Dactive

Dactive

zolpidem

Manufacturer:

Cadila Healthcare

Distributor:

Metro Drug

Marketer:

Zydus Healthcare Phils
Full Prescribing Info
Contents
Zolpidem tartrate.
Description
Each film-coated tablet contains: Zolpidem Tartrate 10 mg.
Zolpidem tartrate is (±) - N, N-dimethyl-2-(6-methyl-2-p-tolylimidazo [1,2-a]pyridin-3-yl)acetamide. Zolpidem is one of the most common GABA-potentiating sleeping medications. It is used for the treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to GABAA receptors at the same location as benzodiazepines. It works quickly (usually within 15 minutes) and has a short half-life (two to three hours).
Action
Pharmacology: Pharmacodynamics: Zolpidem is an imidazopyridine which selectively binds the omega-1 receptor subtype (also known as the benzodiazepine-1 subtype) which is the alpha unit of the GABA-A receptor complex. Whereas benzodiazepines non-selectively bind all three omega receptor subtypes, Zolpidem preferentially binds the omega-1 subtype. The modulation of the chloride anion channel via this receptor leads to the specific sedative effects demonstrated by zolpidem. These effects are reversed by the benzodiazepine antagonist flumazenil.
In animals: The selective binding of Zolpidem to omega-1 receptors may explain the virtual absence at hypnotic doses of myorelaxant and anti-convulsant effects in animals which are normally exhibited by benzodiazepines which are not selective for omega-1 sites.
In humans: The preservation of deep sleep (stages 3 and 4 - slow-wave sleep) may be explained by the selective omega-1 binding by zolpidem. All identified effects of Zolpidem are reversed by the benzodiazepine antagonist flumazenil.
Pharmacokinetics: The pharmacokinetic profile of Zolpidem tartrate is characterized by rapid absorption from the gastrointestinal tract and a short elimination half-life (T1/2) in healthy subjects.
In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg Zolpidem tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean Zolpidem tartrate elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. Zolpidem tartrate is converted to inactive metabolites that are eliminated primarily by renal excretion. Zolpidem tartrate demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg Zolpidem tartrate tablets for 2 weeks.
A food-effect study in 30 healthy male subjects compared the pharmacokinetics of Zolpidem tartrate 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, Zolpidem tartrate should not be administered with or immediately after a meal.
Special Populations: Elderly: In the elderly, the dose for Zolpidem tartrate should be 5 mg. This recommendation is based on several studies in which the mean Cmax, T1/2, and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (> 70 years), the means for Cmax, T1/2, and AUC significantly increased by 50% (255 vs. 384 ng/mL), 32% (2.2 vs. 2.9 hr), and 64% (955 vs. 1,562 ng·hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose. Zolpidem tartrate did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.
Hepatic Impairment: The pharmacokinetics of Zolpidem tartrate in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20 mg oral Zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs. 499 ng/mL) and five times (788 vs. 4,203 ng·hr/mL) higher, respectively, in hepatically-compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency.
Renal Impairment: The pharmacokinetics of Zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with Zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. On day 1, Cmax was 172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was 203 ± 32 ng/mL (range: 28 to 316 ng/mL). On day 1, Tmax was 1.7 ± 0.3 hr (range: 0.5 to 3.0 hr); after repeated dosing Tmax was 0.8 ± 0.2 hr (range: 0.5 to 2.0 hr). This variation is accounted for by noting that last-day serum sampling began 10 hours after the previous dose, rather than after 24 hours. This resulted in residual drug concentration and a shorter period to reach maximal serum concentration. On day 1, T1/2 was 2.4 ± 0.4 hr (range: 0.4 to 5.1 hr). After repeated dosing, T1/2 was 2.5 ± 0.4 hr (range: 0.7 to 4.2 hr). AUC was 796 ± 159 ng·hr/mL after the first dose and 818 ± 170 ng·hr/mL after repeated dosing. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function. However, as a general precaution, these patients should be closely monitored.
Indications/Uses
Zolpidem tartrate is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
Dosage/Direction for Use
The dose of Zolpidem tartrate should be individualized.
Dosage in adults: The recommended dose for adults is 10 mg once daily immediately before bedtime. The total Zolpidem tartrate dose should not exceed 10 mg per day.
Special populations: Elderly or debilitated patients may be especially sensitive to the effects of Zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of Zolpidem tartrate in both of these patient populations is 5 mg once daily immediately before bedtime.
Use with CNS depressants: Dosage adjustment may be necessary when Zolpidem tartrate is combined with other CNS depressant drugs because of the potentially additive effects.
Administration: The effect of Zolpidem tartrate may be slowed by ingestion with or immediately after a meal.
Overdosage
Signs and symptoms: 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.
Recommended treatment: General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem's sedative hypnotic effect was shown to be reduced by flumazenil and therefore 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 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.
Contraindications
Zolpidem tartrate is contraindicated in patients with known hypersensitivity to Zolpidem tartrate or to any of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and angioedema.
Special Precautions
Need to evaluate for co-morbid diagnoses: 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.
Severe anaphylactic and anaphylactoid reactions: 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 throat, 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.
Abnormal thinking and behavioral changes: 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. In controlled trials, < 1% of adults with insomnia who received Zolpidem reported hallucinations. In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention deficit/hyperactivity disorder (ADHD), who received Zolpidem reported hallucinations.
Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported with sedative-hypnotics, including zolpidem. 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 tartrate alone at therapeutic doses, the use of alcohol and other CNS depressants with Zolpidem tartrate appears to increase the risk of such behaviors, as does the use of Zolpidem tartrate at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zolpidem tartrate 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 thoughts and actions (including completed suicides), 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 listed previously 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.
Withdrawal effects: 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.
CNS depressant effects: Zolpidem tartrate, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Zolpidem tartrate should only be taken 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 Zolpidem tartrate. Zolpidem tartrate 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 Zolpidem tartrate is administered with such agents because of the potentially additive effects.
Special populations: Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended Zolpidem tartrate dosage is 5 mg in such patients to decrease the possibility of side effects. These patients should be closely monitored.
Use in patients with concomitant illness: Clinical experience with Zolpidem tartrate (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.
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.
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.
Use in Pregnancy: Pregnancy Category C: There are no adequate and well-controlled studies of Zolpidem tartrate in pregnant women. Zolpidem tartrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of Zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the Zolpidem tartrate maximum recommended human dose (MRHD) of 10 mg/day (approximately 8 mg/day Zolpidem base); however, teratogenicity was not observed.
Neonatal Complications: Studies in children to assess the effects of prenatal exposure to Zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when Zolpidem was used at the end of pregnancy, especially when taken with other CNS depressants.
Children born to mothers taking sedative-hypnotic drugs may be at some risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy.
Labor and delivery: Zolpidem tartrate has no established use in labor and delivery.
Use in lactation: Zolpidem is excreted in human milk. Studies in lactating mothers indicate that the half-life of Zolpidem is similar to that in non-lactating women (2.6 ± 0.3 hr). The effect of Zolpidem on the nursing infant is not known. Caution should be exercised when Zolpidem tartrate is administered to a nursing woman.
Use in children: Safety and effectiveness of Zolpidem have not been established in pediatric patients.
Use In Pregnancy & Lactation
Use in Pregnancy: Pregnancy Category C: There are no adequate and well-controlled studies of Zolpidem tartrate in pregnant women. Zolpidem tartrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of Zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the Zolpidem tartrate maximum recommended human dose (MRHD) of 10 mg/day (approximately 8 mg/day Zolpidem base); however, teratogenicity was not observed.
Neonatal Complications: Studies in children to assess the effects of prenatal exposure to Zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when Zolpidem was used at the end of pregnancy, especially when taken with other CNS depressants.
Children born to mothers taking sedative-hypnotic drugs may be at some risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy.
Labor and delivery: Zolpidem tartrate has no established use in labor and delivery.
Use in lactation: Zolpidem is excreted in human milk. Studies in lactating mothers indicate that the half-life of Zolpidem is similar to that in non-lactating women (2.6 ± 0.3 hr). The effect of Zolpidem on the nursing infant is not known. Caution should be exercised when Zolpidem tartrate is administered to a nursing woman.
Adverse Reactions
The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious anaphylactic and anaphylactoid reactions; Abnormal thinking, behavior changes, and complex behaviors; Withdrawal effects; CNS-depressant effects.
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 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. (See Table 1.)

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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. (See Table 2.)

Click on icon to see table/diagram/image

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, 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, 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.
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 Zolpidem. 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 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.
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. 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 Cmax was significantly higher (43%) and 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 T1/2 (-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 a 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 elimination half-life 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 Zolpidem tartrate 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 screens.
Storage
Store at temperatures not exceeding 30°C.
ATC Classification
N05CF02 - zolpidem ; Belongs to the class of benzodiazepine related agents. Used as hypnotics and sedatives.
Presentation/Packing
FC tab 10 mg x 100's.
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