Zaleplon

INDICATIONS AND USAGE Zaleplon capsules are indicated for the short-term treatment of insomnia. Zaleplon capsules have been shown to decrease the time to sleep onset for up to 30 days in controlled clinical studies (see Clinical Trials under CLINICAL PHARMACOLOGY ). It has not been shown to increase total sleep time or decrease the number of awakenings. The clinical trials performed in support of efficacy ranged from a single night to 5 weeks in duration. The final formal assessments of sleep latency were performed at the end of treatment.

DOSAGE AND ADMINISTRATION The dose of zaleplon capsules should be individualized. The recommended dose of zaleplon capsules for most nonelderly adults is 10 mg. For certain low weight individuals, 5 mg may be a sufficient dose. Although the risk of certain adverse events associated with the use of zaleplon capsules appears to be dose dependent, the 20 mg dose has been shown to be adequately tolerated and may be considered for the occasional patient who does not benefit from a trial of a lower dose. Doses above 20 mg have not been adequately evaluated and are not recommended. Zaleplon capsules should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep (see PRECAUTIONS ). Taking zaleplon capsules with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of zaleplon capsules on sleep latency (see Pharmacokinetics under CLINICAL PHARMACOLOGY ). Special Populations Elderly patients and debilitated patients appear to be more sensitive to the effects of hypnotics, and respond to 5 mg of zaleplon capsules. The recommended dose for these patients is therefore 5 mg. Doses over 10 mg are not recommended. Hepatic insufficiency: Patients with mild to moderate hepatic impairment should be treated with zaleplon capsules 5 mg because clearance is reduced in this population. Zaleplon capsules are not recommended for use in patients with severe hepatic impairment. Renal insufficiency: No dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon capsules have not been adequately studied in patients with severe renal impairment. An initial dose of 5 mg should be given to patients concomitantly taking cimetidine because zaleplon clearance is reduced in this population (see Drug Interactions under PRECAUTIONS ).

ADVERSE REACTIONS The premarketing development program for zaleplon included zaleplon exposures in patients and/or normal subjects from 2 different groups of studies: approximately 900 normal subjects in clinical pharmacology/pharmacokinetic studies; and approximately 2,900 exposures from patients in placebo-controlled clinical effectiveness studies, corresponding to approximately 450 patient exposure years. The conditions and duration of treatment with zaleplon varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs. Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, COSTART terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Findings Observed in Short-Term, Placebo-Controlled Trials Adverse Events Associated With Discontinuation of Treatment In premarketing placebo-controlled, parallel-group phase 2 and phase 3 clinical trials, 3.1% of 744 patients who received placebo and 3.7% of 2,149 patients who received zaleplon discontinued treatment because of an adverse clinical event. This difference was not statistically significant. No event that resulted in discontinuation occurred at a rate of ≥1%. Adverse Events Occurring at an Incidence of 1% or More Among Zaleplon 20 mg-Treated Patients Table 1 enumerates the incidence of treatment-emergent adverse events for a pool of three 28-night and one 35-night placebo-controlled studies of zaleplon at doses of 5 mg or 10 mg and 20 mg. The table includes only those events that occurred in 1% or more of patients treated with zaleplon 20 mg and that had a higher incidence in patients treated with zaleplon 20 mg than in placebo-treated patients. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. Table 1 Incidence (%) of Treatment-Emergent Adverse Events in Long-Term (28 and 35 Nights) Placebo-Controlled Clinical Trials of Zaleplon a a Events for which the incidence for zaleplon 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. Body System Placebo Zaleplon 5 mg or 10 mg Zaleplon 20 mg Preferred Term (n=344) (n=569) (n=297) Body as a whole Abdominal pain 3 6 6 Asthenia 5 5 7 Headache 35 30 42 Malaise <1 <1 2 Photosensitivity reaction <1 <1 1 Digestive system Anorexia <1 <1 2 Colitis 0 0 1 Nausea 7 6 8 Metabolic and nutritional Peripheral edema <1 <1 1 Nervous system Amnesia 1 2 4 Confusion <1 <1 1 Depersonalization <1 <1 2 Dizziness 7 7 9 Hallucinations <1 <1 1 Hypertonia <1 1 1 Hypesthesia <1 <1 2 Paresthesia 1 3 3 Somnolence 4 5 6 Tremor 1 2 2 Vertigo <1 <1 1 Respiratory system Epistaxis <1 <1 1 Special senses Abnormal vision <1 <1 2 Ear pain 0 <1 1 Eye pain 2 4 3 Hyperacusis <1 1 2 Parosmia <1 <1 2 Urogenital system Dysmenorrhea 2 3 4 Other Adverse Events Observed During the Premarketing Evaluation of Zaleplon Listed below are COSTART terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section. These events were reported by patients treated with zaleplon at doses in a range of 5 mg/day to 20 mg/day during premarketing phase 2 and phase 3 clinical trials throughout the United States, Canada, and Europe, including approximately 2,900 patients. All reported events are included except those already listed in Table 1 or elsewhere in labeling, those events for which a drug cause was remote, and those event terms that were so general as to be uninformative. It is important to emphasize that although the events reported occurred during treatment with zaleplon, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Body as a whole - Frequent: back pain, chest pain, fever; Infrequent: chest pain substernal, chills, face edema, generalized edema, hangover effect, neck rigidity. Cardiovascular system - Frequent : migraine; Infrequent : angina pectoris, bundle branch block, hypertension, hypotension, palpitation, syncope, tachycardia, vasodilatation, ventricular extrasystoles; Rare: bigeminy, cerebral ischemia, cyanosis, pericardial effusion, postural hypotension, pulmonary embolus, sinus bradycardia, thrombophlebitis, ventricular tachycardia. Digestive system - Frequent : constipation, dry mouth, dyspepsia; Infrequent : eructation, esophagitis, flatulence, gastritis, gastroenteritis, gingivitis, glossitis, increased appetite, melena, mouth ulceration, rectal hemorrhage , stomatitis; Rare: aphthous stomatitis, biliary pain, bruxism, cardiospasm, cheilitis, cholelithiasis, duodenal ulcer, dysphagia, enteritis, gum hemorrhage, increased salivation, intestinal obstruction, abnormal liver function tests, peptic ulcer, tongue discoloration, tongue edema, ulcerative stomatitis. Endocrine system - Rare : diabetes mellitus, goiter, hypothyroidism. Hemic and lymphatic system - Infrequent: anemia, ecchymosis, lymphadenopathy; Rare: eosinophilia, leukocytosis, lymphocytosis, purpura. Metabolic and nutritional - Infrequent: edema, gout, hypercholesteremia, thirst, weight gain; Rare: bilirubinemia, hyperglycemia, hyperuricemia, hypoglycemia, hypoglycemic reaction, ketosis, lactose intolerance, AST (SGOT) increased, ALT (SGPT) increased, weight loss. Musculoskeletal system - Frequent: arthralgia, arthritis, myalgia; Infrequent: arthrosis, bursitis, joint disorder (mainly swelling, stiffness, and pain), myasthenia, tenosynovitis; Rare: myositis, osteoporosis. Nervous system - Frequent: anxiety, depression, nervousness, thinking abnormal (mainly difficulty concentrating); Infrequent: abnormal gait, agitation, apathy, ataxia, circumoral paresthesia, emotional lability, euphoria, hyperesthesia, hyperkinesia, hypotonia, incoordination, insomnia, libido decreased, neuralgia, nystagmus; Rare: CNS stimulation, delusions, dysarthria, dystonia, facial paralysis, hostility, hypokinesia, myoclonus, neuropathy, psychomotor retardation, ptosis, reflexes decreased, reflexes increased, sleep talking, sleep walking, slurred speech, stupor, trismus. Respiratory system - Frequent: bronchitis; Infrequent: asthma, dyspnea, laryngitis, pneumonia, snoring, voice alteration; Rare: apnea, hiccup, hyperventilation, pleural effusion, sputum increased. Skin and appendages - Frequent: pruritus, rash; Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, skin hypertrophy, sweating, urticaria, vesiculobullous rash; Rare: melanosis, psoriasis, pustular rash, skin discoloration. Special senses - Frequent: conjunctivitis, taste perversion; Infrequent: diplopia, dry eyes, photophobia, tinnitus, watery eyes; Rare: abnormality of accommodation, blepharitis, cataract specified, corneal erosion, deafness, eye hemorrhage, glaucoma, labyrinthitis, retinal detachment, taste loss, visual field defect. Urogenital system - Infrequent: bladder pain, breast pain, cystitis, decreased urine stream, dysuria, hematuria, impotence, kidney calculus, kidney pain, menorrhagia, metrorrhagia, urinary frequency, urinary incontinence, urinary urgency, vaginitis; Rare : albuminuria, delayed menstrual period, leukorrhea, menopause, urethritis, urinary retention, vaginal hemorrhage. Postmarketing Reports Anaphylactic/anaphylactoid reactions, including severe reactions, and nightmares.

Pharmacokinetics The pharmacokinetics of zaleplon have been investigated in more than 500 healthy subjects (young and elderly), nursing mothers, and patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile has been examined after single doses of up to 60 mg and once-daily administration at 15 mg and 30 mg for 10 days. Zaleplon was rapidly absorbed with a time to peak concentration (t max ) of approximately 1 hour and a terminal-phase elimination half-life (t 1/2 ) of approximately 1 hour. Zaleplon does not accumulate with once-daily administration and its pharmacokinetics are dose proportional in the therapeutic range. Absorption Zaleplon is rapidly and almost completely absorbed following oral administration. Peak plasma concentrations are attained within approximately 1 hour after oral administration. Although zaleplon is well absorbed, its absolute bioavailability is approximately 30% because it undergoes significant presystemic metabolism. Distribution Zaleplon is a lipophilic compound with a volume of distribution of approximately 1.4 L/kg following intravenous (IV) administration, indicating substantial distribution into extravascular tissues. The in vitro plasma protein binding is approximately 60%±15% and is independent of zaleplon concentration over the range of 10 ng/mL to 1000 ng/mL. This suggests that zaleplon disposition should not be sensitive to alterations in protein binding. The blood to plasma ratio for zaleplon is approximately 1, indicating that zaleplon is uniformly distributed throughout the blood with no extensive distribution into red blood cells. Metabolism After oral administration, zaleplon is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Zaleplon is primarily metabolized by aldehyde oxidase to form 5-oxo-zaleplon. Zaleplon is metabolized to a lesser extent by cytochrome P450 (CYP) 3A4 to form desethylzaleplon, which is quickly converted, presumably by aldehyde oxidase, to 5-oxo-desethylzaleplon. These oxidative metabolites are then converted to glucuronides and eliminated in urine. All of zaleplon's metabolites are pharmacologically inactive. Elimination After either oral or IV administration, zaleplon is rapidly eliminated with a mean t 1/2 of approximately 1 hour. The oral-dose plasma clearance of zaleplon is about 3 L/h/kg and the IV zaleplon plasma clearance is approximately 1 L/h/kg. Assuming normal hepatic blood flow and negligible renal clearance of zaleplon, the estimated hepatic extraction ratio of zaleplon is approximately 0.7, indicating that zaleplon is subject to high first-pass metabolism. After administration of a radiolabeled dose of zaleplon, 70% of the administered dose is recovered in urine within 48 hours (71% recovered within 6 days), almost all as zaleplon metabolites and their glucuronides. An additional 17% is recovered in feces within 6 days, most as 5-oxo-zaleplon. Effect of Food In healthy adults a high-fat/heavy meal prolonged the absorption of zaleplon compared to the fasted state, delaying t max by approximately 2 hours and reducing C max by approximately 35%. Zaleplon AUC and elimination half-life were not significantly affected. These results suggest that the effects of zaleplon on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal. Special Populations Age: The pharmacokinetics of zaleplon have been investigated in three studies with elderly men and women ranging in age from 65 to 85 years. The pharmacokinetics of zaleplon in elderly subjects, including those over 75 years of age, are not significantly different from those in young healthy subjects. Gender: There is no significant difference in the pharmacokinetics of zaleplon in men and women. Race: The pharmacokinetics of zaleplon have been studied in Japanese subjects as representative of Asian populations. For this group, C max and AUC were increased 37% and 64%, respectively. This finding can likely be attributed to differences in body weight, or alternatively, may represent differences in enzyme activities resulting from differences in diet, environment, or other factors. The effects of race on pharmacokinetic characteristics in other ethnic groups have not been well characterized. Hepatic impairment: Zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon was reduced by 70% and 87% in compensated and decompensated cirrhotic patients, respectively, leading to marked increases in mean C max and AUC (up to 4-fold and 7-fold in compensated and decompensated patients, respectively), in comparison with healthy subjects. The dose of zaleplon should therefore be reduced in patients with mild to moderate hepatic impairment (see DOSAGE AND ADMINISTRATION ). Zaleplon is not recommended for use in patients with severe hepatic impairment. Renal impairment: Because renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose, the pharmacokinetics of zaleplon are not altered in patients with renal insufficiency. No dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon has not been adequately studied in patients with severe renal impairment.