Zolpidem Drug Information

Zolpidem Tartrate Tablets is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem Tartrate Tablets has been shown to decrease sleep latency for up to 35 days in controlled clinical studies. 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.

Zolpidem Tartrate Tablets, a gamma-aminobutyric acid (GABA) A receptor positive modulator, is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.

Dosage in Adults Use the lowest effective dose for the patient.

The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next-day impairment of driving and other activities that require full alertness . The total dose of Zolpidem Tartrate Tablets should not exceed 10 mg once daily immediately before bedtime.

Zolpidem Tartrate Tablets should be taken as a single dose and should not be readministered during the same night. The recommended initial doses for women and men are different because Zolpidem clearance is lower in women. Long-term use of Zolpidem Tartrate Tablets is not recommended.

Treatment should be as short as possible. Extended treatment should not take place without re-evaluation of the patient's status because the risk of abuse and dependence increase with the duration of treatment

Special Populations Elderly or debilitated patients may be especially sensitive to the

effects of Zolpidem tartrate. The recommended dose of Zolpidem Tartrate Tablets in these patients is 5 mg once daily immediately before bedtime. Patients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal subjects.

The recommended dose of Zolpidem Tartrate Tablets in these patients is 5 mg once daily immediately before bedtime. Avoid Zolpidem Tartrate Tablets use in patients with severe hepatic impairment as it may contribute to encephalopathy.

Use with

CNS Depressants Dosage adjustment may be necessary when Zolpidem Tartrate Tablets is combined with other CNS-depressant drugs because of the potentially additive effects.

Administration

The effect of Zolpidem Tartrate Tablets may be slowed by ingestion with or immediately after a meal.

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 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%). 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: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (percentage of patients reporting) Body System Adverse Event Reactions reported by at least 1% of patients treated with Zolpidem Tartrate Tablets and at a greater frequency than placebo. Zolpidem (≤10 mg) (N=685) Placebo (N=473) Central and Peripheral Nervous System Headache 7 6 Drowsiness 2 - Dizziness 1 - Gastrointestinal System Diarrhea 1 - The following table was derived from results of three placebo-controlled long-term efficacy trials involving Zolpidem Tartrate Tablets.

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: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (percentage of patients reporting) Body System Adverse Event Reactions reported by at least 1% of patients treated with Zolpidem Tartrate Tablets and at a greater frequency than placebo. 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 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 Tablets 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: 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: edema, falling, fatigue, 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, euphoria, headache, insomnia, vertigo 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.

Gastrointestinal system: Frequent: dyspepsia, hiccup, nausea. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting. 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: Frequent: arthralgia, myalgia.

Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis. Reproductive system: Infrequent: menstrual disorder, vaginitis.

Rare: breast fibroadenosis, breast neoplasm, breast pain. Respiratory system: Frequent: upper respiratory infection, lower respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis.

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.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Zolpidem Tartrate Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Liver and biliary system: acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin >2 × ULN, alkaline phosphatase ≥2 × ULN, transaminase ≥5 × ULN). Psychiatric disorders: delirium

CNS-Active Drugs

CNS Depressants Coadministration 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. 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 Opioids The concomitant use of Zolpidem Tartrate Tablets with opioids may increase the risk of respiratory depression. Limit dosage and duration of concomitant use of Zolpidem Tartrate Tablets and opioids 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.

Sertraline Concomitant administration of Zolpidem and sertraline increases exposure to Zolpidem. 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.

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.

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. 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.

Pregnancy 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. Published data on the use of Zolpidem during pregnancy have not reported a clear association with Zolpidem and major birth defects. Oral administration of Zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses.

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%-4% and 15%-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 Tablets 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/m 2 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.

Pediatric Use Zolpidem Tartrate Tablets 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 6-17 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. Ten patients on Zolpidem (7.4%) discontinued treatment due to an adverse reaction.

Zolpidem Tartrate Tablets is contraindicated in patients who have experienced complex sleep behaviors after taking Zolpidem Tartrate Tablets with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema Patients who have experienced complex sleep behaviors after taking Zolpidem Tartrate Tablets Known hypersensitivity to Zolpidem

Signs and Symptoms

In postmarketing experience of overdose with Zolpidem Tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.

Recommended Treatment General symptomatic and supportive measures should be used along with

immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem's sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed.

Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following Zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that Zolpidem is not dialyzable.

As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.