CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
` 21774Orig1s003
`
` AMBIEN CR
`
`zolpidem tartarte
`
`
`
`
`Trade Name:
`
`Generic or Proper
`Name:
`
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
`Sanofi Aventis
`
`12/20/2007
`
`
`
`Ambien CR is indicated for the treatment of
`insomnia characterized by difficulties with sleep
`onset and/or sleep maintenance.
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`21774Orig1s003
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
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`X
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`
`
`
`
`X
`X
`
`
`X
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`X
`X
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`X
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`

`

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`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`21774Orig1s003
`
`
`APPROVAL LETTER
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21-774/S-003/S-004/S-005/S-007/S-008
`
`Sanofi Aventis U.S., LLC
`300 Somerset Corporate Blvd.
`Bridgewater, NJ 08807
`
`Attention: Qinghua (Sarah) Ji, M.D.
`
`
`Assistant Director, Regulatory Development
`
`Dear Dr. Ji:
`
`Please refer to your supplemental new drug applications noted below submitted under section 505(b)
`of the Federal Food, Drug, and Cosmetic Act for Ambien CR (zolpidem tartrate) tablets.
`
`Application Submitted on:
`S-003
`February 20, 2007
`
`Received on:
`February 20, 2007
`
`Provides for:
`Efficacy Supplement for increase duration
`of use (6 months) of Ambien CR 12.5 mg
`(adults) and 6.25 mg (elderly)
`“Changes Being Effected” Supplement;
`revisions to Warnings and Precautions
`section
`“Changes Being Effected” Supplement;
`revisions to Warnings and Precautions
`section and Overdosage section
`“Prior Approval” Supplement;
`Medication Guide
`September 20, 2007 September 20, 2007 “Prior Approval” Supplement; Drug-Drug
`Interaction
`
`March 7, 2007
`
`March 8, 2007
`
`April 17, 2007
`
`April 18, 2007
`
`August 14, 2007
`
`August 15, 2007
`
`S-004
`
`S-005
`
`S-007
`
`S-008
`
`We also acknowledge receipt of your amendments to these applications dated April 17, 2007, May 23,
`2007, August 28, 2007 and September 20, 2007.
`
`We have completed our review of supplemental new drug applications S-003 and S-007, and they are
`approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon
`labeling and medication guide text.
`
`Content of Labeling
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format as described at
`http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed labeling (text for the
`package insert, text for the Medication Guide). Upon receipt, we will transmit that version to the
`
`

`

`NDA 21-774/S-003/S-004/S-005/S-007/S-008
`Page 2
`
`National Library of Medicine for public dissemination. For administrative purposes, please designate
`this submission, “SPL for approved NDA 21-774/S-003.”
`
`Fulfillment of Pediatric Research Equity Act (PREA) Study Requirements
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We are
`waiving the pediatric study requirement for this application because there is evidence strongly
`suggesting that Ambien (zolpidem) would be ineffective or unsafe in all pediatric age groups. Our
`determination is based upon data submitted and reviewed as part of the pediatric studies for exclusivity
`submitted for your Ambien immediate-release product. That information has been described in the
`pediatric use section of labeling.
`
`Promotional Materials
`
`The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed the
`enclosed product labeling and has determined that it contains significant new risk information relating
`to your drug product. Therefore, we are hereby informing you that all promotional materials that
`include representations about Ambien CR should be revised to include the new risk information
`immediately. These revisions should include prominent disclosure of the important new information
`described in the WARNINGS and PRECAUTIONS sections that appear in the revised package
`labeling. If you have any questions about the promotion of your drug products, please contact
`DDMAC by facsimile at (301)796-9878 or at the address provided below.
`
`In addition, please send one copy to the Division of Neurology Products and two copies of both the
`promotional materials and the proposed package insert directly to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Dear Healthcare Professional Letter
`
`We note that, on March 14, 2007, you issued a Dear Health Care Professional Letter (DHCP) that
`informed healthcare professional about the risks of sleep-driving and anaphylaxis. If you have not yet
`done so, we request that you submit a copy of the letter to this NDA and a copy to the following
`address:
`
`
`
`
`
`
`
`
`
`
`
`MEDWATCH
`Food and Drug Administration
`5515 Security Lane
`HFD-001, Suite 5100
`Rockville, MD 20852
`
`
`
`
`
`
`
`

`

`NDA 21-774/S-003/S-004/S-005/S-007/S-008
`Page 3
`
`Supplemental Applications S-004, S-005 and S-008
`
`We note that additional supplemental applications (S-004, S-005 and S-008), submitted on March 8,
`2007, April 17, 2007, and September 20, 2007 respectively, have been superseded by supplemental
`applications S-003 and S-007. Therefore we will not review supplemental applications S-004, S-005
`and S-008, but they will be retained for our files.
`
`Other
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`If you have any questions, call Cathleen Michaloski, MPH, Regulatory Project Manager, at (301) 796-
`1123.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Katz, M.D.
`Director
`Division of Neurology
`Office of New Drugs 1
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Enclosure: Package Insert (incl Medication Guide)
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Russell Katz
`12/20/2007 03:50:15 PM
`
`

`

`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`21774Orig1s003
`
`
`LABELING
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`Ambien CR safely and effectively. See full prescribing information for
`Ambien CR.
`
`Ambien CR (zolpidem tartrate extended-release) tablets
`Initial U.S. Approval: 1992
`
`
`
`
`
`03/2007
`03/2007
`04/2007
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indications and Usage (1)
`
`
`
`
`
`
`
` 12/2007
`Warnings and Precautions
`
`Severe anaphylactic and anaphylactoid reactions (5.2)
`
`Abnormal thinking and behavioral changes (5.3)
`
`
`Special populations (5.6)
`
`
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Ambien CR is indicated for the treatment of insomnia characterized by
`difficulties with sleep onset and/or sleep maintenance. (1)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`(cid:120) Adult dose: 12.5 mg once daily immediately before bedtime (2.1)
`(cid:120) Elderly/debilitated/hepatically impaired patients: 6.25 mg once daily
`immediately before bedtime (2.2)
`(cid:120) Tablets to be swallowed whole, not to be crushed, divided or chewed.
`Should not be taken with or immediately after a meal (2.4)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`6.25 mg and 12.5 mg extended-release tablets. Tablets not scored (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`Known hypersensitivity to zolpidem tartrate or to any of the inactive
`ingredients in the formulation (4)
`
`----------------------WARNINGS AND PRECAUTIONS-------------------------
`(cid:120) Need to evaluate for co-morbid diagnoses: Revaluate if insomnia persists
`after 7 to 10 days of use (5.1)
`(cid:120) Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis
`have been reported. Do not rechallenge if such reactions occur (5.2)
`(cid:120) Abnormal thinking, behavioral changes, complex behaviors: May include
`“sleep-driving” and hallucinations. Immediately evaluate any new onset
`behavioral changes (5.3)
`(cid:120) Depression: Worsening of depression or, suicidal thinking may occur.
`Prescribe the least amount feasible to avoid intentional overdose (5.3, 5.6)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`2
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1
`Dosage in adults
`2.2
`Special populations
`2.3
`Use with CNS depressants
`2.4
`Administration
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1
`Need to evaluate for co-morbid diagnoses
`5.2
`Severe anaphylactic and anaphylactoid reactions
`5.3
`Abnormal thinking and behavioral changes
`5.4
`Withdrawal effects
`5.5
`CNS depressant effects
`5.6
`Special populations
`ADVERSE REACTIONS
`6.1
`Clinical trials experience
`DRUG INTERACTIONS
`7.1
`CNS active drugs
`7.2
`Drugs that affect drug metabolism via cytochrome P450
`7.3
`Other drugs with no interaction with zolpidem
`7.4
`Drug–laboratory tests interactions
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Labor and delivery
` 8.3 Nursing mothers
` 8.4
`Pediatric use
` 8.5 Geriatric use
` DRUG ABUSE AND DEPENDENCE
`9.1 Controlled substance
`
`6
`
`7
`
`8
`
`9
`
`(cid:120) Withdrawal effects: Symptoms may occur with rapid dose reduction or
`discontinuation (5.4, 9.2)
`(cid:120) CNS depressant effects: Use can impair alertness and motor coordination.
`If used in combination with other CNS depressants, dose reductions may
`be needed due to additive effects. Do not use with alcohol (2.3, 5.5)
`(cid:120) Elderly/debilitated patients: Use lower dose due to impaired motor,
`cognitive performance and increased sensitivity (2.2, 5.6)
`(cid:120) Patients with hepatic impairment, mild to moderate COPD, impaired drug
`metabolism or hemodynamic responses, mild to moderate sleep apnea: Use
`with caution and monitor closely (5.6)
`
`
`-----------------------------ADVERSE REACTIONS--------------------------------
`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 sanofi-aventis
`U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or
`http://www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-------------------------------
`(cid:120) CNS depressants: Enhanced CNS-depressant effects with combination use.
`Use with alcohol causes additive psychomotor impairment (7.1)
`(cid:120) Imipramine: Decreased alertness observed with combination use. (7.1)
`(cid:120) Chlorpromazine: Impaired alertness and psychomotor performance
`observed with combination use (7.1)
`(cid:120) Rifampin: Combination use decreases exposure to and effects of zolpidem
`(7.2)
`(cid:120) Ketoconazole: Combination use increases exposure to and effect of
`zolpidem (7.2)
`
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`Pregnancy: Crosses the placenta. No studies in pregnant women. (8.1)
`(cid:120)
`Nursing mothers: Infant exposure via breast milk (8.3)
`(cid:120)
`Pediatric use: Safety and effectiveness not established. Hallucinations
`(cid:120)
`(incidence rate 7.4%) and other psychiatric and/or nervous system
`adverse reactions were observed frequently in a study of pediatric
`patients with Attention-Deficit/Hyperactivity Disorder (5.6, 8.4)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised 12/2007
`
`11
`12
`
`9.2 Abuse
`9.3
`Dependence
`10 OVERDOSAGE
`10.1 Signs and symptoms
`10.2 Recommended treatment
` DESCRIPTION
` 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
`17.1
`Severe anaphylactoid reactions
`17.2
`Sleep-driving and other complex behaviors
`17.3
`Administration Instructions
`17.4
`Medication Guide
`*Sections or subsections omitted from the full prescribing information are not
`listed
`
`

`

`21774.003.004.005.007.008 FDA approved labeling text 12.20.07
`
`
`
`FULL PRESCRIBING INFORMATION
`
` 1
`
`INDICATIONS AND USAGE
`
`Ambien CR (zolpidem tartrate extended-release tablets) is 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
`The dose of Ambien CR should be individualized.
`
`2.1 Dosage in adults
`The recommended dose of Ambien CR for adults is 12.5 mg once daily immediately before
`bedtime. The total Ambien CR dose should not exceed 12.5 mg per day.
`
`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 normals. The
`recommended dose of Ambien CR in both of these patient populations is 6.25 mg once daily
`immediately before bedtime [see Warnings and Precautions (5.6)].
`
`2.3 Use with CNS depressants
`Dosage adjustments may be necessary when Ambien CR is combined with other CNS depressant
`drugs because of the potentially additive effects [see Warnings and Precautions (5.5)].
`
`2.4 Administration
`Ambien CR extended-release tablets should be swallowed whole, and not be divided, crushed, or
`chewed. The effect of Ambien CR may be slowed by ingestion with or immediately after a
`meal.
`
` 3
`
` DOSAGE FORMS AND STRENGTHS
`Ambien CR is available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem
`tartrate for oral administration. Tablets are not scored.
`
`Ambien CR 6.25 mg tablets are pink, round, bi-convex, and debossed with A~ on one side.
`Ambien CR 12.5 mg tablets are blue, round, bi-convex, and debossed with A~ on one side.
`
`
`
` 4
`
` CONTRAINDICATIONS
`Ambien CR is contraindicated in patients with known hypersensitivity to zolpidem tartrate or to
`any of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and
`angioedema [see Warnings and Precautions (5.2)].
`
`
`
`2
`
`

`

`21774.003.004.005.007.008 FDA approved labeling text 12.20.07
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 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.
`
`5.2 Severe anaphylactic and anaphylactoid reactions
`Rare 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.
`
`5.3 Abnormal thinking and behavioral changes
`A variety of abnormal thinking and behavior changes have been reported to occur in association
`with the use of sedative/hypnotics. Some of these changes may be characterized by decreased
`inhibition (e.g. aggressiveness and extroversion that seemed out of character), similar to effects
`produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been
`reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization.
`In controlled trials, <1% of adults with insomnia who received zolpidem reported hallucinations.
`In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention-
`deficit/hyperactivity disorder (ADHD), who received zolpidem reported hallucinations [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 with sedative-hypnotics,
`including zolpidem. These events can occur in sedative-hypnotic-naive as well as in sedative-
`hypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur with
`Ambien CR alone at therapeutic doses, the use of alcohol and other CNS depressants with
`Ambien CR appears to increase the risk of such behaviors, as does the use of Ambien CR at
`doses exceeding the maximum recommended dose. Due to the risk to the patient and the
`community, discontinuation of Ambien CR 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 occur unpredictably.
`
`In primarily depressed patients, worsening of depression, including suicidal thoughts and actions
`including completed suicides), have been reported in association with the use of
`
`
`
`3
`
`

`

`21774.003.004.005.007.008 FDA approved labeling text 12.20.07
`
`sedative/hypnotics.
`
`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.
`
`5.4 Withdrawal effects
`Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have
`been reports of signs and symptoms similar to those associated with withdrawal from other CNS-
`depressant drugs [see Drug Abuse and Dependence (9)].
`
`5.5 CNS depressant effects
`Ambien CR, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid
`onset of action, Ambien CR should only be taken immediately prior to going to bed. Patients
`should be cautioned against engaging in hazardous occupations requiring complete mental
`alertness or motor coordination such as operating machinery or driving a motor vehicle after
`ingesting the drug, including potential impairment of the performance of such activities that may
`occur the day following ingestion of Ambien CR. Ambien CR showed additive effects when
`combined with alcohol and should not be taken with alcohol. Patients should also be cautioned
`about possible combined effects with other CNS-depressant drugs. Dosage adjustments may be
`necessary when Ambien CR is administered with such agents because of the potentially additive
`effects.
`
`5.6 Special populations
`Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance
`after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the
`treatment of elderly and/or debilitated patients. Therefore, the recommended Ambien CR dosage
`is 6.25 mg in such patients to decrease the possibility of side effects [see Dosage and
`Administration (2.2)]. These patients should be closely monitored.
`
`Use in patients with concomitant illness: Clinical experience with Ambien CR (zolpidem
`tartrate) in patients with concomitant systemic illness is limited. Caution is advisable in using
`Ambien CR in patients with diseases or conditions that could affect metabolism or hemodynamic
`responses.
`
`Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in
`normals 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 an immediate-release formulation of zolpidem
`tartrate (10 mg) when compared to placebo. Since sedative/hypnotics have the capacity to
`depress respiratory drive, precautions should be taken if Ambien CR is prescribed to patients
`with compromised respiratory function. Post-marketing reports of respiratory insufficiency,
`most of which involved patients with pre-existing respiratory impairment, have been received.
`
`
`
`4
`
`

`

`21774.003.004.005.007.008 FDA approved labeling text 12.20.07
`
`Ambien CR should be used with caution in patients with sleep apnea syndrome or myasthenia
`gravis.
`
`Data in end-stage renal failure patients repeatedly treated with an immediate-release formulation
`of zolpidem tartrate (10 mg) did not demonstrate drug accumulation or alterations in
`pharmacokinetic parameters. No dosage adjustment in renally impaired patients is required;
`however, these patients should be closely monitored [see Clinical Pharmacology (12.3)].
`
` study in subjects with hepatic impairment did reveal prolonged elimination in this group;
`therefore, treatment should be initiated with Ambien CR 6.25 mg in patients with hepatic
`compromise, and they should be closely monitored [see Dosage and Administration (2.2) and
`Clinical Pharmacology (12.3)].
`
`Use in patients with depression: As with other sedative/hypnotic drugs, Ambien CR should
`be administered with caution to patients exhibiting signs or symptoms of depression. 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 least amount of drug that is
`feasible should be prescribed for the patient at any one time.
`
` A
`
` 6
`
`Use in pediatric patients: Safety and effectiveness of zolpidem has not been established in
`pediatric patients. In an 8-week study in pediatric patients (aged 6-17 years) with insomnia
`associated with ADHD given an immediate-release oral solution of zolpidem tartrate, zolpidem
`did not decrease sleep latency compared to placebo. Hallucinations were reported in 7.4% of the
`pediatric patients who received zolpidem; none of the pediatric patients who received placebo
`reported hallucinations [see Use in Specific Populations (8.4)].
`
`
` ADVERSE REACTIONS
`The following serious adverse reactions are discussed in greater detail in other sections of the
`labeling:
`(cid:120) Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.2])
`(cid:120) Abnormal thinking, behavior changes, and complex behaviors [see Warnings and Precautions
`(5.3)]
`(cid:120) Withdrawal effects [see Warnings and Precautions (5.4)]
`(cid:120) CNS-depressant effects [see Warnings and Precautions (5.5)]
`
`6.1 Clinical trials experience
`Associated with discontinuation of treatment: In 3-week clinical trials in adults and elderly
`patients (> 65 years), 3.5% (7/201) patients receiving Ambien CR 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 Ambien CR was
`somnolence (1%).
`
`In a 6-month study in adult patients (18-64 years of age), 8.5% (57/669) of patients receiving
`Ambien CR 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 Ambien CR
`
`
`
`5
`
`

`

`21774.003.004.005.007.008 FDA approved labeling text 12.20.07
`
`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.
`
`Most commonly observed adverse reactions in controlled trials: During treatment with
`Ambien CR 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 Ambien
`CR were headache, next-day somnolence, and dizziness.
`
`In the 6-month trial evaluating Ambien CR 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 Ambien
`CR versus 2.6% for placebo).
`
`Adverse reactions observed at an incidence of (cid:149)1% in controlled trials: 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 Ambien CR 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 Ambien CR. These trials involved patients with primary insomnia who were treated
`for 3 weeks with Ambien CR 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
`Ambien CR patients and with an incidence greater than that seen in the placebo patients.
`
`
`Table 1. Incidences of Treatment-Emergent Adverse
`Reactions in
`a 3-Week Placebo-Controlled Clinical Trial in Adults
`(percentage of patients reporting)
`Ambien
`CR
`12.5 mg
`(N = 102)
`
`Infections and infestations
`
`
`
`Body System/Adverse
`Reaction *
`
`
`
`6
`
`Placebo
`
`(N =
`110)
`
`

`

`21774.003.004.005.007.008 FDA approved labeling text 12.20.07
`
`Influenza
`Gastroenteritis
`Labyrinthitis
`Metabolism and nutrition
`disorders
`Appetite disorder
`Psychiatric disorders
`Hallucinations **
`Disorientation
`Anxiety
`Depression
`Psychomotor retardation
`Binge eating
`Depersonalization
`Disinhibition
`Euphoric mood
`Mood swings
`Stress symptoms
`Nervous system disorders
`Headache
`Somnolence
`Dizziness
`Memory disorders ***
`Balance disorder
`Disturbance in attention
`Hypoesthesia
`Ataxia
`Paresthesia
`Eye disorders
`Visual disturbance
`Eye redness
`Vision blurred
`Altered visual depth
`perception
`Asthenopia
`Ear and labyrinth disorders
`Vertigo
`Tinnitus
`Respiratory, thoracic and
`mediastinal disorders
`Throat irritation
`Gastrointestinal disorders
`Nausea
`Constipation
`Abdominal discomfort
`Abdominal tenderness
`Frequent bowel movements
`Gastroesophageal reflux
`disease
`Vomiting
`Skin and subcutaneous
`tissue
`disorders
`
`
`
`
`
`
`
`
`
`
`
`3
`1
`1
`
`1
`
`4
`3
`2
`2
`2
`1
`1
`1
`1
`1
`1
`
`19
`15
`12
`3
`2
`2
`2
`1
`1
`
`3
`2
`2
`1
`
`1
`
`2
`1
`
`
`1
`
`7
`2
`1
`1
`1
`1
`
`1
`
`
`0
`0
`0
`
`0
`
`0
`2
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`16
`2
`5
`0
`0
`0
`1
`0
`0
`
`0
`0
`1
`0
`
`0
`
`0
`0
`
`
`0
`
`4
`0
`0
`0
`0
`0
`
`0
`
`
`
`
`7
`
`

`

`21774.003.004.005.007.008 FDA approved labeling text 12.20.07
`
`Rash
`Skin wrinkling
`Urticaria
`Musculoskeletal and
`connective
`tissue disorders
`Back pain
`Myalgia
`Neck pain
`Reproductive system and
`breast
`disorders
`Menorrhagia
`General disorders and
`administration site
`conditions
`Fatigue
`Asthenia
`Chest discomfort
`Investigations
`Blood pressure increased
`Body temperature increased
`Injury, poisoning and
`procedural complications
`Contusion
`Social circumstances
`Exposure to poisonous plant
`
`1
`1
`1
`
`
`4
`4
`1
`
`
`1
`
`
`3
`1
`1
`
`1
`1
`
`
`1
`
`1
`
`0
`0
`0
`
`
`3
`0
`0
`
`
`0
`
`
`2
`0
`0
`
`0
`0
`
`
`0
`
`0
`
`
`
`
`
`
`
`
`*Reactions reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group.
`**Hallucinations included hallucinations NOS as well as visual and hypnogogic hallucinations.
`***Memory disorders include: memory impairment, amnesia, anterograde amnesia.
`
`Table 2. Incidences of Treatment-Emergent
`Adverse Reactions in a 3-Week Placebo-Controlled
`Clinical Trial in Elderly
`(percentage of patients reporting)
`Ambien
`CR
`6.25 mg
`(N=99)
`
`Placebo
`
`(N=106)
`
`6
`1
`
`1
`1
`
`3
`2
`1
`1
`
`14
`
`
`
`
`
`4
`0
`
`0
`0
`
`2
`0
`0
`0
`
`11
`
`Body System/Adverse
`Reaction *
`
`Infections and infestations
`Nasopharyngitis
`Lower respiratory tract
`infection
`Otitis externa
`Upper respiratory tract
`infection
`Psychiatric disorders
`Anxiety
`Psychomotor retardation
`Apathy
`Depressed mood
`Nervous system disorders
`Headache
`
`
`
`8
`
`

`

`21774.003.004.005.007.008 FDA approved labeling text 12.20.07
`
`Dizziness
`Somnolence
`Burning sensation
`Dizziness postural
`Memory disorders **
`Muscle contractions
`involuntary
`Paresthesia
`Tremor
`Cardiac disorders
`Palpitations
`Respiratory, thoracic and
`mediastinal disorders
`Dry throat
`Gastrointestinal disorders
`Flatulence
`Vomiting
`Skin and subcutaneous
`tissue
`disorders
`Rash
`Urticaria
`Musculoskeletal and
`connective
`tissue disorders
`Arthralgia
`Muscle cramp
`Neck pain
`Renal and urinary
`disorders
`Dysuria
`Reproductive system and
`breast
`disorders
`Vulvovaginal dryness
`General disorders and
`administration site
`conditions
`Influenza like illness
`Pyrexia
`Injury, poisoning and
`procedural complications
`Neck injury
`
`
`
`
`
`
`
`
`
`8
`6
`1
`1
`1
`1
`
`1
`1
`
`2
`
`1
`
`1
`1
`
`1
`1
`
`
`2
`2
`2
`
`
`1
`
`
`1
`
`
`1
`1
`
`
`1
`
`3
`5
`0
`0
`0
`0
`
`0
`0
`
`0
`
`0
`
`0
`0
`
`0
`0
`
`
`0
`1
`0
`
`
`0
`
`
`0
`
`
`0
`0
`
`
`0
`
`
`
`*Reactions reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group.
`**Memory d