ZOLPIDEM: 21,430 Adverse Event Reports & Safety Profile

Zolpidem tartrate extended-release tablets USP contains zolpidem tartrate, a gamma-aminobutyric acid (GABA) A receptor positive modulator of the imidazopyridine class. Zolpidem tartrate extended-release tablets USP are available in 6.25 mg and 12.5 mg strength tablets for oral administration. Chemically, zolpidem 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 or almost white, crystalline powder, hygroscopic that is slightly soluble in water, sparingly soluble in methanol and practically insoluble in methylene chloride. It has a molecular weight of 764.87. Zolpidem tartrate extended-release tablets USP consist of a coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows a slower release of additional drug content.

The

6.25 mg zolpidem tartrate extended-release tablets USP contain the following inactive ingredients: colloidal silicon dioxide, FD&C Blue # 2 aluminium lake, hypromellose, iron oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate and titanium dioxide.

The

12.5 mg zolpidem tartrate extended-release tablets USP contain the following inactive ingredients: colloidal silicon dioxide, FD&C Blue # 2 aluminium lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate and titanium dioxide. Zolpidem tartrate extended-release tablets USP meets USP Dissolution Test 6.

Zolpidem

Tartrate

AND USAGE Zolpidem tartrate sublingual tablets are indicated for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep. Limitations of Use: Zolpidem tartrate sublingual tablets are not indicated for the treatment of middle-of-the-night insomnia when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking. Zolpidem tartrate sublingual tablets are a GABA A agonist indicated for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep Limitation of Use : Not indicated for the treatment of middle-of-the night awakening when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking

AND ADMINISTRATION Zolpidem Tartrate Capsules are only available in 7.5 mg strength. Use another zolpidem tartrate immediate-release product for 5 mg or 10 mg dosage ( 2.1 ) Avoid use of Zolpidem Tartrate Capsules in geriatric patients ( 2.1 ) Recommended dosage of zolpidem tartrate (use the lowest effective zolpidem tartrate dosage): Females: The recommended starting dosage of zolpidem tartrate immediate-release in females is 5 mg once nightly. Use another zolpidem tartrate immediate-release product for dosage initiation in females ( 2.1 , 2.2 , 8.6 ) Males: The recommended starting dosage of zolpidem tartrate immediate-release in males is either zolpidem tartrate immediate-release 5 mg, Zolpidem Tartrate Capsules 7.5 mg, or zolpidem tartrate immediate-release 10 mg, once nightly. Use another zolpidem tartrate immediate-release product for 5 mg and 10 mg dosing ( 2.2 ) In both males and females: If a 5 mg nightly dose of another zolpidem tartrate immediate-release product is not effective, the zolpidem tartrate dosage may be increased to Zolpidem Tartrate Capsules 7.5 mg once nightly or 10 mg once nightly of another zolpidem tartrate immediate-release product. The maximum recommended dosage of zolpidem tartrate immediate-release is 10 mg once nightly ( 2.2 )

Zolpidem Tartrate

Capsules are for short-term use only ( 2.3 )

Administer Zolpidem Tartrate

Capsules orally once per night immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening ( 2.4 )

Zolpidem Tartrate

Capsules should not be taken with or immediately after a meal. Swallow whole. Do not open, crush, or chew ( 2.4 ) Lower doses of CNS depressants may be necessary when taken concomitantly with Zolpidem Tartrate Capsules ( 2.5 )

2.1 Important Dosage Information Zolpidem Tartrate Capsules are only available in a 7.5 mg strength. Use another zolpidem tartrate immediate-release product for the 5 mg or 10 mg dose of zolpidem tartrate immediate-release. Refer to the Prescribing Information of other zolpidem tartrate immediate-release products for the recommended dosage for those products.

Zolpidem Tartrate

Capsules are not indicated in geriatric patients. Avoid use of Zolpidem Tartrate Capsules in geriatric patients because the recommended dosage in these patients cannot be achieved with the Zolpidem Tartrate Capsules 7.5 mg strength [see Use in Specific Populations ( 8.5 )] . Use another zolpidem tartrate product for geriatric patients. The recommended starting dosage for females is different than males because zolpidem clearance is lower in females [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . Do not use Zolpidem Tartrate Capsules to initiate zolpidem tartrate treatment in females because the recommended starting dosage in females cannot be achieved with the Zolpidem Tartrate Capsules 7.5 mg strength. Use another zolpidem tartrate immediate-release product to initiate treatment in females [see Dosage and Administration ( 2.2 )] .

Avoid Zolpidem Tartrate

Capsules in patients with mild or moderate hepatic impairment because the recommended dosage in such patients cannot be achieved with the Zolpidem Tartrate Capsules 7.5 mg strength [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . Avoid any zolpidem tartrate use in patients with severe hepatic impairment because its use may contribute to encephalopathy [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] .

2.2 Recommended Dosage Use the lowest effective zolpidem tartrate dosage. For instructions on administration of Zolpidem Tartrate Capsules, see Dosage and Administration ( 2.4 ) . The recommended starting dosage of zolpidem tartrate immediate-release in females is 5 mg once nightly. Use another zolpidem tartrate immediate-release product for dosage initiation in females <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span> . The recommended starting dosage of zolpidem tartrate immediate-release in males is either zolpidem tartrate immediate-release 5 mg, Zolpidem Tartrate Capsules 7.5 mg, or zolpidem tartrate immediate-release 10 mg, once nightly. In both males and females, if a 5 mg once nightly dose of another zolpidem tartrate immediate-release product is not effective, the zolpidem tartrate dosage may be increased to Zolpidem Tartrate Capsules 7.5 mg once nightly or 10 mg once nightly of another zolpidem tartrate immediate-release product. The maximum recommended dosage of zolpidem tartrate immediate-release is 10 mg once nightly.

Zolpidem Tartrate

Capsules should be taken as a single dose and should not be readministered during the same night.

2.3 Recommended Duration of Treatment Zolpidem Tartrate Capsules are for short-term use only. Re-evaluate the patient’s status during treatment because the risk of abuse and dependence increases with duration of treatment <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9.3 )]</span> .

2.4 Administration Instructions Administer Zolpidem Tartrate Capsules orally once per night immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

Zolpidem Tartrate

Capsules should not be administered with food or immediately after a meal [see Clinical Pharmacology ( 12.3 )] .

Swallow Zolpidem Tartrate

Capsules whole; do not open, crush, or chew.

2.5 Dosage Modifications with CNS Depressants Dosage modifications may be necessary when Zolpidem Tartrate Capsules are combined with other CNS-depressant drugs because of the potentially additive effects <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 , 5.7 )]</span> . Use another zolpidem tartrate immediate-release product for the 5 mg dosage of zolpidem tartrate immediate-release. Refer to the Prescribing Information of other zolpidem tartrate immediate-release products for the recommended dosage for those products.

Patients who have experienced complex sleep behaviors after taking zolpidem tartare tablets ( 4 ) Known hypersensitivity to zolpidem ( 4 ) Zolpidem tartrate tablets are contraindicated in patients Zolpidem tartrate tablets are contraindicated in patients who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions ( 5.4 )].

REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Complex Sleep Behaviors [see Warnings and Precautions (5.1)]
• CNS-Depressant Effects and Next-Day Impairment [see Warnings and Precautions (5.2)]
• Severe Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions (5.4)]
• Abnormal Thinking and Behavior Changes [see Warnings and Precautions (5.5)]
• Withdrawal Effects [see Warnings and Precautions (5.9)] Most commonly observed adverse reactions (>10% in either elderly or adult patients) are: headache, next-day somnolence and dizziness ( ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Associated with Discontinuation of Treatment In 3-week clinical trials in adults and elderly patients (&gt;65 years), 3.5% (7/201) patients receiving zolpidem tartrate extended-release tablets 6.25 mg 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets were headache, next-day somnolence, and dizziness. In the 6-month trial evaluating zolpidem tartrate extended-release tablets 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 tablets versus 2.6% for placebo).

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 extended-release tablets 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 tablets. These trials involved patients with primary insomnia who were treated for 3 weeks with zolpidem tartrate extended-release tablets 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 tablets 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* Zolpidem Tartrate Extended-Release Tablets 12.5 mg (N = 102) Placebo (N = 110) Infections and infestations Influenza 3 0 Gastroenteritis 1 0 Labyrinthitis 1 0 Metabolism and nutrition disorders Appetite disorder 1 0 Psychiatric disorders Hallucinations † 4 0 Disorientation 3 2 Anxiety 2 0 Depression 2 0 Psychomotor retardation 2 0 Binge eating 1 0 Depersonalization 1 0 Disinhibition 1 0 Euphoric mood 1 0 Mood swings 1 0 Stress symptoms 1 0 Nervous system disorders Headache 19 16 Somnolence 15 2 Dizziness 12 5 Memory disorders ‡ 3 0 Balance disorder 2 0 Disturbance in attention 2 0 Hypoesthesia 2 1 Ataxia 1 0 Paresthesia 1 0 Eye disorders Visual disturbance 3 0 Eye redness 2 0 Vision blurred 2 1 Altered visual depth perception 1 0 Asthenopia 1 0 Ear and labyrinth disorders Vertigo 2 0 Tinnitus 1 0 Respiratory, thoracic and mediastinal disorders Throat irritation 1 0 Gastrointestinal disorders Nausea 7 4 Constipation 2 0 Abdominal discomfort 1 0 Abdominal tenderness 1 0 Frequent bowel movements 1 0 Gastroesophageal reflux disease 1 0 Vomiting 1 0 Skin and subcutaneous tissue disorders Rash 1 0 Skin wrinkling 1 0 Urticaria 1 0 Musculoskeletal and connective tissue disorders Back pain 4 3 Myalgia 4 0 Neck pain 1 0 Reproductive system and breast disorders Menorrhagia 1 0 General disorders and administration site conditions Fatigue 3 2 Asthenia 1 0 Chest discomfort 1 0 Investigations Blood pressure increased 1 0 Body temperature increased 1 0 Injury, poisoning and procedural complications Contusion 1 0 Social circumstances Exposure to poisonous plant 1 0 * Reactions reported by at least 1% of patients treated with zolpidem tartrate extended-release tablets and at greater frequency than in the placebo group. † Hallucinations included hallucinations NOS as well as visual and hypnagogic hallucinations. ‡ Memory disorders include: memory impairment, amnesia, anterograde amnesia.

Table

2: Incidences of Treatment-Emergent Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial in Elderly (percentage of patients reporting)

Body System Adverse

Reaction* Zolpidem Tartrate Extended-Release Tablets 6.25 mg (N=99) Placebo (N=106) Infections and infestations Nasopharyngitis 6 4 Lower respiratory tract infection 1 0 Otitis externa 1 0 Upper respiratory tract infection 1 0 Psychiatric disorders Anxiety 3 2 Psychomotor retardation 2 0 Apathy 1 0 Depressed mood 1 0 Nervous system disorders Headache 14 11 Dizziness 8 3 Somnolence 6 5 Burning sensation 1 0 Dizziness postural 1 0 Memory disorders † 1 0 Muscle contractions involuntary 1 0 Paresthesia 1 0 Tremor 1 0 Cardiac disorders Palpitations 2 0 Respiratory, thoracic and mediastinal disorders Dry throat 1 0 Gastrointestinal disorders Flatulence 1 0 Vomiting 1 0 Skin and subcutaneous tissue disorders Rash 1 0 Urticaria 1 0 Musculoskeletal and connective tissue disorders Arthralgia 2 0 Muscle cramp 2 1 Neck pain 2 0 Renal and urinary disorders Dysuria 1 0 Reproductive system and breast disorders Vulvovaginal dryness 1 0 General disorders and administration site conditions Influenza like illness 1 0 Pyrexia 1 0 Injury, poisoning and procedural complications Neck injury 1 0 *Reactions reported by at least 1% of patients treated with zolpidem tartrate extended-release tablets and at greater frequency than in the placebo group. † Memory disorders include: memory impairment, amnesia, anterograde amnesia.

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.

Other Adverse Reactions

Observed during the Premarketing Evaluation of Zolpidem Tartrate Extended-Release Tablets Other treatment-emergent adverse reactions associated with participation in zolpidem tartrate extended-release tablets studies (those reported at frequencies of <1%) were not different in nature or frequency to those seen in studies with immediate-release zolpidem tartrate, which are listed below.

Adverse Events

Observed during the Premarketing Evaluation of Immediate-Release Zolpidem Tartrate Immediate-release zolpidem tartrate was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms. The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with zolpidem tartrate 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 : Frequent: dry mouth. 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: chest pain, 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, drowsiness, drugged feeling, euphoria, insomnia, lethargy, lightheadedness, vertigo. Infrequent: agitation, 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: diarrhea, dyspepsia, hiccup. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis. 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 : Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis. Reproductive system : Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain. Respiratory system : Frequent: sinusitis. Infrequent: bronchitis, coughing, dyspnea. 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.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of zolpidem. 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 &gt;2x ULN, alkaline phosphatase ≥2x ULN, transaminase ≥5x ULN). Psychiatric disorders: delirium

AND PRECAUTIONS CNS depressant effects: Impairs alertness and motor coordination, including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Instruct patients on correct use (5.2) Evaluate for co-morbid diagnoses: Re-evaluate if insomnia persists after 7 to 10 days of use (5.2) Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not re-challenge if such reactions occur (5.3)

Abnormal

Thinking and Behavioral Changes: Changes including decreased inhibition, bizarre behavior, agitation and depersonalization have been reported. Immediately evaluate any new onset behavioral changes (5.5) Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least number of tablets feasible to avoid intentional overdose (5.6)

Respiratory

Depression: Consider this risk before prescribing in patients with compromised respiratory function (5.7)

5.1 COMPLEX SLEEP BEHAVIORS Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following the first or any subsequent use of zolpidem. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a fatal outcome. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Post-marketing reports have shown that complex sleep behaviors may occur with zolpidem alone at recommended dosages, with or without the concomitant use of alcohol or other central nervous system (CNS) depressant s <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span> . Discontinue zolpidem tartrate immediately if a patient experiences a complex sleep behavior.

5.2 CNS Depressant Effects and Next-Day Impairment Zolpidem tartrate, like other sedative-hypnotic drugs, has CNS depressant effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of zolpidem tartrate and of other concomitant CNS depressants may be necessary when zolpidem tartrate is administered with such agents because of the potentially additive effects. The use of zolpidem tartrate with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended <span class="opacity-50 text-xs">[see Dosage and Administration (2.3)]</span> . In a driving study, healthy subjects who received zolpidem tartrate with fewer than four hours of bedtime remaining had evidence of impaired driving compared to subjects who received placebo <span class="opacity-50 text-xs">[see Clinical Studies (14.2)]</span>. The risk of next-day driving impairment (and psychomotor impairment) is increased if zolpidem tartrate is taken with less than 4 hours of bedtime remaining, if higher than recommended dose is taken, if co-administered with other CNS depressants, or co-administered with other drugs that increase the blood levels of zolpidem. Because zolpidem tartrate can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at a higher risk of falls.

5.3 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.

5.4 Severe 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 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 or anaphylaxis after treatment with zolpidem should not be rechallenged with zolpidem tartrate.

5.5 Abnormal Thinking and Behavioral Changes Abnormal thinking and behavior changes have been reported in patients treated with sedative-hypnotics including zolpidem. 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 also been reported. In controlled trials of zolpidem tartrate 10 mg taken at bedtime, &lt; 1% of adults with insomnia who received zolpidem 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4)]</span>. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

5.6 Use 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.

5.7 Respiratory Depression Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild-to-moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%, was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if zolpidem tartrate is prescribed to patients with compromised respiratory function. 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 risks of respiratory depression should be considered prior to prescribing zolpidem tartrate in patients with respiratory impairment including sleep apnea and myasthenia gravis.

5.8 Withdrawal 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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9.2) and (9.3)]</span>.

5.1 COMPLEX SLEEP BEHAVIORS Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following the first or any subsequent use of zolpidem. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a fatal outcome. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Post-marketing reports have shown that complex sleep behaviors may occur with zolpidem alone at recommended dosages, with or without the concomitant use of alcohol or other central nervous system (CNS) depressant s <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span> . Discontinue zolpidem tartrate immediately if a patient experiences a complex sleep behavior.

5.2 CNS Depressant Effects and Next-Day Impairment Zolpidem tartrate, like other sedative-hypnotic drugs, has CNS depressant effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of zolpidem tartrate and of other concomitant CNS depressants may be necessary when zolpidem tartrate is administered with such agents because of the potentially additive effects. The use of zolpidem tartrate with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended <span class="opacity-50 text-xs">[see Dosage and Administration (2.3)]</span> . In a driving study, healthy subjects who received zolpidem tartrate with fewer than four hours of bedtime remaining had evidence of impaired driving compared to subjects who received placebo <span class="opacity-50 text-xs">[see Clinical Studies (14.2)]</span>. The risk of next-day driving impairment (and psychomotor impairment) is increased if zolpidem tartrate is taken with less than 4 hours of bedtime remaining, if higher than recommended dose is taken, if co-administered with other CNS depressants, or co-administered with other drugs that increase the blood levels of zolpidem. Because zolpidem tartrate can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at a higher risk of falls.

5.3 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.

5.4 Severe 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 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 or anaphylaxis after treatment with zolpidem should not be rechallenged with zolpidem tartrate.

5.5 Abnormal Thinking and Behavioral Changes Abnormal thinking and behavior changes have been reported in patients treated with sedative-hypnotics including zolpidem. 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 also been reported. In controlled trials of zolpidem tartrate 10 mg taken at bedtime, &lt; 1% of adults with insomnia who received zolpidem 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4)]</span>. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

5.6 Use 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.

5.7 Respiratory Depression Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild-to-moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%, was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if zolpidem tartrate is prescribed to patients with compromised respiratory function. 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 risks of respiratory depression should be considered prior to prescribing zolpidem tartrate in patients with respiratory impairment including sleep apnea and myasthenia gravis.

5.8 Withdrawal 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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9.2) and (9.3)]</span>.

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 effects ( 7.2 )
• Ketoconazole: combination use may increase effect ( 7.2 )

7.1 CNS-active Drugs CNS Depressants Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Alcohol An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

Sertraline

Concomitant administration of zolpidem and sertraline increases exposure to zolpidem and may increase the pharmacodynamics effect of 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 other P450 enzymes on the exposure to zolpidem is not known.

Rifampin

Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamics effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of zolpidem.

Ketoconazole

Ketoconazole, a potent CYP3A4 inhibitor, increased the pharmacodynamics effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

Drug

Interactions CNS-depressants: 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 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 the absence of an effect following chronic administration. An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.1) ] . Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem C max was significantly higher (43%) and T max was significantly decreased (-53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem. A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamics interactions. When multiple doses of zolpidem and fluoxetine were given at steady-state and the concentrations evaluated in healthy females, an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance. 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 on the pharmacokinetics of zolpidem is unknown. A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-state levels in male volunteers resulted in a 34% increase in AUC 0-∞ of zolpidem tartrate. There were no pharmacodynamics effects of zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance. A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects showed significant reductions of the AUC (-73%), C max (-58%), and T ½ (-36 %) of zolpidem together with significant reductions in the pharmacodynamics effects of zolpidem tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamics effects of zolpidem. A single-dose interaction study with zolpidem 5 mg and ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased C max 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 pharmacodynamics effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

Other

Drugs with No Interactions with Zolpidem A study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem. Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects.