ADVERSE REACTIONS
Clinical trial experience
Associated with discontinuation of treatment
In clinical trials with Ambien CR, 3.5% of 201 patients receiving 6.25-mg or 12.5-mg of Ambien CR discontinued treatment because of an adverse event. Events most commonly associated with discontinuation were somnolence (1.0%) and dizziness (1.0%).
Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given immediate-release zolpidem tartrate 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 events 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 events associated with the use of Ambien CR were headache, somnolence, and dizziness.
Adverse events observed at an incidence of ≥1% in controlled trials of Ambien CR
The following tables enumerate treatment-emergent adverse event 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 events 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 Events in a 3-Week Placebo-Controlled Clinical Trial in Adults (percentage of patients reporting) | Body System/Adverse Event Events reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group. | Ambien CR
12.5 mg
(N = 102) | Placebo
(N = 110) |
|---|
| Infections and infestations | |
| Influenza | 3 | 0 |
| Gastroenteritis | 1 | 0 |
| Labyrinthitis | 1 | 0 |
| Metabolism and nutrition disorders | |
| Appetite disorder | 1 | 0 |
| Psychiatric disorders | |
| Hallucinations Hallucinations included hallucinations NOS as well as visual and hypnogogic hallucinations. | 4 | 0 |
| Disorientation | 3 | 2 |
| Anxiety | 2 | 0 |
| Depression | 2 | 0 |
| Psychomotor retardation | 2 | 0 |
| Binge eating | 1 | 0 |
| Depersonalization | 1 | 0 |
| Disinhibition | 1 | 0 |
| Euphoric mood | 1 | 0 |
| Mood swings | 1 | 0 |
| Stress symptoms | 1 | 0 |
| Nervous system disorders | |
| Headache | 19 | 16 |
| Somnolence | 15 | 2 |
| Dizziness | 12 | 5 |
| Memory disorders Memory disorders include: memory impairment, amnesia, anterograde amnesia. | 3 | 0 |
| Balance disorder | 2 | 0 |
| Disturbance in attention | 2 | 0 |
| Hypoesthesia | 2 | 1 |
| Ataxia | 1 | 0 |
| Paresthesia | 1 | 0 |
| Eye disorders | |
| Visual disturbance | 3 | 0 |
| Eye redness | 2 | 0 |
| Vision blurred | 2 | 1 |
| Altered visual depth perception | 1 | 0 |
| Asthenopia | 1 | 0 |
| Ear and labyrinth disorders | |
| Vertigo | 2 | 0 |
| Tinnitus | 1 | 0 |
| Respiratory, thoracic and mediastinal disorders | | |
| Throat irritation | 1 | 0 |
| Gastrointestinal disorders | | |
| Nausea | 7 | 4 |
| Constipation | 2 | 0 |
| Abdominal discomfort | 1 | 0 |
| Abdominal tenderness | 1 | 0 |
| Frequent bowel movements | 1 | 0 |
| Gastroesophageal reflux disease | 1 | 0 |
| Vomiting | 1 | 0 |
Skin and subcutaneous tissue
disorders | | |
| Rash | 1 | 0 |
| Skin wrinkling | 1 | 0 |
| Urticaria | 1 | 0 |
| Musculoskeletal and connective tissue disorders | | |
| Back pain | 4 | 3 |
| Myalgia | 4 | 0 |
| Neck pain | 1 | 0 |
| Reproductive system and breast disorders | | |
| Menorrhagia | 1 | 0 |
| General disorders and administration site conditions | | |
| Fatigue | 3 | 2 |
| Asthenia | 1 | 0 |
| Chest discomfort | 1 | 0 |
| Investigations | | |
| Blood pressure increased | 1 | 0 |
| Body temperature increased | 1 | 0 |
| Injury, poisoning and procedural complications | | |
| Contusion | 1 | 0 |
| Social circumstances | | |
| Exposure to poisonous plant | 1 | 0 |
Table 2. Incidences of Treatment-Emergent Adverse Events in a 3-Week Placebo-Controlled Clinical Trial in Elderly (percentage of patients reporting) | Body System/Adverse Event Events reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group. | Ambien CR
6.25 mg
(N=99) | Placebo
(N=106) |
|---|
| Infections and infestations |
| Nasopharyngitis | 6 | 4 |
| Lower respiratory tract infection | 1 | 0 |
| Otitis externa | 1 | 0 |
| Upper respiratory tract infection | 1 | 0 |
| Psychiatric disorders | |
| Anxiety | 3 | 2 |
| Psychomotor retardation | 2 | 0 |
| Apathy | 1 | 0 |
| Depressed mood | 1 | 0 |
| Nervous system disorders | |
| Headache | 14 | 11 |
| Dizziness | 8 | 3 |
| Somnolence | 6 | 5 |
| Burning sensation | 1 | 0 |
| Dizziness postural | 1 | 0 |
| Memory disorders Memory disorders include: memory impairment, amnesia, anterograde amnesia. | 1 | 0 |
| Muscle contractions involuntary | 1 | 0 |
| Paresthesia | 1 | 0 |
| Tremor | 1 | 0 |
| Cardiac disorders | |
| Palpitations | 2 | 0 |
| Respiratory, thoracic and mediastinal disorders | |
| Dry throat | 1 | 0 |
| Gastrointestinal disorders | |
| Flatulence | 1 | 0 |
| Vomiting | 1 | 0 |
| Skin and subcutaneous tissue disorders | |
| Rash | 1 | 0 |
| Urticaria | 1 | 0 |
| Musculoskeletal and connective tissue disorders | | |
| Arthralgia | 2 | 0 |
| Muscle cramp | 2 | 1 |
| Neck pain | 2 | 0 |
| Renal and urinary disorders | | |
| Dysuria | 1 | 0 |
| Reproductive system and breast disorders | | |
| Vulvovaginal dryness | 1 | 0 |
| General disorders and administration site conditions | | |
| Influenza like illness | 1 | 0 |
| Pyrexia | 1 | 0 |
| Injury, poisoning and procedural complications | | |
| Neck injury | 1 | 0 |
Dose relationship for adverse events
There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse events associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.
Other adverse events observed during the premarketing evaluation of Ambien CR
Other treatment-emergent adverse events associated with participation in Ambien CR studies (those reported at frequencies of < 1%) were not different in nature or frequency to those seen in studies with immediate-release zolpidem tartrate, which are listed below.
Adverse events observed during the premarketing evaluation of immediate-release zolpidem tartrate
Immediate-release zolpidem tartrate, was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms. The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving immediate-release zolpidem. All reported treatment-emergent adverse events are included, except those coding terms that are so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with immediate-release zolpidem, they were not necessarily caused by it.
Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.
Autonomic nervous system: Frequent: dry mouth. Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.
Body as a whole: Frequent: allergy, asthenia, back pain, influenza-like symptoms. Infrequent: chest pain, edema, falling, fatigue, fever, malaise, trauma. Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.
Cardiovascular system: Frequent: palpitation. Infrequent: cerebrovascular disorder, hypertension, tachycardia. Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.
Central and peripheral nervous system: Frequent: ataxia, confusion, depression, dizziness, drowsiness, drugged feeling, euphoria, headache, insomnia, lethargy, lightheadedness, vertigo. Infrequent: abnormal dreams, agitation, amnesia, anxiety, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleep disorder, sleeping (after daytime dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.
Gastrointestinal system: Frequent: abdominal pain, diarrhea, dyspepsia, hiccup, nausea. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting. Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.
Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.
Immunologic system: Infrequent: infection. Rare: abscess, herpes simplex, herpes zoster, otitis externa, otitis media.
Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare: bilirubinemia, increased SGOT.
Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.
Musculoskeletal system: Frequent: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.
Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.
Respiratory system: Frequent: pharyngitis, sinusitis, upper respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.
Skin and appendages: Frequent: rash. Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.
Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.
Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence. Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.
Postmarketing Experience
In addition to adverse events reported in clinical trials, angioneurotic edema has been reported spontaneously in postmarketing experience with zolpidem tartrate.
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REPORTS OF SUSPECTED AMBIEN CR SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Ambien CR. The information is not vetted and should not be considered as verified clinical evidence.
Possible Ambien CR side effects / adverse reactions in 44 year old male
Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-14
Patient: 44 year old male weighing 73.0 kg (160.6 pounds)
Reactions: Suicide Attempt, Multiple Drug Overdose
Adverse event resulted in: hospitalization
Suspect drug(s):
Lexapro
Dosage: oral ; oral
Administration route: Oral
Indication: Depression
Start date: 2011-01-01
End date: 2011-01-01
Ambien CR
Dosage: 12.5 mg (12.5 mg,1 in 1 d),oral ; oral
Administration route: Oral
Indication: Insomnia
Start date: 2010-12-01
Ambien CR
Dosage: 12.5 mg (12.5 mg,1 in 1 d),oral ; oral
Administration route: Oral
Indication: Insomnia
Start date: 2011-01-01
End date: 2011-01-01
Lunesta
Dosage: 2 mg (2 mg,1 in 1 d),oral ; oral
Administration route: Oral
Indication: Insomnia
Start date: 2010-10-01
End date: 2010-12-01
Lunesta
Dosage: 2 mg (2 mg,1 in 1 d),oral ; oral
Administration route: Oral
Indication: Insomnia
Start date: 2011-01-01
End date: 2011-01-01
Xanax
Dosage: oral ; oral
Administration route: Oral
Indication: Depression
Start date: 2011-01-01
End date: 2011-01-01
Possible Ambien CR side effects / adverse reactions in 62 year old male
Reported by a consumer/non-health professional from United States on 2011-12-12
Patient: 62 year old male
Reactions: Glaucoma, Neck Pain, Coronary Artery Occlusion, Skin Warm, Skin Swelling, Back Pain, Pain in Extremity, Wound Infection Fungal, Pain of Skin, Musculoskeletal Pain, Hyperaesthesia, Testicular Pain, Memory Impairment, Arthritis, DRY Eye, Hydrocele, Testicular Cyst
Adverse event resulted in: hospitalization
Suspect drug(s):
Ambien CR
Ambien CR
Administration route: Oral
Start date: 2009-01-01
Possible Ambien CR side effects / adverse reactions in 62 year old male
Reported by a consumer/non-health professional from United States on 2011-12-22
Patient: 62 year old male
Reactions: Glaucoma, Neck Pain, Coronary Artery Occlusion, Skin Swelling, Skin Warm, Back Pain, Pain in Extremity, Pain of Skin, Wound Infection Fungal, Musculoskeletal Pain, Hyperaesthesia, Testicular Pain, Memory Impairment, DRY Eye, Arthritis, Testicular Cyst, Hydrocele
Adverse event resulted in: hospitalization
Suspect drug(s):
Ambien CR
Sertraline Hydrochloride
Ambien CR
Administration route: Oral
Start date: 2009-01-01
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