Zolpidem Tartrate (zolpidem tartrate 10 mg) Dailymed

• • CNS depressant effects: Impairs alertness and motor coordination. Instruct patients on correct use. (5.1)
• • Need to evaluate for co-morbid diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use. (5.2)
• • Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.3)
• •"Sleep-driving" and other complex behaviors while not fully awake. Risk increases with dose and use with other CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes. (5.4)
• • Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose. (5.5)
• • Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function (5.6)
• • Hepatic Impairment: Avoid zolpidem tartrate tablets use in patients with severe hepatic impairment. (5.7)
• • Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation (5.8, 9.3)
• • Severe Injuries: Drowsiness may lead to fall including severe injuries (5.9)

5.1 CNS Depressant Effects and Next-Day Impairment

Zolpidem tartrate, like other sedative-hypnotic drugs, has central nervous system (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 [see Dosage and Administration (2.3) ].

The risk of next-day psychomotor impairment, including impaired driving, is increased if zolpidem tartrate is taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if co-administered with other CNS depressants or alcohol; or if co-administered with other drugs that increase the blood levels of zolpidem. Patients should be warned against driving and other activities requiring complete mental alertness if zolpidem tartrate is taken in these circumstances [see Dosage and Administration (2) andClinical Studies (14.3)].

Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness and impaired driving the morning after therapy. In order to minimize this risk a full night of sleep (7 to 8 hours) is recommended.

5.2 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.

5.3 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 sedative-hypnotics, including zolpidem. Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zolpidem should not be rechallenged with the drug.

5.4 Abnormal Thinking and Behavioral Changes

Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including zolpidem tartrate. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization. Visual and auditory hallucinations have been reported.

In controlled trials of zolpidem tartrate 10 mg taken at bedtime < 1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with zolpidem tartrate 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific Populations (8.4) ].

Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as "sleep-driving" have occurred with zolpidem tartrate alone at therapeutic doses, the co-administration of zolpidem tartrate with alcohol and other CNS depressants increases the risk of such behaviors, as does the use of zolpidem tartrate at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zolpidem tartrate should be strongly considered for patients who report a "sleep-driving" episode.

Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with "sleep-driving", patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may also occur.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors uled 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.

5.5 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.

5.6 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 risk of respiratory depression should be considered prior to prescribing zolpidem tartrate in patients with respiratory impairment including sleep apnea and myasthenia gravis.

5.7 Precipitation of Hepatic Encephalopathy

GABA agonists such as zolpidem tartrate have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency. In addition, patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function. Avoid zolpidem tartrate use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

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 [see Drug Abuse and Dependence (9.2) AND(9.3)].

5.9 Severe Injuries

Zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries. Severe injuries such as hip fractures and intracranial hemorrhage have been reported.

6adverse Reactions

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

• •CNS-depressant effects and next-day impairment [see Warnings and Precautions (5.1) ]
• •Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.3) ]
• •Abnormal thinking and behavior changes, and complex behaviors [see Warnings and Precautions (5.4) ]
• •Withdrawal effects [see Warnings And Precautions (5.8) ]

Most commonly observed adverse reactions were:

Short-term (< 10 nights): Drowsiness, dizziness, and diarrhea

Long-term (28 to 35 nights): Dizziness and drugged feelings (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch

6.1 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 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.

Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (Percentage of Patients Reporting)

Body System/ Adverse Event*	Zolpidem (≤10 mg) (N=685)	Placebo (N=473)
Central and Peripheral Nervous System
  Headache	7	6
  Drowsiness	2	-
  Dizziness	1	-
Gastrointestinal System
  Diarrhea	1	-

*Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo.

The following table was derived from results of three placebo-controlled long-term efficacy trials involving zolpidem tartrate. 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.

Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (Percentage of patients reporting)

Body System/ Adverse Event*	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

*Reactions reported by at least 1% of patients treated with zolpidem and at a greater frequency than placebo.

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 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 uled 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, 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval 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 >2x ULN, alkaline phosphatase ≥2x ULN, transaminase ≥5x ULN).