Zolpidem tartrate tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets 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 are, a gamma-aminobutyric acid (GABA) A receptor positive modulator, is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. ( 1 )
Contraindications
Zolpidem tartrate is contraindicated in patients
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 )].
Patients who have experienced complex sleep behaviors after taking zolpidem tartrate tablets ( 4 )
Known hypersensitivity to zolpidem ( 4 )
Warnings and precautions
CNS-Depressant Effects: Impaired 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 use in patients with severe hepatic impairment. ( 5.8 )
Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation. ( 5.9 , 9.3 )
5.1Complex 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. 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 alone at recommended doses, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants [see Drug Interactions ( 7.1 )]. Discontinue zolpidem tartrate immediately if a patient experiences a complex sleep behavior [see Contraindications ( 4 )].
5.2CNS-Depressant Effects and Next-Day Impairment
Zolpidem tartrate, 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 Interactions ( 7.1 )]. Dosage adjustments of zolpidem tartrate and of other concomitant CNS depressants may be necessary when zolpidem tartrate is administered with such agents because of the potentially additive effects.
The use of zolpidem tartrate 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 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 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 to 8 hours) is recommended. Because zolpidem tartrate can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls.
5.3Need 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.
5.4Severe 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.
5.5Abnormal Thinking and Behavioral Changes
Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including zolpidem tartrate. 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 10 mg taken at bedtime < 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 )]. 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.
5.6Use 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.
5.7Respiratory 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 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. The risk of respiratory depression should be considered prior to prescribing zolpidem tartrat
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Interactions
CNS depressants, including alcohol: Possible adverse additive CNS-depressant effects ( 5.2 , 7.1 )
Opioids: Concomitant use may increase risk of respiratory depression ( 5.7 , 7.1 )
Imipramine: Decreased alertness observed ( 7.1 )
Chlorpromazine: Impaired alertness and psychomotor performance observed ( 7.1 )
CYP3A4 inducers (rifampin or St.John’s wort): Combination use may decrease effect ( 7.2 )
Ketoconazole: Combination use may increase effect ( 7.2 )
of zolpidem with other CNS depressants increases the risk of CNS depression. Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor impairment, including impaired driving ability [see Warnings and Precautions ( 5.1 , 5.2 )]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Alcohol An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions ( 5.1 , 5.2 )].
Opioids The concomitant use of zolpidem tartrate with opioids may increase the risk of respiratory depression. Limit dosage and duration of concomitant use of zolpidem tartrate and opioids [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.7 )] . Imipramine, Chlorpromazine 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 [see Clinical Pharmacology ( 12.3 )]. 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 )]. 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 )].
7.2 Drugs that Affect Drug Metabolism via Cytochrome P450 Some compounds known to induce or inhibit CYP3A may affect exposure to zolpidem. The effect of drugs that induce or inhibit other P450 enzymes on the exposure to zolpidem is not known. CYP3A4 Inducers 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 and is not recommended [see Clinical Pharmacology ( 12.3 )].
St. John’s wort Use of St. John’s wort, a CYP3A4 inducer, in combination with zolpidem may decrease blood levels of zolpidem and is not recommended. CYP3A4 Inhibitors Ketoconazole Ketoconazole, a potent CYP3A4 inhibitor, increased the exposure to and pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when a potent CYP3A4 inhibitor and zolpidem are given together [see Clinical Pharmacology ( 12.3 )].
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Neonates born to mothers using zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation [see Clinical Considerations and Data]. Published data on the use of zolpidem during pregnancy have not reported a clear association with zolpidem and major birth defects [ see Data ]. Oral administration of zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/neonatal adverse reactions Zolpidem crosses the placenta and may produce respiratory depression and sedation in neonates.
Monitor neonates exposed to zolpidem tartrate during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly. Data Human data Published data from observational studies, birth registries, and case reports on the use of zolpidem during pregnancy do not report a clear association with zolpidem and major birth defects. There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy.
These cases required artificial ventilation or intratracheal intubation. The majority of neonates recovered within hours to a few weeks after birth once treated. Zolpidem has been shown to cross the placenta. Animal data Oral administration of zolpidem to pregnant rats during the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 25 and 120 times the MRHD based on mg/m 2 body surface area.
Oral administration of zolpidem to pregnant rabbits during the period of organogenesis at 1, 4, and 16 mg base/kg/day, which are approximately 2.5, 10, and 40 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m 2 body surface area caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at a maternally toxic (decreased body weight gain) dose 40 times the MRHD based on mg/m 2 body surface area.
Oral administration of zolpidem to pregnant rats from day 15 of gestation through lactation at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m 2 body surface area, delayed offspring growth and decreased survival at doses 25 and 120 times, respectively, the MRHD based on mg/m 2 body surface area.
Adverse reactions
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Complex Sleep Behaviors [see Warnings and Precautions ( 5.1 )]
CNS-Depressant Effects and Next-Day Impairment [see Warnings and Precautions ( 5.2 )]
Severe Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions ( 5.4 )]
Abnormal Thinking and Behavior Changes [see Warnings and Precautions ( 5.5 )]
Withdrawal effects [see Warnings and Precautions ( 5.9 )] Most commonly observed adverse reactions were: Short-term (< 10 nights): Drowsiness, dizziness, and diarrhea Long-term (28 to 35 nights): Dizziness and drugged feelings ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1 Clinical Trials Experience Associated with Discontinuation of Treatment: Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).
Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%). 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 short-term treatment (up to 10 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).
Adverse Reactions Observed at an Incidence of ≥ 1% in Controlled Trials : The following tables enumerate treatment-emergent adverse reactions frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms 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 table was derived from results of 11 placebo-controlled short-term U.S. efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.
Table 1: Incidences of Treatment-Emergent Adverse Reactions in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (percentage of patients reporting) Table 1: Incidences of Treatment-Emergent Adverse Reactions in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (percentage of patients reporting) Body System Adverse Reaction* Zolpidem (≤10 mg) (N=685) Placebo (N=473) Central and Peripheral Nervous System Headache 7 6 Drowsiness 2 - Dizziness 1 - Gastrointestinal System Diarrhea 1 - *Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo.
The following table was derived from results of three placebo-controlled long-term efficacy trials involving zolpidem tartrate. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.
Table 2: Incidences of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (percentage of patients reporting) Table 2: Incidences of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (percentage of patients reporting) Body System Adverse Event* Zolpidem (≤10 mg) (N=152) Placebo (N=161) Autonomic Nervous System Dry mouth 3 1 Body as a Whole Allergy 4 1 Back pain 3 2 Influenza-like symptoms 2 - Chest pain 1 - Cardiovascular System Palpitation 2 - Central and Peripheral Nervous System Drowsiness 8 5 Dizziness 5 1 Lethargy 3 1 Drugged feeling 3 - Lightheadedness 2 1 Depression 2 1 Abnormal dreams 1 - Amnesia 1 - Sleep disorder 1 - Gastrointestinal System Diarrhea 3 2 Abdominal pain 2 2 Constipation 2 1 Respiratory System Sinusitis 4 2 Pharyngitis 3 1 Skin and Appendages Rash 2 1 *Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo.
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. Adverse Event Incidence Across the Entire Preapproval Database 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, 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
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Composition
Active ingredients
ZOLPIDEM TARTRATE 5MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
