1 INDICATIONS AND USAGE Zolpidem Tartrate is a GABAA 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.
3 DOSAGE FORMS AND STRENGTHS 1.75 mg and 3.5 mg sublingual tablets (3) Zolpidem Tartrate Sublingual Tablets are available as 1.75 mg and 3.5 mg tablets for sublingual administration. Zolpidem Tartrate Sublingual Tablets 1.75 mg are white to off white, round, flat faced beveled edged tablets debossed with "N2"on one side and plain on the other side. Zolpidem Tartrate Sublingual Tablets 3.5 mg are white to off white, round, flat faced beveled edged tablets debossed with "NP"on one side and plain on the other side.
4 CONTRAINDICATIONS Known hypersensitivity to zolpidem (4) 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)].
5 WARNINGS AND PRECAUTIONS CNS depressant effects: Impairs alertness and motor coordination. Instruct patients on correct use (5.1) 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) "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 number of tablets feasible to avoid intentional overdose (5.5) Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function (5.6) 5.1 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. 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 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. 5.4 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)]. 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 alone at therapeutic doses, the co-administration of zolpidem with alcohol and other CNS depressants increases the risk of such behaviors, as does the use of zolpidem at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zolpidem Tartrate Sublingual Tablets 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. 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 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. 5.7 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 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.
6 ADVERSE REACTIONS Most commonly observed adverse reactions (> 1% in adult patients) are headache, nausea, and fatigue. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novel Laboratories, Inc. at 1-866-403-7592 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions in zolpidem-treated patients 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 behavioral changes, and complex behaviors [see Warnings and Precautions (5.4)] Withdrawal effects [see Warnings and Precautions (5.7)] 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% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Zolpidem Tartrate Sublingual Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure. Application site reactions, primarily in the sublingual area, have been reported. These application site reactions included oral ulcers, blisters, and mucosal inflammation.
7 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 (5.1)]. 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 (5.1)]. 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.
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, zolpidem may cause fetal harm. (8.1) Pediatric use: Safety and effectiveness of zolpidem not established. With bedtime dosing of zolpidem, hallucinations observed (incidence 7%) (8.4) 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of zolpidem in pregnant women. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS-depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. Zolpidem Tartrate Sublingual Tablets should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring at doses greater than the recommended human dose (RHD) of 3.5 mg/day (approximately 2.8 mg/day zolpidem base); however, teratogenicity was not observed. When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification were observed at all but the lowest dose, which is approximately 15 times the RHD on a mg/m2 basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skull ossification were seen at the highest dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 30 times the RHD on a mg/m2 basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 15 times the RHD on a mg/m2 basis. 8.3 Nursing Mothers Zolpidem is excreted in human milk. The effect of zolpidem on the nursing infant is not known. 8.4 Pediatric Use Zolpidem Tartrate Sublingual Tablets are not recommended for use in children. Safety and effectiveness of Zolpidem Tartrate Sublingual Tablets have not been established in pediatric patients below the age of 18. In an 8-week study in pediatric patients (aged 6 to 17 years) with insomnia associated with ADHD, an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations. 8.5 Geriatric Use Zolpidem Tartrate Sublingual Tablets dosage adjustment is necessary in geriatric patients. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Zolpidem Tartrate Sublingual Tablets and observed closely [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)]. Clinical trial experience with other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime: A total of 154 patients in U.S.-controlled clinical trials and 897 patients in non-U.S. clinical trials who received oral zolpidem were ≥ 60 years of age. For a pool of U.S. patients receiving oral zolpidem tartrate at doses of ≤ 10 mg or placebo, there were three adverse reactions occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (see Table 2). Falls in geriatric patients: A total of 30/1,959 (2%) non-U.S. patients receiving other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) reported falls, including 28/30 (93%) who were ≥ 70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem tartrate doses > 10 mg. A total of 24/1,959 (1%) non-U.S. patients receiving zolpidem reported confusion, including 18/24 (75%) who were ≥70 years of age. Of these 18 patients, 14 (78%) were receiving zolpidem tartrate doses >10 mg. The dose of Zolpidem Tartrate Sublingual Tablets in elderly patients is 1.75 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative-hypnotic drugs. Table 2: Adverse Reactions in Geriatric Patients in Pooled Trials of 5 mg to 10 mg of Oral Zolpidem Tartrate Given at Bedtime Adverse Reaction 5 to 10 mg Oral Zolpidem Tartrate Placebo Dizziness 3% 0% Drowsiness 5% 2% Diarrhea 3% 1% 8.6 Gender Difference in Pharmacokinetics Women cleared zolpidem tartrate from the body after sublingual administration of a 3.5 mg dose of Zolpidem Tartrate Sublingual Tablets at a lower rate than men (2.7 mL/min/kg vs. 4.0 mL/min/kg). Cmax and AUC parameters of zolpidem were approximately 45% higher at the same dose in female subjects compared with male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended dose of Zolpidem Tartrate Sublingual Tablets for women is 1.75 mg, and the recommended dose for adult men is 3.5 mg.