Ambien CR (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are approximately 2, 9, and 40 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m 2 body surface area and in rats, these doses are approximately 4, 18, and 80 times the MRHD based on mg/m 2 body surface area. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid and high doses.

Mutagenesis

Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.

Impairment of Fertility

Zolpidem was administered to rats at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m 2 body surface area, prior to and during mating, and continuing in females through postpartum day 25. Zolpidem caused irregular estrus cycles and prolonged precoital intervals at the highest dose tested, which is approximately 100 times the MRHD based on mg/m 2 body surface area. The NOAEL for these effects is 20 times the MRHD based on mg/m 2 body surface area. There was no impairment of fertility at any dose tested.

14 CLINICAL STUDIES

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

AMBIEN CR 12.5 mg extended-release tablets are composed of two layers and are coated, blue, round, biconvex, debossed with A~ on one side and supplied as:

NDC Number Size
55289-205-30 bottle of 30

Store between 15°C–25°C (59°F–77°F). Limited excursions permissible up to 30°C (86°F).

17 PATIENT COUNSELING INFORMATION

Advise the patient 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.

Complex Sleep Behaviors

Instruct patients and their families that AMBIEN CR may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake. Serious injuries and death have occurred during complex sleep behavior episodes. Tell patients to discontinue AMBIEN CR and notify their healthcare provider immediately if they develop any of these symptoms [see Boxed Warning, Warnings and Precautions (5.1)] .

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. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients [see Warnings and Precautions (5.2)] .

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 [see Warnings and Precautions (5.4)] .

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.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with AMBIEN CR. Advise patients that use of AMBIEN CR late in the third trimester may cause respiratory depression and sedation in neonates. Advise mothers who used AMBIEN CR during the late third trimester of pregnancy to monitor neonates for signs of sleepiness (more than usual), breathing difficulties, or limpness [see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding mothers using AMBIEN CR to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding mothers to seek immediate medical care if they notice these signs. A lactating woman may consider pumping and discarding breastmilk during treatment and for 23 hours after AMBIEN CR administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)] .

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