Zolpidem (Page 2 of 7)

Use in patients with concomitant illness

Clinical experience with zolpidem tartrate in patients with concomitant systemic illness is limited. Caution is advisable in using zolpidem tartrate 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 normal 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 tartrate (10 mg) when compared to placebo. Since sedative/hypnotics have the capacity to depress respiratory drive, precautions should be taken if zolpidem tartrate 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. Zolpidem tartrate should be used with caution in patients with sleep apnea syndrome or myasthenia gravis. Data in end-stage renal failure patients repeatedly treated with zolpidem tartrate 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)].

A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored. [See Dosage andd Administration (2.2) and Clinical Pharmacology (12.3)].

Use in patients with depression

As with other sedative/hypnotic drugs, zolpidem tartrate 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 over-dosage 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.

Use in pediatric patients

Safety and effectiveness of zolpidem have not been established in pediatric patients. In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with ADHD, 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)].

5.7 Laboratory tests

Monitoring : There are no specific laboratory tests recommended to monitor zolpidem levels.

Interference with laboratory tests : 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.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

  • Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.2)]
  • Abnormal thinking, behavior changes, and complex behaviors. [see Warnings and Precautions (5.3)]
  • Withdrawal effects [see Warnings and Precautions (5.4)]
  • CNS-depressant effects [see Warnings and Precautions (5.5)]

6.1 Clinical trials experience

Associated with discontinuation of treatment

Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).

Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).

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 short-term treatment (up to 10 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).

Adverse reactions observed at an incidence of1% in controlled trials

The following tables enumerate treatment-emergent adverse reactions frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms 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 table was derived from a pool of 11 placebo-controlled short-term U.S. efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.

Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials lasting up to 10 nights

*Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo.

(Percentage of patients reporting)
Zolpidem
Body System/ (≤ 10mg) Placebo
Adverse Event* (N=685) (N=473)
Central and Peripheral Nervous System
Headache 7 6
Drowsiness 2 _
Dizziness 1 _
Gastrointestinal System
Diarrhea 1 -

The following table was derived from results of three placebo-controlled long-term efficacy trials involving zolpidem tartrate. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.

Incidence of Treatment-Emergent Adverse Experiences Placebo-Controlled Clinical Trials lasting up to 35 nights

*Reactions reported by at least 1% of patients treated with Zolpidem tartrate tablets and at a greater frequency than placebo.

(Percentage of patients reporting)
Zolpidem
Body System/ (≤ 10mg) Placebo
Adverse Event* (N=152) (N=161)
Autonomic Nervous System
Dry mouth 3 1
Body as a Whole
Allergy 4 1
Back Pain 3 2
Influenza-like symptoms 2 -
Chest pain 1 -
Cardiovascular System 2 -
Palpitation
Central and Peripheral Nervous System
Drowsiness
Dizziness 8 5
Lethargy 5 1
Drugged feeling 3 1
Lightheadedness 3 -
Depression 2 1
Abnormal dreams 2 1
Amnesia 1 -
Sleep disorder 1 -
1 -
Gastrointestinal System
Diarrhea
Abdominal pain 3 2
Constipation 2 2
2 1
Respiratory System
Sinusitis 4 2
Pharyngitis 3 1
Skin and Appendages
Rash 2 1

Dose relationship for adverse reactions: There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.

Adverse event incidence across the entire preapproval database: 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 zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, 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 zolpidem tartrate, 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: Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.

Body as a whole: Frequent: asthenia. Infrequent: edema, falling, 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: 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, euphoria, insomnia, vertigo. Infrequent: agitation, anxiety, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, 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: 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: athralgia, 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: upper respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.

Skin and appendages: 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.

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