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 ). They have 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 ).

CONTRAINDICATIONS Zaleplon capsules are contraindicated in patients: who have experienced complex sleep behaviors after taking zaleplon capsules (see WARNINGS ). with hypersensitivity to zaleplon or any excipients in the formulation (see 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 Body System Preferred Term Placebo (n = 344) Zaleplon 5 mg or 10 mg (n = 569) Zaleplon 20 mg (n = 297) 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 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 …

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: Co-administration of single doses of zaleplon 20 mg and imipramine 75 mg produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration. The interaction was pharmacodynamic with no alteration of the pharmacokinetics of either drug. Paroxetine: Co-administration of a single dose of zaleplon 20 mg and paroxetine 20 mg daily for 7 days did not produce any interaction on psychomotor performance. Additionally, paroxetine did not alter the pharmacokinetics of zaleplon, reflecting the absence of a role of CYP2D6 in zaleplon’s metabolism. Thioridazine: Co-administration of single doses of zaleplon 20 mg and thioridazine 50 mg produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration. The interaction was pharmacodynamic with no alteration of the pharmacokinetics of either drug. Venlafaxine: Co-administration 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 co-administration of zaleplon and venlafaxine ER. Promethazine: Co-administration 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 co-administration of zaleplon and promethazine have not been evaluated. Caution should be exercised when these 2 agents are co-administered. 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 co-administration 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, accounts for only 9% of the urinary recovery of a zaleplon dose. Co-administration 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 li …

DESCRIPTION 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 molecular formula is C 17 H 15 N 5 O, and its molecular weight is 305.34. The structural formula is shown below. Zaleplon, USP 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, USP are available for oral administration containing either 5 mg or 10 mg of zaleplon. Each capsule contains the following inactive ingredients: colloidal silicon dioxide, lactose (anhydrous), magnesium stearate, microcrystalline cellulose, pregelatinized starch and sodium lauryl sulfate. Each capsule shell contains: D&C Yellow #10, FD&C Blue #1, FD&C Yellow #6 (10 mg capsule shell only), gelatin, monogramming ink and titanium dioxide. The monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze. chem.jpg

OVERDOSAGE 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.

HOW SUPPLIED Zaleplon Capsules USP, 5 mg are Opaque green/opaque pale green colored, size ‘4’ hard gelatin capsule filled with white to off-white powder and imprinted with ‘E19’ on opaque green cap and ‘5 mg’ on opaque pale green body with black ink. Bottles of 100 NDC 65862-214-01 Bottles of 500 NDC 65862-214-05 Zaleplon Capsules USP, 10 mg are Opaque green/opaque light green colored, size ‘4’ hard gelatin capsule filled with white to off-white powder and imprinted with ‘E20’ on opaque green cap and ‘10 mg’ on opaque light green body with black ink. Bottles of 100 NDC 65862-215-01 Bottles of 500 NDC 65862-215-05 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a light-resistant container as defined in the USP. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 10/2021