CIV

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DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Zaleplon is classified as a Schedule IV controlled substance by federal regulation.

Abuse, Dependence, and Tolerance

Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaption that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaption in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.

Abuse

Two studies assessed the abuse liability of Zaleplon at doses of 25 mg, 50 mg, and 75 mg in subjects with known histories of sedative drug abuse. The results of these studies indicate that Zaleplon has an abuse potential similar to benzodiazepine and benzodiazepine-like hypnotics.

Dependence

The potential for developing physical dependence on Zaleplon and a subsequent withdrawal syndrome was assessed in controlled studies of 14-, 28-, and 35-night durations and in open-label studies of 6- and 12-month durations by examining for the emergence of rebound insomnia following drug discontinuation. Some patients (mostly those treated with 20 mg) experienced a mild rebound insomnia on the first night following withdrawal that appeared to be resolved by the second night. The use of the Benzodiazepine Withdrawal Symptom Questionnaire and examination of any other withdrawal-emergent events did not detect any other evidence for a withdrawal syndrome following abrupt discontinuation of Zaleplon therapy in pre-marketing studies.

However, available data cannot provide a reliable estimate of the incidence of dependence during treatment at recommended doses of Zaleplon. Other sedative/hypnotics have been associated with various signs and symptoms following abrupt discontinuation, ranging from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Seizures have been observed in two patients, one of which had a prior seizure, in clinical trials with Zaleplon. Seizures and death have been seen following the withdrawal of zaleplon from animals at doses many times higher than those proposed for human use. Because individuals with a history of addiction to, or abuse of, drugs or alcohol are at risk of habituation and dependence, they should be under careful surveillance when receiving Zaleplon or any other hypnotic.

Tolerance

Possible tolerance to the hypnotic effects of Zaleplon 10 mg and 20 mg was assessed by evaluating time to sleep onset for Zaleplon compared with placebo in two 28-night placebo-controlled studies and latency to persistent sleep in one 35-night placebo-controlled study where tolerance was evaluated on nights 29 and 30. No development of tolerance to Zaleplon was observed for time to sleep onset over 4 weeks.