好获得整晚睡眠时服用Silenor，而且应在睡前30 min服用。应指导患者在服药期间戒除酒精饮料或停用其他可产生睡意的药物。另外，还应告诉患者避免从事危险作业，如夜间服用Silenor后骑摩托车等，而且应告诫患者白天服用Silenor后从事这类活动可能会带来危害。

对存在未治疗的窄角型青光眼、重度尿潴留及重度睡眠呼吸暂停的患者不应开具Silenor处方。

根据该药品的处方说明，Silenor的活性成分多塞平是催眠类药物的组成部分。多塞平用作抗抑郁药时的剂量较Silenor中的高10-100倍。有研究报道，原发性抑郁症患者抑郁加重(包括自杀意念和行为)与服用催眠药有关。由于服用催眠药的患者理论上存在精神病风险，故医生在开具Silenor处方前应询问患者有关精神病、自杀意念和抑郁等情况。

SILENOR

Indication(s):

Treatment of insomnia characterized by difficulty with sleep maintenance.

Pharmacology:

Doxepin binds with high affinity to the histamine H₁ receptor where it functions as an antagonist. The sleep maintenance effects of doxepin are believed to be due to the antagonism of the H₁ receptor which depresses CNS activity.

Clinical Trials:

The efficacy of Silenor in the improvement of sleep maintenance was evaluated in six randomized, double-blind clinical trials involving 1,423 adult patients with a three-month history of chronic insomnia, or transient insomnia. Duration of the studies was up to three months. Primary efficacy measures of sleep maintenance were the objective and subjective time spent awake after sleep onset (objective Wake After Sleep Onset [WASO] and subjective WASO).

The first study, a 30-day placebo-controlled trial involving 221 adult patients with chronic insomnia, demonstrated that Silenor 3mg and 6mg were superior to placebo on objective WASO. Silenor 3mg was superior to placebo on subjective WASO at night 1 only. Silenor 6mg was superior to placebo on subjective WASO at night 1, and nominally superior at some later time points out to Day 30. Two randomized, double-blind studies of three months and four weeks duration, respectively, were conducted in 494 total elderly patients with chronic insomnia. Data from the studies respectively demonstrated Silenor 3mg to be superior to placebo on objective WASO and Silenor 6mg to be superior to placebo on subjective WASO. A randomized, single-dose study conducted in 565 adults with transient insomnia during the first night in a sleep laboratory showed Silenor 6mg to be superior to placebo on objective and subjective WASO.

Legal Classification:

Rx

Adults:

Individualize. Take within 30mins of bedtime. Do not take within 3 hours of a meal. Initially 6mg once daily. Max: 6mg/day. Elderly, hepatic impairment, tendency to urinary retention: initially 3mg once daily.

Children:

Not recommended.

Contraindication(s):

During or within 14 days of MAOIs. Untreated narrow angle glaucoma. Severe urinary retention.

Warnings/Precautions:

Evaluate for co-morbid diagnoses (eg, physical or psychiatric disorders) prior to treatment. Reevaluate if insomnia persists after 7–10 days of use. Monitor for new onset behavioral changes, worsening of depression, or suicidal thinking. Hepatic impairment. Respiratory dysfunction. Severe sleep apnea: not recommended. Poor metabolizers (those with reduced CYP2D6/2C19 activity). Reevaluate periodically. Elderly. Pregnancy (Cat.C). Nursing mothers.

Interaction(s):

Additive effects with concomitant CNS depressants, antihistamines, or alcohol (avoid); reduce dose. Potentiated by cimetidine. Possible hypoglycemia with tolazamide.

Adverse Reaction(s):

Somnolence, sedation, nausea, upper respiratory tract infection, dizziness, photosensitivity, skin rash; abnormal thinking, behavioral changes, complex behaviors, sleep-driving (discontinue if occurs), amnesia, anxiety, other neuropsychiatric symptoms.

How Supplied:

Tabs—30, 100, 500

Last Updated:

9/24/2010