Margaret Moline, PhD, recently provided additional clarity about gender-specific dosing for Intermezzo, the Purdue Pharma drug that addresses middle-of-the-night insomnia.
Intermezzo* (zolpidem tartrate) sublingual tablets are currently approved for use as needed for the treatment of insomnia when a middle-of-the-night (MOTN) awakening is followed by difficulty returning to sleep. Many sleep physicians already know that Intermezzo is indicated for the treatment of MOTN insomnia when the patient has at least 4 hours of time in bed remaining.
Gender-specific doses are recommended, but many clinicians may not understand the clinicial support for the efficacy of 1.75 milligrams for women and 3.5 milligrams in men. Margaret Moline, PhD, set about to clear this up with a poster presentation at SLEEP 2012—the 26th Annual Meeting of the Associated Professional Sleep Societies (APSS).
“This is a new set of analyses that we performed on data that were already published,” said Moline, director, Medical Research, Purdue Pharma Inc, Stamford, Conn. “The original analyses were based on the entire patient population, and not broken down by gender.”
In November 2011, when the FDA approved the drug, they stipulated gender-specific dosing, but few clinicians understood the “why” of the government’s decision. “When you are evaluating drugs for approval, it’s important to take into consideration the entire package of efficacy and safety,” said Moline during a discussion of her poster titled “Gender Effects of 1.75 mg and 3.5 mg Zolpidem Tartrate Sublingual Tablets Formulated with a Carbonate-Bicarbonate Buffer on Sleep Onset Following Middle-of-the-Night Awakening and on Next-Day Residual Effects”. “There were two pivotal trials, and this trial we are reporting on for the poster tested two different doses — 1.75 milligrams and 3.5 mg.”
Moline’s analyses specifically investigated the 1.75mg and 3.5mg zolpidem tartrate sublingual tablets (Intermezzo®), formulated with a carbonate-bicarbonate buffer.
Post-hoc analysis was performed to examine response by gender in this double-blind, placebo-controlled 3-way cross-over study in patients with a diagnosis of primary insomnia as defined by the DSM-IV-TR and a history of prolonged MOTN awakenings. Patients had a history of MOTN awakening with difficulty returning to sleep and had to demonstrate polysomnographic (PSG) mean latency to persistent sleep of ≥20 minutes following scheduled awakenings on screening nights.
Treatments consisted of 2 nights of dosing followed by a 5- to 12-day washout. Fifty-eight female and 24 male patients were randomized. Patients were awakened and dosed with 3.5 mg, 1.75 mg or placebo 4 hours after lights out, kept awake for 30 minutes, then returned to bed for 4 hours. Time to return to sleep was assessed by PSG and post-sleep questionnaires. Residual effects were measured by objective/subjective measures.
In both genders, compared to placebo, both the 3.5 mg and 1.75 mg doses of Intermezzo significantly decreased sleep latency based on PSG and post-sleep questionnaires. Following the 1.75 mg dose, 60% and 44% of the females and males, respectively, were asleep within 20 minutes. The rates following the 3.5 mg dose were 80% and 63% in females and males, respectively. Placebo response rates were significantly lower: 26% (females) and 33% (males). Neither dose in either gender showed significant residual effects compared to placebo based on the assessments performed during the study.
These data demonstrated that Intermezzo was effective in reducing time to return to sleep in MOTN insomnia without producing residual effects. Further, the effects of 1.75 mg in females and 3.5 mg in males were comparable. This gender-specific related dosing is consistent with previously reported differences in zolpidem pharmacokinetics.
PSG and patient-reported measures indicate that Intermezzo doses of 1.75 mg and 3.5 mg significantly shortened time to return to sleep and improved total sleep time in MOTN insomnia, and that the effects of 1.75 mg in females and 3.5 mg in males were comparable.
Minimal residual sedative or other adverse effects were observed with Intermezzo versus placebo, and there were no differences between females and males on any parameter.
* Intermezzo is contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions with zolpidem include anaphylaxis and angioedema.
Co-administration with Intermezzo and other CNS depressants increases the risk of CNS depression. Intermezzo should not be taken with alcohol. The use of Intermezzo with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended.
The risk of next-day driving impairment (and psychomotor impairment) is increased if Intermezzo is taken with less than 4 hours of bedtime remaining; if higher than recommended dose is taken; if co-administered with other CNS depressants; or co-administered with other drugs that increase the blood levels of zolpidem. A small negative effect on SDLP (standard deviation of lateral position, a measure of driving impairment) may remain in some patients 4 hours after the 1.75 mg dose in women, and after the 3.5 mg dose in men, such that a potential negative effect on driving cannot be completely excluded.
The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.
Cases of angioedema involving the tongue, glottis, or larynx have been reported in patients after taking the first or subsequent doses of zolpidem. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. Angioedema and additional symptoms suggesting anaphylaxis may be fatal. Patients who develop angioedema or anaphylaxis should not be re-challenged.
Abnormal thinking and behavior changes have been reported in patients treated with a sedative-hypnotic, including zolpidem. Complex behaviors, including driving or eating while not fully awake, with amnesia for the event, as well as visual and auditory hallucinations and abnormal behaviors such as decreased inhibition, bizarre behavior, agitation, and depersonalization may occur. Although behaviors such as “sleep-driving” have occurred with zolpidem alone at therapeutic doses, the co-administration of zolpidem with alcohol and other CNS depressants increases the risk of such behaviors, as does the use of zolpidem at doses exceeding the maximum recommended dose. Discontinuation of Intermezzo should be strongly considered for patients reporting a “sleep-driving” episode.
In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides) have been reported with the use of sedative-hypnotics. Intentional over dosage is more common in this group of patients; therefore, protective measures may be required and prescribe the least amount of Intermezzo that is feasible.
Because persons with a history of addiction to or abuse of drugs or alcohol are at increased risk for misuse, abuse, and addiction of zolpidem, they should be monitored carefully when receiving Intermezzo. Zolpidem tartrate is a Schedule IV controlled substance. Post-marketing reports of abuse, dependence, and withdrawal resulting from use of oral zolpidem tartrate have been received. Zolpidem has produced withdrawal signs and symptoms following a rapid dose decrease or abrupt discontinuation.
The most commonly reported adverse reactions in all treatment groups were headache, nausea, and fatigue.
For additional information, please read the Intermezzo Full Prescribing Information available at http://app.purduepharma.com/xmlpublishing/pi.aspx?id=i