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. Dose relationship for adverse reactions:.
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.
The clinical trials performed in support of efficacy were 4–5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.
A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. In controlled trials, <1% of adults with insomnia who received zolpidem reported hallucinations. Visual and auditory hallucinations have been reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization. Use in Specific Populations (8.4). Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), similar to effects produced by alcohol and other CNS depressants. In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), who received zolpidem reported hallucinations.
Dosage and Administration (2.2) Clinical Pharmacology (12.3). A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored.
Zolpidem tartrate tablets have been shown to decrease sleep latency for up to 35 days in controlled clinical studies ( ) 1. Zolpidem tartrate tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
Dosage adjustment may be necessary when zolpidem tartrate tablets are combined with other CNS depressant drugs because of the potentially additive effects. Warnings and Precautions (5.5).
The effect of zolpidem tartrate tablets may be slowed by ingestion with or immediay after a meal.
Infrequent: agitation, anxiety, 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. Frequent: ataxia, confusion, euphoria, headache, insomnia, vertigo. Central and peripheral nervous system:.
Hematologic and lymphatic system:. Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.
Pregnancy: Based on animal data, zolpidem may cause fetal harm ( ) 8.1.
Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema. Metabolic and nutritional:. Infrequent: hyperglycemia, thirst.
Approximay 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%).
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.
Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably. 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. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. 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 with sedative hypnotics, including zolpidem. As with "sleep-driving", patients usually do not remember these events. Due to the risk to the patient and the community, discontinuation of zolpidem tartrate tablets should be strongly considered for patients who report a "sleep-driving" episode. Although behaviors such as "sleep-driving" may occur with zolpidem tartrate tablets alone at therapeutic doses, the use of alcohol and other CNS depressants with zolpidem tartrate tablets appears to increase the risk of such behaviors, as does the use of zolpidem tartrate tablets at doses exceeding the maximum recommended dose.
Revised: 9/2010. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Warnings and Precautions (5.2). Zolpidem tartrate tablets are contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and angioedema.
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 least amount of drug that is feasible should be prescribed for the patient at any one time. Use in patients with depression:. As with other sedative/hypnotic drugs, zolpidem tartrate tablets should be administered with caution to patients exhibiting signs or symptoms of depression.
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Approximay 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. Associated with discontinuation of treatment:. Reactions most commonly associated with discontinuation from U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).
Clinical experience with zolpidem tartrate tablets in patients with concomitant systemic illness is limited. Caution is advisable in using zolpidem tartrate tablets in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Use in patients with concomitant illness:.
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.
Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations Use in Specific Populations (8.4). Use in pediatric patients: Safety and effectiveness of zolpidem has not been established in pediatric patients. In an 8-week study in pediatric patients (aged 6–17 years) with insomnia associated with ADHD, zolpidem did not decrease sleep latency compared to placebo.
Indications and Usage ( ) 03/2007 1.
Data in end-stage renal failure patients repeatedly treated with zolpidem tartrate tablets did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment in renally impaired patients is required; however, these patients should be closely monitored. Clinical Pharmacology (12.3).
5 mg and 10 mg tablets. Tablets scored ( ) not 3.
Therefore, the recommended zolpidem tartrate tablets dosage is 5 mg in such patients to decrease the possibility of side effects. Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. These patients should be closely monitored. Use in the elderly and/or debilitated patients: Dosage and Administration (2.2).
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.
Autonomic nervous system:. Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.
Nursing mothers: Zolpidem is excreted in human milk ( ) 8.3.
Warnings and Precautions Severe anaphylactic and anaphylactoid reactions ( ) 03/2007 Abnormal thinking and behavioral changes ( ) 03/2007 Special populations ( ) 03/2007 5.2 5.3 5.6.
Infrequent: bronchitis, coughing, dyspnea, rhinitis. Respiratory system:. Frequent: upper respiratory infection. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.
Zolpidem tartrate tablets were 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. Adverse event incidence across the entire preapproval database:. 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.
Infrequent: arthritis. Musculoskeletal system:. Frequent: arthralgia, myalgia. Rare: arthrosis, muscle weakness, sciatica, tendinitis.
In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.
Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The recommended dose of zolpidem tartrate in both of these patient populations is 5 mg once daily immediay before bedtime. Warnings and Precautions (5.6).
The table includes only adverse events occurring at an incidence of at least 1% for zolpidem patients. 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 following table was derived from results of three placebo-controlled long-term efficacy trials involving zolpidem tartrate tablets.
Zolpidem tartrate tablets 5 mg are pink, film-coated, capsule-shaped, unscored, upper debossed "6468" and lower debossed "V". The 10 mg tablets are white, film-coated, capsule-shaped, unscored, upper debossed "6469" and lower debossed "V".
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 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. 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 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. 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.
To report SUSPECTED ADVERSE REACTIONS, contact Vintage Pharmaceuticals, LLC at or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch.
Most commonly observed adverse reactions in controlled trials:. 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%). During short-term treatment (up to 10 nights) with zolpidem tartrate tablets 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%).
Tablets are not scored. Zolpidem tartrate tablets are available in 5 mg and 10 mg strength tablets for oral administration.
Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries. Gastrointestinal system:. Frequent: dyspepsia, hiccup, nausea. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting.
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.
Zolpidem tartrate tablets should be used with caution in patients with sleep apnea syndrome or myasthenia gravis. Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in normal 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 tartrate tablets (10 mg) when compared to placebo. Since sedative/hypnotics have the capacity to depress respiratory drive, precautions should be taken if zolpidem tartrate tablets are prescribed to patients with compromised respiratory function. Postmarketing reports of respiratory insufficiency, most of which involved patients with pre-existing respiratory impairment, have been received.
The dose of zolpidem tartrate tablets should be individualized.
Infrequent: infection. Immunologic system:. Rare: abscess, herpes simplex, herpes zoster, otitis externa, otitis media.
The recommended dose for adults is 10 mg once daily immediay before bedtime. The total zolpidem tartrate tablet dose should not exceed 10 mg per day.
Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs. Drug Abuse and Dependence (9).
Rare: breast fibroadenosis, breast neoplasm, breast pain. Infrequent: menstrual disorder, vaginitis. Reproductive system:.
Liver and biliary system:. Infrequent: abnormal hepatic function, increased SGPT. Rare: bilirubinemia, increased SGOT.
Updated September 1, 2010.
Known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation ( ) 4.
Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease. Frequent: asthenia. Infrequent: edema, falling, fatigue, fever, malaise, trauma. Body as a whole:.
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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. 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.
Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Patients who develop angioedema after treatment with zolpidem should not be rechallenged with the drug. 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. Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zolpidem.
Patients should also be cautioned about possible combined effects with other CNS-depressant drugs. Zolpidem tartrate tablets showed additive effects when combined with alcohol and should not be taken with alcohol. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of zolpidem tartrate tablets. Zolpidem tartrate tablets, like other sedative/hypnotic drugs, have CNS-depressant effects. Due to the rapid onset of action, zolpidem tartrate tablets should only be taken immediay prior to going to bed. Dosage adjustments may be necessary when zolpidem tartrate tablets are administered with such agents because of the potentially additive effects.
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 Clinical Studies (14).
efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The following table was derived from results of 11 placebo-controlled short-term U.S. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.Zolpidem tartrate