ZOLPIDEM TARTRATE: Package Insert and Label Information

ZOLPIDEM TARTRATE- zolpidem tartrate tablet
Major Pharmaceuticals

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 tartare tablets. Some of these events may result in serious injuries, including death. Discontinue zolpidem tartare tablets immediately if a patient experiences a complex sleep behavior [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )].

1 INDICATIONS AND USAGE

Zolpidem tartrate tablets, USP are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets, USP have 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 to 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 to 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 ( 5.2)] . The total dose of zolpidem tartrate tablets should not exceed 10 mg once daily immediately before bedtime. Zolpidem tartrate tablets should be taken as a single dose and should not be readministered during the same night.

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. The recommended dose of zolpidem tartrate in these patient is 5 mg once daily immediately before bedtime [see Warnings and Precautions ( 5.2), Use in Specific Populations ( 8.5)].

Patients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal subjects. The recommended dose of zolpidem tartrate tablets in these patients is 5 mg once daily immediately before bedtime. Avoid zolpidem tartrate tablets use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Warnings and Precautions ( 5.8), Use in Specific Populations ( 8.7), Clinical Pharmacology ( 12.3)].

2.3 Use with CNS Depressants

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

2.4 Administration

The effect of zolpidem tartrate tablets may be slowed by ingestion with or immediately after a meal.

3 DOSAGE FORMS AND STRENGTHS

Zolpidem tartrate tablets are available in 5 mg and 10 mg strength tablets for oral administration. Tablets are not scored.

Zolpidem tartrate 5 mg tablets are red colored, capsule shaped tablets with the Torrent logo debossed on one side and ’5 MG’ debossed on the other side.

Zolpidem tartrate 10 mg tablets are peach-yellow colored, capsule shaped tablets with the Torrent logo debossed on one side and ’10 MG’ debossed on the other side.

4 CONTRAINDICATIONS

Zolpidem tartrate tablets are contraindicated in patients Zolpidem tartrate tablets are contraindicated in patients

who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )].
with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions ( 5.4)].

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 tartrate tablets. 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. Postmarketing reports have shown that complex sleep behaviors may occur with zolpidem tartrate tablets alone at recommended doses, with or without the concomitant use of alcohol or other Central Nervous System (CNS) depressants [see Drug Interactions ( 7.1 )] . Discontinue zolpidem tartrate tablets immediately if a patient experiences a complex sleep behavior [see Contraindications ( 4 )] .

5.2 CNS-Depressant Effects and Next-Day Impairment

Zolpidem tartrate tablets, like other sedative-hypnotic drugs, has CNS-depressant effects. Coadministration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression . Dosage adjustments of zolpidem tartrate tablets and of other concomitant CNS depressants may be necessary when zolpidem tartrate tablets are administered with such agents because of the potentially additive effects. The use of zolpidem tartrate tablets with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended Zolpidem tartrate tablets, like other sedative-hypnotic drugs, has CNS-depressant effects. Coadministration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression [see Drug Interactions ( 7.1 )] . Dosage adjustments of zolpidem tartrate tablets and of other concomitant CNS depressants may be necessary when zolpidem tartrate tablets are administered with such agents because of the potentially additive effects. The use of zolpidem tartrate 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 )].

The risk of next-day psychomotor impairment, including impaired driving, is increased if zolpidem tartrate tablets are taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if coadministered with other CNS depressants or alcohol; or if coadministered with other drugs that increase the blood levels of zolpidem. Patients should be warned against driving and other activities requiring complete mental alertness if zolpidem tartrate tablets are taken in these circumstances The risk of next-day psychomotor impairment, including impaired driving, is increased if zolpidem tartrate tablets are taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if coadministered with other CNS depressants or alcohol; or if coadministered with other drugs that increase the blood levels of zolpidem. Patients should be warned against driving and other activities requiring complete mental alertness if zolpidem tartrate tablets are taken in these circumstances [see Dosage and Administration ( 2 ), Clinical Studies ( 14.3 )].

Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness, and impaired driving the morning after therapy. In order to minimize this risk a full night of sleep (7 to 8 hours) is recommended.Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness, and impaired driving the morning after therapy. In order to minimize this risk a full night of sleep (7 to 8 hours) is recommended.

Because zolpidem 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 Comorbid 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 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

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 been reported.

In controlled trials of zolpidem 10 mg taken at bedtime <1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with zolpidem 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [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 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 is 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 risk of respiratory depression should be considered prior to prescribing zolpidem in patients with respiratory impairment including sleep apnea and myasthenia gravis.

5.8 Precipitation of Hepatic Encephalopathy

Drugs affecting GABA receptors, such as zolpidem tartrate, have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency. In addition, patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function. Avoid zolpidem tartrate tablets use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration ( 2.2), Use in Specific Populations ( 8.7), Clinical Pharmacology ( 12.3)].

5.9 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, 9.3)] .

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 Behavior Changes [see Warnings and Precautions ( 5.5)]
Withdrawal effects [see Warnings and Precautions ( 5.9)]

6.1 Clinical Trials Experience

Associated with Discontinuation of Treatment

Approximately 4% of 1,701 patients who received zolpidem 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 tablets 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 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.

Table 1 Incidences of Treatment-Emergent Adverse Reactions in Placebo Controlled Clinical Trials Lasting up to 10 Nights (Percentage of patients reporting)
*
Reactions reported by at least 1% of patients treated with zolpidem tartrate tablets and at a greater frequency than placebo.

Body System Adverse Reaction *

Zolpidem (≤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 results of three placebo-controlled long-term efficacy trials involving zolpidem tartrate tablets. 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 Lasting up to 35 Nights (percentage of patients reporting)
*
Reactions reported by at least 1% of patients treated with zolpidem tartrate tablets and at a greater frequency than placebo.

Body System Adverse Event *

Zolpidem (≤10 mg) (N=152)

Placebo (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 use, particularly for certain CNS and gastrointestinal adverse events.

Adverse Event Incidence Across the Entire Preapproval Database

Zolpidem tartrate tablets were 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 tartrate tablets, 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, tendinitis.

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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