Zolpidem Tartrate

American Health Packaging

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Zolpidem Tartrate safely and effectively. See full prescribing information for Zolpidem Tartrate. Zolpidem Tartrate (Zolpidem Tartrate) TABLET, FILM COATED, EXTENDED RELEASE for ORAL use.Initial U.S. Approval: 1992RECENT MAJOR CHANGES Dosage and Administration (2)                                          4/2013 Dosage and Administration, Dosage in Adults (2.1)         4/2013Warnings and Precautions (5)                                            4/2013INDICATIONS AND USAGE Zolpidem tartrate extended-release tablets, USP a gamma-aminobutyric acid (GABA) A agonist are indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. (1)DOSAGE AND ADMINISTRATION • Use the lowest dose effective for the patient (2.1) • Recommended initial dose is 6.25 mg for women, and 6.25 or 12.5 mg for men, immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening (2.1) • Geriatric patients and patients with hepatic impairment: Recommended dose is 6.25 mg for men and women (2.2) • Lower doses of CNS depressants may be necessary when taken concomitantly with zolpidem tartrate extend-release tablets (2.3) • Tablets to be swallowed whole, not to be crushed, divided or chewed (2.4) • The effect of zolpidem tartrate extend-release tablets may be slowed if taken with or immediately after a meal (2.4) DOSAGE FORMS AND STRENGTHS Tablets: 6.25 mg and 12.5 mg extended-release tablets. Tablets not scored (3)CONTRAINDICATIONS Known hypersensitivity to zolpidem (4)WARNINGS AND PRECAUTIONS • CNS depressant effects: Impaired alertness and motor coordination, including risk of morning impairment. Caution patients against driving and other activities requiring complete mental alertness the morning after use. (5.1) • Need to evaluate for co-morbid diagnoses: Revaluate if insomnia persists after 7 to 10 days of use (5.2) • Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge 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 amount of tablets feasible to avoid intentional overdose. (5.5) • Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function (5.6 ) • Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation (5.7, 9.3) Side Effects Most commonly observed adverse reactions (> 10% in either elderly or adult patients) are: headache, next-day somnolence and dizziness (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 effect (7.2) • Ketoconazole: Combination use may increase effect (7.2) USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, zolpidem may cause fetal harm (8.1) •Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder (5.4, 8.4)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1  ZOLPIDEM TARTRATE INDICATIONS AND USAGE
• 2  ZOLPIDEM TARTRATE DOSAGE AND ADMINISTRATION
  • 2.1 Dosage in Adults
  • 2.2 Special Populations
  • 2.3 Use with CNS Depressants
  • 2.4 Administration
• 3  DOSAGE FORMS AND STRENGTHS
• 4  ZOLPIDEM TARTRATE CONTRAINDICATIONS
• 5  WARNINGS AND PRECAUTIONS
  • 5.1 CNS Depressant Effects and Next-Day Impairment
  • 5.2 Need to Evaluate for Co-morbid Diagnoses
  • 5.3 Severe Anaphylactic and Anaphylactoid Reactions
  • 5.4 Abnormal Thinking and Behavioral Changes
  • 5.5 Use in Patients with Depression
  • 5.6 Respiratory Depression
  • 5.7 Withdrawal Effects
• 6  ZOLPIDEM TARTRATE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
• 7  DRUG INTERACTIONS
  • 7.1 CNS-active Drugs
  • 7.2 Drugs that Affect Drug Metabolism via Cytochrome P450
• 8  USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Gender Difference in Pharmacokinetics
• 9  DRUG ABUSE AND DEPENDENCE
  • 9.1 Controlled Substance
  • 9.2 Abuse
  • 9.3 Dependence
• 10  OVERDOSAGE
  • 10.1 Signs and Symptoms
  • 10.2 Recommended Treatment
• 11  ZOLPIDEM TARTRATE DESCRIPTION
• 12  CLINICAL PHARMACOLOGY
  • 12.1  MECHANISM OF ACTION
  • 12.3  PHARMACOKINETICS
• 13  NONCLINICAL TOXICOLOGY
  • 13.1 CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
• 14  CLINICAL STUDIES
  • 14.1 Controlled Clinical Trials
  • 14.2 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs
• 16  HOW SUPPLIED/STORAGE AND HANDLING
• 17  PATIENT COUNSELING INFORMATION
• Package/Label Display Panel

FULL PRESCRIBING INFORMATION

1  INDICATIONS AND USAGE

Zolpidem tartrate extended-release tablets are indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset).

The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration [see Clinical Studies (14)].

2  DOSAGE AND ADMINISTRATION

2.1 Dosage in Adults

Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 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 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 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 zolpidem tartrate extended-release tablets should not exceed 12.5 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 zolpidem tartrate extended-release tablets in both of these patient populations is 6.25 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 zolpidem tartrate extended-release tablets are combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.1)].

2.4 Administration

Zolpidem tartrate extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of zolpidem tartrate extended-release tablets may be slowed by ingestion with or immediately after a meal.

3  DOSAGE FORMS AND STRENGTHS

Zolpidem tartrate extended-release tablets, USP are available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem tartrate, USP for oral administration.  Tablets are not scored.

Zolpidem tartrate extended-release tablets, USP 6.25 mg, are coated, white, round, bi-convex and debossed with A2 on one side.

Zolpidem tartrate extended-release tablets, USP 12.5 mg, are coated, yellow, round, bi-convex and debossed with A1 on one side.

4  CONTRAINDICATIONS

Zolpidem tartrate extended-release tablets are contraindicated in patients with known hypersensitivity to zolpidem tartrate. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.3)].

5  WARNINGS AND PRECAUTIONS

5.1 CNS Depressant Effects and Next-Day Impairment

• •Zolpidem tartrate extended-release tablets are a central nervous system (CNS) depressant and can impair daytime function in some patients even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of zolpidem tartrate extended-release tablets may develop, patients using zolpidem tartrate extended-release tablets should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.
• •Additive effects occur with concomitant use of other CNS depressants (e.g. benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of zolpidem tartrate extended-release tablets and concomitant CNS depressants should be considered [see Dosage and Administration (2.3)].
• •The use of zolpidem tartrate extended-release tablets with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended.
• •The risk of next-day psychomotor impairment is increased if zolpidem tartrate extended-release tablets is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if coadministered with other CNS depressants; or co-administered with other drugs that increase the blood levels of zolpidem [see Dosage and Administration (2) and Clinical Studies (14.2)].

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 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.

5.4 Abnormal Thinking and Behavioral Changes

Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics including zolpidem tartrate extended-release tablets. 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, <1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with zolpidem tartrate extended-release tablets 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 tartrate extended-release tablets alone at therapeutic doses, the co-administration of alcohol and other CNS depressants increases the risk of such behaviors, as does the use of zolpidem tartrate extended-release tablets at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zolpidem tartrate extended-release 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.

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.

5.5 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 extended-release 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 risk of respiratory depression should be considered prior to prescribing zolpidem tartrate extended-release 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)].

6  ADVERSE REACTIONS

The following serious adverse reactions 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 behavior changes, and complex behaviors [see Warnings and Precautions (5.4)]
• •Withdrawal effects [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

In 3-week clinical trials in adults and elderly patients (>65 years), 3.5% (7/201) patients receiving zolpidem tartrate extended-release tablets 6.25 or 12.5 mg discontinued treatment due to an adverse reaction as compared to 0.9% (2/216) of patients on placebo.  The reaction most commonly associated with discontinuation in patients treated with zolpidem tartrate extended-release tablets was somnolence (1%).

In a 6-month study in adult patients (18 to 64 years of age), 8.5% (57/669) of patients receiving zolpidem tartrate extended-release tablets 12.5 mg as compared to 4.6% on placebo (16/349) discontinued treatment due to an adverse reaction.  Reactions most commonly associated with discontinuation of zolpidem tartrate extended-release tablets included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo.

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.

During treatment with zolpidem tartrate extended-release tablets in adults and elderly at daily doses of 12.5 mg and 6.25 mg, respectively, each for three weeks, the most commonly observed adverse reactions associated with the use of zolpidem tartrate extended-release tablets were headache, next-day somnolence, and dizziness.

In the 6-month trial evaluating zolpidem tartrate extended-release tablets 12.5 mg, the adverse reaction profile was consistent with that reported in short-term trials, except for a higher incidence of anxiety (6.3% for zolpidem tartrate extended-release tablets versus 2.6% for placebo).

The following tables enumerate treatment-emergent adverse reaction frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate extended-release tablets in placebo-controlled trials. Events reported by investigators were classified utilizing the MedDRA dictionary 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 tables were derived from results of two placebo-controlled efficacy trials involving zolpidem tartrate extended-release tablets. These trials involved patients with primary insomnia who were treated for 3 weeks with zolpidem tartrate extended-release tablets at doses of 12.5 mg (Table 1) or 6.25 mg (Table 2), respectively.  The tables include only adverse reactions occurring at an incidence of at least 1% for zolpidem tartrate extended-release tablets patients and with an incidence greater than that seen in the placebo patients.

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.

Other treatment-emergent adverse reactions associated with participation in zolpidem tartrate extended-release tablets studies (those reported at frequencies of <1%) were not different in nature or frequency to those seen in studies with immediate-release zolpidem tartrate, which are listed below.

Immediate-release zolpidem tartrate 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 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: Frequent: dry mouth. 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: chest pain, 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, drowsiness, drugged feeling, euphoria, insomnia, lethargy, lightheadedness, vertigo.  Infrequent: agitation, 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: diarrhea, dyspepsia, hiccup.  Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis. 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: Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.

Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.

Respiratory system: Frequent: sinusitis.  Infrequent: bronchitis, coughing, dyspnea. 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.

7  DRUG INTERACTIONS

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, Chlorpromazine

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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

Fluoxetine

After multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life (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 drugs on 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

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of zolpidem tartrate extended-release tablets 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 extended-release 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 development at doses greater than the zolpidem tartrate extended-release tablets maximum recommended human dose (MRHD) of 12.5 mg/day (approximately 10 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 occurred at all but the lowest dose, which is approximately 4 times the MRHD 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 skeletal ossification occurred at the highest dose. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 8 times the MRHD 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 4 times the MRHD on a mg/m² basis.

8.2 Labor and Delivery

Zolpidem tartrate extended-release tablets have no established use in labor and delivery [see Pregnancy (8.1)].

8.3 Nursing Mothers

Zolpidem is excreted in human milk. Caution should be exercised when the zolpidem tartrate extended-release tablets is administered to a nursing woman.

8.4 Pediatric Use

Zolpidem tartrate extended-release tablets are not recommended for use in children. Safety and effectiveness of zolpidem in pediatric patients below the age of 18 years have not been established.

In an 8-week study in pediatric patients (aged 6 to 17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Warnings and Precautions (5.4)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

FDA has not required pediatric studies of zolpidem tartrate extended-release tablets in the pediatric population based on these efficacy and safety findings.

8.5 Geriatric Use

A total of 99 elderly (≥65 years of age) received daily doses of 6.25 mg zolpidem tartrate extended-release tablets in a 3-week placebo-controlled study. The adverse reaction profile of zolpidem tartrate extended-release tablets 6.25 mg in this population was similar to that of zolpidem tartrate extended-release tablets 12.5 mg in younger adults (≤ 64 years of age). Dizziness was reported in 8% of zolpidem tartrate extended-release tablets-treated patients compared with 3% of those treated with placebo.

The dose of zolpidem tartrate extended-release tablets in elderly patients is 6.25 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Warnings and Precautions (5.1)].

8.6 Gender Difference in Pharmacokinetics

Women clear zolpidem tartrate from the body at a lower rate than men. C_max and AUC parameters of zolpidem from zolpidem tartrate extended-release tablets were, respectively, approximately 50% and 75% higher at the same dose in adult female subjects compared to adult male subjects. Between 6 and 12 hours after dosing, zolpidem concentrations were 2 to 3 fold higher in adult female compared to adult male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended initial dose of zolpidem tartrate extended-release tablets for adult women is 6.25 mg, and the recommended dose for adult men is 6.25 or 12.5 mg.

In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose of zolpidem tartrate extended-release tablets in geriatric patients is 6.25 mg regardless of gender.

9  DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.

9.2 Abuse

Abuse and addiction are separate and distinct from physical dependence and tolerance.  Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances.  Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time.  Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations.  It is characterized by behaviors that include one or more of the following:  impaired control over drug use, compulsive use, continued use despite harm, and craving.  Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.

Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg effects were difficult to distinguish from placebo.

Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving zolpidem or any other hypnotic.

9.3 Dependence

Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events, which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal, were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Post-marketing reports of abuse, dependence and withdrawal have been received.

10  OVERDOSAGE

10.1 Signs and Symptoms

In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise and fatal outcomes have been reported.

10.2 Recommended Treatment

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem’s sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions).  As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.

As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.

11  DESCRIPTION

Zolpidem tartrate extended-release tablets, USP contain zolpidem tartrate, a gamma-aminobutyric acid (GABA) A agonist of the imidazopyridine class. Zolpidem tartrate extended-release tablets are available in 6.25 mg and 12.5 mg strength tablets for oral administration.

Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure: