zolpidem tartrate 5 MG Oral Tablet

INDICATIONS AND USAGE Zolpidem tartrate tablets,USP are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets, USP have been shown to decrease sleep latency for up to 35 days in controlled clinical studies [see CLINICAL STUDIES (14) ]. The clinical trials performed in support of efficacy were 4 to 5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment. Zolpidem tartrate tablets, USP are a gamma-aminobutyric acid (GABA) A agonist, is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets, USP have been shown to decrease sleep latency for up to 35 days in controlled clinical studies. ( 1 )

DOSAGE AND ADMINISTRATION Zolpidem Tartrate Capsules are only available in 7.5 mg strength. Use another zolpidem tartrate immediate-release product for 5 mg or 10 mg dosage ( 2.1 ) Avoid use of Zolpidem Tartrate Capsules in geriatric patients ( 2.1 ) Recommended dosage of zolpidem tartrate (use the lowest effective zolpidem tartrate dosage): Females: The recommended starting dosage of zolpidem tartrate immediate-release in females is 5 mg once nightly. Use another zolpidem tartrate immediate-release product for dosage initiation in females ( 2.1 , 2.2 , 8.6 ) Males: The recommended starting dosage of zolpidem tartrate immediate-release in males is either zolpidem tartrate immediate-release 5 mg, Zolpidem Tartrate Capsules 7.5 mg, or zolpidem tartrate immediate-release 10 mg, once nightly. Use another zolpidem tartrate immediate-release product for 5 mg and 10 mg dosing ( 2.2 ) In both males and females: If a 5 mg nightly dose of another zolpidem tartrate immediate-release product is not effective, the zolpidem tartrate dosage may be increased to Zolpidem Tartrate Capsules 7.5 mg once nightly or 10 mg once nightly of another zolpidem tartrate immediate-release product. The maximum recommended dosage of zolpidem tartrate immediate-release is 10 mg once nightly ( 2.2 ) Zolpidem Tartrate Capsules are for short-term use only ( 2.3 ) Administer Zolpidem Tartrate Capsules orally once per night immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening ( 2.4 ) Zolpidem Tartrate Capsules should not be taken with or immediately after a meal. Swallow whole. Do not open, crush, or chew ( 2.4 ) Lower doses of CNS depressants may be necessary when taken concomitantly with Zolpidem Tartrate Capsules ( 2.5 ) 2.1 Important Dosage Information Zolpidem Tartrate Capsules are only available in a 7.5 mg strength. Use another zolpidem tartrate immediate-release product for the 5 mg or 10 mg dose of zolpidem tartrate immediate-release. Refer to the Prescribing Information of other zolpidem tartrate immediate-release products for the recommended dosage for those products. Zolpidem Tartrate Capsules are not indicated in geriatric patients. Avoid use of Zolpidem Tartrate Capsules in geriatric patients because the recommended dosage in these patients cannot be achieved with the Zolpidem Tartrate Capsules 7.5 mg strength [see Use in Specific Populations ( 8.5 )] . Use another zolpidem tartrate product for geriatric patients. The recommended starting dosage for females is different than males because zolpidem clearance is lower in females [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . Do not use Zolpidem Tartrate Capsules to initiate zolpidem tartrate treatment in females because the recommended starting dosage in females cannot be achieved with the Zolpidem Tartrate Capsules 7.5 mg strength. Use another zolpidem tartrate immediate-release product to initiate treatment in females [see Dosage and Administration ( 2.2 )] . Avoid Zolpidem Tartrate Capsules in patients with mild or moderate hepatic impairment because the recommended dosage in such patients cannot be achieved with the Zolpidem Tartrate Capsules 7.5 mg strength [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . Avoid any zolpidem tartrate use in patients with severe hepatic impairment because its use may contribute to encephalopathy [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] . 2.2 Recommended Dosage Use the lowest effective zolpidem tartrate dosage. For instructions on administration of Zolpidem Tartrate Capsules, see Dosage and Administration ( 2.4 ) . The recommended starting dosage of zolpidem tartrate immediate-release in females is 5 mg once nightly. Use another zolpidem tartrate immediate-release product for dosage initiation in females [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . The recommended starting dosage of zolpidem tartrate immediate-release in males is either zolpidem tartrate immediate-release 5 mg, Zolpidem Tartrate Capsules 7.5 mg, or zolpidem tartrate immediate-release 10 mg, once nightly. In both males and females, if a 5 mg once nightly dose of another zolpidem tartrate immediate-release product is not effective, the zolpidem tartrate dosage may be increased to Zolpidem Tartrate Capsules 7.5 mg once nightly or 10 mg once nightly of another zolpidem tartrate immediate-release product. The maximum recommended dosage of zolpidem tartrate immediate-release is 10 mg once nightly. Zolpidem Tartrate Capsules should be taken as a single dose and should not be readministered during the same night. 2.3 Recommended Duration of Treatment Zolpidem Tartrate Capsules are for short-term use only. Re-evaluate the patient’s status during treatment because the risk of abuse and dependence increases with duration of treatment [see Drug Abuse and Dependence ( 9.3 )] . 2.4 Administration Instructions Administer Zolpidem Tartrate Capsules orally once per night immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening [see Warnings and Precautions ( 5.2 )] . Zolpidem Tartrate Capsules should not be administered with food or immediately after a meal [see Clinical Pharmacology ( 12.3 )] . Swallow Zolpidem Tartrate Capsules whole; do not open, crush, or chew. 2.5 Dosage Modifications with CNS Depressants Dosage modifications may be necessary when Zolpidem Tartrate Capsules are combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions ( 5.2 , 5.7 )] . Use another zolpidem tartrate immediate-release product for the 5 mg dosage of zolpidem tartrate immediate-release. Refer to the Prescribing Information of other zolpidem tartrate immediate-release products for the recommended dosage for those products.

WARNINGS AND PRECAUTIONS CNS-Depressant Effects: Impairs alertness and motor coordination including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Caution patients against driving and other activities requiring mental alertness the morning after use. Instruct patients on correct use. ( 5.2 ) Need to Evaluate for Comorbid Diagnoses: Re-evaluate if insomnia persists after 7 to 10 days of use. ( 5.3 ) Severe Anaphylactic/Anaphylactoid Reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. ( 5.4 ) Abnormal Thinking and Behavioral Changes: Changes including decreased inhibition, bizarre behavior, agitation, and depersonalization have been reported. Immediately evaluate any new onset behavioral changes. ( 5.5 ) Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose. ( 5.6 ) Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function. ( 5.7 ) Hepatic Impairment: Avoid Zolpidem Tartrate Tablets use in patients with severe hepatic impairment. ( 5.8 ) Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation. ( 5.9 , 9.3 ) 5.1 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 Zolpidem Tartrate Tablets. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a fatal outcome. 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. Postmarketing reports have shown that complex sleep behaviors may occur with Zolpidem Tartrate Tablets alone at recommended doses, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants [see Drug Interaction ( 7.1 )]. Discontinue Zolpidem Tartrate Tablets immediately if a patient experiences a complex sleep behavior [see Contraindications ( 4 )]. 5.2 CNS-Depressant Effects and Next-Day Impairment Zolpidem Tartrate Tablets, like other sedative-hypnotic drugs, has CNS-depressant effects. Coadministration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression [see Drug Interaction ( 7.1 )]. Dosage adjustments of Zolpidem Tartrate Tablets and of other concomitant CNS depressants may be necessary when Zolpidem Tartrate Tablets is administered with such agents because of the potentially additive effects. The use of Zolpidem Tartrate Tablets with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see Dosage and Administration ( 2.3 )] The risk of next-day psychomotor impairment, including impaired driving, is increased if Zolpidem Tartrate Tablets 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 zolpidem. Patients should be warned against driving and other activities requiring complete mental alertness if Zolpidem Tartrate Tablets is taken in these circumstances [see Dosage and Administration ( 2 ), Clinical Studies ( 14.3 )] 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 Zolpidem Tartrate Tablets can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls. 5.3 Need to Evaluate for Comorbid 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 zolpidem. 5.4 Severe Anaphylactic and Anaphylactoid Reactions 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 zolpidem. 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 throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zolpidem should not be rechallenged with the drug. 5.5 Abnormal Thinking and Behavioral Changes Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including Zolpidem Tartrate Tablets. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization. Visual and auditory hallucinations have been reported. In controlled trials of Zolpidem Tartrate Tablets 10 mg taken at bedtime <1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with Zolpidem Tartrate Tablets 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific Populations ( 8.4 )]. There have been postmarketing reports of delirium with zolpidem use [Adverse Reactions ( 6.2 )] . 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. 5.6 Use in Patients with Depression In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time. 5.7 Respiratory Depression Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%, was observed in patients with mild to moderate sleep apnea when treated with zolpidem compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if Zolpidem Tartrate Tablets is prescribed to patients with compromised respiratory function or concomitant use with opioids or other CNS depressants. Postmarketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported

CONTRAINDICATIONS Patients who have experienced complex sleep behaviors after taking zolpidem tartare tablets ( 4 ) Known hypersensitivity to zolpidem ( 4 ) Zolpidem tartrate tablets are contraindicated in patients Zolpidem tartrate tablets are contraindicated in patients who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions ( 5.4 )].

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Zolpidem is a GABA A receptor positive modulator presumed to exert its therapeutic effects in the short-term treatment of insomnia through binding to the benzodiazepine site of α1 subunit containing GABA A receptors, increasing the frequency of chloride channel opening resulting in the inhibition of neuronal excitation. 12.2 Pharmacodynamics Zolpidem binds to GABA A receptors with greater affinity for α1 subunit relative to α2 and α3 subunit containing receptors. Zolpidem has no appreciable binding affinity for α5 subunit containing GABA A receptors. This binding profile may explain the relative absence of myorelaxant effects in animal studies. Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5HT 2 , adrenergic, histaminergic or muscarinic receptors. 12.3 Pharmacokinetics The pharmacokinetic profile of zolpidem tartrate tablets is characterized by rapid absorption from the gastrointestinal tract and a short elimination half-life (T 1/2 ) in healthy subjects. In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate tablets, the mean peak concentrations (C max ) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (T max ) of 1.6 hours for both. The mean zolpidem tartrate tablets elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. Zolpidem tartrate is converted to inactive metabolites that are eliminated primarily by renal excretion. Zolpidem tartrate tablets demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks. A food-effect study in 30 healthy male subjects compared the pharmacokinetics of zolpidem tartrate tablets 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and C max were decreased by 15% and 25%, respectively, while mean T max was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, zolpidem tartrate tablets should not be administered with or immediately after a meal. Special Populations Elderly In the elderly, the dose for zolpidem tartrate tablets should be 5 mg [see Warnings and Precautions (5) , Dosage and Administration (2) ]. This recommendation is based on several studies in which the mean C max , T 1/2 , and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (>70 years), the means for C max , T 1/2 , and AUC significantly increased by 50% (255 vs 384 ng/mL), 32% (2.2 vs 2.9 hr), and 64% (955 vs 1,562 ng·hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose. Zolpidem tartrate tablets did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week. Hepatic impairment The pharmacokinetics of zolpidem tartrate tablets in eight patients with chronic hepatic insufficiency was compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose, mean C max and AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs 4,203 ng·hr/mL) higher, respectively, in hepatically compromised patients. T max did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr) [see Dosage and Administration (2.2) , Warnings and Precautions (5.8) , Use in Specific Populations (8.7) ]. Renal impairment The pharmacokinetics of zolpidem tartrate was studied in 11 patients with end-stage renal failure (mean Cl Cr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for C max , T max , half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics was not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function. Drug Interactions CNS depressants Coadministration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (5.2)]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance. A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict the absence of an effect following chronic administration. An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.2) ]. Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem C max was significantly higher (43%) and T max was significantly decreased (-53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem. A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at steady state and the concentrations evaluated in healthy females, an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance. Drugs that affect drug metabolism via cytochrome P450 Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown. A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-state levels in male volunteers resulted in a 34% increase in AUC 0-∞ of zolpidem tartrate. There were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance. A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects showed significant reductions of the AUC (-73%), C max (-58%), and T 1/2 (-36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem [see Drug Interactions (7.2) ]. Similarly, St. John’s wort, a CYP3A4 inducer, may also decrease the blood levels of zolpidem. A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased C max of zolpidem (30%) and the total AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life (30%) along with an increase in the pharmacodynamic effects of zolpidem [see Drug Interactions (7.2) ]. Additionally, fluvoxamine (a strong i