Indiplon (INN and USAN) is a nonbenzodiazepine, hypnotic sedative being developed in 2 formulations - an immediate release product for sleep onset and a modified-release version for sleep maintenance.
Mode of action
Indiplon is said to work by enhancing the action of the inhibitory neurotransmitter GABA
, like most other nonbenzodiazepine sedatives. It primarily binds to the α1
subunits of the GABAA
receptors in the brain.
Indiplon was originally scheduled for release to doctors and pharmacies sometime in 2007
, most likely in the springtime of that year, which is when Sanofi-Aventis
' popular sleep aid, zolpidem
, lost its patent rights in the United States and thus became available to patients as a much less expensive generic. Neurocrine Biosciences
had planned to comarket indiplon in the US with Pfizer
. However, following the issuing of a nonapprovable letter for the modified-release 15mg formulation and an approvable letter (with stipulations) for the 5mg and 10mg immediate-release version by the FDA (May 2006
decided to end its relationship with Neurocrine.
On December 13, 2007, Neurocrine announced that the FDA deemed their new drug application (NDA) 'approvable'. The 2007 Approvable Letter does not reference the setbacks seen previously in the May 2006 Approvable Letter, bringing the availability of indiplon one step closer to the consumer.
The planned brand name has not yet been revealed to the public. The NDA was initially approved by the FDA in 1998, and since then, Neurocrine has been conducting clinical trials, with purportedly satisfactory results.
A recent analysis of FDA
and clinical trial data shows that nonbenzodiazepine
Z-drugs cause cancer
. The data shows that trial subjects receiving hypnotic drugs
had an increased the risk of developing cancer and malignancies
. There have been 15 epidemiologic
studies which have shown that hypnotic
drugs cause increased mortality
, mainly due to increased cancer deaths. The cancers included cancer of the brain
, and bladder
, and neoplasms
. Initially FDA reviewers did not want to approve the drugs due to concerns of cancer but ultimately changed their mind and approved the drugs despite the concerns. FDA data has shown that zolpidem, zaleplon and eszopiclone are clastogenic
and cause cancer in rodents. Benzodiazepine agonists are associated with an increased risk of ovarian cancer
was reportedly refused a product license by the FDA
due to indications that zopiclone caused cancer.
Development of a malignant neoplasm has been associated with zolpidem
usage but the rate of incidence of neoplasm in zolpidem users is as yet unknown. The rates, in clinical trials for the nonbenzodiazepine Z drugs, of malignancies and neoplasms are significantly higher in hypnotic groups than in placebo groups. Also the analysis of clinical trials and FDA data showed that eszopiclone
, and zolpidem
appeared to have an adverse effect on the immune system
causing an increased rate of infections and colds in hypnotic users. Suppression of immune function might be the cause of the increased rate of cancer in nonbenzodiazepine hypnotic users. Indiplon has also shown an increased rate of cancers in clinical trials.
The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer