Silenor^® (doxepin)

Silenor® (doxepin) is a sleep-specific, low-dose (3mg and 6mg), oral tablet formulation of doxepin that is patent-protected for use in insomnia. In contrast to higher-dose doxepin, Silenor is a potent antagonist that appears to selectively affect histamine at the H1 receptor without a clinically relevant impact on other neurotransmitter systems. Histamine is an important waking neurotransmitter, and the blockade of histamine is believed to play an important role in the promotion of sleep. Doxepin is approved in the United States and Europe for the treatment of depression and anxiety at doses of 75mg-300mg daily. Doxepin at higher doses has been associated with a range of pharmacologic side effects that include anticholenerigic effects (dry mouth, constipation, etc.) and weight gain. In clinical trials, patients taking Silenor generally did not exhibit the side effects associated with higher doses of doxepin.

The leading approved insomnia medications, Ambien®, Ambien CR®, Sonata® and Lunesta®, work by binding to and activating a different set of brain receptors known as GABA receptors. These products induce sleep by non-selectively suppressing the CNS arousal mechanism and are associated with numerous undesirable side effects such as hallucinations, amnesia, complex sleep behaviors (e.g., sleep driving, sleep eating) and the risk that these medications are habit forming. Because they carry a risk of dependency, they are designated by the DEA as Schedule IV controlled substances, which require additional registration and administrative controls. These products tend to be effective at inducing sleep, but continued non-selective suppression of the arousal system upon awaking will likely result in residual sedation, a side effect that is viewed negatively by the overwhelming majority of patients. As a result, these products are designed so that their effects can be expected to wear off prior to the end of the night.

Market research indicates that the clinical profile most desired by patients and doctors is that of a product that will provide 7-8 hours of sleep in adults without causing next day sedation and without the risk of other troubling side effects such as amnesia, hallucinations and other complex behaviors. Importantly, they want to feel confident that their medication can be taken safely over time with no tolerance to the drug’s effects and no risk of dependency.

In clinical trials, Silenor demonstrated the promotion and durable maintenance of sleep, including sleep into the 8th hour of the night, with no meaningful evidence of next day residual effects. Silenor clinical trials also demonstrated a favorable safety and tolerability profile, with the overall incidence of adverse events comparable to placebo, a low discontinuation rate, and no evidence of dependency, withdrawal, tolerance, amnesia, or complex sleep behaviors. Silenor has not been designated as a controlled substance by the DEA and can be used for as long as recommended by the treating physician. It is expected that Silenor will be indicated for the treatment of insomnia characterized by difficulties maintaining sleep after sleep onset.