Label: ZALEPLON capsule

Zaleplon is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. The chemical name of zaleplon is N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide. Its empirical formula is C17H15N5O, and its molecular weight is 305.34. The structural formula is shown below.
 

Zaleplon is a white to off-white powder that is practically insoluble in water and sparingly soluble in alcohol or propylene glycol. Its partition coefficient in octanol/water is constant (log PC = 1.23) over the pH range of 1 to 7.

Zaleplon capsules contain zaleplon as the active ingredient. Inactive ingredients consist of microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, sodium lauryl sulfate, magnesium stearate, lactose, gelatin, titanium dioxide, FD&C blue #1, FD&C red #40 and black iron oxide. Zaleplon 5mg capsules also contain FD&C yellow #5.

Pharmacodynamics and Mechanism of Action

While Zaleplon is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor complex. Subunit modulation of the GABA-BZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models.

Other nonclinical studies have also shown that zaleplon binds selectively to the brain omega-1 receptor situated on the alpha subunit of the GABAA/chloride ion channel receptor complex and potentiates t-butyl-bicyclophosphorothionate (TBPS) binding. Studies of binding of zaleplon to recombinant GABAA receptors (α1β1γ2 [omega-1] and α2β1γ2 [omega-2]) have shown that zaleplon has a low affinity for these receptors, with preferential binding to the omega-1 receptor.

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 (tmax) of approximately 1 hour and a terminal-phase elimination half-life (t1/2) 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 desethyl zaleplon, 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 t1/2 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 radio labeled 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 tmax by approximately 2 hours and reducing Cmax 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, Cmax 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 Cmax 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.

Drug-Drug Interactions

Because zaleplon is primarily metabolized by aldehyde oxidase, and to a lesser extent by CYP3A4, inhibitors of these enzymes might be expected to decrease zaleplon's clearance and inducers of these enzymes might be expected to increase its clearance. Zaleplon has been shown to have minimal effects on the kinetics of warfarin (both R- and S-forms), imipramine, ethanol, ibuprofen, diphenhydramine, thioridazine, and digoxin. However, the effects of zaleplon on inhibition of enzymes involved in the metabolism of other drugs have not been studied. (See Drug Interactions under PRECAUTIONS).

Clinical Trials

Controlled Trials Supporting Effectiveness

Zaleplon (typically administered in doses of 5 mg, 10 mg, or 20 mg) has been studied in patients with chronic insomnia (n = 3,435) in 12 placebo- and active-drug-controlled trials. Three of the trials were in elderly patients (n=1,019). It has also been studied in transient insomnia (n=264). Because of its very short half-life, studies focused on decreasing sleep latency, with less attention to duration of sleep and number of awakenings, for which consistent differences from placebo were not demonstrated. 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 mg and 10 mg) with placebo. Zaleplon 10 mg, but not 5 mg, was superior to placebo in decreasing latency to persistent sleep (LPS), a polysomnographic measure of time to onset of sleep.

Chronic Insomnia

Non-elderly 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 studies), 10 mg, and 20 mg with placebo on a subjective measure of time to sleep onset (TSO). Zaleplon 10 mg and 20 mg were consistently superior to placebo for TSO, generally for the full duration of all three studies. 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 were the 10-mg and 20-mg doses. Sleep latency with Zaleplon 10 mg and 20 mg was on the order of 10-20 minutes (15%-30%) less than with placebo in these studies.

Adult outpatients with chronic insomnia were evaluated in six double-blind, parallel-group sleep laboratory studies that varied in duration from a single night up to 35 nights. Overall, these studies demonstrated a superiority of Zaleplon 10 mg and 20 mg over placebo in reducing LPS on the first 2 nights of treatment. At later time points in 5-, 14-, and 28-night studies, a reduction in LPS from baseline was observed for all treatment groups, including the placebo group, and thus, a significant difference between Zaleplon and placebo was not seen beyond 2 nights. In a 35-night study, Zaleplon 10 mg was significantly more effective than placebo in reducing LPS at the primary efficacy endpoint on nights 29 and 30.

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). Zaleplon at both doses was superior to placebo on TSO, generally for the full duration of both studies, with an effect size generally similar to that seen in younger persons. The 10-mg dose tended to have a greater effect in reducing TSO.

Elderly outpatients with chronic insomnia were also evaluated in a 2-night sleep laboratory study involving doses of 5 mg and 10 mg. Both 5-mg and 10-mg doses of Zaleplon were superior to placebo in reducing latency to persistent sleep (LPS).

Generally in these studies, there was a slight increase in sleep duration, compared to baseline, for all treatment groups, including placebo, and thus, a significant difference from placebo on sleep duration was not demonstrated.

Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs

Memory Impairment

Studies involving the exposure of normal subjects to single fixed doses of Zaleplon (10 mg or 20 mg) with structured assessments of short-term memory at fixed times after dosing (eg, 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 Zaleplon 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 Zaleplon (10 mg 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 Zaleplon 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 hypnotics 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 is believed to be responsible for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics: increased wakefulness during the last quarter of the night and the appearance of increased signs of daytime anxiety.

Zaleplon has a short half-life and no active metabolites. At the primary efficacy endpoint (nights 29 and 30) in a 35-night sleep laboratory study, polysomnographic recordings showed that wakefulness was not significantly longer with Zaleplon than with placebo during the last quarter of the night. No increase in the signs of daytime anxiety was observed in clinical trials with Zaleplon. In two sleep laboratory studies involving 14- and 28-nightly doses of Zaleplon (5 mg and 10 mg in one study and 10 mg and 20 mg in the second) and structured assessments of daytime anxiety, no increases in daytime anxiety were detected. Similarly, in a pooled analysis (all the parallel-group, placebo-controlled studies) of spontaneously reported daytime anxiety, no difference was observed between Zaleplon and placebo.

Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters (latency, total sleep time, and number of awakenings) compared to baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. Rebound insomnia following discontinuation of Zaleplon relative to baseline was examined at both nights 1 and 2 following discontinuation in three sleep laboratory studies (14, 28, and 35 nights) and five outpatient studies utilizing patient diaries (14 and 28 nights). Overall, the data suggest that rebound insomnia may be dose dependent. At 20 mg, there appeared to be both objective (polysomnographic) and subjective (diary) evidence of rebound insomnia on the first night after discontinuation of treatment with Zaleplon. At 5 mg and 10 mg, there was no objective and minimal subjective evidence of rebound insomnia on the first night after discontinuation of treatment with Zaleplon. At all doses, the rebound effect appeared to resolve by the second night following withdrawal. In the 35-night study, there was a worsening in sleep on the first night off for both the 10-mg and 20-mg groups compared to placebo, but not to baseline. This discontinuation-emergent effect was mild, had the characteristics of the return of the symptoms of chronic insomnia, and appeared to resolve by the second night after zaleplon discontinuation.

Other Withdrawal-Emergent Phenomena

The potential for other withdrawal phenomena was also assessed in 14- to 28-night 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 then 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 mg, 10 mg, 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.

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 (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.

Hypersensitivity to zaleplon or any excipients in the formulation (see also PRECAUTIONS).

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 (see DOSAGE AND ADMINISTRATION).

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 (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 Thinking and Behavioral Changes

Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with Zaleplon alone at therapeutic doses, the use of alcohol and other CNS depressants with Zaleplon appears to increase the risk of such behaviors, as does the use of Zaleplon at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zaleplon should be strongly considered for patients who report a "sleep-driving" episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.

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.

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 (see DRUG ABUSE AND DEPENDENCE).

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. 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, including potential impairment of the performance of such activities that may occur the day following ingestion of Zaleplon. Zaleplon, as well as other hypnotics, may produce additive CNS-depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, narcotic analgesics, anesthetics, ethanol, and other drugs that themselves produce CNS depression. Zaleplon should not be taken with alcohol. Dosage adjustment may be necessary when Zaleplon is administered with other CNS-depressant agents because of the potentially additive effects.

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.

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.

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 REACTIONSsection. 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, circumoralparesthesia, 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.

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.

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.

Loss of consciousness, in addition to signs and symptoms consistent with CNS depressants as described above, have been reported following zaleplon overdose. Individuals have fully recovered from zaleplon overdoses of greater than 200 mg (10 times the maximum recommended dose of zaleplon). Rare instances of fatal outcomes following overdose with zaleplon, most often associated with overdose of additional CNS depressants, have been reported.

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.

Poison Control Center

As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.

The dose of Zaleplon should be individualized. The recommended dose of Zaleplon 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 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 (see PRECAUTIONS). 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 (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. 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 (see Drug Interactions  under PRECAUTIONS).

Zaleplon capsules 5 mg are available as hard gelatin capsules with light blue cap and light blue body imprinted with "ASC" on cap and "210" on the body in black ink along the horizontal axis.
Bottles of 30's: NDC 67877-210-30
Bottles of 100's: NDC 67877-210-01
Bottles of 500's: NDC 67877-210-05
 
Zaleplon capsules 10 mg are available as hard gelatin capsules with dark blue cap and dark blue body imprinted with "ASC" on cap and "211" on the body in black ink along the horizontal axis.
Bottles of 100's: NDC 67877-211-01
Bottles of 500's: NDC 67877-211-05
Bottles of 1000's: NDC 67877-211-10

STORAGE CONDITIONS
Store at controlled room temperature, 20°C to 25°C (68°F to 77°F) [see USP].
Dispense in a light-resistant container as defined in the USP.
 
Manufactured by:
UNICHEM LABORATORIES LTD.
Pilerne Ind. Estate, Pilerne,
Bardez, Goa 403 511, India
 
Marketed by:
Ascend Laboratories, LLC
Montvale, NJ 07645

Zaleplon Capsules C-IV

Read this Medication Guide before you start taking Zaleplon and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. You and your doctor should talk about Zaleplon when you start taking it and at regular checkups.
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What is the most important information I should know about Zaleplon?

After taking Zaleplon, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with Zaleplon.

Reported activities include:

• driving a car ("sleep-driving")
• making and eating food
• talking on the phone
• having sex
• sleep-walking

Important:

1. Take Zaleplon exactly as prescribed
   • Do not take more Zaleplon than prescribed.
   • Take Zaleplon right before you get in bed, not sooner.
2. Do not take Zaleplon if you:
   • drink alcohol
   • take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take Zaleplon with your other medicines
   • cannot get a full night’s sleep
3. Call your doctor right away if you find out that you have done any of the above activities after taking Zaleplon.

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What is Zaleplon?

Zaleplon is a sedative-hypnotic (sleep) medicine. Zaleplon is used in adults for the short-term treatment of the symptom of trouble falling asleep from insomnia. Zaleplon does not treat other symptoms of insomnia which include waking up too early in the morning and waking up often during the night.

Zaleplon is not for children.

Zaleplon is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep Zaleplon in a safe place to prevent misuse and abuse. Selling or giving away Zaleplon may harm others, and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.

Who should not take Zaleplon?

Do not take Zaleplon if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in Zaleplon.

Zaleplon may not be right for you. Before starting Zaleplon, tell your doctor about all of your health conditions, including if you:

• have a history of depression, mental illness, or suicidal thoughts
• have a history of drug or alcohol abuse or addiction
• have kidney or liver disease
• have a lung disease or breathing problems
• are pregnant, planning to become pregnant, or breastfeeding

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact, sometimes causing side effects. Do not take Zaleplon with other medicines that can make you sleepy.

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.

How should I take Zaleplon?

• Take Zaleplon exactly as prescribed. Do not take more Zaleplon than prescribed for you.
• Take Zaleplon right before you get into bed. Or you can take Zaleplon after you have been in bed and have trouble falling asleep
• Do not take Zaleplon with or right after a meal.
• Do not take Zaleplon unless you are able to get a full night’s sleep before you must be active again.
• Call your healthcare provider if your insomnia worsens or is not better within 7 to10 days. This may mean that there is another condition causing your sleep problem.
• If you take too much Zaleplon or overdose, call your doctor or poison control center right away, or get emergency treatment.

What are the possible side effects of Zaleplon?

Serious side effects of Zaleplon include:

• getting out of bed while not being fully awake and do an activity that you do not know you are doing. (See "What is the most important information I should know about Zaleplon?")
• abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.
• memory loss
• anxiety
• severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking Zaleplon.

Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using Zaleplon.

Common side effects of Zaleplon include:

• drowsiness
• lightheadedness
• dizziness
• "pins and needles" feeling on your skin
• difficulty with coordination
• You may still feel drowsy the next day after taking Zaleplon. Do not drive or do other dangerous activities after taking Zaleplon until you feel fully awake.
• You may have withdrawal symptoms when you stop taking Zaleplon. Withdrawal symptoms include unpleasant feelings, stomach and muscle cramps, vomiting, sweating, shakiness, and rarely seizures. You may also have more trouble sleeping the first few nights after Zaleplon is stopped. The problem usually goes away on its own after 1 or 2 nights.

These are not all the side effects of Zaleplon. Ask your doctor or pharmacist for more information.

How should I store Zaleplon?

• Store Zaleplon at room temperature between 68° and 77° F (20° to 25°C) [see USP].
• Protect from light.
• Keep Zaleplon and all medicines out of the reach of children.

General Information about Zaleplon

• Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide.
• Do not use Zaleplon for a condition for which it was not prescribed.
• Do not give Zaleplon to other people, even if they have the same condition. It may harm them and it is against the law.

This Medication Guide summarizes the most important information about Zaleplon. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Zaleplon that was written for healthcare professionals.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What are the ingredients in ZALEPLON?

Active Ingredient: zaleplon

Inactive Ingredients: microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, sodium lauryl sulfate, magnesium stearate, lactose, gelatin, titanium dioxide, FD&C blue #1, FD&C red #40 and black iron oxide. Zaleplon 5mg capsules also contain FD&C yellow #5.

• Zaleplon 5 mg –A hard gelatin capsule with light blue cap and light blue body imprinted with "ASC" on cap and "210" on the body in black ink along the horizontal axis.
• Zaleplon 10 mg - A hard gelatin capsule with dark blue cap and dark blue body imprinted with "ASC" on cap and "211" on the body in black ink along the horizontal axis.

Rx only

Manufactured by:
UNICHEM LABORATORIES LTD.
Pilerne Ind. Estate, Pilerne,
Bardez, Goa 403 511, India
 
Marketed by:
Ascend Laboratories, LLC
Montvale, NJ 07645
 This Medication guide has been approved by the U.S. Food and Drug Administration.

ZALEPLON CAPSULES 5 mg - Container Label

NDC 67877-210-30
ZALEPLONCIV
CAPSULES
5mg
Pharmacist:
dispense with Medication Guide
Rx Only
30 Capsules

ZALEPLON CAPSULES 10 mg - Container Label
  
NDC 67877-211-01
ZALEPLONCIV
CAPSULES
10 mg
Pharmacist:
Dispense with Medication Guide
Rx Only
100 Capsules