FDA label 95ef6f01-021c-14af-e053-2a95a90a548c

5 WARNINGS AND PRECAUTIONS CNS depressant effects: Impairs alertness and motor coordination. Instruct patients on correct use. ( 5.1 ) Need to evaluate for co-morbid diagnosis: 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 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 sprays feasible to avoid intentional overdose. ( 5.5 ) Respiratory depression: Consider this risk before prescribing in patients with compromised respiratory function. ( 5.6 ) Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation. ( 5.7 , 9.3 ) 5.1 CNS Depressant Effects and Next-day Impairment Zolpimist (zolpidem tartrate) Oral Spray, 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 Zolpimist (zolpidem tartrate) Oral Spray and of other concomitant CNS depressants may be necessary when Zolpimist (zolpidem tartrate) Oral Spray is administered with such agents because of the potentially additive effects. The use of Zolpimist (zolpidem tartrate) Oral Spray 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 Zolpimist (zolpidem tartrate) Oral Spray 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 if co-administered with other drugs that increase the blood levels of zolpidem. Patients should be cautioned against driving and other activities requiring complete mental alertness if Zolpimist (zolpidem tartrate) Oral Spray is taken in these circumstances [see Dosage and Administration (2) and Clinical Studies (14.3) ] . 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 behavioral 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 behavioral 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 oral spray (Zolpimist) 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 neuropsychiatric symptoms may also occur. 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.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. 5.5 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 least amount of drug 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 Zolpimist (zolpidem tartrate) Oral Spray is prescribed to patients with compromised respiratory function. Postmarketing 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 Zolpimist (zolpidem tartrate) Oral Spray in patients with respiratory impairment including sleep apnea and myasthenia gravis. 5.7 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 (9.2) and Dependence (9.3) ] .

6 ADVERSE 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 (5.7) ] . Most commonly observed adverse reactions were: Short-term (<10 nights): Drowsiness, dizziness, and diarrhea Long-term (28-35 nights): Dizziness and drugged feelings ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact MAGNA Pharmaceuticals at 1.888.206.5525; FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Associated with discontinuation of treatment: Approximately 4% of 1,701 patients who received zolpidem tartrate at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%). Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%). Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n=97) was discontinued after an attempted suicide. Most commonly observed adverse reactions in controlled trials: During short-term treatment (up to 10 nights) with zolpidem tartrate 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 tartrate 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 Reactions in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (Percentage of patients reporting) Body System/Adverse Reaction Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo. Zolpidem (ʺ10mg) (n=685) Placebo (n=473) Central and Peripheral Nervous System Headache 7 6 Drowsiness 2 - Dizziness 1 - Gastrointestinal System Diarrhea 1 - The following table was derived from results of three placebo-controlled long-term efficacy trials involving zolpidem tartrate. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem tartrate 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 reactions occurring at an incidence of at least 1% for zolpidem tartrate patients. Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (Percentage of patients reporting) Zolpidem (ʺ10mg) Placebo Body System/Adverse Reaction Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo. (n=152) (n=161) Autonomic Nervous System Dry mouth 3 1 Body as a Whole Allergy 4 1 Back pain 3 2 Influenza-like symptoms 2 - Chest pain 1 - Cardiovascular System Palpitation 2 - Central and Peripheral Nervous System Drowsiness 8 5 Dizziness 5 1 Lethargy 3 1 Drugged feeling 3 - Lightheadedness 2 1 Depression 2 1 Abnormal dreams 1 - Amnesia 1 - Sleep disorder 1 - Gastrointestinal System Diarrhea 3 2 Abdominal pain 2 2 Constipation 2 1 Respiratory System Sinusitis 4 2 Pharyngitis 3 1 Skin and Appendages Rash 2 1 Dose relationship for adverse reactions: There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem tartrate use, particularly for certain CNS and gastrointestinal adverse reactions. Oral tissue-related adverse reactions in Zolpimist (zolpidem tartrate) Oral Spray pharmacokinetics studies: The effect of chronic daily administrations of Zolpimist (zolpidem tartrate) Oral Spray on oral tissue has not been evaluated. In pharmacokinetic studies conducted with Zolpimist (zolpidem tartrate) Oral Spray in healthy subjects, an oral soft tissue exam was performed and no signs of oral irritation were noted following administration of single doses of Zolpimist (zolpidem tartrate) Oral Spray. Adverse event incidence across the entire preapproval database: Zolpidem tartrate was administered to 3,660 subjects in clinical trials throughout the United States, Canada, and Europe. Treatment-emergent adverse event 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 WHO dictionary of preferred terms. The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem tartrate, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem tartrate. 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, 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, tendonitis. 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.

<table width="80%"> <caption>Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (Percentage of patients reporting)</caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th align="left" styleCode="Toprule" valign="bottom">Body System/Adverse Reaction <footnote ID="K898">Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo.</footnote> </th> <th styleCode="Toprule" valign="top">Zolpidem (&#x2BA;10mg) (n=685) </th> <th valign="bottom">Placebo (n=473) </th> </tr> </thead> <tbody> <tr> <td align="left" styleCode="Toprule" valign="bottom">Central and Peripheral Nervous System </td> <td styleCode="Toprule" valign="top"/> <td valign="top"/> </tr> <tr> <td align="left" valign="bottom"> Headache</td> <td valign="top">7</td> <td valign="top">6</td> </tr> <tr> <td align="left" valign="bottom"> Drowsiness</td> <td valign="top">2</td> <td valign="top">-</td> </tr> <tr> <td align="left" valign="bottom"> Dizziness</td> <td valign="top">1</td> <td valign="top"/> </tr> <tr> <td align="left" valign="bottom"/> <td colspan="2" valign="top">- Gastrointestinal System</td> </tr> <tr> <td align="left" styleCode="Botrule" valign="bottom"> Diarrhea</td> <td styleCode="Botrule" valign="top">1</td> <td styleCode="Botrule" valign="top">-</td> </tr> </tbody> </table>

<table width="80%"> <caption>Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (Percentage of patients reporting)</caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th align="left" valign="top"/> <th valign="top">Zolpidem</th> <th valign="top"/> </tr> <tr> <th align="left" valign="top"/> <th valign="top">(&#x2BA;10mg)</th> <th valign="top">Placebo</th> </tr> <tr> <th align="left" valign="top">Body System/Adverse Reaction <footnote ID="K1022">Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo.</footnote> </th> <th valign="top">(n=152)</th> <th valign="top">(n=161)</th> </tr> </thead> <tbody> <tr> <td align="left" colspan="3" valign="bottom">Autonomic Nervous System</td> </tr> <tr> <td align="left" valign="bottom"> Dry mouth</td> <td valign="top">3</td> <td valign="top">1</td> </tr> <tr> <td align="left" colspan="3" valign="bottom">Body as a Whole</td> </tr> <tr> <td align="left" valign="bottom"> Allergy</td> <td valign="top">4</td> <td valign="top">1</td> </tr> <tr> <td align="left" valign="bottom"> Back pain</td> <td valign="top">3</td> <td valign="top">2</td> </tr> <tr> <td align="left" valign="bottom"> Influenza-like symptoms</td> <td valign="top">2</td> <td valign="top">-</td> </tr> <tr> <td align="left" valign="bottom"> Chest pain</td> <td valign="top">1</td> <td valign="top">-</td> </tr> <tr> <td align="left" colspan="3" valign="bottom">Cardiovascular System</td> </tr> <tr> <td align="left" valign="bottom"> Palpitation</td> <td valign="top">2</td> <td valign="top"/> </tr> <tr> <td align="center" valign="bottom"/> <td colspan="2" valign="top">- Central and Peripheral Nervous System</td> </tr> <tr> <td align="left" valign="bottom"> Drowsiness</td> <td valign="top">8</td> <td valign="top">5</td> </tr> <tr> <td align="left" valign="bottom"> Dizziness</td> <td valign="top">5</td> <td valign="top">1</td> </tr> <tr> <td align="left" valign="bottom"> Lethargy</td> <td valign="top">3</td> <td valign="top">1</td> </tr> <tr> <td align="left" valign="bottom"> Drugged feeling</td> <td valign="top">3</td> <td valign="top">-</td> </tr> <tr> <td align="left" valign="bottom"> Lightheadedness</td> <td valign="top">2</td> <td valign="top">1</td> </tr> <tr> <td align="left" valign="bottom"> Depression</td> <td valign="top">2</td> <td valign="top">1</td> </tr> <tr> <td align="left" valign="bottom"> Abnormal dreams</td> <td valign="top">1</td> <td valign="top">-</td> </tr> <tr> <td align="left" valign="bottom"> Amnesia</td> <td valign="top">1</td> <td valign="top">-</td> </tr> <tr> <td align="left" valign="bottom"> Sleep disorder</td> <td valign="top">1</td> <td valign="top">-</td> </tr> <tr> <td align="left" colspan="3" valign="bottom">Gastrointestinal System</td> </tr> <tr> <td align="left" valign="bottom"> Diarrhea</td> <td valign="top">3</td> <td valign="top">2</td> </tr> <tr> <td align="left" valign="bottom"> Abdominal pain</td> <td valign="top">2</td> <td valign="top">2</td> </tr> <tr> <td align="left" valign="bottom"> Constipation</td> <td valign="top">2</td> <td valign="top">1</td> </tr> <tr> <td align="left" colspan="3" valign="bottom">Respiratory System</td> </tr> <tr> <td align="left" valign="bottom"> Sinusitis</td> <td valign="top">4</td> <td valign="top">2</td> </tr> <tr> <td align="left" valign="bottom"> Pharyngitis</td> <td valign="top">3</td> <td valign="top">1</td> </tr> <tr> <td align="left" colspan="3" valign="bottom">Skin and Appendages</td> </tr> <tr> <td align="left" styleCode="Botrule" valign="bottom"> Rash</td> <td styleCode="Botrule" valign="top">2</td> <td styleCode="Botrule" valign="top">1</td> </tr> </tbody> </table>