Edluar

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 0037-6010

Application: NDA021997

Effective: 20220815

1 INDICATIONS AND USAGE Edluar (zolpidem tartrate) sublingual tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation [see Clinical Studies (14) ] . The clinical trials performed with zolpidem tartrate in support of efficacy were 4-5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment. Edluar, a gamma-aminobutyric acid (GABA) A receptor positive modulator, 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. ( 1 )

2 DOSAGE AND ADMINISTRATION • Use the lowest dose effective for the patient ( 2.1 ) • Recommended dose is 5 mg for women and 5 or 10 mg for men, immediately before bedtime. ( 2.1 ) • Geriatric patients and patients with hepatic impairment: Recommended dose is 5 mg for men and women. ( 2.2 ) • Lower doses of CNS depressants may be necessary when taken concomitantly with Edluar. ( 2.3 ) • Co-administration with CNS depressants: Recommended dose is 5 mg for men and women. ( 2.3 ) • The effect of Edluar may be slowed if taken with or immediately after a meal. ( 2.4 ) • Edluar sublingual tablet should be placed under the tongue, where it will disintegrate. ( 2.4 ) • The tablet should not be swallowed and the tablet should not be taken with water. ( 2.4 ) 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 Edluar 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 Edluar in both of these patient populations is 5 mg once daily immediately before bedtime [see Warnings and Precautions (5.1) ; Use in Specific Populations (8.5) ] . 2.3 Use with CNS Depressants Dosage adjustment may be necessary when Edluar is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.1) ] . 2.4 Administration The effect of Edluar may be slowed by ingestion with or immediately after a meal. Edluar sublingual tablet should be placed under the tongue, where it will disintegrate. The tablet should not be swallowed and the tablet should not be taken with water.

4 CONTRAINDICATIONS Edluar is contraindicated in patients: • who have experienced complex sleep behaviors after taking Edluar [see Warnings and Precautions (5.1) ]. • with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.4) ] . • Patients who have experienced complex sleep behaviors after taking Edluar. ( 4 , 5.1 ) • Known hypersensitivity to zolpidem. ( 4 )

Not available.

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 Warning and Precautions (5.4) ] • Abnormal Thinking and Behavioral Changes [see Warning and Precautions (5.5) ] • Withdrawal Effects [see Warning and Precautions (5.8) ] 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 Meda Pharmaceuticals Inc. at 1-866-444-7799 or 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 tartrate 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 tartrate 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 event 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 a pool 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. TABLE 1: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials with zolpidem tartrate lasting up to 10 nights (Percentage of patients reporting) *Reactions reported by at least 1% of patients treated with oral zolpidem and at a greater frequency than placebo. Body System/ Adverse Event* Zolipidem tartrate (≤ 10 mg) (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 a pool of three placebo-controlled long-term efficacy trials involving oral zolpidem. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring at an incidence of at least 1% for zolpidem patients. TABLE 2: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials with zolpidem tartrate lasting up to 35 nights (Percentage of patients reporting) *Reactions reported by at least 1% of patients treated with oral zolpidem and at a greater frequency than placebo. Body System/ Adverse Event* Zolpidem tartrate (≤ 10 mg) (N=152) Placebo (N=161) Autonomic Nervous System 3 1 Dry mouth 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 associated with oral zolpidem: There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with oral zolpidem use, particularly for certain CNS and gastrointestinal adverse events. Oral tissue-related adverse reactions to Edluar: The effect of chronic daily administration of Edluar on oral tissue was evaluated in a 60-day open-label study in 60 insomniac patients. One patient developed transient sublingual erythema, and another transient paresthesia of the tongue. Adverse event incidence across the entire preapproval oral zolpidem database: Zolpidem was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms. The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already 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, 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, 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, hypercholesterolemia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema. Musculoskeletal system: Frequent: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis. Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain. Respiratory system: Frequent: upper respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, 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.