Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Each Zolpidem Tartrate Sublingual Tablet is individually packaged in a blister inside a unit-dose pouch. Zolpidem Tartrate Sublingual Tablets 1.75 mg are white to off white, round, flat faced beveled edged debossed with "N2" on one side and plain on the other side and supplied as: NDC 43386-762-30: Carton of 30 unit-dose pouches Zolpidem Tartrate Sublingual Tablets 3.5 mg are white to off white, round, flat faced beveled edged debossed with "NP" on one side and plain on the other side and supplied as: NDC 43386-761-30: Carton of 30 unit-dose pouches Storage and Handling Store between 20°C to 25°C (68°F to 77°F), [see USP Controlled Room Temperature]. Protect from moisture. The patient should be instructed not to remove the blister from the unit-dose pouch until the patient is ready to consume the sublingual tablet inside. Do not use if blister seal is broken or missing.; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 1.75 mg - Carton 3.5 mg – Carton 1.75 mg – Pouch 3.5 mg – Pouch 1.75 mg – Blister 3.5 mg – Blister 1.75-car-1 3.5-car-1 1.75-pouch 3.5-pouch 1.75-blister 3.5-blister
- 16 HOW SUPPLIED/STORAGE AND HANDLING Each Zolpidem Tartrate Sublingual Tablet is individually packaged in a blister inside a unit-dose pouch. Zolpidem Tartrate Sublingual Tablets 1.75 mg are white to off white, round, flat faced beveled edged debossed with "N2" on one side and plain on the other side and supplied as: NDC 43386-762-30: Carton of 30 unit-dose pouches Zolpidem Tartrate Sublingual Tablets 3.5 mg are white to off white, round, flat faced beveled edged debossed with "NP" on one side and plain on the other side and supplied as: NDC 43386-761-30: Carton of 30 unit-dose pouches Storage and Handling Store between 20°C to 25°C (68°F to 77°F), [see USP Controlled Room Temperature]. Protect from moisture. The patient should be instructed not to remove the blister from the unit-dose pouch until the patient is ready to consume the sublingual tablet inside. Do not use if blister seal is broken or missing.
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 1.75 mg - Carton 3.5 mg – Carton 1.75 mg – Pouch 3.5 mg – Pouch 1.75 mg – Blister 3.5 mg – Blister 1.75-car-1 3.5-car-1 1.75-pouch 3.5-pouch 1.75-blister 3.5-blister
Overview
Zolpidem Tartrate Sublingual Tablets contains zolpidem tartrate, a non-benzodiazepine hypnotic of the imidazopyridine class. Zolpidem Tartrate Sublingual Tablets are available in 1.75 mg and 3.5 mg strength tablets for sublingual administration. Zolpidem Tartrate Sublingual Tablets are intended to be placed under the tongue where they will disintegrate. Zolpidem Tartrate Sublingual Tablets contain a bicarbonate-carbonate buffer. Chemically, zolpidem tartrate is N,N -6-trimethyl-2- p -tolylimidazo[1,2- α ]pyridine-3-acetamide L-(+)-tartrate (2:1). Zolpidem tartrate is a white to almost white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88. Each Zolpidem Tartrate Sublingual Tablet includes the following inactive ingredients: Crospovidone, Povidone, Mannitol, Polyvinylacetate, colloidal silicon dioxide, sodium carbonate anhydrous, sodium bicarbonate, natural and artificial spearmint flavor, aspartame, and magnesium stearate. Structure
Indications & Usage
Zolpidem Tartrate is 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 ( 1 ) 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 ( 1 ) Zolpidem Tartrate Sublingual Tablet is 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 Tablet is 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.
Dosage & Administration
Take only if 4 hours of bedtime remain before the planned time of waking ( 2.1 , 5.1 ) Zolpidem Tartrate Sublingual Tablets should be placed under the tongue and allowed to disintegrate completely before swallowing. The tablet should not be swallowed whole. ( 2.1 ) The effect of Zolpidem Tartrate Sublingual Tablets may be slowed if taken with or immediately after a meal ( 2.1 ) Recommended dose is 1.75 mg for women and 3.5 mg for men, taken only once per night if needed ( 2.2 ) Lower doses of CNS depressants may be necessary when taken concomitantly with Zolpidem Tartrate Sublingual Tablets ( 2.3 ) Co-administration with CNS depressants: Recommended dose is 1.75 mg for men and women ( 2.3 ) Geriatric patients and patients with hepatic impairment: Recommended dose is 1.75 mg for men and women ( 2.4 , 2.5 ) 2.1 Important Administration Instructions Zolpidem Tartrate Sublingual Tablet is to be taken in bed when a patient wakes in the middle of the night and has difficulty returning to sleep. Zolpidem Tartrate Sublingual Tablet should only be taken if the patient has at least 4 hours of bedtime remaining before the planned time of waking [see Warnings and Precautions (5.1) ]. Zolpidem Tartrate Sublingual Tablet should be placed under the tongue and allowed to disintegrate completely before swallowing. The tablet should not be swallowed whole. For optimal effect, Zolpidem Tartrate Sublingual Tablet should not be administered with or immediately after a meal. The blister should be removed from the pouch just prior to dosing. 2.2 Basic Dosing Information The recommended and maximum dose of Zolpidem Tartrate Sublingual Tablet is 1.75 mg for women and 3.5 mg for men, taken only once per night as needed if a middle-of-the-night awakening is followed by difficulty returning to sleep. The recommended doses for women and men are different because women clear zolpidem from the body at a lower rate than men [see Use in Specific Populations (8.6) ] . 2.3 Use with CNS Depressants The recommended Zolpidem Tartrate Sublingual Tablet dose for men and women who are taking concomitant CNS depressants is 1.75 mg. Dose adjustment of concomitant CNS depressants may be necessary when co-administered with Zolpidem Tartrate Sublingual Tablet because of potentially additive effects. The use of Zolpidem Tartrate Sublingual Tablet with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see Warnings and Precautions (5.1) ]. 2.4 Use in Geriatric Patients Geriatric patients may be especially sensitive to the effects of zolpidem. The recommended dose of Zolpidem Tartrate Sublingual Tablets in men and women over 65 years old is 1.75 mg, taken only once per night if needed [see Use in Specific Populations (8.5) ]. 2.5 Use in Patients with Hepatic Impairment The recommended dose of Zolpidem Tartrate Sublingual Tablet in patients with hepatic impairment is 1.75 mg, taken only once per night if needed [see Clinical Pharmacology (12.3) ].
Warnings & 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) depressants [ see Drug Interactions (7.1)], .]. Discontinue Zolpidem Tartrate Sublingual Tablets immediately if a patient experiences a complex sleep behavior 5.2 CNS Depressant Effects and Next-Day Impairment Zolpidem Tartrate Sublingual Tablets, 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 Sublingual Tablets and of other concomitant CNS depressants may be necessary when Zolpidem Tartrate Sublingual Tablets are administered with such agents because of the potentially additive effects. The use of Zolpidem Tartrate Sublingual Tablets 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) ] In a driving study, healthy subjects who received Zolpidem Tartrate Sublingual Tablets with fewer than four hours of bedtime remaining had evidence of impaired driving compared to subjects who received placebo [see Clinical Studies (14.2) ]. The risk of next-day driving impairment (and psychomotor impairment) is increased if Zolpidem Tartrate Sublingual Tablets 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 Sublingual Tablets 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 Sublingual Tablets. 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, < 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 [see Use in Specific Populations (8.4) ]. 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 Sublingual Tablets are 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 Sublingual Tablets 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 [see Drug Abuse and Dependence (9.2) and (9.3)]. Phenylketonurics Phenylalanine is a component of aspartame. Each 3.5 mg and 1.75 mg Zolpidem Tartarate Sublingual Tablets contains 4.48 mg and 2.24 mg of phenylalanine.
Boxed 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 Zolpidem Tartrate Sublingual Tablets. Some of these events may result in serious injuries, including death. Discontinue Zolpidem Tartrate Sublingual Tablets immediately if a patient experiences a complex sleep behavior [ see Contraindications (4) and Warnings and Precautions (5.1 )]. WARNING: COMPLEX SLEEP BEHAVIORS See full prescribing information for complete box warning. Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of Zolpidem Tartrate Sublingual Tablets. Some of these events may result in serious injuries, including death. Discontinue Zolpidem Tartrate Sublingual Tablets immediately if a patient experiences a complex sleep behavior (4, 5.1).
Contraindications
Patients who have experienced complex sleep behaviors after taking Zolpidem Tartrate Sublingual Tablets (4, 5.1) Known hypersensitivity to zolpidem (4) Zolpidem Tartrate Sublingual Tablets are contraindicated in patients who have experienced complex sleep behaviors after taking Zolpidem Tartrate Sublingual Tablets [see Warnings and Precautions (5.1) ] Zolpidem Tartrate Sublingual Tablets are contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions with zolpidem include anaphylaxis and angioedema [see Warnings and Precautions (5.3) ].
Adverse Reactions
Most commonly observed adverse reactions (> 1% in adult patients) are headache, nausea, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-866-403-7592 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch The following serious adverse reactions in zolpidem-treated patients 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 (5.2) ] Abnormal Thinking and Behavioral Changes [ see Warnings and Precautions (5.5) ] Withdrawal Effects [ see Warnings and Precautions (5.8) ] 6.1 Clinical Trials Experience The safety data described below are based on two double-blind placebo-controlled trials of Zolpidem Tartrate Sublingual Tablets in adult patients with insomnia characterized by difficulty returning to sleep after a middle-of-the-night awakening [see Clinical Studies (14.1) ]. These two trials included 230 and 82 patients treated with 3.5 mg and 1.75 mg of Zolpidem Tartrate Sublingual Tablets, respectively. The first study was a 3-way crossover sleep-laboratory study in 82 patients (58 female and 24 male; median age 47 years; 51% Caucasian, 44% African-American) of 1.75 mg and 3.5 mg of Zolpidem Tartrate Sublingual Tablets compared to placebo (Study 1). The second study was a 4-week, parallel-group at-home study in 295 patients (201 female and 94 male; median age 43 years) of 3.5 mg of Zolpidem Tartrate Sublingual Tablets compared to placebo, used on an as needed basis after spontaneous middle-of-the-night awakenings (Study 2). In Study 2, patients took Zolpidem Tartrate Sublingual Tablets during the night on 62% of study nights. 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 actual practice. Table 1 shows the incidence of adverse reactions reported in Study 2 that occurred in 2% or more of Zolpidem Tartrate Sublingual Tablet-treated (3.5 mg) patients in which the incidence was greater than the incidence in placebo-treated patients. For women and other patients taking the 1.75 mg dose in Study 1, the incidence of adverse reactions was similar to the incidence seen with 3.5 mg of Zolpidem Tartrate Sublingual Tablets in Table 1. The most commonly reported adverse reactions in all treatment groups were headache, nausea, and fatigue. Table 1: Summary of Adverse Reactions (≥ 2%) in Outpatient, Double-Blind, Parallel-Group, Placebo-Controlled Study (Study 2) MedDRA System Organ Class Preferred Term 3 . 5 mg Zolpidem Tartrate Sublingual Tablets ( n = 150 ) Placebo ( n = 145 ) Gastrointestinal Disorders 4 % 2 % Nausea 1% 1% General Disorders and Administration Site Conditions 3 % 0 % Fatigue 1% 0% Nervous System Disorders 5 % 3 % Headache 3% 1%
Drug 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 effects ( 7.2 ) 7.1 CNS-active Drugs Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (5.2) ]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Imipramine 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. 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. Alcohol An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.2) ]. Sertraline Concomitant administration of zolpidem and sertraline increases exposure to zolpidem and may increase the pharmacodynamic effect of zolpidem. Fluoxetine After multiple doses of zolpidem tartrate and fluoxetine, an increase in the zolpidem halflife (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 pharmacodynamic effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of zolpidem. Ketoconazole Ketoconazole, a potent CYP3A4 inhibitor, increased the pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.
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