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zolpidem tartrate tablet
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Edluar (zolpidem tartrate sublingual tablets) is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
The clinical trials performed with Zolpidem tartrate in support of efficacy were 4-5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
The dose of Edluar should be individualized.
2.1 Dosage in adults
The recommended dose for Edluar for adults is 10 mg once daily immediately before bedtime. The total Edluar daily dose should not exceed 10 mg.
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 Edluar in both of these patient populations is 5 mg once daily immediately before bedtime [see Warnings and Precautions (5.6)].
2.3 Use with CNS depressants
Dosage adjustment may be necessary when Edluar is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.5)].
The effect of Edluar may be slowed by ingestion with or immediately after a meal. Edluar should not be given with or immediately after a meal.
Edluar sublingual tablet should be placed under the tongue, where it will disintegrate. The tablet should not be swallowed and the tablet should not be taken with water.
3 DOSAGE FORMS AND STRENGTHS
Edluar is available in 5 mg and 10 mg strength tablets for sublingual administration. Tablets are not scored.
Edluar 5 mg sublingual tablets are round white, flat-faced, bevel-edged, with debossed V on one side.
Edluar 10 mg sublingual tablets are round white, flat-faced, bevel-edged, with debossed X on one side.
Edluar is 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 [see Warnings and Precautions (5.2) and Description (11)].
5 WARNINGS AND PRECAUTIONS
5.1 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 tartrate.
5.2 Severe anaphylactic and anaphylactoid reactions
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 tartrate. 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 Edluar should not be rechallenged with the drug.
5.3 Abnormal thinking and behavioral changes
A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. 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. Visual and auditory hallucinations have been reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization. In controlled trials, <1% of adults with insomnia who received zolpidem tartrate reported hallucinations. In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), who received zolpidem reported hallucinations [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 with sedative-hypnotics, including zolpidem tartrate. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur with Edluar alone at therapeutic doses, the use of alcohol and other CNS depressants with Edluar appears to increase the risk of such behaviors, as does the use of Edluar at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Edluar 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 occur unpredictably.
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.
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.
5.4 Withdrawal effects
Following 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 [see Drug Abuse and Dependence (9)].
5.5 CNS depressant effects
Edluar, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Edluar should be ingested immediately prior to going to bed. 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 Edluar. Zolpidem tartrate showed additive effects when combined with alcohol and should not be taken with alcohol. Patients should also be cautioned about possible combined effects with other CNS-depressant drugs. Dosage adjustments of Edluar may be necessary when Edluar is administered with such agents because of the potentially additive effects.
5.6 Special Populations
Use in the elderly and/or debilitated patients:
Use in patients with concomitant illness:
Data in end-stage renal failure patients repeatedly treated with zolpidem tartrate did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment of Edluar in renally impaired patients is required; however, these patients should be closely monitored [see Clinical Pharmacology (12.3)].
A study in subjects with hepatic impairment treated with zolpidem tartrate did reveal prolonged elimination in this group; therefore, treatment with Edluar should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Use in patients with depression:
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
6.1 Clinical trials experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating incidence rates.
Associated with discontinuation of treatment:
Approximately 4% of 1,959 patients who received zolpidem tartrate 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 tartrate 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:
Adverse reactions observed at an incidence of ≥1% in controlled trials:
The following table was derived from a pool 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.
The following table was derived from a pool of three placebo-controlled long-term efficacy trials involving oral zolpidem. 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.
Dose relationship for adverse reactions associated with oral zolpidem:
Oral tissue-related adverse reactions to Edluar:
Adverse event incidence across the entire preapproval oral zolpidem database:
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, 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. Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, 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: Infrequent: urinary tract infection. Infrequent: cystitis, urinary incontinence. Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.
7 DRUG INTERACTIONS
For details of drug interactions, please refer to Clinical Pharmacology (12.3).
7.1 CNS-active drugs
Any drug with CNS-depressant effects could potentially enhance the CNS-depressant effects of zolpidem.
Imipramine in combination with zolpidem produced an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced an additive effect of decreased alertness and psychomotor performance. These drugs did not show any significant pharmacokinetic interaction.
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 a lack following chronic administration.
An additive effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions: CNS depressant effects (5.5)]. Concomitant administration of zolpidem and sertraline increased zolpidem Cmax (43%) and decreased Tmax (53%), whether or not these changes alter the pharmacodynamic effect of zolpidem is unknown.
7.2 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 has not been carefully evaluated.
Co-administration of multiple doses of rifampin and a single dose of zolpidem tartrate (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (73%), Cmax (58%), and T1/2 (36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate.
Co-administration of a single dose of zolpidem tartrate with 4 doses of ketoconazole, a potent CYP3A4 inhibitor increased Cmax 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. Patients should be advised that use of Edluar with ketoconazole may enhance the sedative effects.
7.3 Drug-laboratory test interactions
Zolpidem is not known to interfere with commonly employed clinical laboratory tests. In addition, clinical data indicate that zolpidem does not cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C:
Studies to assess the effects on children whose mothers took zolpidem during pregnancy have not been conducted. There is a published case report documenting the presence of zolpidem in human umbilical cord blood. Children born to mothers taking sedative-hypnotic drugs may be at some risk for withdrawal symptoms from the drug during the postnatal period. In addition, neonatal flaccidity has been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy.
Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the maximum recommended human dose (MRHD) of 10 mg/day (8 mg/day zolpidem base); however, teratogenicity was not observed.
When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg (approximately 5, 24, and 120 times the MRHD on a mg/m2 basis) 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 5 times the MRHD on a mg/m2 basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg (approximately 2.5, 10, and 40 times the MRHD on a mg/m2 basis), 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 10 times the MRHD on a mg/m2 basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg (approximately 5, 24, and 120 times the MRHD on a mg/m2 basis) during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis.
8.2 Labor and delivery
Edluar has no established use in labor and delivery [see Pregnancy (8.1)].
8.3 Nursing mothers
Zolpidem is excreted into human milk. Studies in lactating mothers indicate that the T1/2 of zolpidem is similar to that in non-lactating women (2.6 ± 0.3 hours). The effect of zolpidem on the nursing infant is not known. Caution should be exercised when Edluar is administered to a nursing mother.
8.4 Pediatric use
Safety and effectiveness of Edluar have not been established in pediatric patients below the age of 18.
In an 8-week controlled study, 201 pediatric patients (aged 6-17 years) with insomnia associated with attention-deficit/hyperactivity disorder (90% of the patients were using psychoanaleptics) were treated with an oral solution of zolpidem (n=136), or placebo (n=65). Zolpidem did not significantly decrease latency to persistent sleep, compared to placebo, as measured by polysomnography after 4 weeks of treatment. 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 (7.4% vs. 0%) [see Warnings and Precautions (5.6)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.
8.5 Geriatric use
A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials who received oral zolpidem were ≥60 years of age. For a pool of U.S. patients receiving zolpidem tartrate at doses of ≤10 mg or placebo, there were three adverse events occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (i.e., they could be considered drug-related).
A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem tartrate reported falls, including 28/30 (93%) who were ≥70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem doses >10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported confusion, including 18/24 (75%) who were ≥70 years of age. Of these 18 patients, 14 (78%) were receiving zolpidem doses >10 mg.
The dose of Edluar in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Dosage and Administration (2), Warnings and Precautions (5) Clinical Pharmacology (12) and Clinical Studies (14)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled substance
Edluar contains the same active substance, zolpidem tartrate, as zolpidem tartrate oral tablets and is classified as a Schedule IV controlled substance by federal regulation.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.
Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo.
Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse, and addiction of Edluar, they should be monitored carefully when receiving Edluar or any other hypnotic.
Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.
Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem tartrate treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Post-marketing reports of abuse, dependence and withdrawal have been received.
10.1 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.
10.2 Recommended treatment
Based on data obtained for zolpidem tartrate, general symptomatic and supportive measures for overdose with Edluar 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.
Edluar (zolpidem tartrate sublingual tablet) is a non-benzodiazepine hypnotic of the imidazopyridine class and is available in 5 mg and 10 mg strength tablets for sublingual administration.
Chemically, zolpidem tartrate is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:
Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88.
Each Edluar tablet includes the following inactive ingredients: mannitol, colloidal silicon dioxide, silicified microcrystalline cellulose, croscarmellose sodium, saccharin sodium, and magnesium stearate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of action
Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the α1/α5 subunits. This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses.
Following administration of single 10 mg Edluar, in 18 (18-65 years of age) healthy adult subjects, the mean peak concentration (Cmax) of zolpidem was 106 ng/mL (range: 52 to 205 ng/ml) occurring at a median time (Tmax) of 82 minutes (range: 30-180 min).
A food-effect study in 18 healthy volunteers compared the pharmacokinetics of Edluar 10 mg when administered while fasting or within 20 minutes after a high fat meal. The mean AUC and Cmax were decreased by 20% and 31%, respectively, while median Tmax was prolonged by 28% (from 82 to 105 min). The half-life remained unchanged. These results suggest that, for faster sleep onset, Edluar should not be administered with or immediately after a meal.
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 a lack following chronic administration.
An additive effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions: CNS depressant effects (5.5)].
A single-dose interaction study with zolpidem tartrate10 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 at steady state the concentrations were evaluated in healthy females, increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance.
Following five consecutive nightly doses of oral zolpidem tartrate10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.
Drugs that affect drug metabolism via cytochrome P450:
A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem tartrate (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC0-∞ of zolpidem tartrate. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance.
A randomized, placebo-controlled, crossover interaction study in eight healthy female subjects between five consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem tartrate (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (73%), Cmax (58%), and T1/2 (36 %) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate.
A randomized double-blind crossover interaction study in twelve healthy subjects showed that co-administration of a single 5 mg dose of zolpidem tartrate with ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax 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. Patients should be advised that use of Edluar with ketoconazole may enhance the sedative effects.
Other drugs with no interactions with zolpidem:
Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in normal subjects.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, mutagenesis, impairment of fertility
Impairment of fertility:
14 CLINICAL STUDIES
14.1 Chronic insomnia
Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM-IV™). Adult outpatients with chronic insomnia (n = 75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of zolpidem tartrate and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of awakenings at both doses studied.
Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem 10 mg was superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective measures of total sleep time, number of awakenings, and sleep quality for the first treatment week.
Increased wakefulness during the last third of the night as measured by polysomnography has not been observed in clinical trials with zolpidem tartrate.
14.2 Transient insomnia
Normal adults experiencing transient insomnia (n = 462) during the first night in a sleep laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two doses of zolpidem tartrate oral tablets (7.5 and 10 mg) and placebo. Both zolpidem doses were superior to placebo on objective (polysomnographic) measures of sleep latency, sleep duration, and number of awakenings.
Normal elderly adults (mean age 68) experiencing transient insomnia (n = 35) during the first two nights in a sleep laboratory were evaluated in a double-blind, crossover, 2-night trial comparing four doses of zolpidem (5, 10, 15 and 20 mg) and placebo. All zolpidem doses were superior to placebo on the two primary PSG parameters (sleep latency and efficiency) and all four subjective outcome measures (sleep duration, sleep latency, number of awakenings, and sleep quality).
14.3 Studies pertinent to safety concerns for sedative/hypnotic drugs
Next-day residual effects:
Effects on sleep stages:
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How supplied
Edluar is supplied as sublingual tablets in two dosage strengths: Tablets are not scored.
Edluar 5 mg sublingual tablets are round white tablets, flat-faced, bevel-edged with debossed V on one side and supplied as:
NDC Number Size
The blister packs consist of aluminum/aluminum Child Resistant Control (CRC) blisters.
Edluar 10 mg sublingual tablets are round white tablets, flat-faced, bevel-edged with debossed X on one side and supplied as:
NDC Number Size
The blister packs consist of aluminum/aluminum Child Resistant Control (CRC) blisters.
17 PATIENT COUNSELING INFORMATION
Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sedative-hypnotics and should counsel them in its appropriate use, and should instruct them to read the accompanying Medication Guide [see Medication Guide (17.4)].
17.1 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.
17.2 Sleep-Driving and other complex behaviors
There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when Edluar is taken with alcohol or other central nervous system depressants [see Warnings and Precautions (5.3)]. 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.
In addition, patients should be advised to report all concomitant medications to the prescriber. Patients should be instructed to report events such as “sleep-driving” and other complex behaviors immediately to the prescriber.
17.3 Administration instructions
Patients should be counseled to take Edluar right before they get in bed and only when they are able to stay in bed a full night (7-8 hours) before being active again. Edluar tablets should not be taken with or immediately after a meal. Advise patients NOT to take Edluar when drinking alcohol. Edluar sublingual tablet should be placed under the tongue, where it will disintegrate. The tablet should not be swallowed and the tablet should not be taken with water.
Read this Medication Guide Edluar before you start taking Edluar and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.
After taking Edluar, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with Edluar. Reported activities include:
Call your doctor right away if you find out that you have done any of the above activities after taking Edluar.
Do not take Edluar if you:
What is Edluar?
Edluar is not for children.
Who should not take Edluar?
Do not take Edluar if you have had an allergic reaction to zolpidem (Ambien, Ambien CR, Zolpimist, Edluar).
Do not take Edluar if you are allergic to anything in it.
Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects.
How should I take Edluar?
What are the possible side effects of Edluar?
Serious side effects of Edluar include:
Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using Edluar.
The most common side effects of Edluar are:
You may still feel drowsy the next day after taking Edluar.
Do not drive or do any dangerous activities after taking Edluar until you feel fully awake.
After you stop taking a sleep medicine, you may have symptoms for 1 to 2 days such as:
These are not all the side effects of Edluar. Ask your doctor or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Edluar?
General information about Edluar
This Medication Guide summarizes the most important information about Edluar.
If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Edluar that is written for healthcare professionals. For more information about Edluar, call Meda Pharmaceuticals Inc. at 1-800-526-3840.
Active Ingredient: zolpidem tartrate
Inactive Ingredients: mannitol, colloidal silicon dioxide, silicified microcrystalline cellulose, croscarmellose sodium, saccharin sodium, and magnesium stearate.
This Medication Guide has been approved by U.S. Food and Drug Administration.
©2009 Meda Pharmaceuticals Inc. U.S. Patent 6,761,910
Edluar and Meda Pharmaceuticals are trademarks or registered trademarks of Meda Pharmaceuticals Inc.
IG-6010-02 Rev. 5/09
Package Label - Principal Display Panel – 2-Count Blister for 10 mg Tablet
Package Label - Principal Display Panel – 10-Count Blister for 5 mg Tablet
EDLUAR 5 mg CIV
Package Label - Principal Display Panel – 10-Count Blister for 10 mg Tablet
EDLUAR 10 mg CIV
Package Label - Principal Display Panel – 40-Count Sample Carton for 10 mg Tablet
Rx Only NDC 0037-6010-02
Package Label - Principal Display Panel – 30-Count Trade Carton for 5 mg Tablet
Rx Only NDC 0037-6050-30
Package Label - Principal Display Panel – 30-Count Trade Carton for 10 mg Tablet
Rx Only NDC 0037-6010-30
Revised: 07/2009 Meda Pharmaceuticals Inc.
Reproduced with permission of U.S. National Library of Medicine
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