Zaleplon 10 mg Capsule, 100-count — NDC 69452-365-20 (Billing 69452-0365-20)

WARNINGS 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 . Coadministration 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 (see DOSAGE AND ADMINISTRATION ). 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 coadministered with other CNS depressants or alcohol; or if coadministered 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 (see DOSAGE AND ADMINISTRATION and Clinical Trials under CLINICAL PHARMACOLOGY ). 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 (see DOSAGE AND ADMINISTRATION ).

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… [Excerpted — this section continues on DailyMed.]

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 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… [Excerpted — this section continues on DailyMed.]

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; zaleplon did not affect the pharmacokinetics of ethanol.

Imipramine: Coadministration 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 pharmacokinetics of either drug. Paroxetine: Coadministration 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 pharmacokinetics of zaleplon, reflecting the absence of a role of CYP2D6 in zaleplon's metabolism. Thioridazine: Coadministration 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 alteration of the pharmacokinetics of either drug.

Venlafaxine: Coadministration of a single dose of zaleplon 10 mg and multiple doses of venlafaxine ER (extended release) 150 mg did not result in any significant changes in the pharmacokinetics of either zaleplon or venlafaxine. In addition, there was no pharmacodynamic interaction as a result of coadministration of zaleplon and venlafaxine ER. Promethazine: Coadministration of a single dose of zaleplon and promethazine (10 and 25 mg, respectively) resulted in a 15% decrease in maximal plasma concentrations of zaleplon, but no change in the area under the plasma concentration-time curve.

However, the pharmacodynamics of coadministration of zaleplon and promethazine have not been evaluated. Caution should be exercised when these 2 agents are coadministered. Drugs That Induce CYP3A4 Rifampin: CYP3A4 is ordinarily a minor metabolizing enzyme of zaleplon.

Multiple-dose administration of the potent CYP3A4 inducer rifampin (600 mg every 24 hours, q24h, for 14 days), however, reduced zaleplon C max and AUC by approximately 80%. The coadministration of a potent CYP3A4 enzyme inducer, although not posing a safety concern, thus could lead to ineffectiveness of zaleplon. An alternative non-CYP3A4 substrate hypnotic agent may be considered in patients taking CYP3A4 inducers such as rifampin, phenytoin, carbamazepine, and phenobarbital.

Drugs That Inhibit CYP3A4 CYP3A4 is 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, account for only 9% of the urinary recovery of a zaleplon dose. Coadministration of single, oral doses of zaleplon with erythromycin (10 mg and 800 mg respectively), a strong, selective CYP3A4 inhibitor, produced a 34% increase in zaleplon's maximal plasma concentrations and a 20% increase in the area under the plasma concentration-time curve.

The magnitude of interaction with multiple doses of erythromycin is unknown. Other strong selective CYP3A4 inhibitors such as ketoconazole can also be expected to increase the exposure of zaleplon. A routine dosage adjustment of zaleplon is not considered necessary.

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 weak inhibitor of aldehyde oxidase in rat liver, but its inhibitory effects in human liver are not kno… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Timing of Drug Administration Zaleplon 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 zaleplon while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness. Use in the Elderly and/or Debilitated Patients Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients.

A dose of 5 mg is recommended for elderly patients to decrease the possibility of side effects (see DOSAGE AND ADMINISTRATION ). Elderly and/or debilitated patients should be monitored closely. Use in Patients with Concomitant Illness Clinical experience with zaleplon in patients with concomitant systemic illness is limited.

Zaleplon should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Although preliminary studies did not reveal respiratory depressant effects at hypnotic doses of zaleplon in normal subjects, caution should be observed if zaleplon is prescribed to patients with compromised respiratory function, because sedative/hypnotics have the capacity to depress respiratory drive. Controlled trials of acute administration of zaleplon 10 mg in patients with mild to moderate 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. The dose of zaleplon should be reduced to 5 mg in patients with mild to moderate hepatic impairment (see DOSAGE AND ADMINISTRATION ). It is not recommended for use in patients with severe hepatic impairment.

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. Use in Patients with Depression In primarily depressed patients treated with sedative-hypnotics, worsening of depression, including suicidal thoughts and actions (including completed suicides), have been reported.

As with other sedative/hypnotic drugs, zaleplon 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 OVERDOSAGE ); therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.

Allergic-Type Reactions FD&C Yellow No. 5 This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons.

Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Information for Patients A patient Medication Guide is also available for zaleplon.

The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions that they may have. Instruct patients and their families that zaleplon may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake.

Serious injuries and death have occurred during complex sleep behavior episodes. Tell patients to discontinue zaleplon and notify their healthcare provider immediately if they develop any of these symptoms (see BOXED WARNING and WARNINGS ). A… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE Controlled Substance Class Zaleplon is classified as a Schedule IV controlled substance by federal regulation. Abuse, Dependence, and Tolerance Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances.

Physical dependence is a state of adaption that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation 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.

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