Zolpidem tartrate 12.5 MG Extended Release Oral Tablet
DRUG INTERACTIONS
7 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 ) CYP3A4 inducers (rifampin or St.
John’s wort): Combination use may decrease effect ( 7.2 ) Ketoconazole: Combination use may increase effect ( 7.2 ) 7.1 CNS-active Drugs Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression.
Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor impairment, including impaired driving ability [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 induce or inhibit CYP3A may affect exposure to zolpidem.
The effect of drugs that induce or inhibit other P450 enzymes on the exposure to zolpidem is not known.
CYP3A4 Inducers 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 and is not recommended [see Clinical Pharmacology (12.3) ] .
St.
John’s wort Use of St.
John’s wort, a CYP3A4 inducer, in combination with zolpidem may decrease blood levels of zolpidem and is not recommended.
CYP3A4 Inhibitors Ketoconazole Ketoconazole, a potent CYP3A4 inhibitor, increased the exposure to and pharmacodynamic effects of zolpidem.
Consideration should be given to using a lower dose of zolpidem when a potent CYP3A4 inhibitor and zolpidem are given together [see Clinical Pharmacology (12.3) ] .
OVERDOSAGE
10 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.
DESCRIPTION
11 AMBIEN CR contains zolpidem tartrate, a gamma-aminobutyric acid (GABA) A agonist of the imidazopyridine class.
AMBIEN CR (zolpidem tartrate extended-release tablets) is 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: Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol.
It has a molecular weight of 764.88.
AMBIEN CR consists of a coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows a slower release of additional drug content.
The 6.25 mg AMBIEN CR tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, red ferric oxide, sodium starch glycolate, and titanium dioxide.
The 12.5 mg AMBIEN CR tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C Blue #2, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide.
Chemical Structure
CLINICAL STUDIES
14 14.1 Controlled Clinical Trials AMBIEN CR was evaluated in three placebo-controlled studies for the treatment of patients with chronic primary insomnia (as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM IV).
Adult outpatients (18–64 years) with primary insomnia (N=212) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing AMBIEN CR 12.5 mg and placebo.
AMBIEN CR 12.5 mg decreased wake time after sleep onset (WASO) for the first 7 hours during the first 2 nights and for the first 5 hours after 2 weeks of treatment.
AMBIEN CR 12.5 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep [LPS]) during the first 2 nights of treatment and after 2 weeks of treatment.
AMBIEN CR 12.5 mg was also superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.
Elderly outpatients (≥ 65 years) with primary insomnia (N=205) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing AMBIEN CR 6.25 mg and placebo.
AMBIEN CR 6.25 mg decreased wake time after sleep onset (WASO) for the first 6 hours during the first 2 nights and the first 4 hours after 2 weeks of treatment.
AMBIEN CR 6.25 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing LPS) during the first 2 nights of treatment and after 2 weeks on treatment.
AMBIEN CR 6.25 mg was superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.
In both studies, in patients treated with AMBIEN CR, polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients.
In a 24-week double-blind, placebo controlled, randomized study in adult outpatients (18–64 years) with primary insomnia (N=1025), AMBIEN CR 12.5 mg administered as needed (3 to 7 nights per week) was superior to placebo over 24 weeks, on patient global impression regarding aid to sleep, and on patient-reported specific sleep parameters for sleep induction and sleep maintenance with no significant increased frequency of drug intake observed over time.
14.2 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs Next-day residual effects: In five clinical studies [three controlled studies in adults (18–64 years of age) administered AMBIEN CR 12.5 mg and two controlled studies in the elderly (≥ 65 years of age) administered AMBIEN CR 6.25 mg or 12.5 mg], the effect of AMBIEN CR on vigilance, memory, or motor function were assessed using neurocognitive tests.
In these studies, no significant decrease in performance was observed eight hours after a nighttime dose.
In addition, no evidence of next-day residual effects was detected with AMBIEN CR 12.5 mg and 6.25 mg using self-ratings of sedation.
During the 3-week studies, next-day somnolence was reported by 15% of the adult patients who received 12.5 mg AMBIEN CR versus 2% of the placebo group; next-day somnolence was reported by 6% of the elderly patients who received 6.25 mg AMBIEN CR versus 5% of the placebo group [see Adverse Reactions (6) ] .
In a 6-month study, the overall incidence of next-day somnolence was 5.7% in the AMBIEN CR group as compared to 2% in the placebo group.
Rebound effects: Rebound insomnia, defined as a dose-dependent worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics.
In the two 3-week placebo-controlled studies in patients with primary insomnia, a rebound effect was only observed on the first night after abrupt discontinuation of AMBIEN CR.
On the second night, there was no worsening compared to baseline in the AMBIEN CR group.
In a 6-month placebo-controlled study in which AMBIEN CR was taken as needed (3 to 7 nights per week), within the first month a rebound effect was observed for Total Sleep Time (not for WASO) during the first night off medication.
After this first month period, no further rebound insomnia was observed.
After final treatment discontinuation no rebound was observed.
HOW SUPPLIED
16 /STORAGE AND HANDLING Product: 63629-3141
RECENT MAJOR CHANGES
Dosage and Administration, Dosage in Adults ( 2.1 ) 08/2016 Dosage and Administration, Special Populations ( 2.2 ) 12/2016 Warnings and Precautions, CNS Depressant Effects and Next-Day Impairment ( 5.1 ) 08/2016 Warnings and Precautions, Precipitation of Hepatic Encephalopathy ( 5.7 ) 12/2016
GERIATRIC USE
8.5 Geriatric Use A total of 99 elderly (≥ 65 years of age) received daily doses of 6.25 mg AMBIEN CR in a 3-week placebo-controlled study.
The adverse reaction profile of AMBIEN CR 6.25 mg in this population was similar to that of AMBIEN CR 12.5 mg in younger adults (≤ 64 years of age).
Dizziness was reported in 8% of AMBIEN CR-treated patients compared with 3% of those treated with placebo.
The dose of AMBIEN CR 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) ] .
DOSAGE FORMS AND STRENGTHS
3 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.
Tablets: 6.25 mg and 12.5 mg extended-release tablets.
Tablets not scored.
( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties.
It interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines.
In contrast to the benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ 1 receptor preferentially with a high affinity ratio of the α 1 /α 5 subunits.
This selective binding of zolpidem on the BZ 1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses.
INDICATIONS AND USAGE
1 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) ] .
AMBIEN CR, a gamma-aminobutyric acid (GABA) A agonist, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use AMBIEN CR is 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 6–17 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 AMBIEN CR in the pediatric population based on these efficacy and safety findings.
PREGNANCY
8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of AMBIEN CR 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.
AMBIEN CR 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 AMBIEN CR 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/m 2 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/m 2 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/m 2 basis.
NUSRING MOTHERS
8.3 Nursing Mothers Zolpidem is excreted in human milk.
Caution should be exercised when AMBIEN CR is administered to a nursing woman.
WARNING AND CAUTIONS
5 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 ) Hepatic Impairment: Avoid AMBIEN CR use in patients with severe hepatic impairment.
( 5.7 ) Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation.
( 5.8 , 9.3 ) Severe Injuries: Drowsiness may lead to fall including severe injuries.
( 5.9 ) 5.1 CNS Depressant Effects and Next-Day Impairment AMBIEN CR is 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 AMBIEN CR may develop, patients using AMBIEN CR 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 AMBIEN CR and concomitant CNS depressants should be considered [see Dosage and Administration (2.3) ] .
The use of AMBIEN CR 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 AMBIEN CR is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if co-administered with other CNS depressants or alcohol; or co-administered with other drugs that increase the blood levels of zolpidem.
Patients should be warned against driving and other activities requiring complete mental alertness if Ambien CR is taken in these circumstances [see Dosage and Administration (2) and Clinical Studies (14.2) ] .
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 (7-8 hours) is recommended.
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 AMBIEN CR.
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 AMBIEN 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 AMBIEN CR alone at therapeutic doses, the co-administration of alcohol and other CNS depressants increases 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 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 AMBIEN CR 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 AMBIEN CR in patients with respiratory impairment including sleep apnea and myasthenia gravis.
5.7 Precipitation of Hepatic Encephalopathy GABA agonists 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 AMBIEN CR 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) ] .
5.8 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) ] .
5.9 Severe Injuries Zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries.
Severe injuries such as hip fractures and intracranial hemorrhage have been reported.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide).
Inform patients and their families about the benefits and risks of treatment with AMBIEN CR.
Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with AMBIEN CR and with each prescription refill.
Review the AMBIEN CR Medication Guide with every patient prior to initiation of treatment.
Instruct patients or caregivers that AMBIEN CR should be taken only as prescribed.
CNS Depressant Effects and Next-Day Impairment Tell patients that AMBIEN CR can cause next-day impairment even when used as prescribed, and that this risk is increased if dosing instructions are not carefully followed.
Caution patients against driving and other activities requiring complete mental alertness the day after use.
Inform patients that impairment can be present despite feeling fully awake.
Severe Anaphylactic and Anaphylactoid Reactions Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with zolpidem.
Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur.
Sleep-driving and Other Complex Behaviors Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including “sleep driving” and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex).
Tell patients to call you immediately if they develop any of these symptoms.
Suicide Tell patients to immediately report any suicidal thoughts.
Alcohol and Other Drugs Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription.
Advise patients not to use AMBIEN CR if they drank alcohol that evening or before bed.
Tolerance, Abuse, and Dependence Tell patients not to increase the dose of AMBIEN CR on their own, and to inform you if they believe the drug “does not work”.
Administration Instructions Patients should be counseled to take AMBIEN CR right before they get into bed and only when they are able to stay in bed a full night (7–8 hours) before being active again.
AMBIEN CR tablets should not be taken with or immediately after a meal.
Advise patients NOT to take AMBIEN CR if they drank alcohol that evening.
DOSAGE AND ADMINISTRATION
2 Use the lowest dose effective for the patient and must not exceed a total of 12.5 mg daily ( 2.1 ) Recommended initial dose is a single dose of 6.25 mg for women, and a single dose of 6.25 or 12.5 mg for men, immediately before bedtime with at least 7–8 hours remaining before the planned time of awakening ( 2.1 ) Geriatric patients and patients with mild to moderate 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 AMBIEN CR ( 2.3 ) Tablets to be swallowed whole, not to be crushed, divided or chewed ( 2.4 ) The effect of AMBIEN CR may be slowed if taken with or immediately after a meal ( 2.4 ) 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 7–8 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 AMBIEN CR should not exceed 12.5 mg once daily immediately before bedtime.
Ambien CR 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 AMBIEN CR in these patients is 6.25 mg once daily immediately before bedtime [see Warnings and Precautions (5.1) , 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 AMBIEN CR in these patients is 6.25 mg once daily immediately before bedtime.
Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Warnings and Precautions (5.7) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] .
2.3 Use with CNS Depressants Dosage adjustment may be necessary when AMBIEN CR is combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.1) ] .
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.