ZALEPLON: 381 Adverse Event Reports & Safety Profile

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

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 Placebo Zaleplon 5 mg or 10 mg Zaleplon 20 mg Preferred Term (n=344) (n=569) (n=297) Body as a whole Abdominal pain 3 6 6 Asthenia 5 5 7 Headache 35 30 42 Malaise < 1 < 1 2 Photosensitivity reaction < 1 < 1 1 Digestive system Anorexia < 1 < 1 2 Colitis 0 0 1 Nausea 7 6 8 Metabolic and nutritional Peripheral edema < 1 < 1 1 Nervous system Amnesia 1 2 4 Confusion < 1 < 1 1 Depersonalization < 1 < 1 2 Dizziness 7 7 9 Hallucinations < 1 < 1 1 Hypertonia < 1 1 1 Hypesthesia < 1 < 1 2 Paresthesia 1 3 3 Somnolence 4 5 6 Tremor 1 2 2 Vertigo < 1 < 1 1 Respiratory system Epistaxis < 1 < 1 1 Special senses Abnormal vision < 1 < 1 2 Ear pain 0 < 1 1 Eye pain 2 4 3 Hyperacusis < 1 1 2 Parosmia < 1 < 1 2 Urogenital system Dysmenorrhea 2 3 4 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.

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.

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. 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 (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 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 (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 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 (see DRUG ABUSE AND DEPENDENCE ).

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 Zaleplon 5 mg capsules contain 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 ). Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients (see WARNINGS ).

Laboratory Tests

There are no specific laboratory tests recommended.

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 known. There is no pharmacokinetic interaction between zaleplon and diphenhydramine following the administration of a single dose (10 mg and 50 mg, respectively) of each drug. However, because both of these compounds have CNS effects, an additive pharmacodynamic effect is possible.

Drugs That Inhibit Both Aldehyde

Oxidase and CYP3A4 Cimetidine: Cimetidine inhibits both aldehyde oxidase (in vitro) and CYP3A4 (in vitro and in vivo), the primary and secondary enzymes, respectively, responsible for zaleplon metabolism. Concomitant administration of zaleplon (10 mg) and cimetidine (800 mg) produced an 85% increase in the mean C max and AUC of zaleplon. An initial dose of 5 mg should be given to patients who are concomitantly being treated with cimetidine (see DOSAGE AND ADMINISTRATION ).

Drugs Highly

Bound to Plasma Protein Zaleplon is not highly bound to plasma proteins (fraction bound 60% 15%); therefore, the disposition of zaleplon is not expected to be sensitive to alterations in protein binding. In addition, administration of zaleplon to a patient taking another drug that is highly protein bound should not cause transient increase in free concentrations of the other drug. Drugs with a Narrow Therapeutic Index Digoxin: Zaleplon (10 mg) did not affect the pharmacokinetic or pharmacodynamic profile of digoxin (0.375 mg q24h for 8 days). Warfarin: Multiple oral doses of zaleplon (20 mg q24h for 13 days) did not affect the pharmacokinetics of warfarin (R+)- or (S-)-enantiomers or the pharmacodynamics (prothrombin time) following a single 25-mg oral dose of warfarin.

Drugs That Alter Renal Excretion

Ibuprofen: Ibuprofen is known to affect renal function and, consequently, alter the renal excretion of other drugs. There was no apparent pharmacokinetic interaction between zaleplon and ibuprofen following single dose administration (10 mg and 600 mg, respectively) of each drug. This was expected because zaleplon is primarily metabolized and renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose. Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Lifetime carcinogenicity studies of zaleplon were conducted in mice and rats. Mice received doses of 25 mg/kg/day, 50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day in the diet for two years. These doses are equivalent to 6 to 49 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m 2 basis. There was a significant increase in the incidence of hepatocellular adenomas in female mice in the high dose group. Rats received doses of 1 mg/kg/day, 10 mg/kg/day, and 20 mg/kg/day in the diet for two years. These doses are equivalent to 0.5 to 10 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m 2 basis. Zaleplon was not carcinogenic in rats.

Mutagenesis

Zaleplon was clastogenic, both in the presence and absence of metabolic activation, causing structural and numerical aberrations (polyploidy and endoreduplication), when tested for chromosomal aberrations in the in vitro Chinese hamster ovary cell assay. In the in vitro human lymphocyte assay, zaleplon caused numerical, but not structural, aberrations only in the presence of metabolic activation at the highest concentrations tested. In other in vitro assays, zaleplon was not mutagenic in the Ames bacterial gene mutation assay or the Chinese hamster ovary HGPRT gene mutation assay. Zaleplon was not clastogenic in two in vivo assays, the mouse bone marrow micronucleus assay and the rat bone marrow chromosomal aberration assay, and did not cause DNA damage in the rat hepatocyte unscheduled DNA synthesis assay. Impairment of Fertility In a fertility and reproductive performance study in rats, mortality and decreased fertility were associated with administration of an oral dose of zaleplon of 100 mg/kg/day to males and females prior to and during mating. This dose is equivalent to 49 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m 2 basis. Follow-up studies indicated that impaired fertility was due to an effect on the female. 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. Labor and Delivery Zaleplon has no established use in labor and delivery.

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.

Pediatric Use

The safety and effectiveness of zaleplon in pediatric patients have not been established.

Geriatric

Use A total of 628 patients in double-blind, placebo-controlled, parallel-group clinical trials who received zaleplon were at least 65 years of age; of these, 311 received 5 mg and 317 received 10 mg. In both sleep laboratory and outpatient studies, elderly patients with insomnia responded to a 5 mg dose with a reduced sleep latency, and thus 5 mg is the recommended dose in this population. During short-term treatment (14 night studies) of elderly patients with zaleplon, no adverse event with a frequency of at least 1% occurred at a significantly higher rate with either 5 mg or 10 mg zaleplon than with placebo.

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 liver are not known. There is no pharmacokinetic interaction between zaleplon and diphenhydramine following the administration of a single dose (10 mg and 50 mg, respectively) of each drug. However, because both of these compounds have CNS effects, an additive pharmacodynamic effect is possible.

Drugs That Inhibit Both Aldehyde

Oxidase and CYP3A4: Cimetidine: Cimetidine inhibits both aldehyde oxidase (in vitro) and CYP3A4 (in vitro and in vivo), the primary and secondary enzymes, respectively, responsible for zaleplon metabolism. Concomitant administration of zaleplon (10 mg) and cimetidine (800 mg) produced an 85% increase in the mean C max and AUC of zaleplon. An initial dose of 5 mg should be given to patients who are concomitantly being treated with cimetidine (see DOSAGE AND ADMINISTRATION ).

Drugs Highly

Bound to Plasma Protein: Zaleplon is not highly bound to plasma proteins (fraction bound 60%±15%); therefore, the disposition of zaleplon is not expected to be sensitive to alterations in protein binding. In addition, administration of zaleplon to a patient taking another drug that is highly protein bound should not cause transient increase in free concentrations of the other drug. Drugs with a Narrow Therapeutic Index: Digoxin: Zaleplon (10 mg) did not affect the pharmacokinetic or pharmacodynamic profile of digoxin (0.375 mg q24h for 8 days). Warfarin : Multiple oral doses of zaleplon (20 mg q24h for 13 days) did not affect the pharmacokinetics of warfarin (R+)- or (S-)-enantiomers or the pharmacodynamics (prothrombin time) following a single 25 mg oral dose of warfarin.

Drugs That Alter Renal

Excretion: Ibuprofen: Ibuprofen is known to affect renal function and, consequently, alter the renal excretion of other drugs. There was no apparent pharmacokinetic interaction between zaleplon and ibuprofen following single dose administration (10 mg and 600 mg, respectively) of each drug. This was expected because zaleplon is primarily metabolized and renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose.