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Zolpimist

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Zolpimist

Zolpimist

SIDE EFFECTS

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].
  • Abnormal thinking, behavior changes, and complex behaviors [see WARNINGS AND PRECAUTIONS].
  • Withdrawal effects [see WARNINGS AND PRECAUTIONS].
  • CNS-depressant effects [see WARNINGS AND PRECAUTIONS].

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating incidence rates.

Associated with discontinuation of treatment

Approximately 4% of 1,701 patients who received zolpidem tartrate 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 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 dizziness (5%) and drugged feelings (3%).

Adverse reactions observed at an incidence of ≥ 1% 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 results 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 Reactions in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (Percentage of patients reporting)

Body System/Adverse Reaction* Zolpidem
( ≤ 10mg)
(n=685)
Placebo
(n=473)
Central and Peripheral Nervous System
  Headache 7 6
  Drowsiness 2
  Dizziness 1
Gastrointestinal System
  Diarrhea 1
*Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo.

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 tartrate 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 reactions occurring at an incidence of at least 1% for zolpidem tartrate patients.

Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (Percentage of patients reporting)

Body System/Adverse Reaction* Zolpidem
( ≤ 10mg)
(n=152)
Placebo
(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
  Palpitation 2 -
Central and Peripheral Nervous System
  Drowsiness 8 5
  Dizziness 5 1
  Lethargy 3 1
  Drugged feeling 3 -
  Lightheadedness 2 1
  Depression 2 1
  Abnormal dreams 1 -
  Amnesia 1 -
  Sleep disorder 1 -
Gastrointestinal System
  Diarrhea 3 2
  Abdominal pain 2 2
  Constipation 2 1
Respiratory System
  Sinusitis 4 2
  Pharyngitis 3 1
Skin and Appendages
  Rash 2 1
*Reactions reported by at least 1% of patients treated with zolpidem tartrate and at a greater frequency than placebo.

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 tartrate use, particularly for certain CNS and gastrointestinal adverse reactions.

Oral tissue-related adverse reactions in Zolpimist (zolpidem tartrate oral spray) pharmacokinetics studies

The effect of chronic daily administrations of Zolpimist (zolpidem tartrate oral spray) on oral tissue has not been evaluated. In pharmacokinetic studies conducted with Zolpimist (zolpidem tartrate oral spray) in healthy subjects, an oral soft tissue exam was performed and no signs of oral irritation were noted following administration of single doses of Zolpimist (zolpidem tartrate oral spray) .

Adverse event incidence across the entire preapproval database

Zolpidem tartrate was administered to 3,660 subjects in clinical trials throughout the United States, Canada, and Europe. Treatment-emergent adverse event 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 WHO dictionary of preferred terms.

The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem tartrate, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem tartrate. 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, 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: 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, headache, 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: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendonitis.

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.

Read the Zolpimist (zolpidem tartrate oral spray) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

CNS-active drugs

Since the systematic evaluations of zolpidem in combination with other CNS-active drugs have been limited, careful consideration should be given to the pharmacology of any CNS-active drug to be used with Zolpimist (zolpidem tartrate oral spray) . Any drug with CNS-depressant effects could potentially enhance the CNS-depressant effects of zolpidem.

Zolpidem tartrate was evaluated in healthy subjects in single-dose interaction studies for several CNS drugs. 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 tartrate produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance. 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 a lack following chronic administration.

An additive effect on psychomotor performance between alcohol and zolpidem was demonstrated [see WARNINGS AND PRECAUTIONS].

A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine at steady-state concentrations were evaluated in healthy females, the only significant change was a 17% increase in the zolpidem half-life (t½). There was no evidence of an additive effect in psychomotor performance.

Following five consecutive nightly doses of zolpidem 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses at 7:00 am in healthy female volunteers), zolpidem maximum concentration (Cmax) was significantly higher (43%) and time to maximum concentration (Tmax) was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.

Drugs that affect drug metabolism via cytochrome P450

Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes has not been carefully evaluated.

A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC0–∞ of zolpidem. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance.

A randomized, placebo-controlled, crossover interaction study in eight healthy female subjects between five consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (– 73%), Cmax (–58%), and t½ (–36%) of zolpidem, together with significant reductions in the pharmacodynamic effects of zolpidem.

A randomized double-blind crossover interaction study in twelve healthy subjects showed that co-administration of single 5 mg dose of zolpidem tartrate with ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem by a factor of 1.3 and increased the total AUC of zolpidem by a factor of 1.7 compared to zolpidem alone and prolonged the t1/2 by approximately 30% along with an increase in the pharmacodynamic effects of zolpidem. Caution should be used when ketoconazole is given with zolpidem and consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together. Patients should be advised that use of Zolpimist (zolpidem tartrate oral spray) with ketoconazole may enhance the sedative effects.

Other drugs with no interaction with zolpidem

A study involving cimetidine/zolpidem and ranitidine/zolpidem combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.

Zolpidem had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in normal subjects.

Drug-laboratory test interactions

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 screen.

Drug Abuse And Dependence

Controlled Substance

Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.

Abuse

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. 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 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 zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo.

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.

Dependence

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.

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 following adverse reactions which are considered to meet the 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 reactions 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. Post-marketing reports of abuse, dependence, and withdrawal have been received.

Read the Zolpimist Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 2/23/2009
This monograph has been modified to include the generic and brand name in many instances.

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