e effect of decreased alertness and psychomotor performance [see clinical pharmacology (12.3) ]. haloperidol 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 [see clinical pharmacology (12.3) ]. alcohol an additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see warnings and precautions (5.1) ]. sertraline concomitant administration of zolpidem and sertraline increases exposure to zolpidem [see clinical pharmacology (12.3) ]. fluoxetine after multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life (17%) was observed. there was no evidence of an additive effect in psychomotor performance [see clinical pharmacology (12.3) ]. 7.2 drugs that affect drug metabolism via cytochrome p450 some compounds known to inhibit cyp3a may increase exposure to zolpidem. the effect of drugs on other p450 enzymes on the exposure to zolpidem is not known. rifampin rifampin, a cyp3a4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem. use of rifampin in combination with zolpidem may decrease the efficacy of zolpidem. ketoconazole ketoconazole, a potent cyp3a4 inhibitor, increased the pharmacodynamic effects of zolpidem. consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

atory function ( 5.6 ) • withdrawal effects: symptoms may occur with rapid dose reduction or discontinuation ( 5.7 , 9.3 ) 5.1 cns depressant effects and next-day impairment zolpidem tartrate extended-release are a central nervous system (cns) depressant and can impair daytime function in some patients even when used as prescribed. prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). while pharmacodynamic tolerance or adaptation to some adverse depressant effects of zolpidem tartrate extended-release may develop, patients using zolpidem tartrate extended-release should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use. additive effects occur with concomitant use of other cns depressants (e.g. benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. downward dose adjustment of zolpidem tartrate extended-release tablet are and concomitant cns depressants should be considered [see dosage and administration (2.3) ]. the use of zolpidem tartrate extended-release with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended. the risk of next-day psychomotor impairment is increased if zolpidem tartrate extended-release is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if co-administered with other cns depressants; or co-administered with other drugs that increase the blood levels of zolpidem [see dosage and administration (2) and clinical studies (14.2) ]. 5.2 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 zolpidem. 5.3 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. 5.4 abnormal thinking and behavioral changes abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including zolpidem tartrate extended-release. 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, <1% of adults with insomnia reported hallucinations. in a clinical trial, 7% of pediatric patients treated with zolpidem tartrate 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see use in specific populations (8.4) ]. complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. although behaviors such as "sleep-driving" have occurred with zolpidem tartrate extended-release alone at therapeutic doses, the co-administration of alcohol and other cns depressants increases the risk of such behaviors, as does the use of zolpidem tartrate extended-release at doses exceeding the maximum recommended dose. due to the risk to the patient and the community, discontinuation of zolpidem tartrate extended-release should be strongly considered for patients who report a "sleep-driving" episode. other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. as with "sleep-driving", patients usually do not remember these events. amnesia, anxiety and other neuro-psychiatric symptoms may also occur. 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. 5.5 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. 5.6 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 extended-release is prescribed to patients with compromised respiratory function. post-marketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported. the risk of respiratory depression should be considered prior to prescribing zolpidem tartrate extended-release in patients with respiratory impairment including sleep apnea and myasthenia gravis. 5.7 withdrawal effects there have been reports of withdrawal signs and symptoms following the rapid dose decrease or abrupt discontinuation of zolpidem. monitor patients for tolerance, abuse, and dependence [see drug abuse and dependence (9.2) and (9.3) ].

fore the planned time of awakening. if the 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. in some patients, the higher morning blood levels following use of the 12.5 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see warnings and precautions (5.1) ]. the total dose of zolpidem tartrate extended-release tablet, usp should not exceed 12.5 mg once daily immediately before bedtime. the recommended initial doses for women and men are different because zolpidem clearance is lower in women. 2.2 special populations elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. the recommended dose of zolpidem tartrate extended-release tablets in both of these patient populations is 6.25 mg once daily immediately before bedtime [see warnings and precautions (5.1) ; use in specific populations (8.5) ]. 2.3 use with cns depressants dosage adjustment may be necessary when zolpidem tartrate extended-release tablets are combined with other cns depressant drugs because of the potentially additive effects [see warnings and precautions (5.1) ]. 2.4 administration zolpidem tartrate extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. the effect of zolpidem tartrate extended-release tablets may be slowed by ingestion with or immediately after a meal.

ed treatment due to an adverse reaction as compared to 0.9% (2/216) of patients on placebo. the reaction most commonly associated with discontinuation in patients treated with zolpidem tartrate extended-release was somnolence (1%). in a 6-month study in adult patients (18 to 64 years of age), 8.5% (57/669) of patients receiving zolpidem tartrate extended-release 12.5 mg as compared to 4.6% on placebo (16/349) discontinued treatment due to an adverse reaction. reactions most commonly associated with discontinuation of zolpidem tartrate extended-release included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo. data from a clinical study in which selective serotonin reuptake inhibitor- (ssri-) treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n =97) was discontinued after an attempted suicide. most commonly observed adverse reactions in controlled trials: during treatment with zolpidem tartrate extended-release in adults and elderly at daily doses of 12.5 mg and 6.25 mg, respectively, each for three weeks, the most commonly observed adverse reactions associated with the use of zolpidem tartrate extended-release were headache, next-day somnolence, and dizziness. in the 6-month trial evaluating zolpidem tartrate extended-release 12.5 mg, the adverse reaction profile was consistent with that reported in short-term trials, except for a higher incidence of anxiety (6.3% for zolpidem tartrate extended-release versus 2.6% for placebo). adverse reactions observed at an incidence of ≥1% in controlled trials: the following tables enumerate treatment-emergent adverse reaction frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate extended-release in placebo-controlled trials. events reported by investigators were classified utilizing the meddra dictionary for the purpose of establishing event frequencies. the prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. however, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied. the following tables were derived from results of two placebo-controlled efficacy trials involving zolpidem tartrate extended-release. these trials involved patients with primary insomnia who were treated for 3 weeks with zolpidem tartrate extended-release at doses of 12.5 mg ( table 1) or 6.25 mg ( table 2 ), respectively. the tables include only adverse reactions occurring at an incidence of at least 1% for zolpidem tartrate extended-release patients and with an incidence greater than that seen in the placebo patients. table 1. incidences of treatment-emergent adverse reactions in a 3-week placebo-controlled clinical trial in adults (percentage of patients reporting) body system/adverse reaction reactions reported by at least 1% of patients treated with zolpidem tartrate extended-release and at greater frequency than in the placebo group. zolpidem tartrate extended-release 12.5 mg placebo (n = 102) (n = 110) infections and infestations influenza 3 0 gastroenteritis 1 0 labyrinthitis 1 0 metabolism and nutrition disorders appetite disorder 1 0 psychiatric disorders hallucinations hallucinations included hallucinations nos as well as visual and hypnogogic hallucinations. 4 0 disorientation 3 2 anxiety 2 0 depression 2 0 psychomotor retardation 2 0 binge eating 1 0 depersonalization 1 0 disinhibition 1 0 euphoric mood 1 0 mood swings 1 0 stress symptoms 1 0 nervous system disorders headache 19 16 somnolence 15 2 dizziness 12 5 memory disorders memory disorders include: memory impairment, amnesia, anterograde amnesia. 3 0 balance disorder 2 0 disturbance in attention 2 0 hypoesthesia 2 1 ataxia 1 0 paresthesia 1 0 eye disorders visual disturbance 3 0 eye redness 2 0 vision blurred 2 1 altered visual depth perception 1 0 asthenopia 1 0 ear and labyrinth disorders vertigo 2 0 tinnitus 1 0 respiratory, thoracic and mediastinal disorders throat irritation 1 0 gastrointestinal disorders nausea 7 4 constipation 2 0 abdominal discomfort 1 0 abdominal tenderness 1 0 frequent bowel movements 1 0 gastroesophageal reflux disease 1 0 vomiting 1 0 skin and subcutaneous tissue disorders rash 1 0 skin wrinkling 1 0 urticaria 1 0 musculoskeletal and connective tissue disorders back pain 4 3 myalgia 4 0 neck pain 1 0 reproductive system and breast disorders menorrhagia 1 0 general disorders and administration site conditions fatigue 3 2 asthenia 1 0 chest discomfort 1 0 investigations blood pressure increased 1 0 body temperature increased 1 0 injury, poisoning and procedural complications contusion 1 0 social circumstances exposure to poisonous plant 1 0 table 2. incidences of treatment-emergent adverse reactions in a 3-week placebo-controlled clinical trial in elderly (percentage of patients reporting) body system/adverse reaction reactions reported by at least 1% of patients treated with zolpidem tartrate extended-release and at greater frequency than in the placebo group. zolpidem tartrate extended-release 6.25 mg placebo (n=99) (n=106) infections and infestations nasopharyngitis 6 4 lower respiratory tract infection 1 0 otitis externa 1 0 upper respiratory tract infection 1 0 psychiatric disorders anxiety 3 2 psychomotor retardation 2 0 apathy 1 0 depressed mood 1 0 nervous system disorders headache 14 11 dizziness 8 3 somnolence 6 5 burning sensation 1 0 dizziness postural 1 0 memory disorders memory disorders include: memory impairment, amnesia, anterograde amnesia. 1 0 muscle contractions involuntary 1 0 paresthesia 1 0 tremor 1 0 cardiac disorders palpitations 2 0 respiratory, thoracic and mediastinal disorders dry throat 1 0 gastrointestinal disorders flatulence 1 0 vomiting 1 0 skin and subcutaneous tissue disorders rash 1 0 urticaria 1 0 musculoskeletal and connective tissue disorders arthralgia 2 0 muscle cramp 2 1 neck pain 2 0 renal and urinary disorders dysuria 1 0 reproductive system and breast disorders vulvovaginal dryness 1 0 general disorders and administration site conditions influenza like illness 1 0 pyrexia 1 0 injury, poisoning and procedural complications neck injury 1 0 dose relationship for adverse reactions: there is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem use, particularly for certain cns and gastrointestinal adverse events. other adverse reactions observed during the premarketing evaluation of zolpidem tartrate extended-release: other treatment-emergent adverse reactions associated with participation in zolpidem tartrate extended-release studies (those reported at frequencies of <1%) were not different in nature or frequency to those seen in studies with immediate-release zolpidem tartrate, which are listed below. adverse events observed during the premarketing evaluation of immediate-release zolpidem tartrate: immediate-release zolpidem tartrate was administered to 3,660 subjects in clinical trials throughout the u.s., canada, and europe. treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. to provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified world health organization (who) dictionary of preferred terms. the frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. all reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. it is important to emphasize that, although the events reported did occur during treatment with zolpidem tartrate tablets, they were not necessarily caused by it. adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients. autonomic nervous system: frequent: dry mouth. infrequent: increased sweating, pallor, postural hypotension, syncope. rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus. body as a whole: frequent: asthenia. infrequent: chest pain, edema, falling, fever, malaise, trauma. rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased esr, pain, restless legs, rigors, tolerance increased, weight decrease. cardiovascular system: infrequent: cerebrovascular disorder, hypertension, tachycardia. rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia. central and peripheral nervous system: frequent: ataxia, confusion, drowsiness, drugged feeling, euphoria, insomnia, lethargy, lightheadedness, vertigo. infrequent: agitation, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor. rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning. gastrointestinal system: frequent: diarrhea, dyspepsia, hiccup. infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis. rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries. hematologic and lymphatic system: rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis. immunologic system: infrequent: infection. rare: abscess herpes simplex herpes zoster, otitis externa, otitis media. liver and biliary system: infrequent: abnormal hepatic function, increased sgpt. rare: bilirubinemia, increased sgot. metabolic and nutritional: infrequent: hyperglycemia, thirst. rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased bun, periorbital edema. musculoskeletal system: infrequent: arthritis. rare: arthrosis, muscle weakness, sciatica, tendinitis. reproductive system: infrequent: menstrual disorder, vaginitis. rare: breast fibroadenosis, breast neoplasm, breast pain. respiratory system: frequent: sinusitis. infrequent: bronchitis, coughing, dyspnea. rare: bronchospasm, respiratory depression, epistaxis, hypoxia, laryngitis, pneumonia. skin and appendages: infrequent: pruritus. rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria. special senses: frequent: diplopia, vision abnormal. infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus. rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia. urogenital system: frequent: urinary tract infection. infrequent: cystitis, urinary incontinence. rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.

e effect of decreased alertness and psychomotor performance [see clinical pharmacology (12.3) ]. haloperidol 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 [see clinical pharmacology (12.3) ]. alcohol an additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see warnings and precautions (5.1) ]. sertraline concomitant administration of zolpidem and sertraline increases exposure to zolpidem [see clinical pharmacology (12.3) ]. fluoxetine after multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life (17%) was observed. there was no evidence of an additive effect in psychomotor performance [see clinical pharmacology (12.3) ]. 7.2 drugs that affect drug metabolism via cytochrome p450 some compounds known to inhibit cyp3a may increase exposure to zolpidem. the effect of drugs on other p450 enzymes on the exposure to zolpidem is not known. rifampin rifampin, a cyp3a4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem. use of rifampin in combination with zolpidem may decrease the efficacy of zolpidem. ketoconazole ketoconazole, a potent cyp3a4 inhibitor, increased the pharmacodynamic effects of zolpidem. consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

edative-hypnotic drugs during pregnancy. zolpidem tartrate extended-release should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the zolpidem tartrate extended-release maximum recommended human dose (mrhd) of 12.5 mg/day (approximately 10 mg/day zolpidem base); however, teratogenicity was not observed. when zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 4 times the mrhd on a mg/m 2 basis. in rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose. the no-effect dose for embryo-fetal toxicity in rabbits is approximately 8 times the mrhd on a mg/m 2 basis. administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 4 times the mrhd on a mg/m 2 basis. 8.2 labor and delivery zolpidem tartrate extended-release tablet has no established use in labor and delivery [see pregnancy (8.1) ]. 8.3 nursing mothers zolpidem is excreted in human milk. caution should be exercised when zolpidem tartrate extended-release tablet is administered to a nursing woman. 8.4 pediatric use zolpidem tartrate extended-release is not recommended for use in children. safety and effectiveness of zolpidem in pediatric patients below the age of 18 years have not been established. in an 8-week study in pediatric patients (aged 6 to 17 years) with insomnia associated with attention-deficit/hyperactivity disorder (adhd) an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo.. psychiatric and nervous system disorders comprised the most frequent (> 5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see warnings and precautions (5.4) ]. ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction. fda has not required pediatric studies of zolpidem tartrate extended-release tablets in the pediatric population based on these efficacy and safety findings. 8.5 geriatric use a total of 99 elderly (≥ 65 years of age) received daily doses of 6.25 mg zolpidem tartrate extended-release in a 3-week placebo-controlled study. the adverse reaction profile of zolpidem tartrate extended-release 6.25 mg in this population was similar to that of zolpidem tartrate extended-release 12.5 mg in younger adults (≤ 64 years of age). dizziness was reported in 8% of zolpidem tartrate extended-release-treated patients compared with 3% of those treated with placebo. the dose of zolpidem tartrate extended-release in elderly patients is 6.25 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see warnings and precautions (5.1) ] . 8.6 gender difference in pharmacokinetics women clear zolpidem tartrate from the body at a lower rate than men. c max and auc parameters of zolpidem from zolpidem tartrate extended-release were, respectively, approximately 50% and 75% higher at the same dose in adult female subjects compared to adult male subjects. between 6 and 12 hours after dosing, zolpidem concentrations were 2- to 3 fold higher in adult female compared to adult male subjects. given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended initial dose of zolpidem tartrate extended-release for adult women is 6.25 mg, and the recommended dose for adult men is 6.25 or 12.5 mg. in geriatric patients, clearance of zolpidem is similar in men and women. the recommended dose of zolpidem tartrate extended-release in geriatric patients is 6.25 mg regardless of gender.

dose (mrhd) of 12.5 mg/day (approximately 10 mg/day zolpidem base); however, teratogenicity was not observed. when zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 4 times the mrhd on a mg/m 2 basis. in rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose. the no-effect dose for embryo-fetal toxicity in rabbits is approximately 8 times the mrhd on a mg/m 2 basis. administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 4 times the mrhd on a mg/m 2 basis.

ic studies of zolpidem tartrate extended-release tablets in the pediatric population based on these efficacy and safety findings.

bsorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. a study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of zolpidem tartrate extended-release 12.5 mg and of an immediate-release formulation of zolpidem tartrate (10 mg). the terminal elimination half-life observed with zolpidem tartrate extended-release (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). the mean plasma concentration-time profiles are shown in figure 1 . figure 1: mean plasma concentration-time profiles for zolpidem tartrate extended-release (12.5 mg) and immediate-release zolpidem tartrate (10 mg) figure 1: mean plasma concentration-time profiles for zolpidem tartrate extended-release (12.5 mg) and immediate-release zolpidem tartrate (10 mg) in adult and elderly patients treated with zolpidem tartrate extended-release, there was no evidence of accumulation after repeated once-daily dosing for up to two weeks. absorption: following administration of zolpidem tartrate extended-release, administered as a single 12.5 mg dose in healthy male adult subjects, the mean peak concentration (c max ) of zolpidem was 134 ng/ml (range: 68.9 to 197 ng/ml) occurring at a median time (t max ) of 1.5 hours. the mean auc of zolpidem was 740 ng∙hr/ml (range: 295 to 1359 ng∙hr/ml). a food-effect study in 45 healthy subjects compared the pharmacokinetics of zolpidem tartrate extended-release 12.5 mg when administered while fasting or within 30 minutes after a meal. results demonstrated that with food, mean auc and c max were decreased by 23% and 30%, respectively, while median t max was increased from 2 hours to 4 hours. the half-life was not changed. these results suggest that, for faster sleep onset, zolpidem tartrate extended-release should not be administered with or immediately after a meal. distribution: total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/ml. metabolism: zolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion. elimination: when zolpidem tartrate extended-release was administered as a single 12.5 mg dose in healthy male adult subjects, the mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr). special populations elderly: in 24 elderly (≥ 65 years) healthy subjects administered a single 6.25 mg dose of zolpidem tartrate extended-release, the mean peak concentration (c max ) of zolpidem was 70.6 (range: 35 to 161) ng/ml occurring at a median time (t max ) of 2 hours. the mean auc of zolpidem was 413 ng∙hr/ml (range: 124 to 1190 ng∙hr/ml) and the mean elimination half-life was 2.9 hours (range: 1.59 to 5.50 hours). hepatic impairment: zolpidem tartrate extended-release was not studied in patients with hepatic impairment. the pharmacokinetics of an immediate-release formulation of zolpidem tartrate in eight patients with chronic hepatic insufficiency were 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). dosing should be modified accordingly in patients with hepatic insufficiency [see dosage and administration (2.2) ]. renal impairment: zolpidem tartrate extended-release was not studied in patients with renal impairment. the pharmacokinetics of an immediate-release formulation of zolpidem tartrate were 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 were not significantly different in renally-impaired patients. no dosage adjustment is necessary in patients with compromised renal function. drug interactions cns-depressants co-administration of zolpidem with other cns depressants increases the risk of cns depression [see warnings and precautions (5.1) ].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 (5.1) ] . 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. 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. consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together. other drugs with no interactions with zolpidem a study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem. zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects. figure 1

on-time profiles for zolpidem tartrate extended-release (12.5 mg) and immediate-release zolpidem tartrate (10 mg) in adult and elderly patients treated with zolpidem tartrate extended-release, there was no evidence of accumulation after repeated once-daily dosing for up to two weeks. absorption: following administration of zolpidem tartrate extended-release, administered as a single 12.5 mg dose in healthy male adult subjects, the mean peak concentration (c max ) of zolpidem was 134 ng/ml (range: 68.9 to 197 ng/ml) occurring at a median time (t max ) of 1.5 hours. the mean auc of zolpidem was 740 ng∙hr/ml (range: 295 to 1359 ng∙hr/ml). a food-effect study in 45 healthy subjects compared the pharmacokinetics of zolpidem tartrate extended-release 12.5 mg when administered while fasting or within 30 minutes after a meal. results demonstrated that with food, mean auc and c max were decreased by 23% and 30%, respectively, while median t max was increased from 2 hours to 4 hours. the half-life was not changed. these results suggest that, for faster sleep onset, zolpidem tartrate extended-release should not be administered with or immediately after a meal. distribution: total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/ml. metabolism: zolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion. elimination: when zolpidem tartrate extended-release was administered as a single 12.5 mg dose in healthy male adult subjects, the mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr). special populations elderly: in 24 elderly (≥ 65 years) healthy subjects administered a single 6.25 mg dose of zolpidem tartrate extended-release, the mean peak concentration (c max ) of zolpidem was 70.6 (range: 35 to 161) ng/ml occurring at a median time (t max ) of 2 hours. the mean auc of zolpidem was 413 ng∙hr/ml (range: 124 to 1190 ng∙hr/ml) and the mean elimination half-life was 2.9 hours (range: 1.59 to 5.50 hours). hepatic impairment: zolpidem tartrate extended-release was not studied in patients with hepatic impairment. the pharmacokinetics of an immediate-release formulation of zolpidem tartrate in eight patients with chronic hepatic insufficiency were 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). dosing should be modified accordingly in patients with hepatic insufficiency [see dosage and administration (2.2) ]. renal impairment: zolpidem tartrate extended-release was not studied in patients with renal impairment. the pharmacokinetics of an immediate-release formulation of zolpidem tartrate were 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 were not significantly different in renally-impaired patients. no dosage adjustment is necessary in patients with compromised renal function. drug interactions cns-depressants co-administration of zolpidem with other cns depressants increases the risk of cns depression [see warnings and precautions (5.1) ].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 (5.1) ] . 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. 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. consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together. other drugs with no interactions with zolpidem a study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem. zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects. figure 1

precoital intervals at the highest dose tested. the no-effect dose for these findings is approximately 20 times the mrhd on a mg/m 2 basis. there was no impairment of fertility at any dose tested.

e highest dose tested. the no-effect dose for these findings is approximately 20 times the mrhd on a mg/m 2 basis. there was no impairment of fertility at any dose tested.

placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment. elderly outpatients (≥ 65 years) with primary insomnia (n=205) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing zolpidem tartrate extended-release 6.25 mg and placebo. zolpidem tartrate extended-release 6.25 mg decreased wake time after sleep onset (waso) for the first 6 hours during the first 2 nights and the first 4 hours after 2 weeks of treatment. zolpidem tartrate extended-release 6.25 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing lps) during the first 2 nights of treatment and after 2 weeks on treatment. zolpidem tartrate extended-release 6.25 mg was superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment. in both studies, in patients treated with zolpidem tartrate extended-release, polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients. in a 24-week double-blind, placebo controlled, randomized study in adult outpatients (18 to 64 years) with primary insomnia (n=1025), zolpidem tartrate extended-release 12.5 mg administered as needed (3 to 7 nights per week) was superior to placebo over 24 weeks, on patient global impression regarding aid to sleep, and on patient-reported specific sleep parameters for sleep induction and sleep maintenance with no significant increased frequency of drug intake observed over time. 14.2 studies pertinent to safety concerns for sedative/hypnotic drugs next-day residual effects: in five clinical studies [three controlled studies in adults (18 to 64 years of age) administered zolpidem tartrate extended-release 12.5 mg and two controlled studies in the elderly (≥ 65 years of age) administered zolpidem tartrate extended-release 6.25 mg or 12.5 mg], the effect of zolpidem tartrate extended-release on vigilance, memory, or motor function were assessed using neurocognitive tests. in these studies, no significant decrease in performance was observed eight hours after a nighttime dose. in addition, no evidence of next-day residual effects was detected with zolpidem tartrate extended-release 12.5 mg and 6.25 mg using self-ratings of sedation. during the 3-week studies, next-day somnolence was reported by 15% of the adult patients who received 12.5 mg zolpidem tartrate extended-release versus 2% of the placebo group; next-day somnolence was reported by 6% of the elderly patients who received 6.25 mg zolpidem tartrate extended-release versus 5% of the placebo group [see adverse reactions (6) ]. in a 6-month study, the overall incidence of next-day somnolence was 5.7% in the zolpidem tartrate extended-release group as compared to 2% in the placebo group. rebound effects: rebound insomnia, defined as a dose-dependent worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. in the two 3-week placebo-controlled studies in patients with primary insomnia, a rebound effect was only observed on the first night after abrupt discontinuation of zolpidem tartrate extended-release. on the second night, there was no worsening compared to baseline in the zolpidem tartrate extended-release group. in a 6-month placebo-controlled study in which zolpidem tartrate extended-release was taken as needed (3 to 7 nights per week), within the first month a rebound effect was observed for total sleep time (not for waso) during the first night off medication. after this first month period, no further rebound insomnia was observed. after final treatment discontinuation no rebound was observed.

ntal alertness the day after use. inform patients that impairment can be present despite feeling fully awake. severe anaphylactic and anaphylactoid reactions inform patients that severe anaphylactic and anaphylactoid reactions have occurred with zolpidem. describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur. sleep-driving and other complex behaviors instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including "sleep driving" and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). tell patients to call you immediately if they develop any of these symptoms. suicide tell patients to immediately report any suicidal thoughts. alcohol and other drugs ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. advise patients not to use zolpidem tartrate extended-release tablets if they drank alcohol that evening or before bed. tolerance, abuse, and dependence tell patients not to increase the dose of zolpidem tartrate extended-release tablets on their own, and to inform you if they believe the drug "does not work". administration instructions patients should be counseled to take zolpidem tartrate extended-release tablets right before they get into bed and only when they are able to stay in bed a full night (7–8 hours) before being active again. zolpidem tartrate extended-release tablets should not be taken with or immediately after a meal. advise patients not to take zolpidem tartrate extended-release tablets if they drank alcohol that evening.