1INDICATIONS AND USAGE Zolpidem tartrate extended-release tablet, USP is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset). The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration[see CLINICAL STUDIES (14) ].
Zolpidem tartrate extended-release tablet, USP a gamma-aminobutyric acid (GABA) A agonist, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. ( 1 )
Contraindications
Zolpidem tartrate extended-release tablets are contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see WARNINGS AND PRECAUTIONS (5.3) ] . Known hypersensitivity to zolpidem ( 4 )
Warnings and precautions
5WARNINGS AND PRECAUTIONS
CNS depressant effects: Impaired alertness and motor coordination, including risk of morning impairment. Caution patients against driving and other activities requiring complete mental alertness the morning after use. ( 5.1 )
Need to evaluate for co-morbid diagnoses: Revaluate if insomnia persists after 7 to 10 days of use ( 5.2 )
Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. ( 5.3 )
"Sleep-driving" and other complex behaviors while not fully awake. Risk increases with dose and use with other CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes. ( 5.4 )
Depression: Worsening of depression or, suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose. ( 5.5 )
Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function ( 5.6 )
Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation ( 5.7 , 9.3 )
5.1CNS 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) ].
5.2Need 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.
5.3Severe 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.
5.4Abnormal 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.
5.5Use 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.
5.6Respiratory 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.
5.7Withdrawal 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 (
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
7DRUG INTERACTIONS
CNS depressants, including alcohol: Possible adverse additive CNS-depressant effects ( 5.1 , 7.1 )
Imipramine: Decreased alertness observed ( 7.1 )
Chlorpromazine: Impaired alertness and psychomotor performance observed ( 7.1 )
Rifampin: Combination use may decrease effect ( 7.2 )
Ketoconazole: Combination use may increase effect ( 7.2 )
7.1CNS-Active Drugs 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, 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) ]. 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.
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Category C
There are no adequate and well-controlled studies of zolpidem tartrate extended-release in pregnant women. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period.
Neonatal flaccidity has also been reported in infants born to mothers who received sedative-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.
Adverse reactions
6ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
CNS-depressant effects and next-day impairment [see WARNINGS AND PRECAUTIONS (5.1) ]
Serious anaphylactic and anaphylactoid reactions [see WARNINGS AND PRECAUTIONS (5.3) ]
Abnormal thinking and behavior changes, and complex behaviors [see WARNINGS AND PRECAUTIONS (5.4) ]
Withdrawal effects [see WARNINGS AND PRECAUTIONS (5.7) ] Most commonly observed adverse reactions (> 10% in either elderly or adult patients) are: headache, next-day somnolence and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.
6.1Clinical Trials Experience Associated
with discontinuation of treatment: In 3-week clinical trials in adults and elderly patients (> 65 years), 3.5% (7/201) patients receiving zolpidem tartrate extended-release 6.25 or 12.5 mg discontinued 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.
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.
