Starnoc Product Monograph

Clinical Trials

Controlled Trials Supporting Effectiveness

Zaleplon (typically administered in doses of 5, 10, or 20 mg) has been studied in patients with chronic insomnia (n =

Studies were also carried out to examine the time course of effects on memory and psychomotor function, and to examine withdrawal phenomena.

Transient Insomnia

Normal adults experiencing transient insomnia during the first night in a sleep laboratory were evaluated in a double-blind, parallel-group trial comparing the effects of two doses of zaleplon

(5 and 10 mg) with placebo. Zaleplon 10 mg, but not 5 mg, was significantly superior to placebo in decreasing latency to persistent sleep (LPS), a polysomnographic measure of time to onset of sleep.

Chronic Insomnia

Adult Patients:

Adult outpatients with chronic insomnia were evaluated in three double-blind, parallel-group outpatient studies, one of 2-weeks duration and two of 4-weeks duration, that compared the effects of zaleplon at doses of 5 mg (in two of the studies), and 10 and 20 mg (in all three studies) to placebo. Primary efficacy measure in the outpatient studies was the subjective measure of time to sleep onset (TSO). Zaleplon 10mg and 20 mg were consistently superior to placebo for TSO, usually for the full duration of the study. Although both doses were effective, the effect was greater and more consistent for the 20-mg dose. The 5-mg dose was less consistently effective than the 10- and 20-mg doses. Sleep latency with zaleplon 10 mg and

20 mg was in the order of 10-20 minutes (15%-30%) less than with placebo in these studies.

Adult outpatients with chronic insomnia were also evaluated in five double-blind, parallel-group sleep laboratory studies that varied in duration from a single night up to 28 days. These studies demonstrated a superiority of zaleplon 10 mg and 20 mg over placebo in reducing latency to persistent sleep (LPS) on the first 2 nights of treatment.

Elderly Patients:

Elderly outpatients with chronic insomnia were evaluated in two 2-week, double-blind, parallel-group outpatient studies that compared the effects of zaleplon 5 mg and 10 mg with placebo on a subjective measure of time to sleep onset (TSO). The 10-mg dose tended to have a greater effect in reducing TSO. Zaleplon 10 mg was superior to placebo on TSO for the full duration of both studies. The magnitude of effect was generally similar to that seen in younger persons.

Zaleplon 5 mg was superior to placebo on TSO for both weeks in one of the studies, and for week two in the other study.

Elderly outpatients with chronic insomnia were also evaluated in one 2-night sleep laboratory study involving zaleplon doses of 5 and 10 mg. All doses of zaleplon were significantly superior to placebo in reducing latency to persistent sleep (LPS). The magnitude of decrease in LPS was dose-related.

Studies Pertinent to Safety Concerns for benzodiazepine and benzodiazepine-like agents

Memory Impairment

Benzodiazepine and benzodiazepine-like agents may induce anterograde amnesia. Studies involving the exposure of normal subjects to single fixed doses of STARNOC (10 or 20 mg)

with structured assessments of short-term memory at fixed times after dosing (e.g., 1, 2, 3, 4, 5,

8, and 10 hours) generally revealed the expected impairment of short-term memory at 1 hour, the time of peak exposure to zaleplon, for both doses, with a tendency for the effect to be greater after 20 mg. Consistent with the rapid clearance of zaleplon, memory impairment was no longer present as early as 2 hours post-dosing in one study, and in none of the studies after 3-4 hours.

Nevertheless, spontaneous reporting of adverse events in larger premarketing clinical trials revealed a difference between STARNOC and placebo in the risk of next-day amnesia (3% vs

1%), and an apparent dose-dependency for this event (see ADVERSE REACTIONS).

Sedative/Psychomotor Effects

Studies involving the exposure of normal subjects to single fixed doses of STARNOC (10 or 20 mg) with structured assessments of sedation and psychomotor function (eg, reaction time and subjective ratings of alertness) at fixed times after dosing (eg, 1, 2, 3, 4, 5, 8, and 10 hours)

generally revealed the expected sedation and impairment of psychomotor function at 1 hour, the time of peak exposure to zaleplon, for both doses. Consistent with the rapid clearance of zaleplon, impairment of psychomotor function was no longer present as early as 2 hours post dosing in one study, and in none of the studies after 3-4 hours. Spontaneous reporting of adverse events in larger premarketing clinical trials did not suggest a difference between STARNOC and placebo in the risk of next-day somnolence (see ADVERSE REACTIONS).

Withdrawal Emergent Anxiety and Insomnia

During nightly use for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine and benzodiazepine-like agents may develop. If the drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites

(ie, in relationship to the receptor site) may occur at some point in the interval between each night’s use. This sequence of events may be responsible for two events that have been reported to occur after regular use of rapidly eliminated hypnotics: increased wakefulness during the later part of the night, and increased daytime anxiety.

Zaleplon has a short half-life and no active metabolites. There is insufficient evidence to assess whether or not zaleplon use is associated with increased wakefulness during the latter part of the night. No increase in signs of daytime anxiety were observed in clinical trials with zaleplon.

Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters

(latency, total sleep time, and number of awakenings) following discontinuation of treatment, may be observed with short- and intermediate-acting benzodiazepines or benzodiazepine-like agents. Rebound insomnia following discontinuation of zaleplon relative to baseline was examined for up to three nights following drug discontinuation in two sleep laboratory studies

(14 and 28 nights) and five outpatient studies utilizing patient diaries (14 and 28 nights).

Overall, rebound insomnia appears to occur to a limited extent with zaleplon compared to placebo. Only some studies demonstrate statistically significant differences from placebo, at some doses and time-points, while not at others. The data suggest that rebound insomnia may be dose dependent, with rebound effects most frequently associated with a 20 mg dose of zaleplon. Day 1 following treatment discontinuation was the most common time to see rebound effects. Rebound effects were rarely observed by day 2 after treatment discontinuation.

Other Withdrawal-Emergent Phenomena

The potential for other withdrawal phenomena was also assessed in 14 to 28 day studies, including both the sleep laboratory studies and the outpatient studies, and in open-label studies of 6- and 12-month durations. The Benzodiazepine Withdrawal Symptom Questionnaire was used in several of these studies, both at baseline and during days 1 and 2 following discontinuation. Withdrawal was operationally defined as the emergence of 3 or more new symptoms after discontinuation. Zaleplon was not distinguishable from placebo at doses of 5,

10, or 20 mg on this measure, nor was zaleplon distinguishable from placebo on spontaneously reported withdrawal emergent adverse events. There were no instances of withdrawal delirium, withdrawal associated hallucinations, or any other manifestations of severe sedative/hypnotic withdrawal.

INDICATIONS AND CLINICAL USE

patients who have difficulty falling asleep.

usually not exceed 7 to 10 days of consecutive use.

Complete reevaluation of the patient is recommended if use continues for more than 2 to 3 consecutive weeks.

not be prescribed in quantities exceeding a 1-month supply (see

WARNINGS)

The use of hypnotics should be restricted to insomnia where disturbed sleep results in impaired daytime functioning.

CONTRAINDICATIONS

Zaleplon is contraindicated in patients with known hypersensitivity to the drug or any component of its formulation.

WARNINGS

General

Benzodiazepine and benzodiazepine-like agents should be used with extreme caution in patients with a history of substance or alcohol abuse, or in patients who in the past have manifested paradoxical reactions to alcohol and/or sedative medications and in patients who have myasthenia gravis.

Zaleplon, like other hypnotics, has CNS-depressant effects. Patients receiving zaleplon should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination (eg, operating machinery or driving a motor vehicle) after ingesting the drug.

Zaleplon, as well as other hypnotics, may produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs that themselves produce CNS depression.

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. 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 which should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with benzodiazepine and benzodiazepine-like agents including zaleplon.

Because some of the important adverse effects of sedative/hypnotics may be dose related, it is important to use the lowest possible effective dose, especially in the elderly (see DOSAGE

AND ADMINISTRATION). Use of benzodiazepine and benzodiazepine-like agents in the elderly has also been associated with an increased incidence in accidental events/falls.

Timing of Drug Administration

STARNOC should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep. As with all sedative/hypnotics, taking STARNOC while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness.

be active again.

Abnormal Thinking and Behavioural Changes

A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepines or benzodiazepine-like agents. Some of these changes may be characterized by decreased inhibition (eg. aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Abnormal behaviours associated with the use of benzodiazepines or benzodiazepine-like agents have more usually been reported with chronic use and/or high doses, but they may occur during the acute, maintenance or withdrawal phases of treatment.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Memory disturbance:

Anterograde amnesia of varying severity has been reported following therapeutic doses of benzodiazepines or benzodiazepine-like agents. Anterograde amnesia is a dose-related phenomenon and elderly subjects may be at particular risk.

Cases of transient global amnesia and “traveller’s amnesia” have also been reported in association with benzodiazepines, the latter in individuals who have taken the drug, often in the middle of the night, to induce sleep while travelling. Transient global amnesia and traveller’s amnesia are unpredictable and not necessarily dose-related phenomena.

Confusion:

The benzodiazepines and benzodiazepine-like agents affect mental efficiency, e.g., concentration, attention and vigilance. The risk of confusion is greater in the elderly and in patients with cerebral impairment.

Depression:

In primarily depressed patients, worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines or benzodiazepine-like agents. The potential for self-harm (e.g., intentional overdose) is high in patients with depression and thus, the least amount of drug that is feasible should be available to them at any one time

Pregnancy:

Benzodiazepines may cause fetal damage when administered during pregnancy. During the first trimester of pregnancy, several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepines.

Insufficient data are available on zaleplon to assess its safety during human pregnancy. Thus, the use of zaleplon during pregnancy is not recommended. If zaleplon is prescribed to a woman of child-bearing potential, the patient should be warned of the potential risk to a fetus and advised to consult her physician regarding the discontinuation of the drug if she intends to become pregnant or suspects that she is pregnant.

During the last weeks of pregnancy, ingestion of therapeutic doses of a benzodiazepine hypnotic has resulted in neonatal CNS depression due to transplacental distribution. Similar effects might occur with zaleplon, due to its pharmacological effects.

PRECAUTIONS

Drug Abuse, Dependence and Tolerance:

Abuse

Two studies assessed the abuse liability of zaleplon in subjects with known histories of sedative drug abuse. Due to tolerance to the sedative effects of CNS depressants in this subject population, zaleplon doses of 25, 50 and 75 mg were examined. The results of these studies indicate that zaleplon has an abuse potential comparable to benzodiazepine and benzodiazepine-like hypnotics among known sedative drug abusers.

Dependence

The potential for developing physical dependence and a subsequent withdrawal syndrome was examined in controlled studies of 14 and 28 day durations and in open label studies of 6 and 12 month durations using the Benzodiazepine Withdrawal Symptom Questionnaire or by the examination of withdrawal emergent study events. Other than mild rebound insomnia in patients

(occurring most frequently the first day post-discontinuation of a 20 mg dose), a withdrawal syndrome was not observed following abrupt discontinuation of zaleplon therapy in pre-marketing studies.

However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses of STARNOC. 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 STARNOC or any other hypnotic. If physical dependence has developed, abrupt termination of treatment may be accompanied by withdrawal symptoms. These symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions.

use.

Tolerance

time to sleep onset for STARNOC compared with placebo in two placebo-controlled 28-day studies. No development of tolerance to STARNOC was observed for time to sleep onset over

4 weeks.

Use in Pregnancy, Labour and Delivery

Studies to assess the effects of zaleplon on human reproduction and development have not been conducted. However, STARNOC is not recommended for use during pregnancy. Zaleplon has no established use in labor and delivery.

Use in Nursing Mothers

A study in lactating mothers indicated that the clearance and half-life of zaleplon is similar to that of young normal subjects. A very small amount of zaleplon is excreted in breast milk, with the highest excreted amount (0.013% to 0.017% of the maternal dose) occurring during a feeding at approximately one hour after zaleplon administration. The amount of zaleplon excreted in milk beyond that time is negligible. However, the effects of very small amounts of zaleplon on a nursing infant are not known. It is recommended that nursing mothers not take STARNOC.

Pediatric Use

The safety and efficacy of zaleplon in children below the age of 18 have not been established.

Use in the Elderly

There is no substantial difference in the pharmacokinetic profile of zaleplon in young and elderly adults, including those over 75 years of age (see ACTIONS and CLINICAL

PHARMACOLOGY). A total of 851 patients in phase II and III clinical trials who received Zaleplon were at least 65 years of age; of these,

received doses of 5 or 10 mg. In both sleep laboratory and outpatient studies, elderly patients with insomnia responded to a 5-mg dose with a reduced sleep latency, and thus 5 mg is the recommended dose in this population

(see DOSAGE AND ADMINISTRATION).

As impaired motor and/or cognitive performance, including accidental events/falls, after repeated exposure or unusual sensitivity to benzodiazepine and benzodiazepine-like agents is a concern in the elderly, such patients should be treated cautiously and monitored closely.

Use in Patients with Concomitant Illness

Clinical experience with zaleplon in patients with concomitant systemic illness is limited.

STARNOC should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Compromised respiratory function: Although preliminary studies did not reveal respiratory depressant effects at hypnotic doses of zaleplon in normal subjects, cautions should be observed if zaleplon is prescribed to patients with compromised respiratory function, because hypnotics have the capacity to depress respiratory drive. Controlled trials of acute administration of

STARNOC 10 mg in patients with chronic obstructive pulmonary disease or moderate obstructive sleep apnea showed no evidence of alterations in blood gases or apnea/hypopnea index, respectively. However, patients with compromised respiration due to preexisting illness should be monitored carefully.

Hepatic impairment: The dose of

use in patients with severe hepatic impairment.

Renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment. STARNOC has not been adequately studied in patients with severe renal impairment.

Use in Patients with Depression: As with other hypnotics, STARNOC should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients (see SYMPTOMS & TREATMENT OF

OVERDOSAGE); therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.

Discontinuation Symptoms

See CLINICAL PHARMACOLOGY AND ADVERSE REACTIONS

Drug Interactions

As with all drugs, the potential exists for interaction with other drugs by a variety of mechanisms.

CNS-active Drugs

Ethanol: Zaleplon 10 mg potentiated the CNS-impairing effects of ethanol 0.75 g/kg on balance testing and reaction time for 1 hour after ethanol administration and on the digit symbol substitution test (DSST), symbol copying test, and the variability component of the divided attention test for 2.5 hours after ethanol administration. The potentiation resulted from a CNS pharmacodynamic interaction because zaleplon did not affect the pharmacokinetic profile of ethanol.

Imipramine: Co-administration of single doses of zaleplon 20 mg and imipramine 75 mg produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration. The interaction was pharmacodynamic with no alteration of the pharmacokinetic profile of either drug.

Paroxetine: Co-administration of a single dose of zaleplon 20 mg and paroxetine 20 mg daily for 7 days did not produce any interaction on psychomotor performance. Additionally, paroxetine did not alter the pharmacokinetic profile of Zaleplon in a clinically relevant manner.

Thioridazine: Co-administration of single doses of zaleplon 20 mg and thioridazine 50 mg produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration. The interaction was pharmacodynamic with no clinically meaningful alteration of the pharmacokinetic profile of either drug.

Drugs that Induce CYP3A4

Rifampin: CYP3A4 is typically a minor metabolizing enzyme of zaleplon. Multiple-dose administration of the potent CYP3A4 inducer rifampin (600 mg every 24 hours, for 14 days)

reduced zaleplon C_max and AUC by approximately 80% (see CLINICAL PHARMACOLOGY).

These results indicate that the coadministration of a potent CYP3A4 enzyme inducer, although not posing a safety concern, could reduce the hypnotic effect of zaleplon.

Drugs that Inhibit CYP3A4

Clinical studies have not been performed to evaluate the effect of a selective CYP3A4 inhibitor on the pharmacokinetic profile of zaleplon. However, CYP3A4 is considered a minor metabolic pathway for the elimination of zaleplon because the sum of desethylzaleplon (formed via

CYP3A4 in vitro) and its metabolites, 5-oxo-desethylzaleplon and 5-oxo-desethylzaleplon glucuronide, accounts for only 9% of the urinary recovery of a zaleplon dose. Therefore, coadministration of a CYP3A4 inhibitor (e.g., ketoconazole, erythromycin) is not expected to produce a clinically important interaction with zaleplon; however no clinical studies have specifically addressed this question.

Drugs that Inhibit Aldehyde Oxidase

The aldehyde oxidase enzyme system is less well studied than the cytochrome P450 enzyme system.

Diphenhydramine: Diphenhydramine is reported to be a moderate inhibitor of aldehyde oxidase in rat liver, but its inhibitory effects in human liver are not known. There is no pharmacokinetic interaction between zaleplon and diphenhydramine following the administration of a single dose

(10 mg and 50 mg, respectively) of each drug. However, because both of these compounds have

CNS effects, an additive pharmacodynamic effect is possible.

Drugs that Inhibit Both Aldehyde Oxidase and CYP3A4

Cimetidine: Cimetidine inhibits both aldehyde oxidase (in vitro) and CYP3A4 (in vitro and in vivo), the primary and secondary enzymes, respectively, responsible for zaleplon metabolism.

Concomitant administration of zaleplon (10 mg) and cimetidine (800 mg) produced an 85% increase in the mean C_max and AUC of zaleplon. Thus, the initial dose of STARNOC should be 5 mg in patients who are concomitantly being treated with cimetidine (see DOSAGE AND

ADMINISTRATION).

Drugs Highly Bound to Plasma Protein

Zaleplon is not highly bound to plasma proteins (fraction bound = 60%±15%); therefore, the disposition of zaleplon is not expected to be sensitive to alterations in protein binding. In addition, administration of zaleplon to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

Drugs with a Narrow Therapeutic Index

Digoxin: Zaleplon (10 mg for 7 days) did not affect the pharmacokinetic or pharmacodynamic profile of digoxin (0.375 mg q24h for 8 days) in any clinically meaningful manner.

Warfarin: Multiple oral doses of zaleplon (20 mg q24h for 13 days) did not result in any clinically meaningful alteration in pharmacokinetics of warfarin (R+)- or (S-)-enantiomers or the pharmacodynamics (prothrombin time) following a single 25 mg oral dose of warfarin.

Drugs that Alter Renal Excretion

Ibuprofen: Ibuprofen is known to affect renal function and, consequently, alter the renal excretion of other drugs. There was no apparent pharmacokinetic interaction between zaleplon and ibuprofen following single dose administration (10 mg and 600 mg, respectively) of each drug. This was expected because zaleplon is primarily metabolized and renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose.

Drug-Laboratory Test Interactions

Zaleplon is not known to interfere with commonly employed clinical laboratory tests.

Laboratory Tests

There are no specific laboratory tests recommended.

ADVERSE REACTIONS

The pre-marketing database includes clinical experience with 2,831 patients, including 211 adult and 119 elderly patients (65 years of age or older) who were followed for more than

6 months.

Cause for Discontinuation of Treatment

In premarketing placebo-controlled, parallel-group phase 2-3 clinical trials, 3.1% of 744 patients who received placebo and 3.5% of 2,069 patients who received zaleplon discontinued treatment because of an adverse clinical event. This difference was not statistically significant. The incidence of any event that resulted in discontinuation was

<1%.

The study events cited most often as a reason for discontinuation by zaleplon-treated patients were somnolence (9 patients, 0.43%), headache (8, 0.39%), depression (6, 0.29%), dizziness (6, 0.29%), and nervousness (6, 0.29%). The most commonly cited study events in the placebo group were headache (3, 0.40%), fever (2, 0.27%), anxiety (2, 0.27%), depression (2, 0.27%), and dizziness (2, 0.27%).

Most commonly observed adverse events in controlled trials

The overall incidence of adverse events associated with short-term and long-term treatment with zaleplon (5 to 20 mg) in controlled clinical trials was comparable with that observed with placebo. During short-term treatment (5 or 14 night studies), the most common adverse events were headache (25% vs 22% with placebo), dizziness (5% vs 4%) and somnolence (5% vs 4%). During long-term treatment (28 night studies), the most common adverse events were headache (31% vs 31% for placebo) and dizziness (8% vs 7%).

Adverse events observed at an incidence of $ 1% in controlled trials The following tables list the treatment-emergent adverse events that were observed at an incidence equal to 1% or greater among patients who received zaleplon in placebo-controlled phase 2-3 trials. Events reported by investigators were classified using the

COSTART dictionary of preferred terms for the purpose of establishing event frequencies.

Table 1 provides these data from a pool of 8 placebo-controlled short-term (5 to 28 nights)

trials of zaleplon for doses ranging from 5 to 20 mg. The tables include only adverse events occurring at an incidence of at least 1% for zaleplon-treated patients and of an incidence greater than that for placebo-treated patients.

Table 1. INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS IN

PLACEBO-CONTROLLED ZALEPLON CLINICAL TRIALS (5 to 28 NIGHTS)

Table 1

Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled Clinical Trials

(5 to 28 nights) of Zaleplon¹

---------------------------Zaleplon---------------------------

Body system Placebo 5 mg 5 or 10 mg 10 mg 20 mg

Preferred Term (n = 744) (n = 609) (n = 1741) (n = 1132) (n = 300)

Body as a whole

Abdominal pain 3 3 3 3 6 Asthenia 4 3 4 5 8 Fever 1 1 <1 <1 2 Flu syndrome 1 1 1 2 2 Headache 25 20 26 30 36 Infection 3 3 3 3 6 Malaise <1 <1 <1 <1 2 Pain 5 6 5 5 6 Photosensitivity

reaction

<1 - <1 <1 1

Digestive system

Anorexia <1 <1 <1 <1 2 Colitis <1 - <1 <1 1 Dyspepsia 3 3 3 3 6 Nausea 5 4 4 4 7 Vomiting <1 1 <1 <1 1

Metabolic and nutritional

Peripheral edema <1 <1 <1 <1 1

Musculoskeletal system

Myalgia 3 3 4 4 4

Nervous system

Amnesia <1 1 1 2 4 Anxiety 1 <1 <1 1 2 Depersonalization <1 <1 <1 <1 2 Depression 1 1 1 2 2 Dizziness 5 4 6 6 8 Hallucinations <1 <1 <1 <1 1 Hypertonia <1 1 <1 <1 1 Hypesthesia <1 <1 <1 <1 2 Paresthesia <1 <1 1 2 3 Somnolence 4 4 5 6 5 Thinking abnormal <1 1 <1 <1 1 Tremor <1 <1 <1 <1 2 Twitching <1 <1 <1 <1 1 Vertigo <1 <1 <1 <1 2

Table 1

Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled Clinical Trials

(5 to 28 nights) of Zaleplon¹

------------------------------Zaleplon------------------------

Body system Placebo 5 mg 5 or 10 mg 10 mg 20 mg

Preferred Term (n = 744) (n = 609) (n = 1741) (n = 1132) (n = 300)

Respiratory system

Cough increased 2 2 2 1 3 Epistaxis <1 <1 <1 <1 1 Pharyngitis 4 3 3 4 5 Sinusitis <1 <1 1 1 2

Skin and appendages

Herpes simplex <1 <1 <1 <1 2

Special senses

Abnormal vision <1 1 1 <1 2 Conjunctivitis <1 <1 <1 <1 1 Ear pain <1 <1 <1 <1 1 Eye pain 2 2 2 2 4 Hyperacusis <1 <1 <1 <1 2 Parosmia <1 <1 <1 <1 2 Photophobia <1 <1 <1 <1 1 Taste perversion 1 1 2 2 2

Urogenital system

Dysmenorrhea 2 1 1 2 4

1: Event for which the incidence for STARNOC 20 mg-treated patients was at least 1% and greater than the incidence among placebo-treated patients. Incidence greater than 1% has been rounded to the nearest whole number.

Central Nervous System (CNS) Adverse Events in Parallel-Group, Placebo Controlled Studies

CNS-related adverse-events are of specific concern with benzodiazepines and benzodiazepine-like agents. The Table below summarizes the

verse events for all parallel group placebo controlled phase II/III studies that occurred at a higher rate in at least one of the zaleplon dose groups compared to placebo group.

Incidence (%) of Central Nervous System (CNS) Adverse Events in Parallel-Group, Placebo Controlled Studies

----------------- Zaleplon Dose ---------------5 mg 10 mg 20 mg Placebo Adverse Event (n = 609) (n = 1132) (n = 300) (n = 744) Any nervous system 17 22 31*** 19

Amnesia 1 2 4*** < 1 Depersonalization < 1 < 1 2* < 1 Emotional lability < 1 < 1 < 1 0 Hallucinations < 1 < 1 1* < 1 Hypesthesia < 1 < 1 2* < 1 Paresthesia < 1 2 3* < 1 Somnolence 4 6* 5 4

* 0.01< P < 0.05 *** P < 0.001

Nervous system events occurring at a significantly higher rate than placebo were seen most frequently in zaleplon 20 mg group. These events included amnesia, depersonalization, hallucinations, hypesthesia, and paresthesia. The zaleplon 5 mg dose had event rates similar to placebo. The zaleplon 10 mg dose did not show a significant difference from placebo for any event other than somnolence.

Dose relationship for adverse events:

There is evidence from 28-day dose-comparison trials suggesting a dose relationship for some of the adverse events associated with zaleplon use, including headache, amnesia and hypesthesia.

Other Adverse Events Observed During the Pre-Marketing Evaluation of Zaleplon:

Zaleplon was administered to 2,831 patients in pre-marketing phase II and III clinical trials throughout the United States, Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified by using the COSTART dictionary of preferred terms. The frequencies presented represents the proportions of the 2,831 individuals exposed to zaleplon at all doses, who experienced an event of the type cited on at least one occasion while receiving zaleplon. All treatment-emergent adverse events greater than 1% are included, except those already listed in the tables of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events for which a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with zaleplon, they were not necessarily caused by it. Adverse events are further classified within the body system and the frequent adverse events are provided below.

Frequent adverse events are those occurring in greater than 1/100 patients.

Body as a whole: accidental injury, chest pain, flu syndrome, neck pain, pain.

Cardiovascular system: none.

Digestive system: constipation, diarrhea, dyspepsia, nausea, vomiting.

Endocrine system: none.

Hemic and lymphatic system: none.

Metabolic and nutritional: none.

Musculoskeletal system: arthritis, leg cramps.

Nervous system: abnormal dreams, anxiety, hypertonia, nervousness, thinking abnormal.

Respiratory system: bronchitis, cough increased, rhinitis.

Skin and appendages: pruritus, rash.

Special senses: conjunctivitis, ear pain.

Urogenital system: none.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

There is limited pre-marketing clinical experience with the effects of an overdosage of zaleplon.

Two cases of overdose were reported. One was the accidental ingestion by a 2-year-old boy of

20-40 mg of zaleplon. The second was a 20-year-old man who took 100 mg zaleplon plus 2.25 mg of triazolam. Both were treated and recovered uneventfully.

Signs and Symptoms

Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. Overdose is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma.

In mild cases, symptoms include drowsiness, mental confusion, and lethargy; in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma, and very rarely death.

Recommended Treatment

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Animal studies suggest that flumazenil is an antagonist to zaleplon. However, there is no pre-marketing clinical experience with the use of flumazenil as an antidote to a zaleplon overdose. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention.

DOSAGE AND ADMINISTRATION

Zaleplon should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep. Taking STARNOC with or immediately after a heavy, high-

sleep latency. (See Pharmacokintetics)

Adults: The recommended dose of STARNOC is 10 mg.

Elderly and debilitated patients: The recommended dose of STARNOC is 5 mg.

Special Populations

Hepatic insufficiency: Patients with mild to moderate hepatic impairment should be treated with zaleplon 5 mg because clearance is reduced in this population (see PHARMACOKINETICS,

Special Populations).

in patients with severe hepatic impairment.

Renal insufficiency: No dosage adjustment is necessary in patients with mild to moderate renal impairment. STARNOC has not been adequately studied in patients with severe renal impairment.

Pediatrics: STARNOC is not indicated for use in children under 18 years of age as safety and efficacy in this age group has not been established..

Concomitant Use of Cimetidine. An initial dose of 5 mg should be given to patients concomitantly taking cimetidine because zaleplon clearance is reduced in this population (see PRECAUTIONS,

Drug Interactions).

PHARMACEUTICAL INFORMATION

DESCRIPTION:

Drug Substance:

Proper Name: Zaleplon

Chemical Name: N-[3-(3-cyanopyrazolo[1,5-"]pyrimidin-7-yl)phenyl]-N-ethylacetamide.

or

3'-(3-cyanopyrazolo[1,5-"]pyrimidin-7-yl-N-ethylacetanilide

USAN/INN: Zaleplon

Structural Formula:

Molecular Weight: 305.34

Physical Form: White to off-white powder

Solubility:

Water: 0.2 mg/mL

Alcohol: Sparingly soluble

Propylene Glycol: Sparingly soluble

pKa value: None apparent in pH range 1 to 7

Composition:

STARNOC^® Capsules

Medicinal Ingredient Non-medicinal Ingredients

Zaleplon Microcrystalline cellulose, NF

Starch, pregelatinized, NF

Silicon dioxide, NF

Sodium lauryl sulfate, NF

Magnesium stearate, NF

Lactose, NF/BP

(5 mg strength)

Hard Gelatin capsule shells are composed of: titanium dioxide, gelatin, yellow iron oxide, red iron oxide, black iron oxide and are imprinted with gold ink (S-I-3050)

(10 mg strength)

Hard Gelatin capsule shells are composed of:

titanium dioxide and gelatin and are imprinted with pink ink (SW-

1105)

Stability and Storage Recommendations:

Store at room temperature, 15°-30°C. Protect from light.

Keep out of reach of children.

AVAILABILITY OF DOSAGE FORMS

STARNOC^® (zaleplon) capsules are available in blister packs of 10 or 30 capsules in the following capsule strengths:

5 mg Opaque light brown cap and opaque white body with gold stripe printed on the body.

10 mg Opaque white cap and opaque white body with pink stripe printed on the body.

INFORMATION FOR THE CONSUMER

Information for patients taking STARNOC ^®

Please read this information carefully before you start to take your medicine.

pharmacist.

What you Should Know About STARNOC

Zaleplon belongs to a group of medicines known as the "hypnotics", or simply, sleep medicines.

Zaleplon is used to treat difficulty in falling asleep. Zaleplon works very quickly and has its effect during the first part of the night, since it is rapidly eliminated by the body. You should take zaleplon immediately before going to bed or after you have gone to bed and are having difficulty falling asleep. Your Doctor may decide to change your sleep medicine if you wake up too early in the morning.

How Can STARNOC Help?

C

after you have finished your capsules, contact you doctor again.

Before Taking STARNOC

Tell your doctor if you are or intend to become pregnant, or if you are breast feeding.

Discuss with your Doctor if you have:

C had a bad reaction to zaleplon in the past

C breathing difficulties

C sleep apnea (stopping breathing for short periods while asleep)

C liver disease

C any diseases affecting your muscles (including myasthenia gravis)

C had problems with drug addiction

C had problems with alcohol abuse

If you are in any doubt about whether you have any of these conditions, do ask your doctor.

How To Take STARNOC

C Take the exact dose that the doctor has prescribed. Do not change it without talking to your doctor first.

C Swallow the capsule with a small glass of water.

C There are different doses for adults and elderly/debilitated patients.

Adults: take 1 capsule (10 mg)

Elderly/debilitated patients : take 1 capsule (5 mg)

C You should only take zaleplon when you are ready to get into bed and go to sleep or once in bed and have not been able to fall asleep.

C For STARNOC to help you fall asleep you should not take it with or immediately after a high-fat/heavy meal.

C Children under 18 years of age should not take STARNOC.

When Not To Use STARNOC

•

STARNOC ^® (zaleplon) if you are allergic to it or any of the components of its formulation (see list of components at the end of this section). Stop taking the drug and contact your doctor immediately if you experience an allergic reaction or any severe or unusual side effects.

• Avoid alcohol while using

STARNOC along with other medications without talking to your doctor first.

Side Effects

Most common side effects

• You may experience some side effects such as headache, drowsiness, dizziness, and fatigue.

  Consult your doctor if you experience these or other side effects, as the dose may have to be adjusted.

Special Concerns

Memory Problems

C Sleep medicines may cause a special type of memory loss (amnesia). When this occurs, a person may not remember what has happened for several hours after taking the medicine.

This lapse is usually not a problem since most people fall asleep after taking the medicine.

But it can be a problem when sleep medicines are taken while traveling such as during an airplane flight and the person wakes up before the effect of the medicine is gone. Do not

you are to get 4 or more hours of sleep before you must be active again.

C

Tolerance/Withdrawal Symptoms

C After nightly use for more than a few weeks, sleeping pills may lose some of their effectiveness and you may also develop a degree of dependence.

C You may also experience “withdrawal effects” when you stop the medication after taking it for a long time. Usually these withdrawal effects are more common and severe after long periods of continuous use. On the first few nights after stopping the medication, you may find that insomnia is worse than before taking the sleeping pills. This type of withdrawal symptom is known as “rebound insomnia”.

C Other withdrawal effects following abrupt stopping of sleeping pills may range from unpleasant feelings to a major withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremor, and rarely, seizures. The severe symptoms are uncommon. If you have been taking sleeping pills for a long time, discuss with your physician when and how it would be best for you to stop.

C Dependence/Abuse: All sleep medicines can cause dependence (addiction) especially when used regularly for more than a few weeks, or at high doses. Some people develop a need to continue taking these drugs, not only for continued therapeutic effect, but also to avoid withdrawal symptoms or to achieve nontherapeutic effects.

C Individuals who depend, or have depended at any time in the past, on alcohol or other drugs may be at particular risk of becoming dependent on drugs of this class. But all people are at some risk. Consider this matter before you take these medications beyond a few weeks.

C Mental and Behavioral Changes: a variety of abnormal thinking and behavioral changes may occur when you use prescription sleeping pills. Some of these changes include aggressiveness and extroversion which seem out of character. Other changes, although rare, can be more unusual and extreme. These include confusion, strange behavior, restlessness, illusions, hallucinations, feeling like you are not yourself, and feeling more depressed, which may lead to suicidal thinking.

C Important Note: Regardless of the cause, if you take these medications, report any mental or behavioral changes promptly to your doctor.

Pregnancy and Breast-feeding

C Sleep medicines may cause sedation or other potential effects in the unborn baby when used during the last weeks of pregnancy. Therefore,

use during pregnancy.

C

effects. In addition, after use of the medicine, a very small amount of zaleplon may be

recommended while you are breast-feeding.

Safe Use Of STARNOC

C

STARNOC if it is not prescribed for you.

C Never use STARNOC or any other sleep medicine for longer than directed by your doctor.

C If you notice any unusual and/or disturbing thoughts or behaviour during treatment with

STARNOC or any other sleep medicine, contact your doctor.

C

taking now, including drugs you can buy without a prescription. DO NOT use alcohol while taking STARNOC .

C

be active again.

C Do not increase the prescribed dose of STARNOC .

C Do not take a second dose within a single night

C

or any other sleep medicine until you know whether the medicine will still have some carryover effect in you the next day, use extreme care while doing anything that requires complete alertness, such as driving a car, operating machinery, or piloting an aircraft.

C Be aware that you may have more sleeping problems the first night or two after stopping any sleep medicine.

C Do not take STARNOC at any time during pregnancy. Tell your doctor if you are

this medication. What Does STARNOC ^® (zaleplon) Contain?

STARNOC ^® (zaleplon)

ingredient. Non-medicinal ingredients include: microcrystalline cellulose, NF; starch,

lactose, NF/BP.

STARNOC is sold in blister packs containing 10 or 30 capsules of either 5 mg or 10 mg strength.

Who sells STARNOC ^® in Canada ?

Servier Canada Inc.

235, Boul. Armand-Frappier

Laval, Quebec

H7V 4A7

Tel.: (450) 978-9700

Fax.: (450) 978-0402

What To Do If You Take Too Many Capsules?

Contact your doctor, a Poison Information Centre

or the nearest hospital emergency department, even though you do not feel sick.

STORAGE INSTRUCTIONS

Store at room temperature, 15°-30°C.

Protect from light.

Keep out of reach of children.

REMINDER: This medicine has been prescribed only for you. Do not give it to anybody else. If you have any further questions, please ask your doctor or pharmacist.

PHARMACOLOGY

The pharmacokinetics of zaleplon and its metabolites (desethyl-zaleplon, M1, M2, and M1 and

M2 glucuronide) were studied in mice, rats, rabbits, dogs, monkeys, and humans. ¹⁴C-zaleplon was used to characterize the pharmacokinetics, metabolism, tissue distribution, and excretion of zaleplon in selected studies. Zaleplon’s ability to induce the cytochrome P₄₅₀ system was assessed in mice and rats. Single-dose studies and repeated-dose studies for up to 1 year were conducted to characterize the toxicokinetics of zaleplon in mice, rats, and dogs.

Zaleplon metabolism was studied in vitro in liver microsomes, S9 fractions, cytosol and liver slices, and in vivo in mice, rats, rabbits, dogs, monkeys, and humans. Protein binding of zaleplon was characterized in the species used in toxicocity studies and in humans. The distribution and excretion of ¹⁴C-labelled zaleplon were studied in rats following single and repeated doses and in pregnant rats following a single dose by quantitative distribution studies and by whole body autoradiography. Distribution of zaleplon in rat milk was also evaluated.

Zaleplon was rapidly and well absorbed in mice, rats, rabbits, dogs, and humans following oral dosing. The elimination half-life was approximately 1 hour in all species. Zaleplon is only moderately protein bound (<70%) in all species. In humans, zaleplon plasma concentrations are below the 5 ng/mL assay detection limit by 6 to 8 hours after a 10 mg/day dosage, with no accumulation observed upon repeated dosing. No accumulation of compound-related radioactivity

(metabolites) is expected in humans based on the radioactivity half-life of 3.2 hours in plasma and the undetectable (<4 ng equiv/mL) plasma radioactivity concentrations observed 24 hours after dosing.

Zaleplon is cleared rapidly

animals and humans by metabolism, with only trace amounts of unchanged compound recovered in excreta. A more complex profile of metabolites is observed in animals due to the primary role of the cytochrome P₄₅₀ system in metabolism of zaleplon in animal as compared to the less significant role of P ₄₅₀ in human metabolism. All of zaleplon’s human metabolites have been observed in plasma or excreta of species used in toxicity studies and due to the high doses used in toxicity studies with zaleplon and the 1-month dog study with M2, it can be concluded that adequate testing of the toxic potential of zaleplon and its metabolites was achieved in the animal species utilized.

TOXICOLOGY

studies, repeated-dose studies, range-finding/carcinogenicity studies, special toxicity studies, reproductive toxicity studies, and genotoxicity studies.

Acute Toxicity:

In single-dose studies, mortality occurred in mice at $700 mg/kg PO and $500 mg/kg IP and in rats at $300 mg/kg PO and IP. Mortality was not observed in IV studies in mice, rats, and dogs up to the maximum feasible dosage of 2 mg/kg, or in dogs given oral gavage dosages up to 400 mg/kg. Clinical signs of central nervous system (CNS) depression (eg, inactivity, hypoactivity, ataxia, prostration, unkempt appearance) were consistent with the pharmacological effects of zaleplon, and occurred in mice at $500 mg/kg PO and $300 mg/kg IP; in rats at $100 mg/kg PO and at $300 mg/kg IP; and in dogs at $10 mg/kg PO. In IV studies with zaleplon, there were no compound-related effects in mice and rats at dosages up to 2 mg/kg, while signs of CNS depression occurred in dogs at $0.50 mg/kg.

Administration of the M1 and M2 metabolites did not result in mortality in mice at dosages up to

1000 mg/kg PO and 500 mg/kg IP or in rats at dosages up to 500 mg/kg PO and 100 mg/kg IP.

CNS depression occurred in mice at 500 mg/kg IP; however, there were no compound-related effects in mice up to 1000 mg/kg PO, or in rats up to 500 mg/kg PO and 100 mg/kg IP.

There were no toxicologically significant gross postmortem findings after acute administration of zaleplon, or the M1 and M2 metabolites.

Repeated - Dose Toxicity

The repeated-dose toxicity profile of zaleplon was evaluated in a 2-week PO study in mice; 2-week, 1-month, 3-month, and 1-year PO studies in rats; 2-week, 3-month and 1-year PO studies in dog; and 2-week IV studies in rats and dogs. In addition, the M2 metabolite of zaleplon was evaluated in a 1-month PO study in dogs.

The toxicity of zaleplon was evaluated in 3-month studies in rats and dogs at dosages up to 200 mg/kg/day, and in 1-year studies in rats at dosages of 5, 20, and 50 mg/kg/day and in dogs at dosages of 5, 20 and 40 mg/kg/day.

The major compound-related findings in the 3-month and 1-year toxicity studies in rats and dogs are as follows:

1. 1. CNS depression was observed at all dosages tested ($3 mg/kg/day in rats; $5 mg/kg/day in dogs).
2. 2. Convulsions in rats and dogs were seen at dosages $20 mg/kg/day.
3. 3.

   Increased mortality occurred in the 1-year studies at dosages $5 mg/kg/day (via gavage)

   in rats and $20 mg/kg/day (via capsule) in dogs.

4. 4.

   Reduced erythroid parameters were observed at dosages $100 mg/kg/day in rats and $50 mg/kg/day in dogs in the 3-month studies (decreases in red blood cell count of 3% to 16% in rats and 11% to 37% in dogs), but were not seen in the 1-year studies at dosages up to

   50 mg/kg/day in rats and 40 mg/kg/day in dogs.

erythropoiesis, with evidence of reversibility after a 1 month recovery period.

1. 5. Liver changes consisted of increased liver weights in rats (3% to 175%) and dogs (12% to 50%) and hypertrophy of centrilobular hepatocytes (accompanied by ultrastructural evidence of smooth endoplasmic reticulum [SER] proliferation) in rats, findings which are known to occur with other compounds that bind to benzodiazepine receptors.
2. 6.

   Adrenal gland changes consisted of increased organ weights in rats (16% to 57%) and dogs (15% to 55%) primarily at $20 mg/kg/day and hypertrophy of the zona fasciculata in rats dosed for 3 months (predominantly at $30 mg/kg/day), findings which were reversible and were consistent with effects noted for other compounds of this class.

   In most toxicity studies with zaleplon, plasma concentrations of M2 exceeded that seen in human with the exception of those studies conducted in the dog. Since M2 exposure in dogs was low and variable at the highest dosages used in the 3-month (200 mg/kg/day) and

   1-year (40 mg/kg/day) dog toxicity studies, a separate oral toxicity study was conducted in dogs with administration of M2. No compound-related effects were observed in dogs administered the M2 metabolite at oral dosages up to 4 mg/kg/day for 1 month.

   The nonclinical toxicity profile of zaleplon in repeated-dose studies was characterized by findings generally attributable to the exaggerated pharmacological effects of the compound. Zaleplon exposure in the toxicity studies was well in excess of that observed in humans.

Carcinogenicity

Zaleplon was not carcinogenic in rats at dietary dosage levels of 1, 10, or 20 mg/kg/day for 104 consecutive weeks. These dosages resulted in plasma AUC values of zaleplon that were approximately 6-, 88-, and 240-fold higher than those in humans at 10 mg/day. Zaleplon induced no tumorigenic changes considered relevant to human safety in mice at dietary dosage levels of

25, 50, 100, or 200 mg/kg/day for 104 consecutive weeks. These dosages resulted in plasma levels of zaleplon that were approximately 15-, 36-, 83- and either 225- (males) or 59-fold (females)

higher than those in humans at 10 mg/day. An increased incidence of hepatocellular adenomas occurred in female mice at 100 and 200 mg/kg/day in this study and in male mice at 200 mg/kg/day in a 65-week study. There was no increase in hepatocellular carcinomas. The increased incidence of hepatocellular adenomas in mice was correlated with increased body weight gain and enzyme induction, hepatocyte enlargement, and hepatomegaly at these high dosage levels, and is not considered to be relevant to human safety under the anticipated therapeutic regimen.

Mutagenicity

Zaleplon was positive in vitro for chromosomal aberrations in rodent cells, but was negative in vitro for chromosomal aberrations in human cells. Zaleplon was negative in microbial mutagenicity assays with Salmonella typhimurium (Ames) and Escherichia coli, in a mammalian cell gene mutation assay, in the unscheduled DNA synthesis (UDS) assay, and in three in vivo tests

(mouse micronucleus test, rat cytogenetics assay, UDS assay in rat liver). Plasma levels of zaleplon at the highest dosages in the in vivo studies were 2000- to 7000- fold higher than those in humans at 10 mg/day.

Reproductive Toxicity

Zaleplon was evaluated in a fertility and general reproductive performance study in the rat. On the basis of results obtained in the fertility and general reproductive performance study, additional fertility studies were conducted in male or female rats. Zaleplon was evaluated in developmental toxicity studies in the rat and rabbit, and in a perinatal and postnatal development study in the rat.

On the basis of results obtained in the perinatal and postnatal study (a decrease in pup viability index), a perinatal and postnatal cross-fostering study was conducted in rats.

Impairment of Fertility

A slight reduction in fertility index occurred in rats at an oral dosage of 100 mg/kg/day. In follow-up fertility studies, zaleplon caused a slight reduction in female (but not male) fertility index at 100 mg/kg/day. A dosage of 10 mg/kg/day in female rats, where no reduction in fertility index occurred, was associated with AUC values of zaleplon that were approximately 100- to 180-fold higher than those in humans at a zaleplon dosage of 10 mg/day.

Teratogenic Effects

In developmental toxicity studies, zaleplon was not teratogenic at oral dosages up to 100 mg/kg/day in rats or 50 mg/kg/day in rabbits. These dosages in pregnant rats and rabbits resulted in plasma levels of zaleplon that were 2400- and 300-fold higher, respectively, than that in humans at 10 mg/day.

Non-teratogenic Effects

In a perinatal and postnatal reproductive study in rats, reductions in pup survival occurred primarily during postpartum days 0 to 4 at dosages of 7 or 50 mg/kg/day. No pup effects occurred at a dosage of 1 mg/kg/day, for which plasma exposure to zaleplon in the dams was 5-fold higher than in human at 10 mg/day. The results of a subsequent cross-fostering study in rats indicated that reduced neonatal survival was likely attributable to both decreased maternal nursing/lactation behaviour and direct toxicity to pups that were exposed to zaleplon in utero or as a result of nursing.

SELECTED REFERENCES

1.

1.

2.

(Protocol No. 0897A1-101-UK)

3.

)

4.

5.

6.

1. 7. Hurst M, Noble S. Zaleplon. CNS Drugs, 1999;11(5):327-409.

8.

115-FR)

9.

S)

(Japanese protocol L846-PSS/940620)

(Japanese studies L846/230992 and L846/240192)

)

No. 0897A1-134-NE)

211-US)