Zaleplon

Zaleplon is indicated for the short-term treatment of insomnia. Zaleplon has been shown to decrease the time to sleep onset for up to 30 days in controlled clinical studies . 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.

The dose of zaleplon should be individualized. The recommended dose of zaleplon for most non-elderly 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 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 should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep . Taking zaleplon with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of zaleplon on sleep latency . Special Populations Elderly patients and debilitated patients appear to be more sensitive to the effects of hypnotics, and respond to 5 mg of zaleplon. 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 5 mg because clearance is reduced in this population. Zaleplon is 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 has 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 .

Complex Sleep Behaviors Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following the first or any subsequent use of zaleplon. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a fatal outcome. a.

Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Post-marketing reports have shown that complex sleep behaviors may occur with zaleplon alone at recommended dosages, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants.

CNS-Depressant Effects and Next-Day Impairment Zaleplon, like other hypnotics, has CNS-depressant effects. Because of the rapid onset of action, zaleplon should only be ingested immediately prior to going to bed or after the patient has gone to bed and has experienced difficulty falling asleep. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression.

Dosage adjustments of zaleplon and of other concomitant CNS depressants may be necessary when zaleplon is administered with such agents because of the potentially additive effects. The use of zaleplon with other sedative-hypnotics at bedtime or the middle of the night is not recommended . The risk of next-day psychomotor impairment, including impaired driving, is increased if zaleplon is taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if co-administered with other CNS depressants or alcohol; or if co-administered with other drugs that increase the blood levels of zaleplon. Patients should be warned against driving and other activities requiring complete mental alertness if zaleplon is taken in these circumstances . Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness, and impaired driving the morning after therapy.

In order to minimize this risk a full night of sleep (7-8 hours) is recommended. Because zaleplon can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls. Need to Evaluate for Co-morbid Diagnoses 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 that 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 sedative/hypnotic drugs, including zaleplon.

Because some of the important adverse effects of zaleplon appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly . Severe Anaphylactic and Anaphylactoid Reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zaleplon. 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.

If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zaleplon should not be rechallenged with the drug. Abnormal Thinking and Behavioral Changes A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics.

Some of these changes may be characterized by decreased inhibition (e.g., 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. Amnesia and other neuropsychiatric symptoms may occur unpredictably.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is 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. Withdrawal Effects Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs .

Zalepon is contraindicated in patients: who have experienced complex sleep behaviors after taking zaleplon . with hypersensitivity to zaleplon or any excipients in the formulation .

Pregnancy In embryofetal development studies in rats and rabbits, oral administration of up to 100 mg/kg/day and 50 mg/kg/day, respectively, to pregnant animals throughout organogenesis produced no evidence of teratogenicity. These doses are equivalent to 49 (rat) and 48 (rabbit) times the maximum recommended human dose (MRHD) of 20 mg on a mg/m 2 basis. In rats, pre- and postnatal growth was reduced in the offspring of dams receiving 100 mg/kg/day.

This dose was also maternally toxic, as evidenced by clinical signs and decreased maternal body weight gain during gestation. The no-effect dose for rat offspring growth reduction was 10 mg/kg (a dose equivalent to 5 times the MRHD of 20 mg on a mg/m 2 basis). No adverse effects on embryofetal development were observed in rabbits at the doses examined.

In a pre- and postnatal development study in rats, increased stillbirth and postnatal mortality, and decreased growth and physical development, were observed in the offspring of females treated with doses of 7 mg/kg/day or greater during the latter part of gestation and throughout lactation. There was no evidence of maternal toxicity at this dose. The no-effect dose for offspring development was 1 mg/kg/day (a dose equivalent to 0.5 times the MRHD of 20 mg on a mg/m 2 basis).

When the adverse effects on offspring viability and growth were examined in a cross-fostering study, they appeared to result from both in utero and lactational exposure to the drug. There are no studies of zaleplon in pregnant women; therefore, zaleplon is not recommended for use in women during pregnancy.

Nursing Mothers A study in lactating mothers indicated that the clearance and half-life of zaleplon is similar to that in young normal subjects. A small amount of zaleplon is excreted in breast milk, with the highest excreted amount occurring during a feeding at approximately 1 hour after zaleplon administration. Since the small amount of the drug from breast milk may result in potentially important concentrations in infants, and because the effects of zaleplon on a nursing infant are not known, it is recommended that nursing mothers not take zaleplon.

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 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 Preferred Term Placebo (n=344) Zaleplon 5 mg or 10 mg (n=569) Zaleplon 20 mg (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.