ZOLPIMIST: Package Insert and Label Information

ZOLPIMIST- zolpidem tartrate spray, metered
Aytu BioPharma, Inc.

WARNING: COMPLEX SLEEP BEHAVIORS

Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of ZOLPIMIST. Some of these events may result in serious injuries, including death. Discontinue ZOLPIMIST immediately if a patient experiences a complex sleep behavior [see Contraindications ( 4) and Warnings and Precautions ( 5.1)].

1 INDICATIONS AND USAGE

ZOLPIMIST (zolpidem tartrate) is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate has been shown to decrease sleep latency for up to 35 days in controlled clinical studies [see Clinical Studies ( 14)].

The clinical trials performed in support of efficacy were 4-5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adults

Use the lowest effective dose for the patient. The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see Warnings and Precautions ( 5.1)] . The total dose of ZOLPIMIST should not exceed 10 mg once daily immediately before bedtime.

The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

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 ZOLPIMIST in both of these patient populations is 5 mg once daily immediately before bedtime [see Warnings and Precautions ( 5.7); Use in Specific Populations( 8.5)].

2.3 Use with CNS Depressants

Dosage adjustment may be necessary when ZOLPIMIST is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions ( 5.2)].

2.4 Administration

ZOLPIMIST is packaged in a child-resistant container. For detailed instructions on how to use ZOLPIMIST, refer to the Patient Instructions for Use (following the Medication Guide). ZOLPIMIST must be primed before it is used for the first time. To prime, patients should be told to point the black spray opening away from their face and other people and spray 5 times. For administration, the child-resistant container should be held upright with the black spray opening pointed directly into the mouth. The patient should fully press down on the pump to make sure a full dose (5 mg) of ZOLPIMIST is sprayed directly into the mouth over the tongue. If a 10 mg dose is prescribed, a second spray should be administered.

If the patient does not use ZOLPIMIST for at least 14 days, it must be primed again with 1 spray. The patient should be referred to the Patient Instructions for Use included at the end of the Medication Guide.

The effect of ZOLPIMIST may be slowed by ingestion with or immediately after a meal.

3 DOSAGE FORMS AND STRENGTHS

ZOLPIMIST is available as a clear, colorless, and cherry flavored solution designed to be sprayed directly into the mouth over the tongue. Each metered actuation (one spray) of ZOLPIMIST delivers 5 mg of zolpidem tartrate in 100 μL. Two actuations deliver 10 mg of zolpidem tartrate. After an initial priming of 5 actuations, there are 60 metered actuations in each child-resistant container. The total number of available doses is dependent on the number of actuations per dose (1 or 2 actuations) and the frequency of priming.

4 CONTRAINDICATIONS

ZOLPIMIST is contraindicated in patients: ZOLPIMIST is contraindicated in patients:

  • who have experienced complex sleep behaviors after taking ZOLPIMIST [see Warnings and Precautions ( 5.1)] [see Warnings and Precautions ( 5.1)]
  • with known hypersensitivity to zolpidem tartrate [ see Warnings and Precautions ( 5.7)].

5 WARNINGS AND PRECAUTIONS

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) depressants Discontinue ZOLPIMIST immediately if a patient experiences a complex sleep behavior. 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) depressants [see Drug Interactions ( 7.1)]. Discontinue ZOLPIMIST 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. Due to the rapid onset of action, ZOLPIMIST should only be administered 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 administration of ZOLPIMIST. 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 may be necessary when ZOLPIMIST is administered with such agents because of the potentially additive effects. Zolpidem tartrate, like other sedative-hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, ZOLPIMIST should only be administered 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 administration of ZOLPIMIST. 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 may be necessary when ZOLPIMIST is administered with such agents because of the potentially additive effects.

Because ZOLPIMIST can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls. Because ZOLPIMIST can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at 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 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.

5.4 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. 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.

5.5 Abnormal Thinking and Behavioral Changes

A variety of abnormal thinking and behavioral 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 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)]

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.

5.6 Withdrawal Effects

Following the 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)]

5.7 Special Populations

Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative-hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended ZOLPIMIST dosage is 5 mg in such patients to decrease the possibility of side effects. [see Dosage and Administration ( 2.2)] These patients should be closely monitored.

Use in patients with concomitant illness: Clinical experience with zolpidem tartrate in patients with concomitant systemic illness is limited. Caution is advisable in using ZOLPIMIST in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in normal 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 tartrate (10 mg) when compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if ZOLPIMIST is prescribed to patients with compromised respiratory function. Post- marketing reports of respiratory insufficiency, most of which involved patients with pre-existing respiratory impairment, have been received. ZOLPIMIST should be used with caution in patients with sleep apnea syndrome or myasthenia gravis.

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 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 did reveal prolonged elimination in this group; therefore, treatment 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: As with other sedative-hypnotic drugs, ZOLPIMIST should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional over-dosage 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.

Use in pediatric patients: Safety and effectiveness of zolpidem have not been established in pediatric patients. In an 8-week study in pediatric patients (6-17 years of age) with insomnia associated with ADHD, zolpidem did not decrease sleep latency compared to placebo. Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem tartrate; none of the pediatric patients who received placebo reported hallucinations. [see Use in Specific Populations ( 8.4)]

6 ADVERSE 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)]
  • Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions ( 5.4)]
  • Abnormal Thinking and Behavioral Changes [see Warnings and Precautions ( 5.5)]
  • Withdrawal Effects [see Warnings and Precautions ( 5.6)]

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 1,701 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* Zolpidem
(≤10mg)
(n=685)
Placebo
(n=473)

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

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)
Body System/Adverse Reaction* Zolpidem
(≤10mg)
(n=152)
Placebo
(n=161)

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

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 pharmacokinetics studies: The effect of chronic daily administrations of ZOLPIMIST on oral tissue has not been evaluated. In pharmacokinetic studies conducted with ZOLPIMIST 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.

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.

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