Ambien CR™    CIV
(zolpidem tartrate extended-release tablets)

Ambien CR contains zolpidem tartrate, a non-benzodiazepine hypnotic 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 tartrate 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 span immediately and another layer that allows a slower release of additional drug span. 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.

Subunit modulation of the GABA_A receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug properties. The major modulatory site of the GABA_A receptor complex is located on its alpha (α) subunit and is referred to as the benzodiazepine (BZ) receptor.

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines, or other drugs with known hypnotic properties. In contrast to the benzodiazepines, which nonselectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ₁ receptor preferentially with a high affinity ratio of the alpha₁/alpha₅ subunits. The BZ₁ receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This selective binding of zolpidem on the BZ₁ 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 at hypnotic doses.

Ambien CR exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. A study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of Ambien CR (12.5 mg) and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with Ambien CR (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). The mean plasma concentration time profiles for Ambien CR (12.5 mg) and for zolpidem tartrate (10 mg) are shown below:

In adult and elderly patients treated with Ambien CR, there was no evidence of accumulation after repeated once-daily dosing for up to two weeks.

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). (See Clinical Pharmacology: Controlled trials supporting safety and efficacy.)

The clinical trials performed in support of efficacy were both 3 weeks in duration, although the final formal assessments of sleep latency and maintenance were performed after 2 weeks of treatment.

Ambien CR is contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation.

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. Because some of the important adverse effects of zolpidem appear to be dose related (see Precautions and Dosage and Administration), it is important to use the smallest possible effective dose, especially in the elderly.

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. Complex behaviorssuch as “sleep-driving” (i.e., driving while not fully awake after ingesting a sedative-hypnotic, with amnesia for the event) have been reported. 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 zolpidem alone at therapeutic doses, the use of alcohol and other CNS depressants with zolpidem appears to increase the risk of such behaviors, as does the use of zolpidem at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zolpidem 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 thinking, has been reported in association with the use of sedative-hypnotics.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors uled 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.

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).

Zolpidem, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Ambien CR should only be ingested 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. Zolpidem 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.

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 tongue, 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.

Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sedative-hypnotics and should counsel them in its appropriate use.

There are no specific laboratory tests recommended.

Zolpidem is not known to interfere with commonly employed clinical laboratory tests. In addition, clinical data indicate that zolpidem does not cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens.

Ambien CR has no established use in labor and delivery. (See also Pregnancy.)

Studies in lactating mothers indicate that the half-life of zolpidem is similar to that in young normal subjects (2.6± 0.3 hr). Between 0.004% and 0.019% of the total administered dose is excreted into milk, but the effect of zolpidem on the infant is unknown.

In addition, in a rat study, zolpidem inhibited the secretion of milk. The no-effect dose was 4 mg base/kg or 6 times the recommended human dose in mg/m².

The use of Ambien CR in nursing mothers is not recommended.

Safety and effectiveness of Ambien CR in patients below the age of 18 have not been established.

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 event 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.

In addition to adverse events reported in clinical trials, angioneurotic edema has been reported spontaneously in postmarketing experience with zolpidem tartrate.

Zolpidem tartrate is classified as a Schedule IV controlled substance under the controlled Substances Act. Examples of other drugs placed in Schedule IV include benzodiazepines (diazepam, alprazolam, etc.) and the non-benzodiazepine hypnotics (zaleplon and eszopiclone).

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. 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. 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’s 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 an immediate-release formulation of zolpidem tartrate (Ambien) 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo.

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 U.S. clinical trial experience from zolpidem does not reveal any clear evidence for withdrawal syndrome. Nevertheless, the following adverse events included in 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. Rare post-marketing reports of abuse, dependence and withdrawal have been received.

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.

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.

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil 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 tartrate 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.

The dose of Ambien CR should be individualized.

Ambien CR is available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem tartrate for oral 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.

The recommended dose of Ambien CR for adults is 12.5 mg immediately before bedtime.

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of Ambien CR in these patients is 6.25 mg immediately before bedtime (see Precautions).

Ambien CR 6.25 mg tablets are composed of two layersLayers are covered by the coating and are indistinguishable. The tablets are to be swallowed whole and should not be crushed, chewed, or divided. and are coated, pink, round, bi-convex, debossed with A~ on one side and supplied as:

NDC Number       Size

0024-5501-31       bottle of 100
0024-5501-50       bottle of 500
0024-5501-10       carton of 30 unit dose
0024-5501-34       carton of 100 unit dose

Ambien CR 12.5-mg tablets are composed of two layers and are coated, blue, round, bi-convex, debossed with A~ on one side and supplied as:

NDC Number       Size

0024-5521-31       bottle of 100
0024-5521-50       bottle of 500
0024-5521-10       carton of 30 unit dose
0024-5521-34       carton of 100 unit dose

Your doctor has prescribed Ambien CR to help you sleep. The following information is intended to guide you in the safe use of this medicine. It is not meant to take the place of your doctor's instructions. If you have any questions about Ambien CR tablets be sure to ask your doctor or pharmacist.

Ambien CR is used to treat different types of sleep problems, such as:

• trouble falling asleep
• waking up often during the night

Some people may have more than one of these problems.

Ambien CR belongs to a group of medicines known as the "sedative/hypnotics", or simply, sleep medicines. There are many different sleep medicines available to help people sleep better. Sleep problems are usually temporary, requiring treatment for only a short time, usually 1 or 2 days up to 1 or 2 weeks. Some people have chronic sleep problems that may require more prolonged use of sleep medicine. However, you should not use these medicines for long periods without talking with your doctor about the risks and benefits of prolonged use.

SIDE EFFECTS

Most common side effects:

• headache
• somnolence (sleepiness)
• dizziness

You may find that these medicines make you sleepy during the day. How drowsy you feel depends upon how your body reacts to the medicine, which sleep medicine you are taking, and how large a dose your doctor has prescribed. Daytime drowsiness is best avoided by taking the lowest dose possible that will still help you sleep at night. Your doctor will work with you to find the dose of Ambien CR that is best for you.

To manage these side effects while you are taking this medicine:

• When you first start taking Ambien CR or any other sleep medicine until you know whether the medicine will still have some carryover effect in you the next day, use extreme care while doing anything that requires complete alertness, such as driving a car, operating machinery, or piloting an aircraft.
• NEVER drink alcohol while you are being treated with Ambien CR or any sleep medicine. Alcohol can increase the side effects of Ambien CR or any other sleep medicine.
• Do not take any other medicines without asking your doctor first. This includes medicines you can buy without a prescription. Some medicines can cause drowsiness and are best avoided while taking Ambien CR.
• Always take the exact dose of Ambien CR prescribed by your doctor. Never change your dose without talking to your doctor first.

SPECIAL CONCERNS

There are some special problems that may occur while taking sleep medicines.

Memory problems: Sleep medicines may cause a special type of memory loss or "amnesia." When this occurs, a person may not remember what has happened for several hours after taking the medicine. This is usually not a problem since most people fall asleep after taking the medicine.

Memory loss can be a problem, however, when sleep medicines are taken while traveling, such as during an airplane flight and the person wakes up before the effect of the medicine is gone. This has been called "traveler's amnesia."

Be sure to talk to your doctor if you think you are having memory problems. Although memory problems are not very common while taking Ambien CR, in most instances, they can be avoided if you take Ambien CR only when you are able to get a full night's sleep (7 to 8 hours) before you need to be active again.

Tolerance: When sleep medicines are used every night for more than a few weeks, they may lose their effectiveness to help you sleep. This is known as “tolerance”. Sleep medicines should, in most cases, be used only for short periods of time, such as 1 or 2 days and generally no longer than 1 or 2 weeks. If your sleep problems continue, consult your doctor, who will determine whether other measures are needed to overcome your sleep problems.

Dependence: Sleep medicines can cause dependence, especially when these medicines are used regularly for longer than a few weeks or at high doses. Some people develop a need to continue taking their medicines. This is known as dependence or "addiction."

When people develop dependence, they may have difficulty stopping the sleep medicine. If the medicine is suddenly stopped, the body is not able to function normally and unpleasant symptoms may occur (see Withdrawal). They may find that they have to keep taking the medicines either at the prescribed dose or at increasing doses just to avoid withdrawal symptoms.

All people taking sleep medicines have some risk of becoming dependent on the medicine. However, people who have been dependent on alcohol or other drugs in the past may have a higher chance of becoming addicted to sleep medicines. This possibility must be considered before using these medicines for more than a few weeks.

If you have been addicted to alcohol or drugs in the past, it is important to tell your doctor before starting Ambien or any sleep medicine.

Withdrawal: Withdrawal symptoms may occur when sleep medicines are stopped suddenly after being used daily for a long time. In some cases, these symptoms can occur even if the medicine has been used for only a week or two.

In mild cases, withdrawal symptoms may include unpleasant feelings. In more severe cases, abdominal and muscle cramps, vomiting, sweating, shakiness, and rarely, seizures may occur. These more severe withdrawal symptoms are very uncommon.

Another problem that may occur when sleep medicines are stopped isknown as "rebound insomnia." This means that a person may have more trouble sleeping the first few nights after the medicine is stopped than before starting the medicine. If you should experience rebound insomnia, do not get discouraged. This problem usually goes away on its own after 1 or 2 nights.

If you have been taking Ambien CR or any other sleep medicine for more than 1 or 2 weeks, do not stop taking it on your own. Always follow your doctor's directions.

Changes in behavior and thinking: Some people using sleep medicines have experienced unusual changes in their thinking and/or behavior. These effects are not common. However, they have included:

• more outgoing or aggressive behavior than normal
• confusion
• strange behavior
• agitation
• hallucinations
• worsening of depression
• suicidal thoughts

How often these effects occur depends on several factors, such as a person's general health, the use of other medicines, and which sleep medicine is being used.

It is also important to realize that it is rarely clear whether these behavior changes are caused by the medicine, an illness, or occur on their own. In fact, sleep problems that do not improve may be due to illnesses that were present before the medicine was used. If you or your family notice any changes in your behavior, or if you have any unusual or disturbing thoughts, call your doctor immediately.

“Sleep-Driving” and other complex behaviors: There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If you experiences such an event, it should be reported to your doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when Ambien CR is taken with alcohol or other drugs such as those for the treatment of depression or anxiety. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in people who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, people usually do not remember these events.

Pregnancy: Sleep medicines may cause sedation of the unborn baby when used during the last weeks of pregnancy.

Be sure to tell your doctor if you are pregnant, if you are planning to become pregnant, or if you become pregnant while taking Ambien CR.

SAFE USE OF SLEEPING MEDICINES

To ensure the safe and effective use of Ambien CR or any other sleep medicine, you should observe the following cautions:

• Ambien CR is a prescription medicine and should be used ONLY as directed by your doctor. Follow your doctor's instructions about how to take, when to take, and how long to take Ambien CR. Ambien CR tablets should not be divided, crushed, or chewed, and must be swallowed whole.
• Never use Ambien CR or any other sleep medicine for longer than directed by your doctor.
• If you develop an allergic reaction such as rash, hives, shortness of breath or swelling of your tongue or throat when using Ambien CR or any other sleep medicine, discontinue Ambien CR or other sleep medicine immediately and contact your doctor.
• If you notice any unusual and/or disturbing thoughts or behavior during treatment with Ambien CR or any other sleep medicine, contact your doctor.
• Tell your doctor about any medicines you may be taking, including medicines you may buy without a prescription. You should also tell your doctor if you drink alcohol. DO NOT use alcohol while taking Ambien CR or any other sleep medicine.
• Do not take Ambien CR unless you are able to get a full night's sleep before you must be active again. For example, Ambien CR should not be taken on an overnight airplane flight of less than 7 to 8 hours since "traveler's amnesia" may occur.
• Do not increase the prescribed dose of Ambien CR or any other sleep medicine unless instructed by your doctor.
• When you first start taking Ambien CR or any other sleep medicine, until you know whether the medicine will still have some carryover effect in you the next day, use extreme care while doing anything that requires complete alertness, such as driving a car, operating machinery, or piloting an aircraft.
• Be aware that you may have more sleeping problems the first night after stopping Ambien CR or any other sleep medicine.
• Be sure to tell your doctor if you are pregnant, if you are planning to become pregnant, or if you become pregnant while taking Ambien CR or any other sleep medicine.
• As with all prescription medicines, never share Ambien CR or any other sleep medicine with anyone else. Always store Ambien CR or any other sleep medicine in the original container that you received it in and store it out of reach of children.
• Ambien CR works very quickly. You should only take Ambien CR right before going to bed and are ready to go to sleep.